Opening a EUDF Italy event, MEP Marino spoke about the importance of prevention, equality and research. He referred to his experience from his surgical practice, where he has seen first-hand the serious consequences of diabetes if it is not managed properly. He endorsed the diabetes community pledge and stressed his commitment to working for health and diabetes in the European Parliament.

A. Ussia · S. Vaccari · A. Lauro · A. Caira · M. L. Tardio · O. Leone · I. R. Marino · V. D’Andrea · M. Cervellera · V. Tonini

Abstract 

Introduction

Amyloidosis is an uncommon disease caused by the deposition of amyloid fibrils in tissues. This disease does not usually require surgical intervention, which could be warranted in the presence of complications such as bleeding, obstruction, or perforation. We present a case of primary amyloidosis of the colon in a patient affected by polymyositis who underwent Hartmann’s procedure after a spontaneous colonic perforation. After 2 months of well-being, the patient underwent two consecutive surgical procedures for stenosis of the ostomy orifice. 

Areas Covered

A review of the literature has been performed, gathering case reports highlighting the distribution of this disease by age, gender, location, and treatment when available. 

Expert Commentary

Gastrointestinal amyloid disease is a rare condition, and it could be considered among the rare causes of intestinal perforation. Timely surgical management is often necessary. 

Case Report and Evolution 

A 67-year-old woman was initially evaluated in the Emergency Department of St. Orsola University Hospital for generalized abdominal pain, fever, and signs of peritonitis. Her PMH included essential hypertension, HCV-related chronic liver disease, and polymyositis. Laboratory tests revealed eukocytosis and high serum levels of CRP. Abdominal CT scan revealed free air and a collection in the left iliac fossa (Fig. 1a, b). Emergency surgery was required and revealed a perforated colon that was resected with the Hartmann’s procedure with colostomy creation. Pathological analysis of the specimen revealed perforated ischemic colitis with diffuse amyloid deposits (Fig. 2). The patient was discharged in good clinical conditions on postoperative day 7. 
In the following 6 months, the patient was seen many times in the outpatient department for low-grade intestinal obstruction secondary to stenosis of the stoma orifice, treated conservatively with dilations of the ostomy, initially as an outpatient and later during two hospital admissions. Endoscopically, the rectal stump displayed red and friable mucosa with geographic ulcers (Fig. 3). Eventually, the patient underwent a limited revision of the stoma and removal of the previous colostomy, resection of the fibrotic tract, and creation of a new colostomy. Histological examination of the specimen showed severe and diffuse amyloidosis of the colon with multifocal ischemic colitis of indeterminate duration and stomal inflammation. Postoperatively, the patient was treated with a 3-month course of mesalamine with periodic digital exploration of the ostomy in order to prevent future stenosis. 

After a period of good health, the patient inquired about the possibility of reversing the stoma. After a multidisciplinary case discussion, multiple full-thickness biopsies of the colon were obtained in order to better ascertain the extent of the disease. The biopsies showed that the disease was present in the entire residual colon. Therefore, in agreement with the patient, it was decided not to perform a stoma reversal in this case. Presently, the patient is in good condition with an adequately performing colostomy. 

Discussion 

Amyloidosis is an uncommon disorder caused by abnormal protein folding. Systemic or localized deposition of these misfolding proteins as insoluble fibrils disrupts tissue structure and function (Fig. 4). Amyloidosis can be acquired or hereditary; the deposition of amyloid fibrils can occur in several situations such as in chronic inflammatory states, in association with the production of an abnormal protein with amyloidogenic propensity (e.g., certain immunoglobulin light chains from plasma cell dyscrasias), and after prolonged exposure to a normal concentrations of a structurally normal protein with weak inherent amyloidogenic potential (e.g., senile systemic amyloidosis). 
The clinical features of amyloidosis are dependent on the organs involved. Systemic amyloidosis is the most common form. It is a very heterogeneous disease in its presentation and clinical course. Kidney involvement initially manifests as proteinuria or renal impairment, whereas cardiac amyloid deposition usually manifests as a restrictive cardiomyopathy and confers a poor prognosis. Among these patients, the median survival is 4–6 months after the appearance of congestive cardiac failure. 

Amyloid deposition in the autonomic nervous system can cause orthostatic hypotension, impotence, urinary retention, and gastrointestinal dysfunction. Distal sensory deficit or a motor neuropathy due to peripheral neuropathy can occur. Cutaneous lesions, carpal tunnel syndrome, periorbital bruising, macroglossia, and lymphadenopathy can also be present.

Hepatomegaly is common due to the infiltration of amyloid fibrils or arises secondary to congestive cardiac failure. The typical biochemical profile of hepatic amyloidosis is characterized by an elevated liver function test. Although the gastrointestinal tract is susceptible to the deposition of amyloid materials, localized amyloidosis in this site is rare and gastrointestinal complications associated with this disease are exceptionally uncommon. 
The diagnosis of amyloidosis is often made long after the onset of symptoms because of its nonspecific and varied clinical presentation, which can mimic many other conditions. Specific symptoms should trigger suspicion for a diagnosis of amyloidosis, such as nephrotic syndrome and heart failure; peripheral and autonomic neuropathy; a combination of carpal tunnel syndrome and heart failure in the elderly; and appropriate family history. Regular testing for the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and urine sampling for albuminuria should be part of standard practice in patients with serum paraproteins such as a monoclonal gammopathy of uncertain significance (MGUS) with abnormal free light chain ratio of lambda/ kappa free light chains, as an abnormality of either may herald development of amyloidosis. Diagnosis requires confirmation of the presence of amyloid fibrils by histology and is achieved by staining suspected amyloid tissue with Congo red; in the presence of amyloid fibrils, apple-green birefringence under cross-polarized light will be visualized by light microscopy. 

Although amyloidosis is essentially a benign condition, systemic amyloidosis is almost invariably fatal and treatment is primarily supportive. Death usually follows a cardiac event or renal failure. Median survival is between 12 and 15 months with most patients succumbing within 3 years from diagnosis. When amyloidosis is associated with multiple myeloma, prognosis is even poorer with a median survival of only 4 months. The outcome is improved for secondary amyloidosis where a survival up to 5 years is common with occasional case reports documenting long-term survival. 
 Digestive localization of amyloidosis ranges from the oral cavity to the rectum, with the most common symptoms including abdominal pain, rectal bleeding, weight loss, and watery diarrhea. Nevertheless, involvement of the intestinal musculature may cause pseudo-obstruction. Organ infiltration by amyloid proteins occurs either in and around the walls of small submucosal blood vessels or within the mucosal or muscular layers of the gut wall. In most cases, the submucosal blood vessels are the earliest and most frequent site of amyloid deposition, with consequent blood vessel narrowing or occlusion, resulting in ischemia, infarction, or perforation, all of which have been reported in the literature although intestinal perforation is exceptionally rare.1The characteristics of the surgical procedures performed in the reported cases of amyloidotic gastrointestinal perforation are described in Table 1. The colon is the most frequent site of perforation since it has been described in 17 cases; most of them managed operatively (Table 2). 
Our case was notable because the patient was asymptomatic until perforation, and there were no previous signs of amyloid disease. Preoperatively, the disease was not suspected and the diagnosis was first made on the histological specimen. We believe that polymyositis may have caused the deposition of amyloid in the colonic vessels leading to pneumoperitoneum, due to perforation by ischemia of the intestinal wall. The absolute lack of prodromal symptoms is unexplained, even if polymyositis often has nuanced symptomatology and a slow progression. 
The patient denied the consent for further diagnostic investigations. After a few months of well-being, the onset of abdominal pain and obstruction in our patient leads us to carry out a revision of the stoma, taking down the previous colostomy and creating a new one. The possibility to reconnect the ostomy was then excluded. 

Conclusions

The data reported in the literature showed that surgical treatment of amyloidosis affecting the gastrointestinal tract should be reserved for emergency procedures only. In patients treated by surgery due to massive bleeding, perforation, or obstruction, there may be an associated hemorrhagic diathesis or anastomotic dehiscence resulting in poor local healing. As in the case presented, any surgical procedure performed in a patient with amyloidosis disease is risky and may lead to complications, but it may be helpful in managing gastrointestinal amyloidosis and repeated if necessary. 

Published online: 14 November 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019

Cataldo Doria , Samuel Goldstein and Ignazio R. Marino

Abstract

The authors have chosen to describe the most commonly used surgical techniques for liver transplantation and their variations, namely, the standard technique with and without venous-venous bypass, the piggy-back technique with and without venous-venous bypass, and the Belghiti modification of the piggy-back. In addition to that, two rare forms of liver transplantation will be discussed: the procedures used for situs viscerus inversus and auxiliary liver transplantation.

Introduction

Thomas E. Starzl performed the first orthotopic liver transplantation in 1963 (Starzl 1969). The introduction of venous-venous bypass, complex immunosuppression regimens, and computer imaging contributed to making this procedure widely available in a span of half a century. Figure 1 indicates the textbook hepatic anatomy.

Fig. 1 - Liver anatomy

Orthotopic Liver Transplant (OLT): Standard Technique With and Without Venous-Venous Bypass 

The standard procedure of orthotopic liver transplant is the preferred surgical method. This technique should be used any time a liver malignancy is growing next to the inferior vena cava (IVC). The standard technique is the simplest of the procedures to perform, and it takes the shortest amount of time. The introduction of the venous-venous bypass has made the training of many surgeons possible and has dramatically decreased the intraoperative mortality experienced during the early days of liver transplantation. Before the introduction of the venous-venous bypass, survival rates were low in the setting of hemodynamic instability (Shaw et al. 1984). Patients were especially vulnerable during the anhepatic phase due to decreased venous return to the heart and hypertension in portal and systemic vessels upon clamping of the IVC and the portal vein (Shaw et al. 1984). The venous-venous bypass shunts blood flow from the portal and caval systems in the lower part of the body into the internal jugular vein, bypassing the inferior vena cava. This shunt provides the surgical team with time to implant the allograft without subjecting the patient to a decreased venous return to the heart during a complete occlusion of the IVC.

The preferred incision of choice is known as the Mercedes-Benz. It consists of a bilateral, subcostal incision with an upper midline extension made with electrocautery. Once the peritoneum is entered, the ascitic fluid, if present, is drained. Specimens are sent for culture and sensitivity studies. The round ligament of the liver is divided between 0 silk ties, and the falciform ligament of the liver is divided with electrocautery. At this stage, the xiphoid process is removed using electrocautery and heavy scissors. Subsequently, the midline peritoneum is tucked to the fascia with interrupted 2/0 silk stitches.

This maneuver facilitates reopening of the midline if needed. In fact, by bringing the peritoneum up to the fascia, the intensity of the adhesions is limited in that area. In addition to that, covering the stump of the xiphoid process with peritoneum prevents injuries during the mobilization of the cirrhotic liver and the implantation of the allograft. A wet folded lap is placed on the tip of the spleen to avoid splenic injury caused by the retractor’s blades. To provide adequate exposure, the surgeon uses a combination of the self-retaining rib-grip (Stieber) and the Iron Intern retractors. The operation begins with an exploratory laparotomy. This phase is particularly important and aims to rule out possible contraindication to transplantation. Contraindication is most commonly lymph node metastasis from primary liver cancers. Subsequently, the elements of the hepatic hilum are skeletonized. First, the common bile duct is isolated and transected between 2/0 silk ties. A sample of bile is collected and sent for culture. This is the second and last standard culture obtained during liver transplantation. Patients undergoing liver transplantation are often colonized with bacteria that can cause infection postoperatively under the effect of the immunosuppressive treatment. Therefore, knowing which bacteria, if any, are colonizing the bile duct and the peritoneal cavity can help expedite antibiotic treatment while waiting for the final culture results. Next, the hepatic artery is divided between 2/0 silk ties. It is a good practice for the surgeon to alert the anesthesiologist before the silk is tied off on the artery. This provides the anesthesiologist enough time to draw the last arterial blood sample while the native liver is perfused with systemic blood flow. In fact, the lactate clearing activity of the liver is predominantly controlled by the blood flow coming from the hepatic artery. Lastly, the portal vein is skeletonized. At this stage we proceed to dissect the hepatic artery proximally to 1 cm below the takeoff of the gastroduodenal artery (GDA). The distance of 1 cm generally provides enough room to place a surgical clamp on the common hepatic artery and to rotate the vessels when performing the anastomosis.

At this stage, the access sites for the venous-venous bypass are prepared. The return cannula is placed in the right internal jugular vein by the anesthesia team after induction of general anesthesia and before prepping the surgical field. The IVC cannula is placed percutaneously through the left groin using a Seldinger technique. Although the left groin is preferred, the right groin can be used if needed. Of note, the IVC is accessed through the iliac-femoral vessels. To safely place the portal vein cannula, the portal vein skeletonization is first maximized to obtain the longest possible vessel trunk. Then, a large surgical clamp is applied distally on the portal vein as far as possible in the porta hepatis, while the proximal end of the vessel is clamped between fingers. The portal vein is divided as close as possible to the clamp in the porta hepatis. To facilitate the cannulation of the portal vein, three tonsils are applied on the edge of the vessel to keep it open. The cannula is secured in place by two wet umbilical tapes. Both cannulas are tested and flushed with a heparinized saline solution. The portal and femoral vein cannulas are connected with a Y connector, and the bypass cannula is connected to the patient, as shown in Fig. 2. The bypass is started and the flow is maintained above 1 l per minute. Below this speed, the patient is subject to thrombosis (Shaw et al. 1984). If the volume flow rate slows to below 1l/min, it may be a sign of hypovolemia or malpositioning of the portal vein cannula. In the first case, administration of fluid boluses can increase the bypass flow rate. At times, low flow results from a cannula facing the wall of one of the vessels, typically at the juncture of the splenic and superior mesenteric veins. To increase the flow in this case, the surgeon must maneuver the cannula away from the wall of the vessel. However, if the flow rate cannot be increased above 1 L/min, the patient is required to go off bypass.

Fig. 2 - Venous-venous bypass anatomy

The distal stump of the portal vein is oversewn with Prolene 3/0. The infra-hepatic IVC is skeletonized and cross-clamped with an adult angle Potts clamp. The left triangular ligament is divided with electrocautery, and the gastrohepatic ligament is divided between 2/0 silk ties. The right triangular ligament is divided with electrocautery. The suprahepatic IVC is encircled and clamped with a German clamp. The liver is removed from the field using blunt and sharp dissection. As soon as the native liver is removed from the surgical field, the right adrenal vein is tied off using a 0 silk tie, which is passed around the area where this vessel merges with the IVC. Further hemostasis is obtained in the bare area of the liver by two running 2/0 Prolene sutures: one vertically placed in the IVC area and one from the tip of the right triangular ligament forward as shown in Fig. 3. These two running sutures are not always necessary. At times, proper hemostasis of the bare area can be achieved with argon beam coagulation.

Fig. 3 - Bare area hemostasis

 Achieving hemostasis by oversewing the bare area tends to decrease the size of the retro-hepatic area, allowing for transplantation of a smaller liver. This change in size of the right upper quadrant of the abdomen should be kept in mind when using large livers that might not fit the anatomical area. In that case, different hemostatic techniques should be considered.

The cuffs of the supra- and infra-hepatic IVC are prepared, and the new liver is brought into the operative field. It is helpful to position two 4/0 silk sutures on the upper left of the suprahepatic IVC cuff. By pulling these two sutures cranially, a better exposure of the posterior wall of the anastomosis is achieved. The suprahepatic IVC anastomosis is done in an end-to-end fashion using running 3/0 Prolene sutures. Subsequently, the infra-hepatic IVC anastomosis is completed in an end-to-end fashion using running 4/0 Prolene sutures. Once the posterior wall of the infra-hepatic IVC anastomosis is completed, the liver is flushed with 1 l of chilled (4 °C) lactated Ringer’s (LR) solution. The allograft is flushed through a cannula that was secured in the portal vein at the time of the back-table preparation. The practice of flushing the liver with chilled LR intends to remove as much University of Wisconsin® solution (UW) as possible from the allograft. UW is rich in potassium. If the UW is not removed from the allograft, a load of potassium would reach the right atrium at the time of reperfusion. This process may be responsible for deadly cardiac arrhythmias. At this stage, in preparation for the portal vein anastomosis, the portal cannula of the venous-venous bypass is clamped with a tubing clamp. The portal cannula is removed from the portal vein, and the portal vein is clamped with a pediatric angled Potts clamp. The surgeon should clamp the tip of the portal vein cannula with a large Kocher clamp to prevent air embolism in the case of failure of the tubing clamp. In preparation for the portal vein anastomosis, three wet lap sponges are placed between the right hemidiaphragm and the dome of the liver. The right arm of the rib-grip retractor is lowered by three complete turns. The combination of these two maneuvers shortens the distance between the donor and recipient’s portal vein stumps. This prevents the creation of a long portal vein that could kink and therefore cause vessel thrombosis in the postoperative time. The donor’s portal vein is then shortened to a sufficient length to obtain a straight and nonredundant anastomosis. The portal vein anastomosis is completed end-to-end with running 6/0 Prolene sutures. When the running suture is tied, a generous growth factor is left behind so the anastomosis can expand at reperfusion and stenosis can be prevented. The laps are removed from the field and the rib-grip retractor is placed in its original position. There are two ways of proceeding at this time. One way is to perfuse the liver solely with portal blood and to reconstruct the hepatic artery once reasonable hemostasis is achieved. The second option consists of reconstructing all of the vessels before reperfusing the allograft. This second option is the one favored. However, in order to safely proceed with four-vessel reconstruction before reperfusion, the total implantation time cannot exceed 1 h. In addition, reperfusing allografts with portal as well as systemic blood can cause more hemodynamic instability that should be taken in account by the anesthesiology team. The four-vessel technique is completed as follows. The GDA is tied off with two 2/0 silk ties. The use of two separate sutures guarantees better control of this vessel. The common hepatic artery is clamped with a spoon clamp, and the recipient’s hepatic artery is opened. A cuff of the recipient’s hepatic artery is prepared at the level of the GDA patch. The donor’s hepatic artery is shortened and beveled in the opposite direction, and a straight and nonredundant anastomosis is made end-to-end using running 7/0 Prolene sutures. Once the anterior wall of the hepatic artery anastomosis is completed, the anesthesia team is alerted that the allograft will be reperfused in approximately 3 min. This gives the anesthesiologist enough time to prepare the drugs needed to counteract possible hemodynamic instability after reperfusion and to record the last potassium level before reperfusion. At this stage the liver is reperfused. The hepatic artery, the portal vein, the infra-hepatic IVC, and the suprahepatic IVC clamps are removed in sequence. It is possible to keep the suprahepatic IVC clamp on until the liver is fully reperfused. In this case, the liver outflow runs into the bypass machine before reaching the heart rather than going directly into the right atrium. This maneuver prevents a potentially fatal, arrhythmogenic potassium load.

If the patient is stable after packing the operative field, it is suggested to go off bypass. After all cannulas are removed, the blood in the circuit can be recuperated in the cell saver. The next step of the operation is to achieve hemostasis. It is customary to proceed in a clockwise fashion starting from the anterior wall of the suprahepatic IVC, moving toward the medial side wall of the same vessel, to the infra-hepatic IVC on its medial aspect, to the hepatic hilum, and lastly to the lateral walls of the infraand suprahepatic IVC. There are several areas not mentioned above that are addressed while moving in the clockwise direction, namely, the falciform ligament on both sides (donor and recipient), the left triangular ligament on both sides, the hepatogastric ligament on the recipient’s side, and the right triangular ligament on the donor’s side. Generally, these areas are addressed with argon beam coagulation. Packing during hemostasis is exceptionally important because pressure alone has been shown to be one of the most effective methods of achieving hemostasis, and because it maintains hemostasis while the anesthesiologist progressively corrects any coagulopathy based on the results of thromboelastography (Kang et al. 1985).

The last step of the operation is the bile duct reconstruction that will be discussed in a separate paragraph.

This same operation can be performed without venous-venous bypass when the degree of portal hypertension is such that cross-clamping the IVC would not cause a significant reduction in the blood flow return to the right heart. Hemodynamic stability in this case can be achieved by maintaining the patient’s electrolyte and volume status (Starzl et al. 1968).

Bile Duct Reconstruction 

The bile duct continuity can be achieved with several techniques. It is preferential to perform an end-to-end choledochocholedochostomy over a T tube. First, the donor’s duct is explored. This is done with a bile duct probe. With this maneuver, the distance between the stump of the donor’s duct and the bifurcation in the right and left duct is assessed. Next, cholecystectomy is carried out in an antegrade fashion using electrocautery. The cystic artery is transected to check for good blood flow from the hepatic artery. The cystic artery is then tied off with a 2/0 silk tie when satisfactory pulsating blood flow is identified. The gallbladder is removed from the surgical field. Hemostasis is achieved in the bed of the gallbladder with argon beam coagulation. The cystic duct is then opened flat with electrocautery to avoid possible mucocele formation in the postoperative time. The stump of the bile duct is trimmed by 1 or 2 mm until arterial bleeding is noted from the edge of the duct. The bleeding vessels are always located in the medial and lateral corner of the bile duct stump; hemostasis is achieved with one transfixed stitch per arterial vessel. Different types of stitches can be used, such as 4/0 silk or 6/0 PDS. At this stage, two 4/0 silk stitches are placed on the lateral and medial corner of the donor’s bile duct stump. The recipient’s duct is opened, explored, and trimmed. Although this anastomosis can be performed with or without a T tube, T tube use is preferred. The T tube gives easy access to the bile duct if a cholangiogram is needed in the postoperative time. Other uses of the T tube include: macroscopic evaluation of the bile characteristics and bile collection for culture in case of postoperative infections. Thick dark bile is considered to be normal. Bile that is light in color, and less dense than normal, is typical in primary non-function or acute cellular rejection. Nine 5/0 PDS sutures are used to complete the anastomosis. Two stitches are placed in the posterior wall, three on each side, and one on the anterior wall. A purse string is placed around the exit site of the T tube. Lastly, the anastomosis is checked for leakage by injecting heparinized saline solution through the T tube first, and air, while the anastomosis is submerged in water, second.

In cases of significant size discrepancy between the donor and recipient’s ducts, the larger duct is partially sutured closed prior to performing the anastomosis, as displayed in Fig. 4 (Busuttil and Klintlalm 1996). Alternatively, a choledochojejunostomy over a Roux-en-Y can be used for the same purpose (Sarmiento 2000). The latter is also indicated for patients with primary sclerosing cholangitis (PSC), a disease that carries an increased risk of malignancies of the bile duct. From a technical standpoint, the Roux-en-Y loop is created in the usual fashion, using a hand-sewn technique in two layers, where the sero-serosa is completed with 4/0 silk interrupted sutures. The inner layer is anastomosed using the Gambee technique with 4/0 PDS. The tip of the afferent loop is oversewn with interrupted 4/0 silk stitches. The Roux loop is placed ante-colic; however, a retrocolic placement is an acceptable choice. The ante-colic option is safer, because although portal hypertension is resolved after reperfusion, enlarged varicosities are spread through the abdominal cavity, including the transverse mesocolon. These varices can be injured when the tunnel in the transverse mesocolon is created. Once the intestine is opened, in the antimesenteric border, the mucosa and the serosa are tucked together in the four cardinal points using 6/0 PDS. A silastic tube, placed across the anastomosis, is anchored to the intestine with 5/0 chromic; the 9 stitches technique previously described is used to complete the choledochojejunostomy.

Fig. 4 - End-to-end choledococholedochostomy without T tube

Piggy-Back Technique 

There are different ways of performing a liver transplantation using the piggy-back technique. The common denominator of the different approaches is that the recipient’s caval blood flow to the heart is never more than partially occluded at any time during the surgery. Uninterrupted flow through the IVC affords ample venous blood flow, proper cardiac filling, and hemodynamic stability throughout the procedure (Calne and Williams 1968). Sir Roy Y. Calne first described the piggy-back technique, but Andreas Tzakis popularized it in 1989 (Tzakis et al. 1989). It is especially indicated in cases when the donor’s liver is smaller than the diseased liver (Tzakis et al. 1989). The procedure is identical to the standard technique up until the skeletonization of the hepatic hilum is completed.

Subsequently, the liver is peeled off the IVC. The accessory hepatic veins are divided between 2/0 silk ties, and the accessory hepatic caval stumps are sutured with transfixed 4/0 silk stitches. This is done to prevent the ties from coming off in the postoperative time due to the swings in the central venous pressure (CVP), which are typical during recovery in the intensive care unit (ICU). The right hepatic vein is skeletonized free and clamped both proximally and distally. It is subsequently divided, and the two stumps are oversewn with running 4/0 Prolene sutures. The portal vein is divided between clamps. A German clamp is applied at the common trunk of the left and middle hepatic veins anterior to the vena cava, and the liver is removed from the surgical field using blunt and sharp dissection. Figure 5 demonstrates the left and middle hepatic veins being opened, and the septa separating both veins being cut, creating a common cuff.

Fig. 5 - Left and middle hepatic vein division and cuff formation

The new liver is brought into the field. The anastomosis between the recipient’s hepatic venous cuff and the donor’s suprahepatic IVC is completed in an end-to-end fashion using 4/0 Prolene sutures. In this case, the upper left of the hepatic veins cuff is kept open by two 4/0 silk stitches while the posterior wall is sewn. Once the posterior wall of this anastomosis is completed, the liver is flushed with 1 l of chilled LR at 4 °C. Subsequently, the allograft’s infra-hepatic IVC is tied off. The portal vein and hepatic artery anastomoses are performed as in the standard technique. At this stage, the liver is reperfused. The hepatic artery, the portal vein, and the hepatic vein clamps are removed in sequence. In the piggy-back procedure as well, the liver reperfusion can be done with or without hepatic arterial flow. After a few complete rounds of hemostasis, the bile duct reconstruction is completed as previously described. More hemostasis is performed, and the field is washed with several liters of antibiotic solution. Three Jackson-Pratt drainages are place in the abdominal cavity.

Since there is no end-to-end infra-hepatic IVC anastomosis, the completed procedure leaves the recipient with a section of the donor’s IVC lying anteriorly to the recipient’s IVC, as diagrammed in Fig. 6. Within 1 week post-operation, a thrombus is often visible by ultrasound in the section of the donor’s IVC sandwiched between the liver and the recipient’s IVC. This is common and is not pathologic, as it does not often result in pulmonary embolus (Tzakis et al. 1989). There is no reason to administer anticoagulant medications in this case.

Fig. 6 - Anatomy post piggy-back procedure

Piggy-Back with Side-to-Side Caval Anastomosis (Also Known as the Belghiti Technique) 

Jacques Belghiti described the side-to-side piggy-back technique. Without removal of the retro-hepatic vena cava, and by requiring only one caval anastomosis, Belghiti claimed to reduce the duration of the anhepatic phase (Belghiti et al. 1992). It is the opinion of the authors that this is not the case. Belghiti describes that often, the piggy-back procedure necessitates temporary caval occlusion when creating the common cuff of the left and middle hepatic veins. This assumption is arguable, especially because in the classic piggy-back technique, the common trunk of the middle and left hepatic veins is clamped, a structure that is distant from the IVC. In the Belghiti technique, the IVC is always partially clamped.

In the following paragraph, discussion of the portions of the operation that are not different form the ones previously discussed is omitted.

The IVC is peeled off retro-hepatically by dividing the accessory hepatic veins between 2/0 silk ties. 
Following this, the left, middle, and right hepatic veins are clamped, divided, and oversewn. The vast majority of the surgeons embracing this technique perform this part of the operation with mechanical staplers, increasing the cost of the operation significantly. The liver is removed from the peritoneal cavity, leaving the full length of the IVC intact.

To perform the cavotomy on the recipient’s IVC, a vascular clamp is placed on a section of the IVC “pinching” the vessel’ side wall, as exhibited in Fig. 7. This incomplete vascular clamp ensures a constant caval flow throughout the procedure. This clamp stays on the recipient vessel until the surgeon is prepared to allow portal blood to flow into the IVC. The donor’s cavotomy is performed on the back table as well as oversewing of the donor’s supra- and infra-hepatic cavas. This ensures that once the caval anastomosis is performed, blood flows from the donor’s IVC stump into the recipient’s IVC. The donor’s liver is then brought into the peritoneal cavity, and a side-to-side caval anastomosis is created, connecting the donor and recipient’s retro-hepatic vena cavas. The vessels of the porta hepatis are anastomosed. Once the portal vein anastomosis is complete, both portal and caval clamps are removed. This is, generally speaking, done in sequence while the running suture on the caval anastomosis is not tied off yet, so that the residual air in the anastomosed vessels can vent out of the blood stream. Supposedly, an advantage of this technique is that the anastomosis formed between the donor and recipient’s vena cavas is large. This ensures that there will not be outflow obstruction.

Fig. 7 - Belghiti modification of the piggy-back procedure

Although this procedure technically is feasible, there are several drawbacks. Following this procedure, there tends to be a large amount of scar tissue formation postoperatively surrounding the side-to-side caval anastomosis. In the event that the patient needs a secondary liver transplant, it is difficult to access the suprahepatic IVC to remove the existing liver. Also, due to the nature of the neo-anatomy, if a TIPS procedure is needed, it is difficult to reach the right hepatic vein from the internal jugular vein, because with the new anatomy, a near right angle is formed at the IVC anastomosis.

Liver Transplantation in Situs Viscerus Inversus 

Situs inversus (SI) is a rare congenital condition in which the abdominal viscera are located in mirror image positions across the midline compared to situs solitus. The inferior vena cava is located to the left of the abdominal aorta. During normal embryological development, the liver forms a larger right lobe compared to the left lobe due to asymmetric venous outflow (Farmer and Busuttil 1996). In SI, asymmetric hepatic venous outflow does not exist, leading to the formation of a symmetric liver. Other complications, presented in Fig. 8, often coexist with SI including polysplenia, aberrant left hepatic artery, aberrant main hepatic artery, preduodenal portal vein, malrotation of the gut, and interrupted IVC with azygous continuation (Farmer and Busuttil 1996). 

Fig. 8 - Common complications with situs inversus

Indications for transplant in SI patients are similar to those with SS anatomy. Often, the discovery of SI anatomy occurs during radio-imaging for nonrelevant procedures. There is much debate on how to position the allograft in a patient diagnosed with SI who needs transplantation. If a SS allograft is positioned without rotation in the recipient’s upper left quadrant, the large right hepatic lobe lays across the stomach and vertebral column where space is restricted. 

Dr. Klintmalm and associates described a case, in 1991, of a liver transplantation into an SI patient (Klintmalm et al. 1993). All vessels and ligaments to the recipient liver are divided, and the retrohepatic IVC is left intact. The native liver is removed, and the allograft, in preparation for the implantation, is rotated clockwise 90°, as in Fig. 9, with the left lobe pointing into the left iliac fossa and the right lobe sitting in the recipient’s hepatic fossa. The donor’s suprahepatic vena cava is oversewn. The donor’s infra-hepatic vena cava is anastomosed end-to-side to the recipient’s left-sided inferior vena cava. The other major vessels are anastomosed end-to-end and blood flow to the allograft is restored. Benefits of this technique are the recipient’s stomach is not obstructed by the donor’s right lobe, there is no risk of venous outflow obstruction, and the size of the allograft is not an exceedingly important factor (Klintmalm et al. 1993). 

Fig. 9 - Situs inversus anastomoses

Auxiliary Liver Transplantation 

Orthotopic liver transplant (OLT) is the treatment of choice for fulminant hepatic failure (FHF) (Bismuth et al. 1995). A suitable alternative is auxiliary liver transplantation, a procedure where the allograft is transplanted either heterotopically or orthotopically in place of a section of the native liver. The allograft is removed after the native liver recovers from the original insult. The main advantage of this procedure is that the patient avoids life-long immunosuppressive treatment once the allograft is removed (Jaeck et al. 2002). The theory behind auxiliary liver transplant is that the implanted allograft will lend the patient hepatic support while the failing liver regenerates. Orthotopic versus heterotopic auxiliary partial liver transplant is debated.

Auxiliary partial orthotopic liver transplantation (APOLT) is completed by removing a section of the failing liver and replacing it with an equal lobe or part of a lobe from a donor. This operation is more commonly done in children using a live donor. Depending on the recipient’s size, the left lobe or the left lateral segment is used (Jaeck et al. 2002). When the left lateral segment is chosen, the donor’s operation requires the resection of the left lateral segment with accompanying vessels. The donor’s vessels procured with the partial allograft consist of the stumps of the left portal vein, hepatic artery, and hepatic vein. The left bile duct is taken with the allograft. 

The allograft’s left hepatic vein is anastomosed end-to-end with the recipient’s vessel. The donor’s hepatic artery is anastomosed, preferably, with the recipient’s left hepatic artery. The portal vein and the bile ducts are anastomosed to their corresponding recipient vessels. The anatomy of the recipient right liver is left untouched. The hepatic function offered by the partial allograft provides the failing liver time to heal. Primary non-function of the graft is not statistically different between OLT and APOLT (van Hoek et al. 1999). 

Gubernatis et al. explain that hypothetically, portal blood flow should be distributed between the two livers by resistance to flow. Early after transplantation, blood should preferentially flow through the allograft due the high resistance in the diseased liver. Once the diseased liver begins to heal, blood flow shifts back to the healing liver due to resistance in the donor allograft. This increased resistance is the result of rejection, once the immunosuppressive medication is discontinued. Conveniently, the blood flow is preferentially distributed to the healthy liver section (Gubernatis et al. 1991). 

Fig. 10 - Heterotopic auxiliary partial liver transplant anastomoses

Heterotopic auxiliary partial liver transplant is a procedure where the recipient’s liver is left intact while a partial donor allograft is implanted into the recipient’s subhepatic space as illustrated in Fig. 10. The goal of this procedure is the same as APOLT, but the efficacy is diminished (van Hoek et al. 1999). This operation can be accomplished using a cadaver or a live donor. In preparation for the allograft’s implantation when a cadaver donor is used, a section of the allograft is resected so it can be accommodated in a small space. On the back table, the suprahepatic IVC is oversewn. Upon implantation, an end-to-side anastomosis of the donor’s infra-hepatic IVC and the recipient’s suprarenal IVC is performed. Anastomoses are created between the recipient’s celiac axis and the donor’s hepatic artery as well as the donor and recipient’s portal veins. An end-to-side choledochojejunostomy is performed between the donor’s bile duct and the recipient’s jejunum. Although the heterotopic implantation of a partial liver should be technically performed as well as APOLT, it does not due to issues such as elevated venous backpressure and inadequate portal perfusion of the donor and recipient’s partial livers (Gubernatis et al. 1991).

Conclusion 

In a span of 50 years, liver transplantation has evolved dramatically and faster than any other known field in medicine. This is partially due to a better understanding of the physiology of patients with end-stage liver disease and the intraoperative management of these patients. Furthermore, the introduction of the venous-venous bypass and the development of structured training programs have made this procedure a routine. It is unfortunate that we have not observed any growth in transplantation in the past several years despite a continuous increase in the number of patients waiting for a liver transplant. As a consequence of that, access to liver transplantation is still restricted to less than 150 centers in the entire United States. It should not be forgotten that although routine, when compared with any other field in surgery, liver transplantation is still a procedure left in the hands of a very limited number of extraordinarily talented surgeons committed to serving a group of patients that for the most part fall into the category of the “underprivileged.”

All images are courtesy of Paul Schiffmacher, Medical Illustrator for Medical Media Services at Thomas Jefferson University.

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Rossella Palma · Stefano Pontone · Ignazio Roberto Marino · Fabio Massimo Magliocca · Stefano Frattaroli ·Valeria Tonini · Vito D’Andrea

Published online: 10 March 2020
© Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract

Introduction Lipomas are the most common non-epithelial benign tumors of the gastrointestinal tract with a reported incidence in the colon of 0.2–4.4%. These lesions are usually asymptomatic with a typical endoscopic finding of a smooth, slightly yellow, circular, polyp that is sessile in most cases, covered with normal colonic mucosa.
Areas Covered There are rare reported cases of alterations of the overlying mucosa such as hyperplasia, atrophy, adenomatous changes, and necrosis.
Expert Commentary We report a rare case of pedunculated colonic lipoma of the transverse colon covered with hyperplastic and ulcerated epithelium easily misdiagnosed as an adenomatous lesion.

Abbreviations
EMR Endoscopic mucosal resection
FOBT Fecal occult blood test

Introduction

Lipomas are the most common non-epithelial benign tumors of the gastrointestinal tract with a reported incidence of 0.2–4.4% [1]. The reported prevalence is higher in women and in patients 50–60 years old, distributed in the ascending (45%), sigmoid (30.3%), descending (15.2%), and transverse colon (9.1%). These lesions are usually asymptomatic with a typical endoscopic finding of a smooth, slightly yellow, circular polyp, sessile in the most of cases, with a normal colonic superficial mucosa [2]. Nevertheless, in about 25% of cases, and especially when their maximum diameter is > 2 cm, clinical symptoms such as iron deficiency anemia, abdominal pain, constipation, bleeding, and intussusception may occur. There are rare reported cases of alterations of the overlying mucosa such as hyperplasia, atrophy, adenomatous changes, and necrosis [3–7].

Herein we report a case of colonic lipoma covered with hyperplastic and ulcerated epithelium that was easily confused with an adenoma.

Case Report

A 74-year-old woman underwent routine screening colonoscopy for positive FOBT detection. She denied constipation, diarrhea, hematochezia, or other gastrointestinal symptoms. Her past medical history and biochemical examinations were unremarkable.

Fig. 1 Endoscopic finding of a pedunculated polyp with ulcerated and slightly irregular superficial epithelium

During colonoscopy, a 30-mm pedunculated polyp in the transverse colon was identified. The superficial epithelium was macroscopically ulcerated, friable, and slightly irregular (Fig. 1). The polyp did not display the characteristic features of a lipoma (such as the “pillow sign”) but more resembled an epithelial lesion. We performed an EMR after submucosal saline solution injection (Fig. 2). Histopathological examination showed a benign tumor arising from the submucosal layer, composed of mature adipose tissue covered by superficially ulcerated hyperplastic epithelium (Fig. 3). The lesion was completely resected.

Fig. 2 Endoscopic Mucosal Resection (EMR): macroscopic aspect

Fig. 3 Microscopic examination showing a colonic lipoma with overlying hyperplastic epithelium

Discussion

Colonic lipomas are benign tumors amply described in the literature. These benign tumors arise from the submucosal layer and in about 10% of cases from the subserosal or intermucosal layer. The usual endoscopic appearance is a smooth, slightly yellow, rounded polyp with a thick stalk or broad-based attachment [2]. Characteristic endoscopic features include the “tenting sign” (when grasping the overlying mucosa), the “pillow sign” (pressing forceps against the lesion results in depression or pillowing of the mass), and the “naked fat sign” (extrusion of yellowish fat after biopsy) [1, 2]. Pathological examination usually shows wellcircumscribed, mature adipose tissue with varying amounts of fibrous stroma covered with intact colonic mucosa.

Categorizing the pathological features of colonic lipomas can be challenging, in particular since their oncological significance is poorly defined [8]. Snover [9] introduced the term “atypical” to indicate lipomas exhibiting cytological alterations in the fat cells (hyperchromasia, pleomorphism, and mitosis), suggestive of sarcomatous changes. Currently, the term could be extended to all lesions with hyperplastic or adenomatous changes of the overlying epithelium, as previously described by Virgilio et al. [8]. They also proposed a classification of “atypical” lipoma in type A, type B, and type C based on the malignant alterations of the covering epithelium, reporting very few cases from the literature. Although the etiology of alterations of the colonic mucosa is unknown, chronic trauma due to the passage of stools may lead to hyperplasia and adenomatous transformation of the overlying mucosa in addition to ischemic and inflammatory
mechanisms [8].

To the best of our knowledge, hyperplastic changes on the surface of a colonic lipoma have been previously reported twice. Radhi et al. [3] reported the case of a large lipoma of the sigmoid colon that was detected during a surgical intervention in a patient with diverticulitis, and Yeom et al. [5] described the case of an EMR performed on a 9-mm colonic lipoma with overlying hyperplastic epithelium located in the ascending colon.

In conclusion, we report a case of a rare pedunculated colonic lipoma, located in the transverse colon, with overlying hyperplastic and ulcerated epithelium. Even though consensus exists such that small (< 2 cm) asymptomatic colonic lipomas do not need any intervention, in our opinion the endoscopic prophylactic removal of these lesions should be considered, paying attention to the overlying mucosal changes, due to their potential for malignant transformation [4, 6–9].

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References

1. Vecchio R, Ferrara M, Mosca F, et al. Lipomas of the large bowel. Eur J Surg. 1996;162:915–919.
2. Bardají M, Roset F, Camps R, et al. Symptomatic colonic lipoma: differential diagnosis of large bowel tumors. Int J Colorectal Dis. 1998;13:1–2.
3. Radhi JM, Haig TH. Lipoma of the colon with overlying hyperplastic epithelium. Can J Gastroenterol. 1997;11:694–695.
4. Seong Jun C, Joon Sung K, Byung WK. Tubular adenoma overlying a colonic lipoma resected by endoscopic resection with use of a detachable endoloop. Gastrointest Endosc. 2019;89:4.
5. Yeom J-O, Kim S-Y, Jang E-C, et al. Colonic lipoma covered by hyperplastic epithelium: case report. World J Clin Cases. 2013;1:124–127.
6. Moschetta M, Virelli R, Laricchia F, et al. Lipoma of the transverse colon covered by Tubulovillous adenoma: a rare indication for surgical treatment. Chir Gastroenterol. 2018;39:63–66.
7. Capra F, Zorcolo L, Scintu F, et al. Giant sigmoid lipoma covered by a villous adenoma. Int J Colorectal Dis. 2007;22:563–564.
8. Virgilio E, Mercantini P, Cavallini M. Is endoscopic resection a correct treatment for atypical gastrointestinal lipomas? World J Clin Cases. 2016;4:30–32.
9. Snover DC. Atypical lipomas of the colon. Report of two cases with pseudomalignant features. Dis Colon Rectum. 1984;27:485–488.

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Ramirez CB, Doria C, Frank AM, Armenti ST, Marino IR.

Abstract: Corticosteroids (CS) have been standard immunosuppression to prevent and treat rejection. However, CS are associated with increased risk of infection, obesity, hypertension, hyperlipidemia, diabetes, and accelerated hepatitis C virus (HCV) recurrence post-orthotopic liver transplantation (OLT). This study assesses the safety and efficacy of CS-free immunosuppressive regimen in adult OLT.

Methods: A two-yr, prospective, randomized study of CS with delayed withdrawal (CS) or CS-free regimen with basiliximab, tacrolimus, and enteric-coated mycophenolate sodium (EC-MPS) was performed in 39 patients (CS=20; CS-free=19). CS group received intra-operative methylprednisolone weaned by six months. HCV patients had HCV PCR pre-OLT and 0.5, one, three, and six months post-OLT. Protocol liver biopsies were performed at OLT, 2 and 24 wk post-OLT or when indicated.

Results: Rejection occurred in two patients. Patient survival at one yr (100% vs. 95%), three yr (85% vs. 63%), and five yr (80% vs. 63%) post- OLT were similar between CS and CS-free group, respectively. Deathcensored graft survival at one yr (100% vs. 95%), three yr (85% vs. 63%), and five yr (75% vs. 63%) were also similar. The risk of new-onset DM, hypertension, hypercholesterolemia, and weight gain was similar between groups.

Conclusion: CS avoidance with basiliximab, calcineurin inhibitor, and EC-MPS is safe and effective as CS- containing immunosuppression in adult OLT.

[...]

Read full article - Clinical Transplant 2013

ANTONIO GIORDANO, UMBERTO GALDERISI AND IGNAZIO R. MARINO

Mesenchymal Stem Cells (MSCs) are non-hematopoietic multi-potent stem-like cells that are capable of differentiating into both mesenchymal and non-mesenchymal lineages. In fact, in addition to bone, cartilage, fat, and myoblasts, it has been demonstrated that MSCs are capable of differentiating into neurons and astrocytes in vitro and in vivo. MSCs are of interest because they are isolated from a small aspirate of bone marrow and can be easily expanded in vitro. As such, these cells are currently being tested for their potential use in cell and gene therapy for a number of human diseases. Nevertheless, there are still some open questions about origin, multipotentiality, and anatomical localization of MSCs. In this review, we discuss clinical trials based on the use of MSCs in cardiovascular diseases, such as treatment of acute myocardial infarction, endstage ischemic heart disease, or prevention of vascular restenosis through stem cell-mediated injury repair. We analyze data from clinical trials for treatment of osteogenesis imperfecta (OI), which is a genetic disease characterized by production of defective type I collagen. We describe progress for neurological disease treatment with MSC transplants. We discuss data on amyotrophic lateral sclerosis (ALS) and on lysosomal storage diseases (Hurler syndrome and metachromatic leukodystrophy). A section of review is dedicated to ongoing clinical trials, involving MSCs in treatment of steroid refractory Graft Versus Host Disease (GVHD); periodontitis, which is a chronic disease affecting periodontium and causing destruction of attachment apparatus, heart failure, and bone fractures. Finally, we will provide information about biotech companies developing MSC therapy.
J. Cell. Physiol. 211: 27–35, 2007. © 2007 Wiley-Liss, Inc.

What are Mesenchymal Stem Cells?

The microenvironment of mammalian bone marrow is composed of several different elements that support hematopoiesis and bone homeostasis (Muller-Sieburg and Deryugina, 1995; Zhang et al., 2003). It includes a heterogeneous population of cells: macrophages, fibroblasts, adipocytes, osteoprogenitors, endothelial cells (ECs), and reticular cells. Among these, there are also non-hematopoietic stem cells that posses a multilineage potential (Deans and Moseley, 2000; Bianco et al., 2001). These stem cells are commonly indicated as marrow stromal stem cells or mesenchymal stem cells (MSCs). Mesenchymal cells are primordial cells of mesodermal origin giving rise to skeletal muscle cells, blood, vascular and urogenital systems, and to connective tissues throughout the body (Prockop, 1997; Beyer Nardi and da Silva Meirelles, 2006; Sethe et al., 2006). For this reason, the word mesenchymal should be referred to stem cells that are also able to produce blood cells. In practice, however, blood cells derive from a distinct stem cell population present in bone marrow: the hemapoietic stem cells (HSCs) (Prockop, 1997; Beyer Nardi and da Silva Meirelles, 2006; Sethe et al., 2006). MSCs can be hence considered non-hematopoietic multipotent stem-like cells that are capable of differentiating into both mesenchymal and non-mesenchymal lineages. In fact, in addition to bone, cartilage, fat, and myoblasts, it has been demonstrated that MSCs are capable of differentiating into neurons and astrocytes in vitro and in vivo (Pittenger et al., 1999; Bianco and Gehron Robey, 2000; Jori et al., 2005; Beyer Nardi and da Silva Meirelles, 2006) (Fig. 1).

MSCs are of interest because they are easily isolated from a small aspirate of bone marrow and can be expanded through as many as 50 population doublings in about 10 weeks. As such, the cells are currently being tested for their potential use in cell and gene therapy for a number of human diseases. Nevertheless, there are still some open questions about origin, multipotentiality and anatomical localization of MSCs. As far as this latter point is concerned, it has been shown that MSCs can be isolated from different tissues other than bone marrow, which, however, is the primary source for obtaining these stem cells. MSCs have been isolated from adipose tissue, liver, tendons, synovial membrane, amniotic fluid, placenta, umbilical cord, and teeth (Prockop, 1997; Bianco and Gehron Robey, 2000; Beyer Nardi and da Silva Meirelles, 2006; Sethe et al., 2006). Another hot issue is the lack of a single marker to clearly define MSCs. In fact, at present, MSCs are identified through a stem cell populations similar to MSCs but which have been defined with a different nomenclature, such as the bone marrow stromal stem cells, stromal precursor cells, recycling stem cells, marrow isolated adult multineage inducible stem cells (MIAMI cells), and multi-potent adult progenitor cells (MAPC) (Reyes et al., 2001; D’Ippolito et al., 2004; Beyer Nardi and da Silva Meirelles, 2006). MIAMI and MAPC stem cells have a higher proliferative and differentiative potential compared to classical MSCs. It has been suggested that these may represent a more primitive subset of stem cells that could be the common precursor of MSCs and HSCs (Reyes et al., 2001; D’Ippolito et al., 2004; Beyer Nardi and da Silva Meirelles, 2006). If this is the case, then the relationship between these cell populations and the hemoangioblasts that are considered the mesodermal precursors of hematopoietic and EC lineages has to be determined (Park et al., 2005; Sethe et al., 2006) (Fig. 1).

Fig. 1. Diagram of mesenchymal stem cell hierarchy. At top of diagram are indicated the MAPCs and the MIAMI cells that posses a higher proliferativeanddifferentiative potentialcomparedto classicalMSCs.Thesemayrepresent amoreprimitive subset ofstemcells that couldbe the common precursor of MSCs,HSCsand EPCs. In the diagram are indicated themesenchymal and non-mesenchymal cell types that originate from these different classes of stem cells. The dashed lines indicate putative differentiation pathways.

MSCs for Cell Therapy

For more than 100 years, aspirin has served as one of the most effective anti-inflammatory, fever-fighting, pain-relieving drugs on the market. However, its mechanism of action was not discovered until 1971, more than 70 years after aspirin had first appeared on the market. This is not an isolated example, as many times physicians really do not know how their ‘‘tools’’ work. This, however, has not prevented their applications in the clinical setting if there are benefits for patients and there are no or minimal side effects. This type of scenario will probably occur also for cell therapy based on MSCs. These cells have a high expansion potential, genetic stability, can be easily collected and shipped from the laboratory to the bedside and are compatible with different delivery methods and formulations. In addition, MSCs have two other extraordinary characteristics: they are able to migrate to sites of tissue injury and have strong immunosuppressive properties that can be exploited for successful autologous as well as heterologous transplantations (Le Blanc and Pittenger, 2005). In the near future, while scientists will try to learn more about MSC biology, physicians will further develop clinical protocols for MSC-based cell therapy treatments.

MSCs in Hematological Pathologies

Allogenic HSC transplantation could be an effective therapy for several hematological pathologies. However, there could be a number of problems related to treatment, such as infections, bleeding, engraftment failure, and graft versus host disease (GVHD) (Armitage, 1994; Tabbara et al., 2002). GVDH is a form of rejection, where transplanted cells begin to attack host tissues and organs, such as the digestive tract, skin, and liver. It is important to find effective ways to eliminate or at least minimize such serious transplant side effects (Ferrara and Yanik, 2005; Ferrara and Reddy, 2006). MSCs have been shown to have immunosuppressive properties and delay skin graft rejection (Bartholomew et al., 2002; Di Nicola et al., 2002; Le Blanc and Pittenger, 2005). Moreover, MSCs produce cytokines that can support hematopoiesis and potentially enhance marrow recovery following chemotherapy or radiotherapy (Koc and Lazarus, 2001; Le Blanc and Pittenger, 2005). On these bases, several authors have tried to exploit MSCs to facilitate engraftment of HSCs and lessen GVDH. Preliminary studies were carried out by Lazarus et al. (1995). They collected autologous MSCs from patients with hematological cancers in complete remission. MSCs were expanded in culture for 4–7 weeks and then were reinfused intravenously into patients. Patients were grouped in three classes and received 1x10⁶, 5x10⁶, and 10x10⁶/kg MSCs, respectively. No toxicity and adverse reactions were observed, suggesting that MSCs could be useful for transplant treatment (Lazarus et al., 1995). Studies on a patient with severe idiopathic aplastic anemia (SAA) further demonstrated the possible beneficial effect of MSC transplant. A 68-year-old female patient suffered from an end-stage SAA, refractory to conventional therapies. She received an allogenic MSC transplant. Before MSC infusion, the biopsy revealed no hematopoietic tissue, interstitial hemorrhage, edema, adipocytic necrosis, or marrow stromal cells. After transplantation, the majority of these phenomena disappeared, although there was no recovery of hematopoietic tissue, suggesting that allogenic MSC can be safely infused without inducing any side effect and/or GVDH. These studies suggested also that co-infusion of HSCs and MSCs could produce beneficial effects on patients suffering from hematological pathologies (Fouillard et al., 2003). Another interesting result was obtained in a 20-year-old woman suffering from myelogenous leukemia (Lee et al., 2002).

She underwent allogenic HSC and MSC transplantation from her haploidentical father. Peripheral blood mononuclear cells from the father were collected by leukapheresis after pre-treatment with granulocyte colony stimulating factor. The products of leukapheresis were further purified to obtain CD34(þ)HSCs and infused into the patient. Bone marrow aspirate from iliac crest of patient’s father was collected and plated in culture to obtain MSCs. The expanded MSCs were infused after transplantation of HSCs. The patient engrafted rapidly and did not show acute or chronic GVDH. For several months since transplantation, the patient exhibited an enduring trilineage hematological response and complete remission from leukemia. In spite of these positive results, chimeric studies on patients’ bone marrow, carried out several months after transplantation, showed that MSCs were of 100% recipient origin, suggesting that donor MSCs did not engraft. Thus, beneficial effects of allogenic MSC co-infusion could not be clearly attributed to immunosuppressive and/or citokine production (Lee et al., 2002). Lazarus et al. (2005) conducted an exhaustive research on patients suffering from hematological malignancies and treated with co-infusion of HSCs and MSCs. In an open-label, multicenter trial, they enrolled 56 patients that had undergone myeloablative therapy and were responsive to treatment or showed non-progressive disease. MSCs and HSCs were obtained from HLA-identical sibling donors. MSC cultures were prepared starting from 30 ml of donor bone marrow aspirate, while HSCs were obtained either from donor bone marrow aspirate or from peripheral blood stem cells. The planned MSC dose escalation scheme was 1x10⁶, 2.5x10⁶, and 5x10⁶/kg in both patients receiving HSCs from bone marrow or peripheral blood. MSCs were infused 4 h before HSC transplantation. Hematopoietic recovery was prompt for most patients and acute GVDH did not develop in 23 of 46 patients who participated in all phases of the clinical trials. Eleven patients experienced a long relapsed time. These results suggest that introducing culture-expanded MSCs together with HSC transplantation is a safe procedure and could potentially reduce transplant side effects and enhance marrow recovery after myeloablative treatment (Lazarus et al., 2005).

Bone Marrow Stem Cells in Cardiovascular Diseases - Heart diseases

Loss of cardiomyocytes following myocardial infarction induces a contractile dysfunction of heart and the dead cardiac muscle cells are replaced by fibroblasts to form scar tissues. In most circumstances, chronic ischemia persists following infarction and leads to negative remodeling that can cause heart failure and death (Ambrose, 2006). Transplantation of fetal cardiomyocytes or skeletal myoblasts has been proposed as a future method for treatment of heart strokes (Soonpaa et al., 1994; Delcarpio and Claycomb, 1995; Leor et al., 1996; Murry et al., 1996; Taylor et al., 1998; Tomita et al., 1999). Nevertheless, this idea remains unfeasible because of the difficulty in obtaining donor cells and the percentage of failures associated with obtaining sufficient recovery of physiological function in transplanted hearts. Several authors have demonstrated that intracoronary injection of mixed populations of bone marrow stem cells or of MSCs could represent a simple and successful approach to the treatment of heart diseases. An interesting study on this topic was performed by Strauer et al. (2002). They enrolled 20 patients that had suffered from transmural infarction. After right and left catheterization, coronary angiography, and left ventriculography, patients underwent balloon angioplasty and stent implantation. Five to 9 days after acute infarction, bone marrow was aspirated from the ilium of 10 patients and mononuclear cells were isolated with classical Ficoll density separation. Cells were then transplanted into the infarcted zone with the use of a balloon catheter, which was placed within the infarct-related artery. Intracoronary transplantation consisted of six to seven fractional high-pressure infusions, each containing 1.5–4x10⁶ cells. Ex vivo experiments demonstrated that these cells were able to generate mesenchymal cultures. Comparison of the two groups 3 months after cell or standard therapy showed several significant differences. In fact, the infarct region as a percentage of hypokinetic, akinetic, or dyskinetic segments of the circumference of the left ventricle decreased significantly in the cell-transplanted group. Ejection fraction increased in both groups. Perfusion defect was considerably decreased in the cell therapy group as detected by thallium scintigraphy (Strauer et al., 2002). Another study on cell therapy for acute myocardial infarction treatment was carried out by Chen et al. (2004). Sixty-nine patients within 12 h of onset of infarction underwent emergency angiography or angioplasty. Patients were candidates for MSC treatment and were randomized to receive cell transplantation (n¼34) or saline treatment (n¼35) after percutaneous coronary intervention (PCI). Sixty milliliters of bone marrow from patients undergoing cell therapy was aspirated and mononuclear cells were cultured for 10 days to obtain MSCs. At the end of in vitro amplification, cells were collected and used for cell therapy. The infarct-related artery was occluded at the proximal edge of the previous angioplasty and 6 ml of MSC suspension (8–10x10⁹ cells/ml) was injected into the target coronary artery. Control patients received standard saline injections. All patients underwent cardiac echocardiography once a month and positron emission tomography was performed 3 and 6 months after implantation. Electrocardiographic monitoring for 24 h was also recorded 3 months after the procedure. The percentage of hypokinetic, akinetic, and dyskinetic segments decreased significantly in the cell therapy group after 3 months compared to that at the beginning of treatment. This result was obtained to a lesser extent also in the control group. Wall movement velocity over the infarcted area increased significantly in cell therapy-treated patients but not in the control group. Also left ventricular ejection was higher in the cell therapy group compared to controls (Chen et al., 2004).

An interesting randomized trial (called BOOST trial) to assess the effectiveness of intracoronary transfer of autologous bone marrow cells for treatment of acute myocardial infarction was carried out by Wollert et al. (2004). They enrolled 60 patients suffering from acute heart infarction. After PCI, patients were randomly assigned to either a control group that received classical post-infarction treatment or to cell therapy. Bone marrow nucleated cells were collected from patients in the cell therapy group and 4–8 days post PCI were injected (about 24x10⁸) into infarcted artery by a balloon catheter. Changes in left-ventricular end diastolic volumes (LVEDV) index, left-ventricular end systolic volumes (LVESV) index, and left-ventricular mass index did not differ significantly between the control group and bone marrow cell group. However, compared with the control group, patients in the cell therapy group had increased left-ventricular ejection fraction (LVEF) and systolic wall motion 6 months after transplantation. It is noteworthy that there were no differences between the two groups with respect to the number of premature ventricular complexes and the occurrence of non-sustained or sustained ventricular tachycardias by Holter monitoring follow-up at 6 weeks, 3 months, and 6 months. The authors suggested that autologous bone marrow cells can be used to enhance left ventricular functional recovery in patients that had acute heart infarction (Wollert et al., 2004).

A different approach for treatment of myocardial infarction was presented by Katritsis et al. (2005). They acknowledged that intracoronary transplantation of autologous bone marrow-derived mononuclear cells has been shown to improve contractility of infarcted hearts. However, the authors stated that while administration of unpurified mononuclear cells avoids problems associated with cell culture expansion, it inevitably consists of a small percentage of pluripotent cells diluted among a huge amount of committed and differentiated cells. They hypothesized that a bone marrow population consisting of culture-expanded MSCs along with endothelial progenitors (EPCs) also present in marrow stroma would be capable of promoting both myogenesis (by MSCs) and angiogenesis (EPCs) at the infarcted area of the myocardium. The hypothesis relies on several studies suggesting that other cell populations besides hematopoietic stem cells also can give rise to ECs. In fact, adult bone marrow-derived stem/ progenitor cells which are distinct from hematopoietic stem cells, have also been shown to differentiate to the endothelial lineage (Urbich and Dimmeler, 2004). These authors enrolled patients with both recent and old anteroseptal myocardial infarction. All patients had been previously subjected to angioplasty and stent implantation of the left anterior descending artery. In a group of patients (n¼11), the day following PCI, bone marrow aspirates were collected and mononuclear cells were isolated by classical Ficoll separation. Cells were plated in cultures and on day 7, the adherent cells were washed, collected, and transferred to the operating room. The left coronary artery was catheterized for cell transplantation. Two cell suspensions (each containing 1–2x10⁶ cells) were infused distally to the occluding balloon of the catheter. Both in the transplantation group and the controls, there was a trend for improvement in end-diastolic and end-systolic diameter, fraction shortening, ejection fraction, end-diastolic, and end-systolic volume. In 5 out 11 patients in the transplantation group, there was improvement of myocardial contractility in one or more previously non-viable myocardial segments. No one in the control group showed this improvement. Overall evaluation of obtained results indicated that the positive effect of cell therapy on myocardial contractility is mainly seen in patients with recent myocardial infarction (Katritsis et al., 2005). All of the above-described results, along with similar studies (Assmus et al., 2002; Stamm et al., 2003), demonstrate that cell therapy with bone marrow-derived stem cells is feasible, safe, and may contribute to regeneration of myocardial tissue following infarction. Nevertheless, several issues are still controversial: which kind of stem cell is suitable for patients? When should cells be transplanted? How should the viability of transplanted cells be monitored? What is the ideal mechanism of action of stem cells: secretion of growth factors or cell-to-cell interactions?

A study performed by Perin et al. (2003) evaluated the hypothesis that transplants of bone marrow mononuclear cells in patients with end-stage ischemic heart disease may promote neovascularization and may prevent impairment of heart functionality which in turn can lead to myocardial infarction. They enrolled 21 patients, 14 were assigned to the cell therapy group and 7 to the control group. The inclusion criteria for patients were: (i) chronic coronary disease; (ii) left ventricular ejection fraction <40%; (iii) ineligibility for percutaneous or surgical revascularization. For patients undergoing cell therapy treatment, 50 ml of bone marrow was aspirated from the iliac crest and bone marrow mononuclear cells were separated using the Ficoll density procedure. Patients underwent heart catheterization on the left side and electromechanical mapping (EMM) of the left ventricle to target the specific treatment area by identifying viable myocardium. In this area, 15 injections of 2 ml were delivered for a total of ~25x10⁶ cells/patient. All patients underwent a complete non-invasive follow-up (clinical evaluation, ramp tread mill protocol, 2D Doppler echocardiogram, and single photon emission computed tomography analysis) 2 months later and an invasive follow-up (left ventricle angiograms and EMM) after 4 months. Two months after treatment, they observed a significant reduction in total reversible defect and improvement in global left ventricular function within the treatment group and between this and the control group. The 4-month follow-up revealed an improvement in ejection fraction and a reduction in end-systolic volume in the treated patients (Perin et al., 2003). This preliminary study demonstrated that cell therapy treatment could improve myocardial blood flow with associated enhancement of left ventricular functions in patients with severe ischemia and could reduce the risk of heart stroke. The same research team further evaluated the effectiveness of their cell therapy protocol by evaluating patients with severe ischemia 6 and 12 months after transendocardial injection of autologous bone marrow cells. They showed that total reversible defect, detected by SPECT perfusion scanning, was reduced in the cell therapy group compared with controls. Moreover, at 12 months, exercise capacity was significantly improved in cell therapy-treated patients (Perin et al., 2004). These data further support the effectiveness of autologous bone marrow infusion for ischemic cardiomyopathy treatment.

Vascular diseases

Arterial (re)stenosis is a pathophysiological phenomenon that can follow angioplasty, arteriotomy, or by-pass creation in humans and experimental vascular injury in animal models, causing an occlusion of the arterial lumen of variable extension that often requires a new revascularization procedure. Vascular injury, with cell loss in the intima and media tunicae, elastic lamina fragmentation and damage to tissue architecture, leads to excessive pathological repair and remodeling that involves vascular smooth muscle cell (SMC) migration and proliferation, resulting in neointimal hyperplasia (Forte et al., 2001; Xu et al., 2004). Recent evidence has shown that vascular function depends not only on cells within the vessels, but is also significantly modulated by circulating cells derived from the bone marrow. Stem cells hold a great potential for the regeneration of damaged tissues in cardiovascular diseases. In particular, in the past, it was believed that the regeneration of injured endothelium and media in arteries was due to migration and proliferation of neighboring ECs and SMCs. Recent studies clearly indicated that different stem cell populations, derived from bone marrow and characterized by different markers and with different behaviors, contribute to vascular remodeling after injury (Tanaka et al., 2003). On this basis, it has been hypothesized that the restenosis process could be prevented through stem cell-mediated early injury repair. One interesting study was carried out using EPCs. The study is part of the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry. HEALING I was a single-center, prospective, non-randomized registry trial. It was conducted by Aoki by applying in patients the GenousTM Bio-engineered Rstent (OrbusNeich Company), the first stent designed to accelerate the natural healing response by capturing a patient’s own EPCs from the blood stream (Aoki et al., 2005). Once captured, EPCs rapidly form a protective endothelial layer over the stent, providing protection against thrombus and minimizing restenosis. This stainless steel stent is coated with a murine monoclonal antibody against human CD34.The first published results of this clinical study were obtained on 16 patients and revealed that this coated stent was safe and feasible. On this basis, the group started with the HEALING II study, which included 63 patients at 10 centers in Europe. Whole blood samples were analyzed to quantify the number of EPCs in each patient. Data showed that the EPC titer directly correlated with angiographic outcomes. There were no target lesion revascularizations in patients with normal numbers of circulating EPCs, while patients with low EPCs were affected by restenotic and cardiac events. It should be mentioned that the large majority of patients with normal EPC levels were on statin therapy, while most in the low EPC group were not. Previous studies revealed that statin injection is effective in EPC mobilization (Walter et al., 2002). On the basis of these encouraging results, the HEALING III study has been designed to verify and substantiate these findings and will be conducted in 2006 (Silber, 2006). The HEALING III study will also assess the effect of combining statin therapy and EPC capturing stents.

MSCs for Treatment of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetic disease characterized by production of defective type I collagen, the principal protein in bone. OI patients have several painful fractures, retarded bone growth with progressive bone deformation. At present, there is no cure for OI and only one class of drug (bisphosphonates) has been proven to be partially effective (Bembi et al., 1997; Marini and Gerber, 1997). A different approach to treating this disease is the use of cell therapy based on MSCs. In fact, in preclinical experiments carried out on animal models, transplanted MSCs migrated and became incorporated into the bone and muscle of recipient animals (Pereira et al., 1995; Ferrari et al., 1998; Onyia et al., 1998). Therefore, MSC transplants could be useful to correct defects associated with OI. Horwitz et al. (1999) demonstrated the feasibility of allogenic bone marrow transplantation for children with severe OI. Three children with OI were selected for cell therapy. They revealed a mutation of either the COL1A1 or COL1A2 gene, which is associated with severe deforming OI. Patients were intravenously infused with unmanipulated bone marrow cells (5.7–7.5x10⁸ cells/kg) from HLA-identical or single-antigen-mismatched siblings after they received ablative conditioning therapy. Chemoprophylaxis against GVHD consisted of cyclosporine treatment (Horwitz et al., 1999). Engraftment was associated with improvements in bone histology as determined by evaluating specimens of trabecular bones taken before implants and 216 days after transplantation. Before transplantation, the bone sample from one patient contained several disorganized osteocytes, enlarged lacunae, and few osteoblasts. After cell therapy, specimens taken near the site used previously showed a reduced number of osteocytes, linearly organized osteoblasts, and lamellar bone formation. Fluorescence microscopy analysis showed an improved bone formation and mineralization. There was also an increase in the total body mineral content (TBBMC) determined with dual energy X-ray absorptiometry (Horwitz et al., 1999). This preliminary study demonstrated that mesenchymal progenitors in transplanted marrow could migrate to bone in children with OI and give rise to osteoblasts that determined an improvement of bone structure. The clinical significance of this study was, however, questionable. In fact, although the increase in TBBMC along with a decrease in fracture rate observed in some patients, the lack of a long-lasting follow-up and the absence of reliable controls did not make it possible to outline definitive conclusions. In a second study, the authors continued their analysis (Horwitz et al., 2001). Seven children with OI were enrolled for a pilot clinical trial, five of them underwent cell therapy treatment, and two were in the control group. Before treatment, all patients had similar growth rate, typical of children with severe type III OI. The study revealed growth acceleration for the children in the cell therapy group 6 months after the transplantation, in contrast to retarded growth for age-matched controls. With extended follow-up, the growth rate slowed but still exceeded the control rate. The authors suggested that the positive effects of bone marrow transplants were to be ascribed to the integration of competent donor cells of the osteoblastic lineage into the developing bone. However, whether the graft included long-living osteogenic precursors or only committed osteoblasts with a short half-life was unclear (Horwitz et al., 2001). The above-described studies could pave the way to correcting defects associated with OI.

MSCs in Neurological and Inherited Diseases - Amyotrophic lateral sclerosis

MSCs have shown to possess great somatic plasticity since they are capable of differentiating into non-mesenchymal lineages. In fact, it has been demonstrated that MSCs are capable of differentiating into neurons and astrocytes in vitro and in vivo (Pittenger et al., 1999; Bianco and Gehron Robey, 2000; Jori et al., 2005; Beyer Nardi and da Silva Meirelles, 2006). Marrow stem cells have been shown to improve neurological performance in rats with brain ischemia. Moreover, in mice with acid sphingomyelinase deficit, MSC transplants delay the onset of neurological abnormalities and extend their lifespan (Chen et al., 2001; Jin et al., 2002; Zhao et al., 2002). On the basis of these studies Mazzini et al. (2003) initiated a study to verify the efficacy of MSC transplantation in patients with amyotrophic lateral sclerosis (ALS). ALS is a pathology that causes a selective loss of motor neurons leading to a progressive decline in muscle functionality and poor prognosis. Current therapies alleviate only symptoms and there is no cure for this pathology (Mazzini et al., 2003). The research group enrolled seven patients with ALS, showing severe functional impairment of lower limbs and mild impairment of upper limbs. A bone marrow aspirate from each patient was used to prepare MSC cultures that were expanded for 3–4 weeks. Cells were then suspended in autologous cerebrospinal fluid and directly transplanted into the surgically exposed spinal cord at T7–T9 levels. No patients experienced severe adverse events following transplantations. Magnetic Resonance Imaging performed 3 and 6 months following transplantation did not show structural changes of the spinal cord or abnormal cell proliferation when compared with the baseline. Three months after cell implantation, a mild trend toward a slowing down of muscular strength decline was observed in the proximal muscle group of lower limbs in four patients (Mazzini et al., 2003). These preliminary results do not allow us to draw any conclusion about the efficacy of MSC transplants for ALS treatment; nevertheless, they pave the way for further studies and trials aiming to treat neurological diseases.

Hurler syndrome and metachromatic leukodystrophy

There are several forms of mucopolysaccharidosis that are lysosomal storage diseases (Peters et al., 1998; Gieselmann, 2003). Hurler syndrome (MPS 1H), a severe form of mucopolysaccharidosis, is an inherited autosomal recessive disease. In Hurler syndrome, the deficiency in a-L-iduronidase results in accumulation of heparan sulfate and dermatan sulfate into lysosomes. As a consequence, patients show progressive hepatosplenomegaly, cardiac failure, muscle diseases, hydrocephalous and mental retardation. These symptoms lead to death during infancy (Peters et al., 1998). Metachromatic leukodystrophy is an autosomal recessive disease due to the deficiency in arylsulfatase A that produces an accumulation of sulfatides, which in turn causes demyelinization of central and peripheral systems. Demyelinazation induces several severe symptoms, such as tetraplegia, spasticity, mental retardation, and total or partial absence of voluntary activities (Koc et al., 2002; Gieselmann, 2003).

In the early 1990’s, hematopoietic bone marrow transplantations were carried out to ameliorate the life of patients with some lysosomal disorders (Field et al., 1994; Krivit et al., 1999). For example, transplantation of allogenic bone marrows in Hurler syndrome patients was shown to halt progression of liver and heart abnormalities; however, muscle alteration still persisted and even progressed. In addition, marrow transplantation in these patients showed a high incidence of graft failure and morbidity. The efficacy of these transplants is believed to be due to tissue infiltration of donor macrophages that express a normal level of a-L-iduronidase and transfer of enzymes into host cells by endocytosis (Koc et al., 2002). To improve the efficacy of cell transplantation for Hurler syndrome and metachromatic leukodystrophy, Koc et al. infused allogenic MSC in patients suffering from such diseases. MSCs have a multipotential lineage differentiation property. The authors hypothesized that after implantation, MSCs could migrate and differentiate into tissue such as bone, cartilage, peripheral and central nervous system, and repair these tissues (Koc et al., 2002). Six patients with Hurler syndrome and five with metachromatic leukodystrophy, who previously underwent successful bone marrow transplantation from HLA-identical siblings, were enrolled for MSC transplantation. Bone marrow aspirates from original donors were collected and MSC cultures were prepared according to classical protocol. A total of 2–10x10⁶ cells/kg were infused intravenously into patients. The authors did not observe infusion-related toxicity. In four patients with metachromatic leukodystrophy, they observed significant improvement in nerve conduction velocities. However, they did not observe any apparent clinical change in patients, such as improvement of mental and physical conditions. The authors concluded that further evaluations have to be carried out before claiming efficacy or failure of MSC transplants for treatment of mucopolysaccharidosis (Koc et al., 2002).

Can MSC Transplants Improve Recovery of Cancer Patients Undergoing Chemotherapy?

The research team of Prof. Lazarus proposed an interesting application of MSC transplants (Koc et al., 2000). They hypothesized that MSC infusions can improve recovery of cancer patients receiving myeloablative therapy. Breast cancer patients treated with high dose chemotherapy generally have complete and rapid neutrophil and platelet engraftment after peripheral blood progenitor cell (PBPC) transplantation. However, low presence of CD34(þ) stem cells into transplant and bone microenvironment damages increase the risk of delayed engraftment or even its failure. The authors proposed that infusion of autologous MSCs along with PBPC transplantation could improve bone marrow microenvironment and, as a consequence, rate and quality of hematopoietic recovery after myeloablative therapy (Koc et al., 2000). In a Phase I/II clinical trial, they enrolled 32 patients with locally advanced or metastatic breast cancer who were eligible for high-dose chemotherapy and PBPC transplantation. Upon enrollment, 35 days before chemotherapy and PBPC transplants, bone marrow aspirates were collected from patients and MSC cultures were prepared according to classical protocol. MSC cultures contained no detectable breast cancer cells as determined after immunostaining with a cocktail of breast cancer-specific antibodies. Patients received PBPC infusion containing 1.5–39x10⁶ CD34(þ) cells/kg. One or 24 h later, 2.2x10⁶ MSCs/kg were infused intravenously into patients. Hematopoietic engraftment was prompt in all patients with neutrophil and platelet recovery in about 8 days. Bone marrow CFU concentrations recovered to 70% of the baseline by 42 days. All patients were discharged from the hospital and only one patient died within 100 days of the transplant. The authors concluded that MSC infusion at the time of PBPC transplantation is feasible and safe and the prompt hematopoietic recovery suggests thatMSCtreatment may have a positive impact on recovery of patients after high-dose chemotherapy (Koc et al., 2000). To our knowledge, even if these results are of interest, there are no other reports on the use of MSCs for prompt recovery after myeloablative therapy for treatment of solid tumors.

Ongoing Clinical Trials

A look at the website: www.Clinical.Trials.gov of United States National Institute of Health provides information on the current clinical trials based on the use of MSCs. In June 2006, the Christian Medical College of Vellore in India started a single center non-randomized, non-blinded Phase I/II clinical trial (NCT00314483) to study the role of MSCs in the treatment of steroid refractory GVHD. This trial will end in December 2008. Physicians will enroll 25 patients who develop GVDH following an allogenic stem cell transplant. MSCs will be expanded from the donors and will be infused at a dose of 1–2x10⁶ cells/kg. In June 2004, the Translational Research Informatics Center in Japan and other collaborators started a non-randomized, open label, uncontrolled, single group Phase I/II clinical trial (NCT 00221130) to evaluate safety and clinical effects of autologous MSC transplants for periodontitis, which is a chronic disease affecting the periodontium and causing destruction of attachment apparatus of teeth and their loss. This trial is scheduled to end in December of 2008. Ten patients with periodontitis have been enrolled and the study will verify the efficacy of cell transplantation. In detail, an injectable gel, made of a mixture of ex vivo expanded MSCs, osteoblast-like cells, will be delivered in the periodontium of patients. In December 2005, the Rigshospitalet in Denmark started a Phase I/II clinical trial (NCT00260338) to evaluate safety and clinical effects of autologousMSCtransplants in 46 patients with severe chronic myocardial ischemia. This trial will end in November 2009. Patients will be treated with direct intramyocardial injections of ex vivo expanded MSCs. Clinical and objective evaluations will be performed at baseline and at 1-year follow-up. The Hadassah Medical Organization in Israel is scheduled to start a randomized, open label, single group Phase I/II clinical trial (NCT 00250302) for treatment of distal tibial fractures. Scientists will enroll 24 patients with third distal tibia fracture without joint involvement. They will undergo autologous implantation of MSC at the fracture site, which should improve healing by avoiding complications associated with bone grafting.

Companies Developing Mesenchymal Stem Cell Therapy

Biotechnology companies developing stem cell therapy are focused on developing and commercializing human stem cell technology in the emerging field of regenerative medicine to treat degeneration of major organ systems. There are dozens of companies that are trying to develop cell therapy (see for example: www.stem-cell-companies.com, a directory of companies involved in stem cell research and development). However, these companies generally disappoint investors. In part, this is because the stem cell company group comprises a relatively small number of enterprises that are early-stage than the wider biotech sector. As human stem cell research is a relatively new area, companies developing cell therapies face several types of risk and some are not able to manage them, thus becoming highly speculative enterprises. Some risks are well described in a commentary by Giebel (2005). The first type of risk is technology risk. For example, is it possible to differentiate stem cells into fully functional cells, cells that will function exactly like the cells destroyed by the degenerative disease? There is also a manufacturing risk: can companies produce all the cells required under current Good Manufacturing Practices? How much does it cost to produce these cells and how high are the profit margins? Will anybody be able to afford the therapy when you are done? Keeping in mind all these problems, it is easy to predict that only a few companies will survive. Among companies dealing with stem cells, there are some specifically devoted to develop cell therapy based on MSCs. Will they be among the winners of these exciting and important ‘‘biotechnological gamble?’’ Osiris Therapeutics, Inc. is a company that currently has three products in clinical trials, based on MSCs: ProchymalTM, ProvacelTM and ChondrogenTM (www.osiristx.com). Ingredients of these products are adult MSCs from healthy adult volunteer donors and are grown and stored with a proprietary procedure. The objective of ongoing clinical trials with ProchymalTM is to evaluate the safety and efficacy in treating GVHD. GVHD is the greatest complication of allogenic bone marrow transplantation and may affect the digestive system, skin, liver, and other body systems. Very often, it is the major cause of death following transplantation (Ferrara and Yanik, 2005; Ferrara and Reddy, 2006). Clinical trials with ProvacelTM will evaluate its safety and efficacy in treating damaged myocardium following an acute myocardial infarction.

The meniscus is responsible for shock absorption, load transmission, and stability within the knee joint. If this tissue is damaged, surgical removal of the meniscus is the current available therapy (Sweigart and Athanasiou, 2001). ChondrogenTM has shown benefit in animal models of meniscectomy. Clinical trials will be carried out on patients who have undergone standard surgical treatment and will receive an injection of ChondrogenTM into the knee to evaluate safety and effectiveness in ameliorating knee injuries. Mesoblast is an Australian company that is devoted to the production of stem cells to be used in pilot clinical trials in patients with orthopedic and cardiovascular diseases (www.mesoblast.com). The proprietary technology of Mesoblast enables extraction, isolation, and scale-up of mesenchymal type stem cells that they have called mesenchymal precursor cells (MPCs). Their technology is based on the identification of unique markers on the surface of MPCs that enable their extraction and purification from human tissues. Osteoarthritis is an inflammatory disease that results in loss of cartilage at the surface of a joint causing pain and interfering with movement (Arden and Nevitt, 2006; Ge et al., 2006). Acute trauma to healthy joints can have a similar outcome to osteoarthritis. Current therapy for this pathology tries to alleviate painful symptoms but is unable to restore the cartilage lining of joints and thus, there is a progressive degeneration of joint surfaces. Mesoblast’s scientists are carrying out clinical trials based on arthroscopic injection of MPCs to enable regeneration of both cushioning and surface cartilage to relieve pain and restore healthy joints. Scientists at this company are also involved in developing MPC-based cell therapy for bone repair. They have claimed to have technology that can generate both new bone and new blood vessels, enabling greater bone regeneration. They are planning to implant autologous MPCs at the site of bone fractures that will improve healing, eliminating complications associated with bone grafting. In fact, this procedure is greatly limited by a lack of blood supply to the new bone and by the small number of regenerating osteocytes in the graft (Sammarco and Chang, 2002). Researchers at Mesoblast are also developing MPC-based cell therapy for heart failure and peripheral arterial disease. These applications are, however, in a preliminary phase. Another biotech company devoted to developing MSC transplantations is BrainStorm Cell Therapeutics, Inc., which has its headquarters in Israel (www.brainstorm-cell.com). They have developed the product NurOwnTM, the ingredients of which are adult MSCs. NurOwnTMshould be utilized for the treatment of neurodegenerative diseases. In fact, the patent protects a procedure for inducing bone marrow-derived stem cells to differentiate into astrocytes, neurons, and oligodendrocytes. The scientists at BrainStorm Cell Therapeutics, Inc. have transplanted astrocytes, derived from MSCs, into rat models of Parkinson’s disease. Within 2 weeks of cell transplantation, they claim to have observed significant improvement in the characteristic disease behavior, including more than 50% reduction in rotational movements and enhancement in paw reaching capacity. Based on the results of these and other pre-clinical studies, the research team is planning to start clinical trials for treatments of neurological diseases.

Conclusions and Outlook

Over the past years, we have witnessed a growing enthusiasm on the part of scientists and physicians regarding gene therapy and related treatments, but the promise has been overshadowed by many difficulties, especially with regard to the efficacy and safety of delivery of exogenous genes to target cells and tissues by viral vectors. There has been great interest in the antisense oligonucleotide technology that has been applied in a number of clinical trials, even though with inconstant success (Galderisi et al., 1999; Forte et al., 2005). As such, researchers, scientists, physicians, and all professionals in the health care system need to be more cautious when dealing with stem cell therapeutic potentials. However, it seems that some have not learned the lessons arising from previous false promises and errors and still look for the ‘‘magic bullet.’’ Traditional cell therapy is founded on the belief that, when healthy cells are injected into patients, cells will automatically find their way to damaged tissues and stimulate the body’s own healing process. Unfortunately, there are a number of potential side effects of which individuals considering this therapy should be aware. Indeed, cell therapy may be dangerous and some cases of patient deaths directly linked to the therapy have been reported in medical literature. Patients may contract bacterial and viral infections carried by the donor cells, and have experienced life-threatening and even fatal allergic reactions. Donor cells may seriously compromise the immune system. Looking at ongoing clinical trials, it is too early to tell whether all therapies based on stem cells will prove to be clinically effective. Thus, despite extensive research, there are still problems with stem cell therapy, since in many cases, deep and exhaustive studies to find out the exact biology of stem cells are omitted, and there are increasing pressures to start with insufficiently controlled clinical trials. It is very important to address all of these issues.

Acknowledgments

This study was partially supported by NIH grants and Sbarro Health Research Organization grants to A.G.

JOURNAL OF CELLULAR PHYSIOLOGY - 2007 WILEY - LISS, INC .

C. Sommariva, A. Lauro, N. Pagano, S. Vaccari, V. D’Andrea, I. R. Marino, M. Cervellera & V. Tonini

Introduction

Hepatic hematoma is a rare but possible complication of ERCP. We describe the case of a 75-year old man with a large, 8 × 12 cm, sub-capsular and intra-parenchymal hematoma post ERCP, affecting the right liver segments and treated conservatively.

Areas covered

A review of literature has been performed, highlighting two possible mechanisms: hematoma may occur as the result of accidental laceration of a small intrahepatic vessel by the guidewire, whereas the other hypothesis posits that the hepatic damage is secondary to traction on the biliary system exerted by the balloon. We speculate that in case of anomalies of the biliary tree, the incidence of this complication is higher than expected.

Expert commentary

In case of hepatic hematoma post ERCP, a conservative approach should always be considered before proceeding to interventional radiologic procedures or to surgical therapy.

Case Report and Evolution

A 75-year-old man was admitted on to the Emergency Department of St. Orsola University Hospital-Bologna due to stabbing, continuous, and worsening epigastric and thoracic pain. During clinical evaluation, he had an episode of vomiting. Vital signs were unremarkable. Relevant past medical history included acute myocardial infarction treated with angioplasty and stents, followed by pacemaker implant for Luciani–Wenckebach second-degree atrioventricular block. He took daily low-dose aspirin. Admission EKG, chest and abdominal X-rays did not reveal significant pathology. Physical examination was remarkable for upper abdominal pain with no rebound tenderness or other signs of peritonitis. Blood tests included Hgb 15.2 g/dL, amylase 1661 U/L, AST 166 U/L, ALT 106 U/L, and total bilirubin 1.8 mg/dL. The patient was admitted to the Internal Medicine Department with the diagnosis of acute pancreatitis. The initial treatment was conservative with fasting without nasogastric tube insertion and therapy with intravenous piperacillin/tazobactam due to low-grade fever. An abdominal CT scan showed evidence of pancreatic inflammation and suspicion of partial biliary obstruction due to choledocholithiasis involving the common bile duct with mild ductular dilation (10 mm) and cholelithiasis. Aspirin therapy was immediately discontinued; 3 days later, ERCP was performed during which the biliary duct was cannulated with a 0.35 inch hydrophilic guidewire (NaviPro™-Boston Scientific) with a sphincterotome (Ultratome™XL-Boston Scientific). Cholangiography revealed a slightly dilated common bile duct with pre-papillary and medium-proximal filling defects. A sphincterotomy was performed with endocut current type using an Erbe™ generator. Eventually, an extraction Fogarty balloon (Extractor™Pro XL-Boston Scientific) was inserted through the guidewire to extract the stones. No residual stones were observed at control cholangiography and a good outflow of contrast dye through the duodenum was documented at the end of the procedure. The immediate post-procedural course was uneventful; the patient left the endoscopic suite asymptomatic with stable vital signs. The ERCP findings and the related cholangiogram are depicted in Figs. 1 and 2.

In the following 2 days, the patient reported the discharge of semifluid dark feces without abdominal pain. Digital rectal examination was negative; since a CBC showed acute severe anemia (Hgb 8.3 g/dL), 1 unit of blood was transfused even though the patient was hemodynamically stable. In order to exclude hemobilia, an EGD was performed, with no signs of active or recent bleeding in the foregut. A repeat abdominal CT scan showed a large 12 × 8 cm subcapsular and intraparenchymal hematoma affecting the right liver segments (VI/VII/VIII) without active bleeding. Pneumobilia was reported, particularly in the left lobe (Fig. 3).

The patient was transferred to the Emergency Surgery Unit, where he was treated conservatively due to clinical stability (subsequent Hgb 8.3 g/dL without additional blood transfusions). In the following days, his clinical condition improved accompanied with increasing Hgb (10.4 g/dL). Abdominal ultrasound with SonoVue™ contrast documented a stable hematoma. The patient was discharged in good clinical condition after 7 days of antibiotic therapy. A CT scan performed after 1 week from discharge showed a stable hematoma.

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Digestive Diseases and Sciences (2019)

Ignazio R. Marino, Lucio Mandalà, and Augusto Lauro

Introduction and Historic Notes

Since the first human liver transplant performed in 1963 by Thomas Starzl (University of Colorado) [1], many advances in surgical techniques and immunosuppressive therapy have helped to increase the numbers of women who undergo allogenic organ transplantation each year. In 1978, Walcott [2] documented the first known pregnancy in a liver transplant recipient, which resulted in a successful delivery with both mother and infant in excellent health. Many times, a transplanted organ normalizes a woman’s hormonal imbalance and restores fertility, thus offering the prospect of pregnancy and providing many women with end-stage organ disease a chance to conceive and bear children. As a result, among liver transplant recipients, a higher survival rate and a return to a good quality of life have been achieved. In 1991, the National Transplantation Pregnancy Registry (NTPR) was established at Thomas Jefferson University in Philadelphia, Pennsylvania, to analyze pregnancy outcomes in solid-organ transplant recipients [3].

Definition/Symptoms and Signs of ESLD

Liver transplantation (LTx): treatment of choice for all nonneoplastic end-stage liver diseases and for selected patients with nonresectable hepatic malignancies. End-stage liver disease (ESLD): any hepatic disease that jeopardizes the survival or that seriously modifies the quality of life of the patient and for which the transplant is the only therapy because no other medical or surgical treatment exists that is able to provide a reasonable chance of recovery. Before undergoing LTx, some patients remain in quite good clinical condition. There may be individual variations in terms of hospital care requirements. As the liver disease progresses, symptoms such as encephalopathy, weakness, and lethargy become more frequent. Intractable ascites, GI bleeding, peripheral edema, anorexia, jaundice, pruritus and cholestasis, peritonitis, and pneumonia may also develop. Often the patient is severely malnourished.

Indications

Although chronic hepatitis C infection (HCV) represents the leading indication for LTx in the United States, autoimmune hepatitis is probably the most frequent reason for transplantation among young female recipients who may become pregnant after transplant [4].

Epidemiology

Approximately one third of all patients who have undergone LTx are women, and about 75% of female recipients are of reproductive age [4]. The incidence indicates that more than 14,000 women of reproductive age are living in the United States after liver transplantation (LTx), and another 500 undergo LTx each year [5].

Pathophysiology

Women with decompensated liver disease commonly have menstrual dysfunction: Infertility is common in women with ESLD because of hypothalamic–pituitary–gonadal dysfunction, which decreased ovulation [6,7] and affects up to 50% of these patients. In fact, menstrual abnormalities may be the first signs of liver disease in females with chronic liver disease. In cirrhotic state, hypothalamic–pituitary dysfunction is associated with an inadequate response to the gonadotropinreleasing hormone agonists and clomiphene citrates as well as diminished gonadotrophin release relative to the reduced levels of circulating sex steroids [8]. Furthermore, serum levels of estradiol and testosterone are increased in patients with porto-systemic shunts. Thus pregnancy in decompensated cirrhosis is very uncommon. A successful transplant almost uniformly leads to a prompt return to normal menstrual cycles and to reproductive functions because of the recovery of the gonadotrophic function [8–11]. This is an important component of the restoration of normality of life for patients of childbearing age, and it is evidenced by the increasing number of post-transplantation pregnancies reported worldwide [12–24].

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Read also: A review on pregnancy after intestinal transplantation - The Journal of Maternal-Fetal & Neonatal Medicine 2016

Augusto Lauro,¹ Ignazio R. Marino ²

Abstract

Chronic rejection affects the long-term survival of solid-organ transplants, accounting for an incidence of between 5% and 10% after intestinal/multivisceral transplant. Because of unclear symptoms and signs and endoscopic findings, the diagnosis is often delayed. Presently, allograft removal represents the only available therapy due to the absence of effective pharmacologic approaches. Extensive research, through animal models, has been performed over the past 20 years to clarify the complex immune- and nonimmune-mediated mechanisms behind the development of chronic allograft enteropathy, with the aim of elucidating how to avert chronic rejection. The role of donor-specific antibodies and the way to challenge them in the clinic have gained acceptance among transplant centers as one of the main steps to prevent chronic rejection, although no common protocol exists that can be applied in a systematic fashion. The adjunct of a liver graft when retrans planting is needed in a sensitized recipient due to its protective effect against humoral immunity. Multicenter studies and clinical trials are required to better understand the pathogenesis of chronic rejection and to find the therapeutic answer to this clinical query.

Introduction

Since publication of studies from the Pittsburgh group dating from the early 1990s,^1-4 chronic rejection (CR) has been viewed as the major cause of late graft loss and reduced late patient survival after intestinal/multivisceral transplant (ITx). This phenomenon has not been changed by recent immunosuppressive preconditioning protocols.5 It presents as enteropathy, which has an incidence ranging from 10% to 20% in historical series,6,7 and follows an insidious, progressive course lacking early or specific clinical symptoms or mucosal findings through endoscopy. The median time to develop - ment of CR is 39 months, with a range of 22 to 67 months.7 The risk increases 2 years after transplant, achieving a nadir during posttransplant year 3. An isolated small bowel transplant appears to render the graft more susceptible to CR than liver-intestine transplant procedures (21% vs 5%).7 A consensus conference (unpublished results) held in June 2015 in Buenos Aires, Argentina during the XIV Intestinal Small Bowel Transplant Symposium (ISBTS; now named Congress of Intestinal Rehabilitation and Transplantation Association) proposed several criteria to identify CR: recipients can present with abdominal pain, mass, or distension with chronic diarrhea, bowel obstruction, enterocutaneous fistulas, intolerance to feeding with recurrent emesis, weight loss, enteropathy with protein loss, failure to thrive, or complications of ostomy site. Similar to acute cellular rejection (ACR), reliable fecal and serum markers are not available. The conference proposed decreased citrullin (concomitant loss of graft mass and function) and elevated C-reactive protein/lipopolysaccharide-binding protein (mucosal translocation) as surrogate CR markers.

Computed tomography and magnetic resonance imaging may support diagnosis by showing thickening of mesentery and/or intestinal wall and rarity of mesenteric vessels. Close endoscopic monitoring is mandatory for all ITx recipients: the common endoscopic presentation of CR is persistent, non-healing, focal mucosal ulceration, which is often preceded by repeated episodes of ACR.8 Later, mucosal folds become effaced with pseudo - membranes, and the bowel appears firm and fibrotic. Biopsy specimens may show mild ischemic changes, low-grade apoptosis, crypt loss, and often mild fibrosis of the lamina propria.8 Mucosal biopsies are often noncontributory, even in front of refractory intestinal dysfunction. In biopsies with fibrosis, the cause may be unclear because fibrosis may be secondary to other causes, such as previous episodes of rejection, ischemic injury, prior infections, medication-associated chronic injury, and prior biopsy site irritation.8 Thus, clinical and endoscopic diagnoses of CR are difficult.

Chronic rejection is characterized by an arterio - pathy with blunting of villi, concentric vasculopathy, luminal occlusion, leukocyte infiltration, and a marked fibrotic change.6 The marked intimal hyperplasia associated with fibrosis leads to impaired vascular perfusion of the graft.8 Unfortunately, this finding is seen in submucosal or mesenteric arteries, which are not normally sampled on an endoscopic biopsy.

There is much discussion among transplant centers on “when” to perform graft explants in cases of irreversible chronic allograft enteropathy (that is, prior or during retransplant), and many pro and con arguments were debated during the already quoted ISBTS 2015 meeting (unpublished results). Nevertheless, diagnosis of CR is usually confirmed only in full-thickness biopsies through explanted failed grafts that show the associated obliterative vasculopathy.8 Studies and discussion on this issue continue. Therefore, it is worthwhile to review the experimental findings and clinical series on this topic to get a wider picture, to clarify the updated knowledge, and to increase the relative awareness in the medical community.

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Experimental and Clinical Transplantation (2019)

Read also: Chronic Rejection After Intestinal Transplant - Digestive Diseases and Sciences - Springer (2018)

C. L. Bryce ^a,b,d,∗, D.C. Angus ^c,d, R. M. Arnold ^a, C.-C. H. Chang ^a,b,e, M. H. Farrell ^a, C. Manzarbeitia ^f, I. R. Marino ^g
and M. S. Roberts ^a,b,d,h

^a Division of General Internal Medicine, Department of Medicine, ^b Section for Decision Sciences and Clinical
Systems Modeling, ^c The Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA)
Laboratory, Department of Critical Care Medicine, ^d Department of Health Policy and Management, Graduate
School of Public Health and ^e Department of Biostatistics, Graduate School of Public Health, University of
Pittsburgh, Pittsburgh, PA ^f(former) Chair, Division of Transplant Surgery, Einstein Medical Center and Department of Surgery and ^g Department of Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA
^h Department of Industrial Engineering, University of Pittsburgh, Pittsburgh, PA
*Corresponding author: Cindy L. Bryce, brycec@upmc.edu

The question of whether health care inequities occur before patients with end-stage liver disease (ESLD) are waitlisted for transplantation has not previously been assessed. To determine the impact of gender, race and insurance on access to transplantation, we linked Pennsylvania sources of data regarding adult patients discharged from nongovernmental hospitals from 1994 to 2001. We followed the patients through 2003 and linked information to records from five centers responsible for 95% of liver transplants in Pennsylvania during this period. Using multinomial logistic regressions, we estimated probabilities that patients would undergo transplant evaluation, transplantwaitlisting and transplantation itself. Of the 144 507 patients in the study, 4361 (3.0%) underwent transplant evaluation. Of those evaluated, 3071 (70.4%) were waitlisted. Of those waitlisted, 1537 (50.0%) received a transplant. Overall, 57 020 (39.5%) died during the study period. Patients were less likely to undergo evaluation, waitlisting and transplantation if they were women, black and lacked commercial insurance (p < 0.001 each). Differences were more pronounced for early stages (evaluation and listing) than for the transplantation stage (in which national oversight and review occur). For early management and treatment decisions of patients with ESLD to be better understood, more comprehensive data concerning referral and listing practices are needed.

Introduction

Policies for the allocation of donated organs to patients who need them have been scrutinized and revised repeatedly in an effort to both enhance the public health benefits of transplantation and improve the process’s equity and fairness (1–7). These changes, however, can only have minimal impact, as the allocation of organs is simply the last step in transplantation, and potential barriers can be encountered at the diagnostic, referral or listing stages as well. Indeed, as Alexander and Sehgal observed in their study of end-stage renal disease, gender- and race-based barriers to care are found at all stages of management, from diagnosis of end-organ disease through the actual receipt of an organ (8).

What allowed Alexander and Sehgal to examine access in the entire system was the availability of information from the US Renal Data System (USRDS), a populationbased registry created by Medicare to track the management of patients with end-stage renal disease from diagnosis/ dialysis through death and/or transplantation (9). No similar registry exists for patients with liver disease. Once patients progress to end-stage liver disease (ESLD) and are placed on the United Network for Organ Sharing (UNOS) liver transplant waiting list, access- and equity-related issues can be monitored. However, the UNOS waitlist includes only those individuals who were listed by transplant centers (10), and it fails to account for potential inequities associated with diagnosis, referral or evaluatedbut- not-listed decisions. The Institute of Medicine (IOM) agrees with this analysis, indicating that ‘the larger problems of equitable access to transplantation occur prior to a patient being put on a waiting list for a transplant; they take the form of inadequate health insurance coverage and inadequate access to primary care, proper diagnosis and treatment, and referral for transplant evaluation’ (11).

Previous evaluation of the early stages of the process leading to liver transplantation has been survey based or limited to descriptions of center-specific practices (12–15). A survey conducted by the American Society of Transplant Physicians reported on practice variation across centers, including both patient factors (e.g. age, compliance and medical condition) and center factors (academic vs. nonacademic medical centers) (12). Trotter et al. described early practices and determinants of successful transplantation in North Carolina, noting that evaluation of candidates included subjective assessments by the team and that exclusionary criteria often varied across centers (e.g. patient age) (13).

Eckhoff et al. provided a more systematic examination of patients referred to the center for liver transplantation and tested explicitly for racial differences (14). The authors reported that although blacks were referred to their center less often than appropriate given their prevalence of liver disease and were sicker at referral than whites, once evaluated, blacks and whites were equally likely to be listed for transplantation, to receive a transplant and had similar 1- and 3-year posttransplant survival rates.

More recently, Julapalli et al. examined liver-related encounters for a large VA Medical Center, following patients for 1 year to analyze referral patterns for transplantation services (15). The mention of liver transplantation in the medical record or other evidence of arranging for referral to a transplant center occurred in only 21% of all cases and was discussed less often if the patient was black or had alcoholic liver disease.

To our knowledge, the only population-based study of early access to transplantation services used discharge data for the state of North Carolina to estimate the prevalence of ESLD and the covariates associated with the likelihood of liver transplantation. Although several nonmedical factors (e.g. source of payment, distance to transplant center) were associated with the likelihood of transplantation, the authors were not able to link hospitalization data to other sources or to follow patients over time (16).

This study follows patients with liver disease who might potentially need a liver transplant in the future, allowing us to examine the early barriers to access and the impact of sociodemographic factors (i.e. gender, race or insurance status) on variation in referrals to and listings by transplant centers. It uses hospitalization data for liver-related discharges as a means of flagging patients who either have or may be ‘at risk’ for ESLD and may eventually require transplantation. We treat the earliest instance for each patient as the index hospitalization and then link discharge records to other data sources that allow us to follow these ‘transplant-potential’ patients over time, using information about subsequent hospitalizations, transplant evaluation, transplant-related care and death. We compare sociodemographics observed prior to listing with those observed after listing, as a way of assessing whether later stages provide an accurate picture in describing the overall equity of the current liver transplantation process.  This study follows patients with liver disease who might potentially need a liver transplant in the future, allowing us to examine the early barriers to access and the impact of sociodemographic factors (i.e. gender, race or insurance status) on variation in referrals to and listings by transplant centers. It uses hospitalization data for liver-related discharges as a means of flagging patients who either have or may be ‘at risk’ for ESLD and may eventually require transplantation. We treat the earliest instance for each patient as the index hospitalization and then link discharge records to other data sources that allow us to follow these ‘transplant-potential’ patients over time, using information about subsequent hospitalizations, transplant evaluation, transplant-related care and death. We compare sociodemographics observed prior to listing with those observed after listing, as a way of assessing whether later stages provide an accurate picture in describing the overall equity of the current liver transplantation process.

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American Journal of Transplantation - 07 May 2009

Ignazio R Marino, MD, FACS, Fabrizio di Francesco, MD, Cataldo Doria, MD, Salvatore Gruttadauria, MD,
Augusto Lauro, MD, Victor L Scott, MD

PATIENT AND TECHNIQUE

In June 2001, a 17-year-old girl was involved in a high-speed motorcycle crash. She was taken to a local hospital, where multiple large, actively bleeding lacerations of the spleen and right lobe of the liver were found. A splenectomy was performed and a profuse hemorrhage from the right lobe of the liver was detected. Silk stitches were placed between the liver and the diaphragm to provide a tamponade effect. Possibly, the sutures created a watertight compartmentable to tamponade the bleeding and to support the systemic venous return and filling pressure.Hemostasiswas unsuccessful and, at this time, no vena caval injury was suspected. After packing, the abdomen was closed and the patient was transported, intubated and ventilated, to our institution by helicopter. The patient had mydriasis and was hypothermic with a temperature of 34.5°C and pH of7.13. Rapid fluid volume resuscitation was performed and the patient was taken to the operating room. Hemoperitoneumof > 5 L was present, and extensive bleeding was noted to be originating from a deep laceration of the VII and VIII hepatic segments. After removing the packing and sutures between the liver parenchyma and diaphragm, the retrohepatic segment of the IVC was exposed. When mobilization of the right lobe was attempted, blood pressure dropped to a critical level. For this reason, a large injury of the suprahepatic IVC was strongly suspected. It was then decided to attempt a direct approach to the juxtadiaphragmatic segment of the IVC by putting the patient on atrialcavalvenous-venous bypass (VVB), which was achieved by performing a sternotomy to gain control of the extrapericardial segment of the IVC and right atrium. At that point,a left saphenofemoral cutdown was obtained to initiateatrial-caval VVB and to perform direct repair of the suspected IVC transection. A purse-string suture in the right atrial appendage was placed and the intrapericardial IVC was snared by umbilical tape. A 26F catheter was placed inside the right atrium. A 20F venous catheter was placed in the IVC through the left femoral and iliac vein and the VVB was initiated using a centrifugal pump. Simultaneously with starting of the VVB, a Pringle maneuver was performed with the snaring of umbilical tape (Fig. 1A).Cannula tubing and connectors were heparin-bonded; no other heparin was used during the operation. The diaphragm was divided in its midportion directly anterior to the IVC. Atthat point, the right lobe of the liver was entirely mobilized,exposing the retrohepatic IVC. The juxtadiaphragmatic IVC was, in fact, completely transected and the right supra hepaticve in was disconnected from the IVC.Two 3-0 polypropylene sutures were placed as right and left corner sutures to expose the transected edges of the IVC. Suprahepatic IVC reconstruction was performed by end to end anastomosis with 3-0 polypropylene running suture, using the same technique as in orthotopic liver transplantation. At the end of this anastomosis,the transected right suprahepatic vein was treated by suturing the proximal and distal stumps by polypropylene 5-0stitches (Fig. 1B). The liver was then reperfused by first releasing the Pringle maneuver, then by opening the clamp, occluding the suprarenal IVC and, finally, by releasing the tourniquet binding the intrapericardial IVC. Total time of the Pringle maneuver was 36 minutes. Total atrial-caval VVB time was 40 minutes. At that point, segments VII and VIII were substantially devitalized and a wedge resection was carried out.
Compressive packing of the liver was performed after irrigation with warm saline and antibiotics.Successful hemostasis was finally achieved. Sternotomy and the abdominal wall were closed and the skin was left open.

During the operation, 26 U packed red blood cells and 18 U fresh-frozen plasma were transfused. The patient was taken to the intensive care unit in hemodynamically stable condition. Six hours after the operation,the patient, remaining hemodynamically stable with an adequate urine output, had awakened and started moving her arms. The fixed mydriasis was resolved.

Figure 1. (A) An atrial-caval venous-venous bypass (1) with a centrifugal pump (Bio-Medicus) was used to achieve total hepatic vascular exclusion. Application of this device was associated with cross-clamping of the suprarenal inferior vena cava (2) and a standard Pringle maneuver (3). Intrapericardial inferior vena cava was also clamped with a tourniquet (4). (B) Reconstruction of the vena cava was obtained by end to end anastomosis of the suprahepatic inferior vena cava (1). Proximal (2) and distal (3) stumps of the right hepatic vein were sutured. Segments VII and VIII were suffering for outflow obstruction and seemed devitalized. A wedge resection was performed. (Reprinted with permission of the artist, Jon Coulter.)

On postoperative day 5, the patient returned to the operating room to have the hepatic packing removed and to achieve complete hemostasis. The liver was still congested and edematous, and there was some oozing from the remnant of segments VII and VIII. After 24hours, the patient was extubated and transferred to the floor. On postoperative day 25, angiogram of the IVC demonstrated no leak and no vena caval stenosis (Fig. 2).On postoperative day 28, the patient was discharged with normal laboratory results. Six years after the operation,the patient is in very good health with normal liver function and is currently attending law school.

DISCUSSION

The exceedingly high mortality of suprahepatic IVC trauma indicates the need for standardization of the surgical technique in patients with this kind of caval injury.

It has long been recognized that abdominal vascular injuries sustained by trauma patients are highly lethal.Among these injuries, those to the IVC, particularly in the retrohepatic portion, and major hepatic veins, are the most fatal.^1-16 The high lethality from IVC injuries has been attributed to its surgically inaccessible location and to the difficulty exposing and controlling the hemorrhage.^10,11
Injury location is the most important determinant of mortality, with a reported rate of 100% when the lesion is a transection of the suprahepatic segment of the IVC.^{1-4,7,8,10,11,17,18}

Figure 2. Angiogram of the inferior vena cava on postoperative day 25, showing no caval strictures.

Often, as in the patient reported here, a key role is played by the presence of a retroperitoneal hematoma. Detection and clinical importance of the retroperitoneal hematoma in penetrating wounds of the IVC were first reported in 1957 by Starzl and colleagues.¹⁹

Figure 3. (A) Bare area and injury pattern. Peritoneal reflections of the liver leave a bare area at the posteromedial surface of the right lobe between the superior and inferior layers of the coronary ligament.
The cava is completely transected by the trauma. (B) The bare area contained the blood from the transection of the suprahepatic inferior vena cava by creating a retroperitoneal hematoma.

It was already emphasized then that active bleeding can cease by the time of laparotomy because of a hematoma surrounding the caval injury and that serious bleeding does not occur until the retroperitoneal space is entered.^19-21
A vena cava injury should always be suspected if a retroperitoneal hematoma is present. Exploring the hematoma blindly is the crucial mistake that should be avoided. As a clinical demonstration of this concept, several reports have described the massive fatal hemorrhage after decompression of a hematoma coveringan IVC injury.^6,19-23 The integrity of the natural structures capable of containing the blood and of tamponading the bleeding around the liver has a remarkable clinical importance. The peritoneal reflections of the liver leave a bare area at the posteromedial surface of the right lobe between the superior and inferior layers of the coronary ligament; this area is extraperitoneal. Because the retrohepatic IVC occupies the left or media llimit of the bare area, any bleeding caused by a retrohepatic IVC trauma is temporarily contained by the ligamentous structures delimiting this bare area. IP bleeding might not immediately occur or can be delayed. The sequence of events presented in this article should serve as an indication to a new strategic approach to this criticalc ondition. Fortunately, in our patient, the retroperitoneal hematoma had not been entered during the firs tlaparotomy performed on the patient at the previous hospital (Fig. 3). These patients warrant a standby VVB.In fact, the other key point in management of our patient was the choice of a direct approach by putting the patient in atrial-caval VVB to work in a bloodless field through complete hepatic vascular exclusion. Liver vascular exclusion requires control of the suprahepatic andi nfrahepatic IVC, the hepatic artery, and the portal vein.Clamping of the IVC in a hypovolemic patient can lead to cardiac arrest because of the sudden decrease in cardiac preload.^23-25
At the time of abdominal exploration,when Pringle maneuver fails to control the hemorrhage or when there is continuous bleeding from behind the right lobe, a suprahepatic IVC injury should always be suspected.¹³
In our patient, presence of the retroperitoneal hematoma and the critical decrease of blood pressure at every attempt to mobilize the liver prompted us to implement a new surgical approach. The hepatic packing and manual compression offered sufficient time to establish an atrial-caval VVB. The VVB provided us the opportunity to work in a bloodless field and safely perform the vascular repairs without compromising venous return. Blunt injuries can also lead to avulsion of the hepatic veins from the IVC in combination with lacerations of the liver surface. Buckman and colleagues²³ described two general juxtahepatic venousinjury-wounding patterns: one (type A) in which the venous injury is intraparenchymal, with bleeding predominantly through the disrupted liver; and the other(type B), in which the venous lesion is extraparenchymal,with bleeding predominantly around the liver. Our patient presented us with a situation similar to the type B wounding pattern with a rupture of the VII and VIII hepatic segments, avulsion of the right hepatic vein, and, mainly, complete transection of the suprahepatic IVC. A concomitant parenchymal hepatic injury is a major aggravating risk factor because of the greater difficulty in achieving a bloodless field and the considerable expertise required for carrying out the necessary surgical repair. For injuries of the suprahepatic IVC segment between the right atrium and the take-off of the hepatic veins, 100% mortality is reported.^{1-4,7,8,10,11,17,18}
The major cause of death is the uncontrollable bleeding,which occurs during the attempt to expose and repair the suprahepatic IVC. This leads to exsanguination and intraoperative death. Any attempt to rotate the liver to achieve better exposure of the IVC increases the blood loss and gives rise to additional risks of air embolism. For these reasons, when bleeding control is not achievable and substantial expertise and technical support are nota vailable, the swift transfer of the patient, after intraabdominal packing of the liver, to a facility where liver operations and liver transplantation are routinely performed,can be a life-saving strategy. Simple vascular clamping, atriocaval surgical shunting, hepatic resection,and perihepatic packing have been the methods oftreatment reported in the literature. Attempts to successfully manage a suprahepatic IVC transection have been reported with negative results.^{1-4,7,8,10,11,17,18}
Standardization of a surgical approach for this kind of rare but lethal condition has yet to be successfully achieved.It is imperative to obtain control of the bleeding and maintain a bloodless surgical field through a short liver ischemia time (fewer than 50 minutes), while the patient is kept hemodynamically stable.We strongly believe that use of a modified atrial-caval VVB played a key role in successfully managing this kind of IVC lesion. We are now convinced that this is the only safe and possible way to achieve anatomic control of the suprahepatic IVC to perform a direct repair. An alternative technique, still borrowing from live rtransplantation experience, could have avoided sternotomya nd atrial bypass and favored instead the classic VVB often used during liver transplantation, performed from the femoral vein into the axillary vein after cutdown,or into one of the ports of a central line placed inthe neck. Adopting such a method, a clamp could be placed on the suprahepatic IVC at the cavoatrial junction after opening the pericardium vertically and entering the pericardial cavity from the abdomen, allowing good visualization of the cavoatrial junction. This can prevent possible morbidity related to a sternotomy. Because of the critical emergency situation and the uncertainties of the anatomy of the lesion, we opted for more direct access to the cavoatrial junction.In similar extreme cases, the first goal is to achieve bleeding control through total vascular occlusion beforere pairing the injury. To the best of our knowledge, this is the first description of successful management of a complete traumatic transection of the suprahepatic IVC.With this article, we would like to introduce a new technique of atrial-caval VVB, which is a ripple extension of the basic technique of liver transplantation. Any retroperitoneal hematoma should not be entered until total vascular exclusion through atrial-caval VVB has been established. Based on our experience and a thorough review of the literature, this approach would seem to be the safest and most successful one to pursue.

REFERENCES

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2. Klein SR, Baumgartner FJ, Bongard FS. Contemporary management strategy for major inferior vena caval injuries. JTrauma1994;37:35–41.

3. Asensio JA, Chahwan S, Hanpeter D, et al. Operative management and outcome of 302 abdominal vascular injuries. Am JSurg 2000;180:528–533.

4. Khoury G, Sfeir R, Khalifeh M, et al. Penetrating trauma to the abdominal vessels. Cardiovasc Surg 1996;4:405–407.

5. Jan WA, Samad A, Anwar R. Mortality and morbidity of abdominal inferior vena-caval injuries. J Coll Physicians Surg Pak2004;14:622–625.

6. Ochsner JL, Crawford ES, De Bakey ME. Injuries of the vena cava caused by external trauma. Surgery 1961;49:397–405.

7. Burch JM, Feliciano DV, Mattox KL, et al. Injuries of the inferiorv ena cava. Am J Surg 1988;156:548–552.

8. Graham JM,Mattox KL, Beall AC Jr, et al.Traumatic injuries of the inferior vena cava. Arch Surg 1978;113:413–418.

9. Burns GR, Sherman RT. Trauma of the abdominal aorta and inferior vena cava. Am Surg 1972;38:303–306.

10. Weichert RF 3rd, Hewitt RL. Injuries to the inferior vena cava:report of 35 cases. J Trauma 1970;10:649–657.

11. Turpin I, State D, Schwartz A. Injuries to the inferior vena cava and their management. Am J Surg 1977;134:25–32.

12. Burch JM, FelicianoDV,Mattox KL.The atriocaval shunt. Facts and fiction. Ann Surg 1988;207:555–568.

13. Chen RJ, Fang JF, Lin BC, et al. Surgical management of juxtahepaticvenous injuries in blunt hepatic trauma. JTrauma 1995;38:886–890.

14. Quast DC, Shirkey AL, Fitzgerald JB, et al. Surgical correction of injuries of the vena cava: an analysis of sixty-one cases.J Trauma 1965;147:3–10.

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17. CogbillTH,Moore EE, Jurkovich GJ, et al. Severe hepatic trauma:a multi-center experience with 1,335 liver injuries. JTrauma 1988;28:1433–1438.

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Surgeon at Work

In 2012, I posted in Science.org my thoughts on the state of meritocracy in Italy, on the allocation of taxpayers' money for research, on the need to adopt rules strictly based on merit and quality for the allocation of research funds, and on the need to invest much more in research and development. According to a report by the Organisation for Economic Co-operation and Development (OECD), around 1.4 million young Italians left the country between 1995 and 2010. Not much has changed since then. The latest available data are from 2020 and they are dramatic: 120,000 young Italians have left the country. And the reasons are always the same: no confidence in the recognition of their own merits and the impossibility of finding employment without a recommendation. Whereas often to find employment abroad it is enough to send an e-mail and be invited for an interview. And each of our graduates through public education has cost Italy around 500,000 euro and 0 euro to the country that values their skills. It should not be difficult to change direction just by reading these figures.

SCIENCE - 4 May 2012 - www.science.org

ITALIAN SCIENTISTS HAVE LONG LAMENTED THE lack of resources, political attention, and meritocracy in assigning taxpayers’ money.

In 2007, things began to change. The 2007 and 2008 national budget laws allocated €81 million (US$107 million) to projects submitted by researchers under 40 years old. They were judged by an international committee of scientists under age 40 that was appointed according to impact factor and citation index scores. Even though this fund accounted for only 10% of the entire public research money, it was a crucial turning point toward meritocracy. Finally, the international rules of peer review were entering the Italian system, acknowledging meritocracy and setting researchers free from the virtual servitude under which they had been kept by old academicians.

Recently, inexplicably, Italy has fallen back to the old way of allocating taxpayers’ research money and has done so in spite of government promises of open competition and meritocracy. The so-called “Simplifi cation Decree” includes anti-crisis measures suggested by several departments, including the one led by the Minister of Education, University, and Research: Francesco Profumo. He has canceled the articles of the laws that brought peer review to Italy, explaining that the method introduced in 2007 was too cumbersome to apply. Minister Profumo now promises a new, simpler law, but for the time being, young researchers applying for grants in Italy will have to rely on the old questionable, nontransparent evaluation method that rewards clients of godfathers, rather than merit.

It is not only money for valuable researchers that will be lacking from now on, but hope for their future and for that of the country. The only way out is to adopt strict peer-review rules for the allocation of all research funds, at all times.

Ignazio Marino
 
Department of Surgery, Jefferson Medical College, Philadelphia, PA 19107, USA, and Senate of the Republic of Italy, Piazza Madama snc, 00186 Rome, Italy. E-mail: ignazio. marino@jefferson.edu

Maddalena Barba, Alfredo Mazza, Carla Guerriero, Massimo Di Maio, Frank Romeo, Pasquale Maranta,
Ignazio R. Marino, Marco G. Paggi and Antonio Giordano

Three decades of illegal practices of waste dumping and consequent environmental abuse have made the Campania Region, Southern Italy, a unique case in the context of wasterelated health outcomes. Scientific evidence is mounting in support of a significant increase in cancer mortality and malformation occurrence in specific areas of the Campania Region, where improper waste management and illegal waste trafficking have been repeatedly documented. However, the currently available evidence suffers from limitations mainly due to study design, lack of consideration of confounders and quality of the exposure data. Recent economic studies have shown the economic benefits of reclaiming toxic waste sites in Campania. Future perspectives include the adoption of different study designs, use of biomarkers and a molecular approach. Current knowledge, both scientific and economic, might be of help in orienting the short and long term governmental policy on waste related health outcomes at a regional level.   

Introduction

Waste management encompasses a wide spectrum of functional elements including generation, processing, transport and disposal of solid waste material. The involved procedures might largely differ based on various determinants, such as waste characteristics (e.g. solid, liquid or gaseous substances), producer profile (residential vs. industrial producers) and involved area (high   population density vs. low population density). Notwithstanding the general trend towards an increasing proportion of waste being recycled, disposal, by landfilling still represents the most common ultimate fate of solid wastes. 
Residential proximity to waste disposals has been associated with adverse health outcomes. The available data mostly relates to cancer and birth outcomes, while data on respiratory, skin and gastrointestinal symptoms or diseases is still sparse.2-6 Overall, the existing evidence does not rule out a clear role of landfilling in determining adverse health effects. In addition, the available data is substantially weakened by a number of methodological issues including inconsistencies in study design, use of surrogate measures of exposures (e.g. distance from the site of waste disposal), lack of control for potential confounders (i.e., factors correlated with both the exposure and outcome of interest, which do not lie on the causal pathway linking the exposure to the disease).

Three decades of illegal practices of waste dumping and consequent environmental abuse have made the Campania Region, Southern Italy, a unique case in the context described so far. Since the 1980s, several illegal and uncontrolled sites of urban, toxic, and industrial waste disposal, including land filling and unauthorized incineration, have been known to be active in this Region, with the highest concentration being reached in the two provinces of Naples and Caserta. Results from a number of recently conducted studies have shown significantly increased cancer mortality (overall and site specific) and congenital malformation rates in the Provinces of Naples and Caserta compared to the expected figures from the regional population.8-10 In the highlighted areas (i.e., the northern part of the Naples Province and the southern part of the Caserta Province), illegal dumping of toxic wastes has been largely documented.11-12

In 1998, Agroaversano and Litorale Domizio, the two areas in Campania most affected by illegal dumping and burning, were included in the national priority list of reclamation sites. Since then, little has been done to clean up the contaminated areas.13 
The task of quantifying the costs and the benefits arising from remedial interventions in monetary terms is pivotal to decisions regarding the prioritization of sites within the National Remediation Program.14 Recent economic evaluations suggest that the high impact of hazardous waste exposure on human health in the two provinces of Naples and Caserta creates a strong economic incentive for reclaiming toxic waste sites (legal and illegal) in the Campania Region.15 
In this review, we summarize and discuss the scientific evidence on waste exposure and health outcomes in the Campania region, with a specific focus on cancer mortality and congenital anomalies. We also discuss the results of the extensive biomonitoring activities conducted in Campania for a wide range of chemical agents (i.e., heavy metals, polychlorinated biphenyls, dioxins and polycyclic aromatic hydrocarbons). We then consider evidence from economic studies seeking to evaluate the economic benefit of reclaiming hazardous waste sites present in the Campania Region.

[...]

Summary and Conclusions 

In summary, scientific evidence is mounting in support of the association between waste exposure and health outcomes in specific areas of the Campania Region, where improper waste management and illegal waste trafficking have been repeatedly documented. However, the currently available evidence suffers from limitations mainly due to study design, lack of consideration of confounders and quality of exposure data. The adoption of different study designs, use of biomarkers and a molecular approach might greatly improve the quality of the upcoming studies. In recent years, the use of a multidisciplinary approach integrating epidemiologic and economic expertises has produced impressive results. The net monetary benefits deriving from the reclamation of hazardous sites present in Campania would be considerably higher than the estimated costs. In a recent study of the effects of US superfund cleanups on human health, the authors observed a 20–25% reduction of congenital anomalies in residents of areas where the remediation of contaminated sites took place. Such a decrease has an equivalent in terms of lives saved and quality of life for future generations. The same goals need to be pursued in the Campania Region.38 
In conclusion, the scientific panorama, along with the results of economic studies, encourage further investigation on the topic addressed. Considering the results of such studies is a must in orienting the short and long term governmental policy on waste related health outcomes at a regional level.  

Acknowledgments

This work has been supported by the Human Health Foundation, Spoleto (PG), Italy (www.hhfonlus.org) and by the Sbarro Health Research Organization, Philadelphia, PA (www.shro.org)

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Scientific research is fascinating and often unpredictable. I want to provide three examples of something that happened to me that demonstrates that imagination and curiosity are essential in discovering scientific development. Still, possibly, persistence is even more critical.

Today, I will describe how we discovered microchimerism. This biological phenomenon allows, at times, donor lymphocytes to survive in the body of a liver transplant recipient and possibly, induce tolerance. In the early '90s, the pioneer of liver transplantation, Thomas E. Starzl, asked to examine all the liver transplant recipients alive for more than five years after transplantation. We discovered that some of them were no longer taking any anti-rejection drugs. That was considered impossible at the time. Studying them, we realized that some patients had donor lymphocytes "living together" with recipient lymphocytes in a sort of "peace treaty," We also learned that in several patients, it was possible to wean the immunosuppression. A concept that was considered heretical until that time.

Weaning of immunosuppression in liver transplant recipients¹²

by GEORGE .V MAZARIEGOS,³ JORGE REYES, IGNAZIO ROBERTO MARINO, ANTHONY .J DEMETRIS, BRIDGET FLYNN, WILLIAM IRISH, JOHN McMICHAEL, JOHN J. FUNG, AND THOMAS E. STARZL

Immunosuppression has been sporadically discontinued by noncompliant liver allograft recipients for whom an additional 4 1/2 years of follow-up is provided. These anecdotal observations prompted a previously reported prospective drug withdrawal program in 59 liver recipients.This prospective series has been increased to 95 patients whose weaning was begun between June 1992 and March 1996, 8.4 +/- 4.4 (SD) years after liver replacement. A further 4 1/2 years follow-up was obtained of the 5 self-weaned patients.

The prospectively weaned recipients (93 livers; 2 liver/ kidney) had undergone transplantation under immunosuppression based on azathioprine (AZA, through 1979), cyclosporine (CsA, 1980-1989), or tacrolimus (TAC, 1989-1994). In patients on CsA or TAC based cocktails, the adjunct drugs were weaned first in the early part of the trial. Since 1994, the T cell-directed drugs were weaned first. Three of the 5 original self-weaned recipients remain well after drug-free intervals of 14 to 17 years. A fourth patient died in a vehicular accident after 11 years off immunosuppression, and the fifth patient underwent retransplantation because of hepatitis C infection after 9 drug-free years; their allografts had no histopathologic evidence of rejection. Eighteen (19%) of the 95 patients in the prospective series have been drug free for from 10 months to 4.8 years. In the total group, 18 (19%) have had biopsy proved acute rejection; 7 (7%) had a presumed acute rejection without biopsy; 37 (39%) are still weaning; and 12 (13%, all well) were withdrawn from the protocol at reduced immunosuppression because of noncompliance (n=8), recurrent PBC (n=2), pregnancy (n=1), and renal failure necessitating kidney transplantation (n= 1). No patients were formally diagnosed with chronic rejection, but 3 (3%) were placed back on preexisting immunosuppression or switched from cyclosporine (CsA) to tacrolimus (TAC) because of histopathologic evidence of duct injury. Two patients with normal liver function died during the trial, both from complications of prior chronic immunosuppression. No grafts suffered permanent functional impairment and only one patient developed temporary jaundice. Long surviving liver transplant recipients are systematically overimmunosuppressed. Consequently, drug weaning, whether incomplete or complete, is an important management strategy providing it is done slowly under careful physician surveillance.

Complete weaning from CsA-based regimens has been difficult. Disease recurrence during drug withdrawal was documented in 2 of 13 patients with PBC and could be a risk with other autoimmune disorders.

The morbidity arising from the chronic use of antirejection medications is an incentive to establish the lowest possible level of immunosuppression necessary to maintain stable graft function. The finding that complete freedom from immunosuppression was sporadically possible in long-surviving recipients of liver (1) and kidney allografts (2) prompted a prospective trial of drug weaning (3). Although it was shown that significant reductions in medication or their discontinuance could be safely accomplished, the danger of consequent rejection has not been completely assessed and guidelines for judicious weaning need to be clarified. We present here further observations on 3 cohorts of liver recipients: 5 who self-weaned many years ago (1), 59 who were in the prospective weaning trial of Ramos et al. (3), and 36 who were subsequently entered.

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REFERENCES

1. StarzI TE, Demetris AJ, Trucco M, et al. Cell migration and chimerism after whole organ transplantation: the basis of graft acceptance. Hepatology 1993; 17: 1127.
2. Mazariegos GV, Ramos H, Shapiro R, Zeevi A. Fung JJ, Starzl TE. Weaning of immunosuppression in long-term recipients of living-related renal transplants: a preliminary study. Transplant Proc 1995; 27: 207.
3. Ramos HC, Reyes J, Abu-Elmagd K, et al. Weaning of immunosuppression in long-term liver transplant recipients. Transplantation 1995; 59: 212.
4. Starzl TE, Iwatsuki S, Van Thiel DH, et al. Evolution of liver transplantation. Hepatology 1982; 2: 614.
5. Fung JJ, Todo S, Jain A, Demetris AJ, McMichael JP, StarzI TE: The Pittsburgh randomized trial of tacrolimus versus cyclosporine for liver transplantation. J Am Coll Surg 1996; 183: 117.
6. Demetris AJ, Fung JJ, Todo S, et al. Conversion of liver allograft recipients from cyclosporine to FK 506 immunosuppressive therapy-a clinicopathologic study of 96 patients. Transplantation 1992; 53: 1056.
7. van Hoek B, Wiener RH, Krom RAF, Ludwig J, Moore SB. Severe ductopenic rejection following liver transplantation: incidence, time of onset, risk factors, treatment, and outcome. Semin Liver Dis 1992; 12: 41.
8. StarzI TE, Demetris AJ, Murase N, Ildstad S, Ricordi C, Trucco Cell migration, chimerism, and graft acceptance. Lancet 1992; 339: 1579.
9. Demetris AJ, Murase N, Fujisaki S, Fung JJ, Rao AS, StarzI TE. Hematolymphoid cell trafficking, microchimerism, and GHD reactions after liver, bone marrow, and heart transplantation. Transplant Proc 1993; 25: 3337.
10. Qian S, Demetris Ad, Murase N, Rao AS, Fung JJ, StarzI TE. Murine liver allograft transplantation: tolerance and donor cell chimerism. Hepatology 1994; 19: 916.
11. StarzI TE, Demetris AJ, Murase N, Trucco M, Thomson AW, Rao AS: The lost chord: microchimerism and allograft survival. Immunol Today, (in press).
12. Murase N, StarzI TE, Tanabe M, et al. Variable chimerism, graft versus host disease, and tolerance after different kinds of cell and whole organ transplantation from Lewis to Brown-Norway rats. Transplantation 1995; 60: 158.
13. StarzI TE, Todo S, Fung J, Demetris AJ, Venkataramanan R, Jain A. FK 506 for human liver, kidney and pancreas trans-plantation. Lancet 1989; 2: 1000.
14. Sanborn WJ, Hay JE, Porayko MK, et al. Cyclosporine withdrawal for nephrotoxicity in liver transplant recipients does not result in sustained improvement in kidney function and causes cellular and ductopenic rejection. Hepatology 1994; 19: 925.
15. Schlitt HJ, Hundrieser J, Ringe B, Pichlmayr R. Donor-type microchimerism associated with graft rejection eight years after liver transplantation. N Engl J Med 1994; 330: 646.
16. Anand AC, Hubscher SG, Gunson BK, McMaster P, Neuberger JM. Timing, significance, and prognosis of late acute liver allograft rejection. Transplantation 1995; 60: 1098.
17. Molleston JP, Alevy YG, Sivasai KSR, Mohanakumar T, Howard TK. Evidence that pediatric liver transplant recipients may undergo late rejection episodes in spite of donor-specific micro-chimerism. Transplantation 1996; 61: 656.
18. Starzl TE, Koep LJ, Halgrimson CG. et al. Fifteen years of clinical liver transplantation. Gastroenterology 1979; 77: 375.
19. Pappo O, Ramos H, StarzI TE, Fung JJ, Demetris AJ. Structural integrity and identification of causes of liver allograft dysfunction occurring more than 5 years after transplantation. Am J Surg Pathol 1995; 19: 192.

Scientific research is fascinating and often unpredictable. I want to provide three examples of something that happened to me that demonstrates that imagination and curiosity are essential in discovering scientific development. Still, possibly, persistence is even more critical.

Today, I will describe how I was wrong in believing that the age and the sex of a liver donor do not have a significant impact on the outcome of liver transplantation. To demonstrate this concept with scientific proof, I examined a few hundred liver transplantations performed by our team in Pittsburgh. Quite differently from what I and others were expecting, our study demonstrated that both the age and sex of the donor have a significant impact on the outcome of liver transplantation with a significant difference in long-term survival. My mentor, Thomas Starzl, was unhappy with the data and asked me to run them by two prominent statisticians working at the Universities of Stanford and at Cambridge University. They confirmed our data, and we published a paper that became important in matching donors and recipients.

Effect of Donor Age and Sex on the Outcome of Liver Transplantation

by IGNAZIO ROBERTO MARINO,^1,2 HOWARD R. DOYLE, ^1,2 LUCA ALDRIGHETTI,¹ CATALDO DORIA,¹ JOHN MCMICHAEL,¹ TIMOTHY GAYOWSKI,^1,2 JOHN J. FUNG,¹ ANDREAS G.TZAKIS, ^1,3 AND THOMAS E. STARZL^1,2

We correlated donor and recipient factors with graft outcome in 436 adult patients who underwent 462 liver transplants. Donor variables analyzed were age, gender, ABO blood group, cause of death, length of stay in the intensive care unit, use of pressors or pitressin, need for cardiopulmonary resuscitation, terminal serum transaminases, and ischemia time. Recipient variables analyzed were age, gender, primary diagnosis, history of previous liver transplant, ABO blood group, cytotoxic antibody crossmatch, United Network for Organ Sharing (UNOS) status, and waiting time (except for the cross-match results, they were all known at the time of the operation). The endpoint of the analysis was graft failure, defined as patient death or retransplantation. Using multivariate analysis, graft failure was significantly associated with donor age, donor gender, previous liver transplantation, and UNOS 4 status of the recipient. The effect of donor age became evident only when they were older than 45 years. Livers from female donors yielded significantly poorer results, with 2-year graft survival of female to male 55% (95% CI, 45% to 67%); female to female, 64% (95% CI, 54% to 77%); male to male, 72% (95% CI, 669’~ to 78%); and male to female, 780/0 (95% CI, 70% to 88%). The only donors identified as questionable for liver procurement were old (260 years) women in whom the adverse age and gender factors were at least additive. However, rather than discard even these livers, in the face of an organ shortage crisis, their individualized use is suggested with case reporting in a special category. (HEPATOLOG1Y9 95;22:1754-1762)

As of January 4, 1995, 37,751 transplant candidates were registered on the national waiting list operated by the United Network for Organ Sharing (UNOS), the agency that coordinates organ allocation in the United States. This was a 391% increase from the 9,632 waiting in December 1986. Of the 37,751 in 1995, 4,039
were liver candidates, up from 449 in 1987 (a 900% increase). The supply of all organ donors had undergone a marginal increase between 1988 and 1990 (from 4,085 to 4,514), but has remained relatively stable since then: 4,531 in 1991, 4,521 in 1992, 4,849 in 1993, and 4,891 in 1994.

The limited supply of organ donors has increasingly influenced the selection of candidates for liver transplantation, and is used at some institutions to justify restricting the availability of the procedure.¹ Although the exact magnitude of the organ deficit is not yet known,^2,3 the obvious gap between supply and need has stimulated the development of bioartificial liver assist devices,⁴ utilization of living related liver donors,^5,6 use of non-heart beating donors, ^7-9 and xenotransplantation.¹⁰ A more immediate impact on organ shortage already has come from the widespread use of livers from “marginal donors,” as first documented by Makowka
et al¹¹ and Pruim et al. ¹²
The definition of a marginal donor has varied in different reports, and recently has included obesity.^13,14 Two potential risk factors-age and gender-are relevant with all donors, no matter what the other circumstances of death. Although it has long been thought that the liver is less affected than other organs by senescence, ^15,16 poor experience with older donors in the original Denver series (including two who were 73 years of age) resulted in an upper donor age limitation of 45 years.¹⁷ The demonstration that satisfactory livers could be obtained from donors well into the seventh decade of life ^18,19 or beyond ²⁰ was followed by a flurry of confirmatory reports, ^13,14,21,22 countered by descriptions of degraded results using geriatric livers.^23-26

Less has been written about the effect of donor sex on outcome after liver transplantation, although there is an extensive literature, recently summarized by Neugarten and Silbiger,²⁷ showing poorer results with kidney allografts from female donors. We have reported similar findings with female livers in adults^28,29 but not in children.³⁰ The gender effect has been disputed by Stratta et al.³¹
In the current study, we have examined with univariate and multivariate analysis the effect on outcome of donor age and sex, singly and together, in a consecutive series of liver recipients, taking into account an array of other risk factors. A clear influence of both donor age and gender on outcome was identifiable.

Patients and Methods

From January 1, 1992 to June 30, 1993, 436 consecutive adult patients received 479 liver transplants at the University of Pittsburgh Medical Center and the Veterans Administration Medical Center, Pittsburgh, PA. The livers in 17 were part of multivisceral transplants that included intestine. These cases were excluded, leaving 419 recipients of 462 allografts who were entered for analysis. The information was obtained from the clinical database maintained by the Pittsburgh Transplantation Institute, and a review of the donor charts that are kept on file at the Center for Organ Recovery and Education (Western Pennsylvania Organ Procurement Organization) Pittsburgh, PA.
All grafts were flushed with the University of Wisconsin solution. No attempt was made to transplant older livers into older recipients, or vice versa. ABO compatibility, size match, and medical urgency (UNOS status, see later discussion), were the only criteria used in recipient selection. All recipients were treated with the same immunosuppressive protocol, based on tacrolimus (Prograf, formerly FK506, Fujisawa USA, Inc., Deerfield, IL) and prednisone, augmented by azathioprine and antilymphocyte globulin in a small minority of cases. Intravenous prostaglandin E¹ was routinely given perioperatively.³²

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REFERENCES

1.  Eghtesad B, Bronsther O, Irish W, Casavilla A, Abu-Elmagd K, Van Thiel D, Tzakis A, et al. Disease gravity and urgency of need as guidelines for liver allocation. HEPATOLOG1Y99 4; 20:56S-62S.
2. Garrison RN, Bentley FOR, Raque GHQ, Polk HC Jr, Sladek LC, Evanisko MJ, Lucas BA. There is an answer to the shortage of organ donors. Surg Gynecol Obstet 1991; 173:391-396.
3. Evans RW, Orians CE, Ascher NL. The potential supply of organ donors. JAMA 1992; 267:239-246.
4. Rozga J, Podesta L, LePage E, Hoffman A, Morsiani A, Sher L, Woolf GM, et al. Control of cerebral oedema by total hepatectomy and extracorporeal liver support in fulminant hepatic failure. Lancet 1993;342:898-899.
5. Strong RW, Lynch SV, Ong TH, Matsunami H, Koido Y, Balderson GA. Successful liver transplantation from a living donor to her son. N Engl J Med 1990;322:1505-1507.
6. Broelsch CE, Emond JC, Whitington PF, Thistlethwaite JR, Baker AL, Lichtor JL. Application of reduced-size liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants. Ann Surg 1990; 212:368-377.
7. Starzl TE, Iwatsuki S, Shaw BW Jr, Gordon RD. Orthotopic liver transplantation in 1984. Transplant Proc 1985; 17:250-258.
8. Ericzon BG, Lundgren G, Wilczek H, Groth CG. Experience with human liver grafts obtained after donor cardiac standstill. Transplant Proc 1987; 19:3862-3863.
9. Yanaga K, Kakizoe S, Ikeda T, Podesta LG, Demetris AJ, Starzl TE. Procurement of liver allografts from non-heart beating donors. Transplant Proc 1990;22:275-278.
10. Starzl TE, Fung JJ, Tzakis A, Todo S, Demetris AJ, Marino IR, Doyle H, et al. Baboon to human liver transplantation. Lancet 1993;341:65-71.
11. Makowka L. Gordon RD. Todo S. Ohkohchi N, Marsh JW, Tzakis AG, Yokoi H, et al. Analysis of donor criteria for the prediction of outcome in clinical liver transplantation. Transplant Proc 1987; 19:2378-2382.
12. Pruim J, Klompmaker IJ, Haagsma EB, Bijleveld CMA, Sloof MJH. Selection criteria for liver donation: a review. Transplant Int 1993;6:226-235.
13. Mor E, Klintmalm GB, Gonwa TA, Solomon H, Holman MJ, Gibbs JF, Watemberg I, et al. The use of marginal donors for liver transplantation: a retrospective study of 365 liver donors. Transplantation 1992; 53:383-386.
14. Post J, Miller CM, Schwartz ME, Kadian M. Is it safe to liberalize donor criteria to include those over age 60 and those weighing over 90 Kg? Transplant Proc 1993;25:1570.
15. Morgan ZR, Feldman M. The liver, biliary tract and pancreas in the aged: an anatomic and laboratory evaluation. J Am Geriatr SOC 1957;5:59-65.
16. Popper H. Aging and the liver. In: Popper H, Schaffner F, eds. Progress in liver disease. Vol VIII. New York: Grune & Stratton, 1985:659-683.
17. Starzl TE. The liver donor, and appendix of case material and bibliography. In: Starzl TE, ed. (with the assistance Putnam CW). Experience in hepatic transplantation. Philadelphia: Saunders, 1969:16-21, 528-545.
18. Teperman L, Podesta L, Mieles L, Starzl TE. The successful use of older donors for liver transplantation. JAMA 1989;262:2837.
19. Wall WJ, Mimeault R, Grant DR, Bloch M. The use of older donor livers for hepatic transplantation. Transplantation 1990;49:377- 381.
20. Wall W, Grant D, Roy A, Asfar S, Block M. Elderly liver donor. Lancet 1993;341:121.
21. Adam R, Astarcioglu I, Azoulay D, Morino M, Bao YM, Castaing D, Bismuth H. Age greater than 50 years is not a contraindication for liver donation. Transplant Proc 1991;23:2602-2603.
22. Grande L, Gonzalez FX, Manterola C, Garcia-Valdecasas JC, Rimola A, Fuster J, de Lacy AM, et al. Does donor age exclude liver grafting? Transplant Proc 1993;25:3151-3153.
23. Greig PD, Forster J, Superina RA, Strasberg SM, Mohamed M, Blendis LM, Taylor BR, et al. Donor-specific factors predict graft function following liver transplantation. Transplant Proc 1990;22:2072-2075.
24. Alexander JW, Vaughn WK: The use of “marginal” donors for organ transplantation: the influence of donor age on outcome. Transplantation 1991;51:135-141.
25. Buckel E, Sanchez-Urdazpal L, Steers J, Sterioff S, Wiesner R, Krom RAF. Impaired initial function in liver grafts from donors >50 years of age. Transplant Proc 1993;25:1558- 1559.
26. Ploeg FLJ, D’Alessandro AM, Knechtle SJ, Stegall MD, Pirsch JD, Hoffmann RM, Sasaki T, et al. Risk factors for primary dysfunction after liver transplantation: a multivariate analysis. Transplantation 1993;55:807-813.
27. Neugarten J, Silbiger SR. The impact of gender on renal transplantation. Transplantation 1994; 58:1145-1152.
28. Kahn D, Makowka L, Gavaler J, Starzl TE, Van Thiel DH. The outcome after clinical liver transplantation is influenced by the gender of the donor [Abstract]. HEPATOLOGY1988; 8:1225.
29. Kahn D, Gavaler JS, Makowka L, Van Thiel DH. Gender of donor influences outcome after orthotopic liver transplantation in adults. Dig Dis Sci 1993;38:1485-1488.
30. Pillay P, Van Thiel DH, Gavaler JS, Starzl TE. Donor gender does not affect liver transplantation outcome in children. Dig Dis Sci 1990;35:686-689.
31. Stratta FLJ, Wood RP, Langnas AN, Duckworth RM, Shaefer MS, Marujo W, Pillen TJ, et al. Donor selection for orthotopic liver transplantation: lack of an effect of gender or cytomegalovirus (CMV) status. Transplant Proc 1990;22:410-413.
32. Takaya S, Iwaki Y, Starzl TE. Liver transplantation in positive cytotoxic crossmatch cases using FK506, high-dose steroids, and prostaglandin El. Transplantation 1992; 54:927-929.
33. Hochberg Y, Tamhane AC. Multiple comparison procedures. New York: John Wiley & Sons; 1987:275-277.
34. Hastie TJ, Tibshirani FLJ. Generalized additive models. London: Chapman & Hall; 1990.
35. Cleveland WS, Grosse E, Shyu WM. Local regression models. In: Chambers JM, Hastie TJ, eds. Statistical models in S. London: Chapman & Hall; 1993:309-376.
36. Hastie TJ, Pregibon D. Generalized linear models. In: Chambers JM, Hastie TJ, eds. Statistical models in S. London: Chapman &   Hall, 1993:195-247.
37. Furukawa H, Todo S, Imventarza 0, Casavilla A, Wu YM, Scotti-Foglieni C, Broznick B, et al. Effect of cold ischemia time on the early outcome of human hepatic allografts preserved with UW solution. Transplantation 1991; 51:lOOO-1004.
38. Davies DF, Shock NW. Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest 1950;29:496-507.
39. Kampmann JP, Sierbaek-Nielsen K, Kristensen M, Hansen JM: Variations in urinary creatinine and endogenous creatinine clearance due to age. Ugeskr Laeger 1971; 133:2369-2372.
40. Kampmann JP, Sinding J, Moller-Jorgesen I. Effect of age on liver function. Geriatrics 1975;30:91-95.
41. Mooney H, Roberts R, Cooksley WGE, Halliday JW, Powell LW. Alterations in the liver with aging. Gastroenterol Clin North Am 1985; 141757-771.
42. Ellison MD, Norman DJ, Breen TJ, Edwards EB, Davies DB, Daily PO. No effect of H-Y minor histocompatibility antigen in zero-mismatched living-donor renal transplants. Transplantation 1994;58:518-520.
43. Takaya S, Duquesnoy R, Iwaki Y, Demetris J, Yagihashi A, Bronsther 0, Iwatsuki S, et al. Positive crossmatch in primary human liver allografts under cyclosporine or FK506 therapy. Transplant Proc 1991;23:396-399.
44. Doyle HR, Marino IR, Jabbour N, Zetti G, McMichael J, Mitchell S, Fung J, et al. Early death or retransplantation in adults after orthotopic liver transplantation. Can outcome be predicted? Transplantation 1994; 57:1028-1036.

Scientific research is fascinating and often unpredictable. I want to provide three examples of something that happened to me that demonstrates that imagination and curiosity are essential in discovering scientific development. Still, possibly, persistence is even more critical. 

Today, I will describe how I demonstrated the successful role of liver transplantation in the epithelioid hemangioendothelioma of the liver. In 1987, the pioneer of liver transplantation, Thomas E. Starzl, asked me to review almost 1,000 liver transplantations performed by his team in Denver and Pittsburgh. Thomas Starzl asked me to focus mainly on the outcome of patients transplanted because of a liver tumor. Several patients underwent liver transplantation with the diagnosis of angiosarcoma. Most of them died shortly after the surgical procedure because of tumor recurrence. Instead, a small group of them were still alive and well, some with a 10-year follow-up. We examined the original pathology again and discovered that the small group of patients doing well did not have an angiosarcoma but an epithelioid hemangioendothelioma. From that moment, this disease became a worldwide indication for treatment with liver transplantation.

Treatment of Hepatic Epithelioid Hemangioendothelioma With Liver Transplantation 

by IGNAZIO R. MARINO, MD, SATORU TODO, MD, ANDREAS G. TZAKIS, MD, GORAN KLINTMALM, MD, PHD,’ MICHAEL KELLEHER, MD, SHUNZABURO IWATSUKI, MD, THOMAS E. STARZL, MD, PHD, AND CARLOS 0. ESQUIVEL, MD, PHD

Ten patients received liver transplants for unresectable epithelioid hemangioendothelioma (EHE). At the time of transplantation, four patients had microscopic metastases to the hilar lymph nodes, and one of the four also had metastases to a rib. The fifth patient had metastases to the lung, pleura, and diaphragm, The remaining five patients were believed to be free of metastatic disease. Two of these five patients died of metastatic disease at 3 and 16 months, respectively, after transplantation. Interestingly, all five patients with metastatic involvement are currently alive 40.6 +/- 22 months (mean +/- standard error of mean [SEMI) after transplantation, although one of these patients currently has metastatic disease to the lungs and mediastinum. Thus, the projected 5-year actuarial survival rate is 76%, with two patients at risk after the thud year. In conclusion, liver transplantation is a reasonable procedure for bulky, otherwise unresectable, EHE even in the presence of metastatic disease.
Cancer 62:2079-2084, 1988. 

EPITHELIOID HEMANGIOENDOTHELIOMA (EHE) is a soft tissue malignant tumor that is characterized by its epithelioid appearance and vascular endothelial histogenesis. It was specifically identified histologically by Weiss and Enzinger¹ in 1982. In 1975, a similar if not identical tumor occurring in the lung was described by Dail and Liebow who proposed the term “intravascular bronchioalveolar tumor.”² In 1984, Ishak el al. reported for the first time 32 patients with primary EHE of the liver.³

The current definition of EHE as a unique form of vascular lesion consisting of endothelial cells is based on the presence of immunohistochemical staining for Factor VIII-related antigen in the tumor.^1-5 Using this specific definition, only a few cases of EHE have been described in the literature, particularly as primary hepatic malignancies, although EHE may occur more often than it is reported.^1,6-8 

The therapeutic approaches used in the clinical management of this tumor have been variable because of the limited clinical experience with this malignancy. There have been two separate single case reports of patients with EHE who have been treated with orthotopic liver transplantation ( OLT). ^9,10 

Herein we report the results with hepatic transplantation in ten patients with EHE. In each of these patients, the tumor was unresectable using any of several different conventional subtotal hepatectomy procedures. 

Patients and Methods

Patient Profile

Between March 1963 and October 1987, 1281 patients had transplants performed at either the University of Colorado or University of Pittsburgh Health Centers or the Baylor University Medical Center. In 9 1 of these patients (7.1%), the indication for OLT was a primary hepatic malignancy that could not otherwise be resected. The histologic diagnosis in ten of these 91 patients was EHE. Only one of these ten patients has been reported currentlly.³ Their ages ranged from 24 to 52.5 years (median age, 29.5 years). Six of ten patients were female.

After OLT, the immunosuppression consisted of azathioprine and prednisone for the first two patients and cyclosporine and prednisone for the subsequent eight patients.

All ten patients were evaluated initially in different institutions. They were referred to one of our hospitals for liver transplantation because the malignant lesions were deemed unresectable except as a total hepatectomy. Before transplantation, the patients were subjected to a thorough evaluation to rule out the presence of any metastatic disease. This included an ultrasonographic examination of the abdomen (with particular attention to the presence of any vascular lesions), computerized axial tomography of the chest, abdomen, and head, a bone scan for the detection of metastases, complete upper and lower gastrointestinal endoscopy, and chest roentgenograms. Occasionally, an arteriogram or laparoscopy also was performed.

The correct diagnosis of EHE was known preoperatively in six patients. In two other patients, the diagnosis was not made until the excised liver was examined histologically and Factor VIII-related antigen was detected immunocytochemically as being present within the tumor cells. The initial histopathologic diagnosis was erroneous in two patients (the first two). A recent review of their histologic material showed the correct diagnosis.

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RERENCES

1. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: A vascular tumor often mistaken for a carcinoma. Cancer 1982; 50:970- 981.

2. Dad DH, Liebow AA. Intravascular bronchioalveolar tumor (Abstr). Am J Pathol 1975; 78:6.

3. Ishak KG, Sesterhenn IA, Goodman MZD, Rabin L, Stromeyer FW. Epithelioid hemangioendothelioma of the liver: A clinicopathologic and follow-up study of 32 cases. Hum Pathol 1984; 15:839-852.

4. Fukayama M, Nihei Z, Takizawa T, Kawaguchi K, Harada H, Koike M. Malignant epithelioid hemangioendothelioma of the liver, spreading through the hepatic veins. Virchaws Arch [A] 1984; 404:275- 287.

5. Sternberger LA, Hardy PH, Cuculis JJ, Meyer HG. The unlabelled antibody enzyme method of immunohistochemistry: Preparation and properties of soluble antigen and antibody complex (horseradish peroxidase-anti-horseradish oxidase) and its use in identification of spirochaetes. J Histochem Cytochem 1970; 18:3 15-333.

6. Echevema RA, Arean VM, Galindo L. Hepatic tumors of long duration with eventual metastases: Two cases of leiomyosarcomatosis possibly arising from hamartomas of liver. Am J Clin Pathol 1978; 69:624-631

7. Ludwig J, Grief MW, Hoffman HN, McGill DB. Calcified mixed malignant tumor of the liver. Arch Pathol 1975; 99:162-166.

8. Persaud V, Bateson EM, Bankay CD. Pleural mesothelioma as- sociated with massive hepatic calcification and unusual metastases. Can- cer 1970; 26:920-928.

9. Dean PJ, Haggitt RC, OHara CG. Malignant epithelioid hemangioendothelioma of the liver in young women: Relationship to oral contraceptive use.. Am J Surg Pathol 1985; 9:695-704.

10. Clements D, Hubscher S, West R, Elias E, McMaster P. Epithelioid hemangioendothelioma: A case report. J Hepatol 1986; 2:44 1-449.

11. Starzl TE, Iwatsuki S, Esquivel CO el a/. Refinements in the surgical technique of liver transplantation. Semin Liver Dis 1985; 5349- 356.

12. Dixon WJ. BMDP Statistical Software Manual. Los Angeles: University of California Press, 1985.

13. Esquivel CO, Iwatsuki S, Marino IR, Markus BH, Van Thiel D, Starzl TE. Liver transplantation for hepatocellular carcinoma and other primary hepatic malignancies. In: Sugahara K, ed. New Trends in Gastroenterology. Kyoto, Japan: Shinkoshu, 1987; 323-332.

14. Stan1 TE, Iwatsuki S, Shaw BW Jr, Gordon RD, Esquivel CO. Immunosuppression and other nonsurgical factors in the improved results of liver transplantation. Semin Liver Dis 1985; 5:334-343.

15. Dail DH, Liebow AA, Gmelich JT el a!. Intravascular, bronchiolar, and alveolar tumor of the lung (IVBAT). Cancer 1983; 51:452-464.

Ignazio R. Marino, Claudia Cirillo

Abstract

Objectives: Organ transplantation is one of the most remarkable therapeutic advances in modern medicine; it started as an experiment and has become a life-saving practice. We briefly describe the major milestones of this multidisciplinary clinical science, the challenges that it still faces, and we consider the crucial contribution that its example could set for other medical fields.
Materials and Methods: A review of the literature was conducted and a selection of images was made to complete a brief history of organ transplantation, with a particular focus on liver transplantation.
Results: The largest problem affecting organ transplantation today is the shortage of organs. Attention should be given to preserving the peculiar high ethical value that characterizes the very nature of organ transplantation.
Conclusions: Methods successfully adopted by organ transplantation during the past 60 years can inspire promising fields, such as stem cell research, and provide useful tools to face the ethical challenges posed by scientific discoveries.  

Introduction

Organ transplantation is among the most remarkable therapeutic advances in the past century. The therapy has progressed from clinical experiments to life-saving procedures. The development and success of organ transplant are associated with developments in other fields including surgery, immunology, critical care medicine, and infectious diseases. Bioethics and medical law have been affected by advances in organ transplant.

Ancient History

An interest in transplant is documented in mythology, religion, and art throughout human history. Descriptions of transplant procedures exist in Hindu texts dating from 2500 to 3000 BC, in which skin grafts cut from a patient’s own buttock or chin were used to reconstruct noses that were mutilated as a punishment for crimes committed.

Lord Ganesha, in a myth from the 12th century BC, was the son of Parvati and Shiva (Figure 1). He was beheaded by his father while guarding the bath of his mother. An elephant’s head was attached to Ganesha’s body, bringing him back to life and making him the recipient of a successful transplant. The earliest known literary reference to a chimera was in Homer's Iliad. In Greek mythology, the chimera was a monstrous fire-breathing creature that had the head of a lion, body of a goat, and backside of a snake (Figure 2).

In a legend from China, the earliest Chinese physician, Pien Chiao, who died in 310 BC, exchanged hearts between a man of strong spirit and weak will and a man of weak spirit and strong will, to achieve a balance.
Several descriptions are found in the Bible that may be interpreted as a transplant. In Christianity, the “miracle of the black leg” was described in Jacopo da Varagine’s Legenda Aura (348 AD); in this transplant operation, the patron saints of surgeons, Cosmas and Damian, replaced a patient’s gangrenous leg with a leg from a recently deceased Ethiopian soldier (Figure 3).

Early Modern Transplantation

Clinical experiments in tissue and organ transplants gave hopes for transplanting as a therapy when Theodor Kocher (1841-1917), the Swiss surgeon, made the goiter operation a safe procedure. In July 1883, he transplanted thyroid tissue into a patient who had undergone radical thyroidectomy. This operation was an attempt to cure hypothyroidism by replacing an organ. It was the first known modern transplant and earned him the Nobel Prize in physiology in 1909 (Figure 4).

In Lyon, France, Alexis Carrel (1873-1844) transplanted a kidney from a dog’s abdomen to its neck (Figure 5). After moving from Europe to the United States, Carrel refined his surgical technique and developed the triangulation method of small vessel anastomosis. He was a Nobel laureate in 1912. Carrel also began collaborating with Charles Lindbergh (1902-1974) in 1930. Lindbergh was curious about developing a heart-lung machine to keep patients alive while surgeons operated inside the heart. Carrel and Lindbergh built the first known functional pump oxygenator that eventually led to the construction of the heart-lung machine (Figure 6).

After World War I and the Great Depression, research in organ transplantation continued. With the increased need for skin therapies for severe burns, the Brazilian-born English scientist Peter Medawar (1915-1987) investigated the mechanisms of skin allograft rejection (Figure 7). He discovered that skin grafts between monozygotic twins were tolerated. Rejection was understood as an immunologic phenomenon. Medawar was awarded the Nobel Prize in 1960.

The field of immunosuppression made marked progress with the collaboration of Gertrude Elion (1918-1999) and George Hitchings (1905-1998) that resulted in new chemotherapeutic drugs. Among these drugs, 6-mercaptopurine was improved by using sulphur-substituted compounds to create azathioprine. Azathioprine inhibited the immune response and was the only drug available for many years to prevent rejection.

Modern Clinical Transplantation

In 1954, the successful transplant of a kidney between living identical twins was performed by Joseph Murray (1919-2012) at the Peter Bent Brigham Hospital in Boston. The procedure was a surgical and immunologic success, and the recipient survived 8 years with no rejection. Murray was awarded the Nobel Prize in 1990 (Figure 8).

In the early 1960s, Thomas Starzl (born in 1926) at the University of Colorado showed that high doses of prednisone added to azathioprine could reverse kidney allograft rejection. This work transformed kidney transplantation into a successful routine procedure and led to the development of many centers of excellence in the United States and Europe. It also enabled the development of other organ transplants. Starzl inaugurated a liver program in Denver and performed the first successful liver transplant in 1967. In 1968, Sir Roy Calne (born in 1930) opened the world’s second liver transplantation program in Cambridge, England. Starzl and Calne established liver transplantation as a common therapy, perfected surgical techniques, and made major discoveries on immunosuppression. They shared the 2012 Lasker-DeBakey Clinical Medical Research Award for changing the field of organ transplantation and restoring normal life to thousands of patients with end-stage liver disease (Figure 9).

Other organ transplant advances during the 1960s included Keith Reemtsma’s (1926-2000) xenotransplant of a kidney from a chimpanzee to a woman who survived for 9 months. In 1963, a lung transplant was performed by James Hardy (1918- 2003) in a prison inmate who had a chronic lung infection; the patient survived only 18 days. Hardy also performed the first known animal-to-human heart transplant. A pancreas transplant was performed in 1968 at the University of Minnesota by C. Walton Lillehei (1918-1999).

The first known heart transplant was performed by Dr. Christiaan Barnard (1922-2001) in Capetown, South Africa (Figure 10); the patient, Louis Washkansky, was a 53-year-old Lithuanian immigrant who was diagnosed with myocardial infarction. Dr. Barnard had worked for 2 years at the University of Minnesota, where Lillehei was developing the field of open-heart surgery. Washkansky survived 18 days with his new heart; as a result, the operation was declared a success, and heart transplantation worldwide followed. There were 21 heart transplants performed during the first 6 months of 1968 in South Africa, the United States, England, India, France, Brazil, Argentina, Canada, and Chile, but results were poor.

The developments in organ transplantation procedures during the 1960s occurred, in part, because of a change in the definition of death. The previous cardiorespiratory definition of death had become inappropriate because of increased capabilities of intensive care life support technology. The concept of brain death was introduced in 1968 by a committee from Harvard Medical School. The report of this committee became influential, but debate about the contents of the report still persists.

Another major advance for transplant procedures was the discovery of the immunomodulatory properties of cyclosporine by Belgian immunologist Jean Borel (born in 1933) in 1977. Cyclosporine was introduced into clinical practice in 1978 and was approved by the United States Food and Drug Administration in 1983. In the early 1990s, FK506 (tacrolimus) was clinically investigated at the University of Pittsburgh by Starzl’s team in human liver transplant recipients who had rejection that was refractory to cyclosporine. The introduction of calcineurin inhibitors such as FK506 caused an improvement in graft and patient survival after liver transplant.

In October 1984, a 2-week-old baby girl (Baby Fae), who had been born with hypoplastic left heart syndrome, underwent a heart transplant with a baboon heart carried out by Leonard Bailey (born in 1942) at Loma Linda University Medical Center. This procedure was reported extensively in the lay media and was rather controversial (Figure 11). Starzl had performed the first known chimpanzee- to-human liver transplant in 1966. In 1992, his team at the University of Pittsburgh achieved patient survival for 70 days after a baboon liver transplant on a man. However, this experimental clinical trial was discontinued because of poor results. Although xenotransplantation may be a potential solution to organ shortage, it has been controversial since it was first attempted. Researchers continue to study new protocols for immune modulation and postoperative care, and the purpose of this research is to achieve long-term survival with solid organ xenografts.

Ethical Issues

Many advances in transplant procedures raise ethical questions. Ethical issues include organ supply and new diagnostic and therapeutic options. After decades of experimentation, organ transplants have been successful, and the primary issue at present is organ availability. Financial incentives for living- and deceased-donor organ donation have been suggested as a possible solution, but concerns exist about black market trade and abuse. To date, organ sale is illegal everywhere, except in Iran.

Conclusions

Transplantation is a field that has had many discoveries that have improved the lives of patients who have organ failure and other diseases. Many immunosuppressive drugs that were developed for use in transplants are also used to treat > 80 autoimmune diseases and several common allergic conditions. Methods that have been adopted in organ transplant procedures may inspire other fields such as stem cell research and may provide useful experience to address difficult ethical challenges posed by new scientific discoveries. Stem cell therapy has technical similarities with transplant procedures. The development of organ transplant procedures enabled treatment that surgery and pharmacology alone could not have achieved; stem cell research has similar potential. In the 1960s, organ transplant contributed to a new definition of death; current embryonic stem cell research may promote a global debate about the definition of the beginning of life. The unique symbolic value of transplant surgery is that its success requires solidarity, collaboration, and sacrifice. Altruism is an integral part of organ donation, hence of organ transplantation, and it remains a key principle for it. In no other surgical field does solidarity play such a crucial role. In no other clinical area are sacrifice and grieving turned into therapy and life so dramatically. Altruism, solidarity, and collaboration among different actors are particularly embedded also in the socioorganizational structure of transplantation, making the multidisciplinary aspect of it a replicable example for complex, emerging fields that raise profound ethical issues.

From the Department of Surgery, Jefferson Medical College, and the Department of Biology,
College of Science and Technology, Temple University, Philadelphia, PA, USA

by Ignazio R. Marino, MD, ScD

Population Health News (April 2018, Volume 5, Issue 4)

Healthcare systems vary consistently between countries but most are facing similar challenges. The changing medical, demographic, technological conditions and the impact of financial and economic austerity create new demands at a time when the public are seeking improvements in access, quality and scope of the services available.

Healthcare systems can be judged by a number of criteria: quality, efficiency and equity, that are seldom evenly balanced. The US system scores very highly on quality, less on equity. In comparison, the British and the Italian systems appear to do better on equity and accessibility.

One common trait, however, is that all existing systems are unlikely to remain sustainable in the longer term, unless additional or new forms of funding are provided and innovative approaches are adopted. Also, differences between systems that were born as opposite in principle, become thinner and decision makers are now facing challenges that are literally global.

Progress in this area is particularly hard to achieve, no matter where we look, partly because of lack of dedicated resources, for political resistance to touch such a sensitive issue running the risk of losing public consensus, and partly because of the difficulty to affect lifestyles and invest in prevention. Nonetheless, general principle sand new guidelines can possibly be derived from international comparisons of different health systems.

When I was a young resident, in the late ‘70s, we used to open a patient’s abdomen to understand what the problem was. CT-scan technology literally revolutionized the way my generation practiced medicine, affecting timing,goals and outcomes. But it was not just about diagnostics. It is hard to believe that my biochemistry book in medical school dedicated only 4 pages to the DNA.

Medicine has changed more in the past few decades than in the entire 19thcentury, and this has affected the way we live, get sick, get treated, and die. If you were born in 1900, you had a pretty good chance of dying by your 50thbirthday. Nowadays, thanks to improved health and safety measures around the world, children, especially girls, have extremely good chances to live as long as 100 years. The National Institute of Aging Report puts this in stark terms: "The 85-and-overpopulation is projected to increase 351% between 2010 and 2050, compared to a 188% increase for the population aged 65 or older and a 22% increase for the population under age 65."1 This explains why most people are in panic mode about health coverage and Social Security.

However, although life expectancy has improved everywhere over the past decades, there are still stark differences among most European states that occupy top positions on the list of countries with the longest life spans, and,say, the United States. Infant and maternal mortality rates are another commonly cited international comparison of health status. Despite spending about 17% of their GDP on healthcare – more than any other industrialized nation – the USA has the worst rate of maternal mortality in the developed world.

Their low ranking is often used to question the direct relation between wealth and health quality. Spain and Italy, countries that certainly can boast the recognized benefits of the Mediterranean diet and reduced risk of several chronic conditions, do indeed have better ranking for life expectancy and death rates. Lifestyle does count when it comes to health and longevity. An incredible impact on health outcomes and on a country’s health conditions could be achieved investing more in prevention and in the promotion of healthy lifestyles. But then again, it is not only about lifestyles.

There are conditions that cannot be affected by prevention or lifestyles, but that can be tackled only through expensive treatments, which introduces another issue for debate: drug price. According to industry executives, high prices cover the expense of developing new medications. One popular study estimates the industry’s cost of creating a single drug at $ 2.6billion. One pill of Sovaldi, for instance, an antiviral medication used to treat chronic hepatitis C costs 1,000 dollars in the United States, and 11 dollars in Egypt. Drug prices in our country are particularly high because, unlike elsewhere, the government does not use its purchasing power to contain them. There is nothing like the UK’s National Institute for Healthand Care Excellence (NICE), or the Italian Agenzia Italiana del Farmaco (AIFA), acting as a gatekeeper for new medicines.US healthcare costs are the highest in the developed world and pharmaceuticals account for only 1 in every $10 spent on health.

Still, they are among the most visible to patients because of the steep co-payments demanded by insurers. In 2015, for the first time in history, the US Senate Committee on Finance wrote to a big pharma CEO expressing concerns about the extent to which the market is operating, probably thinking of pricing strategies for treatments that in non-US markets contemplate significant lower prices than what is set for US patients.2 Despite several Congressional inquiries since the 1980s,the inquiry on the new drug for hepatitis C treatment has become a case study and possibly the basis for a timid attempt at changing the traditional rhetoric between the government and private pay ors – a type of action that is more standard practice in countries with different health care systems.

A possible form of positive monitoring, mutated from the pharma world, could be the introduction of regulatory requirements for clinicians to prove that a new procedure is necessary and not harmful, just like drug companies must do before selling anew pharmaceutical. Howard Brody of the University of Texas Medical Branch maintains that waste, defined as spending on interventions that do not benefit patients, amounts to at least 30% of the US healthcare budget and is a major driver of cost increases.3 A list of 135 procedures, often used for decades, was made by medical specialty groups for medical tests and treatments considered as almost always unnecessary and often harmful.

The list was released in 2013 by the professional societies of 17 medical specialties ranging from neurology and ophthalmology to thoracic surgery and was made without considering costs. It was part of a campaign called Choosing Wisely, organized by the American Board of Internal Medicine’s foundation. Some believe that avoiding waste could allow universal coverage in the United States, but even a more modest goal - saving billions of dollars in wasteful spending –would be a much needed intervention.

If it is not only about lifestyles, as I mentioned before, it must have something to do with the kind of health coverage that people have. Universal health coverage does seem to improve health outcomes and protect people from the risk of impoverishment.And yet the endless debate over the advantages and disadvantages of such a system is getting complicated now that challenges typical of a system mainly based on private insurances start affecting also socialized medicine.

Looking at the Italian National Health Service (Servizio Sanitario Nazionale – SSN), a system ranked second best in the world by the World Health Organization, can provide interesting insight. Created in 1978 and inspired by the British National Health Service, SSN has two underlying principles: every citizen and every foreign resident has the right to healthcare, and all necessary treatments are covered. Over the last thirty years, SSN has assured a good standard of universally accessible services. Today, however, the system finds itself operating in very different circumstances to the past, due to technical advances, demographic trends, increasing demands, economic constraints and ethical considerations. In order to address these challenges, the Italian healths ystem will need to make progress in several key directions: prevention of disease and efficiency of facilities; reduction of regional disparities in performance;formulation of a national health policy integrated with the country’s industrial priorities; simplification of bureaucracy.

Among the measures that seem more urgent, Italy should promote increased accountability and autonomy of medical staff; the creation of new professional roles; the strengthening of IT and digital support tools; and the systematic introduction of monitoring, evaluation, and merit-rewarding mechanisms. In general, the sustainability of Italy’s healths ystem will depend on its ability to embrace change while resolving short-term problems and planning long-term development and innovation. A radical transformation should entail that the healthcare system must change from being a simple cost center to become a center of investment and promotion of excellence, with the introduction of controlled competitive elements, including forms of public-private collaboration.4 Interestingly enough, this seems to be a recipe that is directly inspired by radically different health care systems.

On the other hand, according to many, the fundamental problem in the US health care system is that the structure of healthcare delivery is broken because a dysfunctional kind of competition, not based on value and results, has taken over.5 In other words, the healthcare transformation that is so needed has more chances to happen if the system joins the consumer revolution than through measures imposed by the federal government.6 Millions of vulnerable Americans are better protected after the introduction of the Affordable Care Act, but the expected breakthrough change has only partially occurred, mainly because it is not only through complicated legislation that disparities can be mended.

The goals of medicine (relief of suffering, prevention and cure of disease, promoting of a peaceful death) seem incompatible with managed care, if this is intended as a system of integrated healthcare delivery designed to control costs.This depends on how legitimate profit is sought, whether the integrity of physicians' medical judgment is protected, and whether government regulations effectively prevent abuse and enhance the quality of care.

The principle of value-based competition applies to any health care system. There is a growing recognition of the need to focus on value, to introduce competition into state-dominated systems, and – conversely – to rethink how providers are organized in private systems.

Talking about sustainable development of global health, Richard Horton, Editor-in-Chief of The Lancet, has advocated for a shift from a public health model to a planetary health model, defining planetary health as “the health of human civilization and the state of the natural systems on which it depends—the way we organize our political, economic, social,environmental and technological systems to address the predicaments we face.”7 According to Horton, considering how codependent on a healthy population economic growth and development are, but also how limited our resources are, we really should start looking beyond the health system, work at the interface between all sectors for sustainable development,engage with industry to address conflicts of interest, and communicate better to improve solidarity and achieve goals together for ourselves and future generations. Not an easy task, but certainly one that international dialogue andi nterdisciplinary collaboration must undertake.

1. Mahishale V. Ageing World: Health Care Challenges. J Sci Soc 2015;42:138-43.

2. Senators Ron Wyden and Charles E. Grassley (2015), “The Price of Sovaldi and Its Impact in the U.S. Health Care System” Committee on Finance, United States Senate

3. Brody H. From an Ethics of Rationing to an Ethics of Waste Avoidance. N Engl J Med 2012; 366:1949-1951.

4. Aspen Institute Italia, Rome, 21/09/2016, National Roundtable

5. Porter, Michael E., and Elizabeth O. Teisberg. Redefining Health Care: Creating Value-Based Competition on Results. Boston:Harvard Business School Press, 2006.

6. Stephen K. Klasko, Gregory P. Shea, Michael Hoad We Can Fix Healthcare: The Future is Now . Mary Ann Liebert, Incorporated,Publishers, 2016.

7. Richard Horton. “Sustainable Development Is about More than Global Health”. Keynote speech at the Duke Global HealthInstitute’s 10th anniversary symposium, October 11, 2016.

Acknowledgement

I am thankful to Claudia Cirillo who assisted with background research and preparation of the paper.

Ignazio R. Marino is Professor of Surgery, Sidney Kimmel Medical College at Thomas Jefferson University, Senior Vice President for Strategic Affairs and Director of the Italy Center, Global Jefferson.

Noemi Zorzetti, Augusto Lauro, Simone Khouzam, Ignazio Roberto Marino

Orthotopic liver transplantation is the treatment of choice for several otherwise irreversible forms of acute and chronic liver diseases. Early implemented immunosuppressant regimens have had disappointing results with high rejection rates. However, new drugs have reduced the daily immunosuppression requirements, thereby improving graft and patient survival as well as kidney function. Liver rejection is a T-cell-driven immune response and is the active target of immunosuppressive agents. Immunosuppressants can be divided into pharmacological or biological drugs: the gold standard is the calcineurin inhibitors, steroids, mycophenolate mofetil, and mechanistic target of rapamycin inhibitors. Compliance with these agents is essential, although they can increase the risk of infections and neoplastic diseases. In some patients, graft tolerance can be achieved. Graft tolerance is defined as the absence of acute and chronic rejection in a graft, with normal function and histology in an immunosuppression-free, fully immunocompetent host, usually as the final result of a successful attempt at immunosuppression withdrawal. The occurrence of immunosuppressive-related complications has led to new protocols aimed at protecting renal function and preventing de novo cancer and dysmetabolic syndrome. The backbone of immunosuppression remains calcineurin inhibitors in association with other drugs, mainly over the short-term period. To avoid rejection and the side effects on renal dysfunction, de novo cancer, and cardiovascular syndrome, optimal long-term immunosuppressive therapy should be tailored in liver transplant recipients.

Introduction

Since the first human liver transplantation, performed in 1963 by T. E. Starzl in Denver, Colorado,¹ orthotopic liver transplant (OLT) has been considered an experimental procedure up to the 1980s. Today, it is regarded as the treatment of choice for a number of otherwise irreversible forms of acute and chronic liver diseases.²

Following the success shown with regimens for kidney transplantation, early OLT immunosuppressant cocktails were based on azathioprine, corticosteroids, and antithymocyte globulins (ATGs). The results with these were disappointing with high rejection rates.³ However, with the introduction of cyclosporine, a new immunosuppressant in the early 1980s, rapid and significant improvements in survival were shown.⁴

Eventually, with the discovery of tacrolimus in the 1990s, outcomes of liver transplant recipients dramatically changed, with increased long-term graft and patient survival rates.^5,6

Moreover, several later introduced new drugs (such as mycophenolate mofetil [MMF] or everolimus) (Figure 1) reduced the daily requirement of immunosuppression drugs among liver transplant recipients, improving their kidney function.

Immunosuppressive Therapy After Orthotopic Liver Transplant: State of the Art

Apart from hyperacute rejection, T-cell activation acts as the starter of the rejection cascade, with the key to controlling the rejection represented by immunosuppressive drugs. As stated earlier, the first regimens were characterized by high rejection rates, lower graft survival, and lower patient survival. Presently, there are different classes of immunosuppressive drugs that target the mechanisms of action focused on T-cell activation. Immunosuppressive agents can be divided into pharmacological or biological types (Table 1 and Table 2).

The corticosteroids are the first class of hormones and have lymphocytolytic effects.⁷ They interact with the immune system at various levels, reducing the number and size of lymphoid cells and inhibiting the production of inflammatory mediators such as platelet-activating factor, leukotrienes, and prostaglandins. Moreover, they inhibit monocyte and neutrophil chemotaxis and produce lympho- and neutropenia, not through direct cytotoxicity but by altering the diffusion of these cell populations. Corticosteroids are common components of combined immunosuppressant regimens and are also administered as intravenous boluses to treat acute rejection events. Glucocorticoids, particularly when used for long periods, have several side effects: glucose intolerance, hypertension, osteoporosis, muscle mass reduction, weight gain with central obesity, moon facies, striae rubrae, psychosis, cataract, glaucoma, and even iatrogenic Cushing syndrome.⁸,⁹

Cyclosporine, introduced in the 1980s,4 reduced the rates of rejection from 15% (reported by various groups) to 2% to 5%,¹⁰ validating calcineurin inhibitors (CNIs) as the backbone of immunosuppression. Tacrolimus (FK506), first used in clinical practice in the 1990s,^11-13 and cyclosporine are CNIs, a serine-threonine phosphatase involved in the activation of various transcription factors. With activated T lymphocytes, the inhibition of calcineurin blocks the transcription of various cytokines, including interleukin 2, which plays a fundamental role in activating the immune response. Tacrolimus is more potent than cyclosporine in suppressing the immune response. The selected administered dose is based on drug levels in the blood, which need to be monitored at regular intervals. Both drugs are metabolized in the liver by the P450 IIIA cytochrome system, allowing reactions with other drugs to increase (erythromycin, fluconazole, verapamil, cimetidine) or reduce (phenobarbital, phenytoin, carbamazepine) cyclosporine or tacrolimus levels in the blood.

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Ignazio Marino

1. Starzl TE, Marchioro TL, Vonkaulla KN, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the liver in humans. Surg Gynecol Obstet. 1963;117:659-676.
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3. Rolles K, Williams R, Neuberger J, Calne R. The Cambridge and King’s College Hospital experience of liver transplantation, 1968-1983. Hepatology. 1984;4(1 Suppl):50S-55S. doi:10.1002/hep.1840040715
4. Calne RY, Rolles K, White DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979;2(8151):1033-1036. doi:10.1016/s0140-6736(79)92440-1
5. Jain A, Reyes J, Kashyap R, et al. Long-term survival after liver transplantation in 4,000 consecutive patients at a single center. Ann Surg. 2000;232(4):490-500. doi:10.1097/00000658-200010000-00004
6. Busuttil RW, Farmer DG, Yersiz H, et al. Analysis of long-term outcomes of 3200 liver transplantations over two decades: a single-center experience. Ann Surg. 2005;241(6):905-916; discussion 916-908. doi:10.1097/01.sla.0000164077.77912.98
7. Starzl TE, Marchioro TL, Rowlands DT, Jr., et al. Immunosuppression after experimental and clinical homotransplantation of the liver. Ann Surg. 1964;160:411-439. doi:10.1097/00000658-196409000-00007
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Ignazio R. Marino • Claudia Cirillo
Published online: 30 July 2014
Springer Science+Business Media New York 2014

Research is facing declining funding rates everywhere, affecting the cultural and economic growth of some of major world powers. We looked at the choices on funding allocation made by the USA and by Europe, to compare priorities and analyze consequences. Also, within Europe, we focused on Italy and on its consistent braindrain phenomenon, as an example of short-sighted research policies that appear to require not only the urgent infusion of monetary resources and the creation of new job opportunities, but also and especially a general change of cultural approach.

The Current State of Research Funding in the USA and in the EU

Biomedical investigators everywhere are facing declining funding rates, with many forced, due to lack of funding, to seek careers in other areas. Young investigators, due to their vulnerability, are especially exposed to these cutbacks. Researchers on both sides of the Atlantic lament a growing lack of resources and a narrowing national vision.
As investigators familiar with the US and EU systems, we would like to comment on how this funding decline has affected the research enterprises of these two major world powers, with particular attention to differences in fund allocation and the setting of standards and priorities that go beyond national economic characteristics, but are rather informed by cultural idiosyncrasies and national priorities inconsistent with a thriving research enterprise, with special attention to the plight of young investigators.

A Comparison Between Research Investments in Europe and in the USA

The allocations and the main areas of investment planned by the US Congress and the European Union (EU) for research for 2014 and 2015 were obtained through review of the US budget through the FY2014 Omnibus Appropriation Bill and, more recently, through President Obama’s USD 3.9 tr budget request to Congress, and the First Amending Letter to 2014 Budget and the Horizon 2020 (H2020) program, the principal financial tool for research and innovation in Europe, consisting of nearly EUR 80 bn (*USD 111 bn) available over 2014–2020. With these tools at our disposal, we can compare priorities and approaches of the research and development (R&D) agendas of the two principal global powers.
Many in the USA are convinced that the national budget no longer has the potential to advance scientific discovery.
The USA, as the uncontested global leader in the life sciences, now faces challenges from other world powers. For instance, allocations to the National Institutes of Health (NIH) and the Food and Drug Administration are generally considered insufficient to maintain the country’s global leadership in the field of medical innovation and science.
Due to budgetary declines, the ‘‘purchasing power’’ of the NIH has recently declined 20 %, with the consequence that it can fund only one in every seven research proposals that it receives. These declines are tempered by the recent uptick in research and development (R&D) funding from private and industrial sources. According to the National Science Foundation, these invested USD 428.2 bn in R&D in 2011, 5.4 % more than in 2010, increasing by 7.7 % in 2012 to USD 452.6 bn, with the trend likely to persist well into the future. Federal government studies have reported that 75 % of the US new wealth produced after World War II originated from the application of scientific discoveries.
More importantly, similar positive effects are manifest in the short term. R&D Magazine calculated that 69 % of the 2014 R&D investments (USD 465 bn) originated from private businesses, directly employing 2.7 million people (1.4 million of which are researchers) and indirectly another 2.0 million, creating 4.0 million new jobs in several areas, translating into 8.0 % of the US economy being based on scientific research and technological innovation.
These numbers, in spite of the legitimate complaints of research institutions and individual scientists and scholars who still feel that more should be done, are a testament to salient characteristics of the US system, namely that: (1) investments in R&D are considered to impact the economy in the long and short term; (2) global competitiveness can be maintained only by raising the investment quotas, since other world emerging leaders are adopting this strategy; and (3) there is political consensus across the US Congress about the need to invest public money to sustain the country’s leadership in the field of innovative scientific research as a source for economic development. The USA invests ~2.8 % of its GDP in R&D, whereas China invests 2.0 %, and the EU, 1.9 %. Only Japan can boast an allocation of 3.4 %.
The preoccupation with the current EU economic and financial crisis has channeled 25 % of the 2014 H2020 budget to mostly support research conducted by industry in continental Europe, almost five times more than is allocated to the life science industry in the USA (where it receives6 % of total funding), where discoveries can be transferred directly to the market. Another fundamental difference is the focus on applied science in Europe, whereas the USA invests mostly in fundamental research.
Similarly, in Europe, modest resources are still channeled to the health and energy sectors, which typically take several years to mature to market.
While the USA promotes a long-term approach investing in fundamental research and advanced technology, Europe has adopted a more prudent, short-term strategy, due mostly to cultural and political biases. The case of Italy, within the EU, perfectly exemplifies the limitations and the incentives of this approach.

The Italian Case

One of the goals of the H2020 Program is to increase the GDP allocations to R&D for all EU members to at least 3 %. As an example, Italy currently invests only 1.25 % of its GDP in R&D, below the EU average (Eurostat 2011), which is nearly 2 %, and further below the USA. In 2010, in Italy, 1.52 % of employed adults were working in R&D. Again this quota is below the EU average.3 Out of 54,414 patents registered in Europe, in 2010, only 4,423 (8 %) were Italian, below the EU average and far below that of France (8,700) and especially of Germany (21,700). Nevertheless, the quality of Italian research is excellent.
A database of the Italian Research Map documents the Italian contribution to the 7th Framework Program of the European Commission (FP7) through more than 2,000 of 100,000 projects conducted or participated by the 173 countries admitted to FP7, up to December 2013. Italy is featured among the top five countries as project coordinator (1,767 projects), after Spain (2,112), France (2,377), Germany (2,828), and the UK (4,441). On the whole, Italy contributed to FP7 with 37,867 proposals. Among the Italian contractors admitted, the most important universities and research centers are featured, such as CNR (National Research Council), FIAT Research Centre, ENEA (Energia Nucleare ed Energie Alternative), the Agency for the Promotion of Research in Europe (APRE), the Italian Institute for Technology Foundation, STMicroelectronics, and the National Institute for Nuclear Physics.
Nevertheless, Italy’s national research system is functioning sub-optimally.
The Italian deficit is due to the paucity of public and private sector participation: The former is about half the European average with public fund investment 0.18 percentage points below the OECD (Organisation for Economic Cooperation and Development)’s average. Less money translates into fewer resources, fewer researchers and a much smaller innovation potential. Besides less funding, blind political choices, cultural paternalism, and procedural hurdles impair the ability of Italian researchers to realize their full potential. In terms of publications and outcomes, Italians can boast exceptional quality and productivity— two achievements that unfortunately mostly occur out of their country.
The phenomenon by which highly educated and skilled Italians take their talent abroad in search of better career opportunities and payoffs is termed the ‘‘brain-drain.’’
Within twelve months of graduation, 7 % of Italian graduates find employment abroad, which in 2012 amounted to more than 14,000 (Source: Istituto Nazionale di Statistica (ISTAT), Italian National Institute of Statistics). Despite Europe’s attempts to retain qualified investigators, each year 30,000 Italian researchers leave while only 3,000 scientists move to Italy from other countries, making Italy the one European state where affirmative action to quell the exodus of young scientists is most needed, in order to stop enriching the scientific communities of competing countries at its expense. Considering an average cost of EUR 3,000 per semester, times five years of university course per student, Italy ends up losing at least EUR 175 mn annually for the students that it lets go. After having been educated and trained at the expense of Italy, these skilled engineers, economists, and physicians contribute to the research and development enterprise and the economic growth of other nations. The reasons they leave include superior employment opportunities, salaries, and above all, the growth opportunities that accrue from being granted credit and responsibility in their field of expertise. Scientists need to leave Italy to advance their careers, but they also face reintegration problems when they return. This has to do with the Italian anachronistic system of distributing jobs in research. It’s who you know, not what you know, that often counts the most.
Italy’s problem with patronage is a major cause of weakness not only within the academia, but also in the broader world of professionalism and production, with heavy consequences on the national economy.
Another issue, especially in the field of medical education, is the lack of mentoring that supports the professional development of students, residents, and faculty. Leaders have the responsibility to share knowledge and offer insight, providing a unique perspective for students and research faculty. Far too often, however, the Italian academic system protects the privileges of established faculty members rather than fostering the growth of students, another reason to leave for countries where academic research involves frequent data exchange with peers combined with concrete opportunities to advance professionally in order to gain scientific maturity and job market value.
As one of us (IM) has often stressed, ‘‘Italy is still far behind in research investment, and this needs to change.
But the crucial switch is not simply to increase funding.
The way the new government should proceed is to reform the allocation criteria for funding and to start applying across-the-board the selection and evaluation rules of peer review. Such a system would acknowledge meritocracy and free researchers from the virtual slavery under which they have been kept by old academicians.’’ (Marino IR. Acceptance of peer review will free Italy’s research slaves, Nature, 453, 449, 22 May 2008)

Italy is, however, not exceptional in Europe: Recently, in France, the Scientific Council of CNRS (Comite` National de la Recherche Scientifique) has warned politicians and the civil society in regard to the risks that the research system is running as a consequence of poor availability of human and financial resources. The negative example of Italy is quoted by CNRS as an outcome that France should avoid at all costs. The reference to Italy shows France’s preoccupation ‘‘with extremely rapid consequences in terms of deep destruction of the research system.’’

Conclusions

Italy is a paradigm of a G8 country that has not realized its enormous potential as a scientific power in Europe and in the world. A cultural revolution is needed, starting from a new definition of the role of education and culture at large within a society that aims at innovating and promoting technological progress.
It is necessary to invest in technologically advanced and scientifically outstanding research that can be achieved by creating and supporting a strong and direct tie between basic research and innovative biotechnology companies.
This model requires years to develop, a time frame incompatible with the short-lived governments of Italy, given its notorious political instability. In less than 70 years of republican history, the country has churned through 63 governments, each one lasting on average for a little more than a year. Evidence of unwise or too timid provisions by economic and legal authorities, instead of systematic and long-term efforts, has reduced faith among Italian researchers—and the citizens at large—in the ability of Italy to grow its scientific infrastructure and enterprise.
Indeed, there is a strong connection between scientific R&D and a healthy democracy.
The 2013 Eurobarometer ‘‘Responsible Research and Innovation,’’ funded by the Science and Society program of the EU’s FP7, shows that 65 % of Europeans think that their government is doing too little to stimulate young people’s interest in science. There is a need to support formal and informal science education, especially in Southern and Eastern EU member states. Also, within OECD, women earn more than half of the total number of university degrees, but still hold only 30 % of those in the field of science and technology. Given the current highly successful trend for women to excel in science in the USA and elsewhere, one fundamental objective is to expose school-age girls to more and better science and technology teaching and practice.
In Italy, research institutes need to be less static, procedures must gain transparency, and researchers should be able to develop a more competitive character and an entrepreneurial spirit. In order to achieve these goals, even before allocating more funds, there is a need to make political and industrial strategic choices. The three main goals to re-launch Italian (and European) research are as follows: (a) improve international competitiveness; (b) fight the brain-drain; and (c) design new access routes for young skilled researchers. This can be done essentially by:

• applying the strict criteria of scholarly peer review to all selection and evaluation processes, promoting merit versus favoring the ancient and ossified rigid hierarchies of acquired power;
• raising the amount of international cooperation with countries that are particularly dynamic in R&D such as Germany and the USA;
• opening the doors to the business sector, facilitating partnerships between academia and industry; and
• providing enhanced support and resources for young investigators.

All told, a much needed change of perception, culture, and approach would likely achieve far more benefit that an infusion of new resources.

This morning I had the honour to attend the Inauguration ceremony of the 2022-23 Academic Year at Università Cattolica del Sacro Cuore, Rome campus, in the presence of Rector Prof. Franco Anelli, the Dean of the School of Medicine Prof. Antonio Gasbarrini, Cardinal Jose Tolentino de Mendonca, as well as the Ministers of Health, of the Interior and of Culture, and many other personalities.
I would like to thank the Dean and dear friend Antonio Gasbarrini for his generous words on the collaboration promoted with Thomas Jefferson University for the development of the dual MD degree programme, a unique offer within the international academic landscape, that allows graduates to practice medicine both in Europe and the USA.
I will jealously hold the Cattolica Alumni pin that Prof. Gasbarrini took off his jacket and gave to me.

"

Eminenze ed Eccellenze Reverendissime, Onorevoli Ministri, Autorità Civili e Militari, Magnifico Rettore e Magnifici Rettori, Amplissimi Presidi, Membri dei CdA di Toniolo, Cattolica e Fondazione Gemelli, Direttori Generali, Dirigenti e Personale Sanitario e Amministrativo, Cari Colleghi, Cari Studenti, Specializzandi e Dottorandi, Cari Amici, è per me un grande onore tenere per la prima volta la Relazione alla Cerimonia di Apertura dell’Anno accademico 2022/23 presso la sede romana dell’Università Cattolica del Sacro Cuore in qualità di Preside della Facoltà di Medicina e Chirurgia, una Facoltà che mi ha accolto nel 1995 proveniente dall’Alma Mater Studiorum, l’Università di Bologna, e dopo un lungo periodo trascorso negli Stati Uniti, nell’Università di Pittsburgh, un periodo estremamente formativo della mia vita che mi ha permesso di conoscere grandi Maestri della Medicina e Chirurgia.

Nanos gigantum humeris insidentes diceva 8 secoli fa Bernardo di Chartres: quanta verità! Non dobbiamo infatti mai dimenticare che è proprio sulle spalle dei grandi Maestri che noi siamo stati in grado di crescere.

Da allora ho trascorso 28 anni incredibili ed entusiasmanti in questa Facoltà avendo la fortuna e l’onore di conoscere altri grandi Maestri di Medicina e di Chirurgia.…quanti insegnamenti, quanta saggezza! Tra loro Rocco Bellantone, un Preside che ci ha condotto per 12 anni in acque talora tempestose con equilibrio, grinta, saggezza e lungimiranza e che la nostra Comunita’ non smetterà mai di ringraziare. E poi grandi Maestri di Accademia, come Franco Anelli, giurista eccelso e mente raffinata che ha lottato per mantenere il nostro Ateneo libero, indipendente, meritocratico. Grazie Franco per ciò che hai fatto per noi, per quanto hai creduto nel nostro progetto di Facoltà e di Ospedale, impegnandoti sempre in prima persona, condividendo successi e supportandoci sempre con tenacia e coerenza anche nelle fasi più difficili.

La nostra Facoltà di Medicina e Chirurgia è una delle 12 Facoltà dell’Università Cattolica del Sacro Cuore, oggi rappresentate dai Presidi che saluto affettuosamente, l’unica che, insieme alla Facoltà di Economia, ha sede a Roma in questo meraviglioso Campus dedicato al fondatore padre Agostino Gemelli. Un Campus che è una vera e propria città della della Cultura, della Scienza, dell’Assistenza, della Misericordia, caratterizzato dall’ospitare oltre alle nostre Facoltà, il Policlinico Gemelli, un polo sanitario di eccellenza mondiale che con la guida di Marco Elefanti si è posizionato tra i primi Ospedali al mondo nei ranking internazionali. Un luogo in cui i cittadini di Roma, del Lazio, dell’Italia possono trovare risposte per ogni tipo di problema di salute, dalle malattie rare a quelle più comuni, dotato di un Pronto Soccorso spesso troppo affollato ma che rappresenta un approdo sicuro per la città di Roma, porta di ingresso sicura per le reti dell’urgenza tempo dipendenti dell’ictus, dell’infarto, dei trapianti. Un ospedale che e’ primo in Italia per numero di pazienti oncologici trattati, primo in Italia per numero di studi clinici di fase II e III con i farmaci più innovativi e sede di un IRCCS che, diretto da un’altra delle nostre eccellenze: Giovanni Scambia, si è posizionato in pochi anni nei primi posti in Italia per numero di pubblicazioni e finanziamenti vinti.

Il nostro Policlinico Gemelli, così fortemente voluto dal nostro Fondatore, è diventato nei suoi quasi 60 anni di vita una vera e propria “macchina da pace” che dobbiamo proteggere e preservare anche nei momenti di difficolta’ evitando la facile tentazione di rimodulare l’offerta assistenziale limitandone l’accesso alle patologie piuù redditizie. Una macchina da pace che per continuare a fornire tanta eccellenza ha pero’ bisogno di una rimodulazione delle tariffe e dei DRG, da troppi anni non aggiornati nella nostra Regione.

Veniamo ora alla nostra Facoltà di Medicina e ai 4 obiettivi che ci siamo dati per il prossimo anno accademico.

1)       Didattica:

Nella Facolta’ vi sono 37 corsi di Laurea che accolgono oltre 5215 studenti distribuiti in 6 regioni e 9 citta’, al Sud (Campobasso e Potenza), al centro (Roma, Viterbo e Rieti), al nord (Brescia, Bolzano, Vercelli, Torino). E 2 corsi interfacolta’ nella sede di Milano.

Tra essi, 4 corsi di laurea magistrali a ciclo unico nella sede romana: Farmacia, Odontoiatria, Medicina e Chirurgia, Medicine and Surgery. Quest’ultimo, un corso in inglese che accoglie studenti provenienti da oltre 20 paesi di tutte le parti del mondo e che ben rappresenta lo straordinario incubatore internazionale che e’ diventato in questi anni il nostro Campus. A tale proposito ricordo l’accordo di collaborazione tra la nostra Facoltà e la Thomas Jefferson University di Philadelphia negli Stati Uniti, oggi qui rappresentata da un nostro illustre laureato, il suo vice presidente prof Ignazio Marino.

Il rapporto con Jefferson University, in particolare, è ormai un rapporto consolidato che esita in uno scambio internazionale continuo di docenti e specializzandi e che permette ad alcuni nostri studenti di ottenere un double degree in Medicina riconosciuto bilateralmente sia negli Stati Uniti che in Italia.

Inoltre, 29 corsi di laurea triennali e 4 magistrali dedicati alle professioni sanitarie presenti nelle 9 sedi che coprono tutta l’offerta necessaria per formare eccellenti professionisti delle Salute.

Per tutto ciò ringrazio i 37 Presidenti dei corsi di laurea e i nostri straordinari Docenti, che insieme a un instancabile personale amministrativo, riescono a formare Sanitari in grado di coniugare eccellenza tecnica, partecipazione e misericordia verso le persone che soffrono. 

La formazione post laurea è un altro dei nostri punti di forza:

54 scuole di specializzazione per 1921 specializzandi. Medici in formazione competenti, dedicati, appassionati, che nel loro percorso di crescita ci supportano quotidianamente per assistere i pazienti che si affidano al nostro Policlinico e dei quali non dimenticheremo mai l’incredibile impegno con cui ci hanno supportato durante la pandemia Covid.

E poi 90 master di I e II livello in tutte i settori della medicina e dell’economia sanitaria, 7 scuole di dottorato e 41 corsi di perfezionamento. Molti dei quali in collaborazione con quella incredibile macchina di formazione sanitaria che e’ ALTEMS, Alta Scuola di Economia e Management dei Sistemi Sanitari, diretta così bene da Americo Cicchetti.

2)       Ricerca:

Le 3 macroaree in cui è divisa la nostra Facoltà (Biologica, Medica e Chirurgica) comprendono 493 docenti: 62 professori ordinari, 172 professori associati, 259 ricercatori. Colleghi di valore assoluto che producono costantemente ricerche di eccellenza che nel solo 2022 hanno esitato, in:

- oltre 2000 lavori pubblicati su Pubmed per oltre 8.000 punti di impact factor

-355 progetti universitari nazionali finanziati

-12 progetti europei finanziati

-12 progetti a valere sul PNRR e sul piano complementare del PNRR

Per un totale di oltre 20 milioni di euro vinti nel solo 2022.

Questi risultati si sono potuti raggiungere solo grazie ai nostri Professori e ai nostri Ricercatori, oltre ai tanti giovani talentuosi che, con contratti di lavoro precario, contribuiscono alle attività di ricerca assistenza e didattica del nostro Campus.

Proprio a questi giovani sarà importante garantire una possibilità di crescita e di stabilizzazione per favorire il reclutamento dei giovani migliori. A questo proposito la Facolta’ ha appena istituito una Commissione dedicata alle rising stars del Campus, volta a valorizzare i migliori under 40 presenti nei vari settori scientifico-disciplinari, un vivaio prezioso di ragazzi gia’ noti a livello internazionale e da valorizzare con iniziative “straordinarie” allo studio dell’Ateneo.

Vi rendete conto cosa vuole dire avere così tanti Maradona o Pelè nel vivaio? Vale la lungimiranza del passato, la certezza del presente, la speranza del futuro.

Naturalmente, la valorizzazione dei giovani non dovrà avvenire a scapito della generazione intermedia che è stata, viceversa, svilita e sfavorita dalle tante riforme del reclutamento universitario che si sono succedute negli ultimi anni ma che, ciononostante, ha continuato a reggere la nostra Facoltà impegnandosi nella ricerca e, come ricordavo precedentemente, nella didattica dei tanti corsi di laurea della nostra Facoltà. Anche per questi colleghi dovremo trovare la corretta modalità di valorizzazione e gratificazione come riconoscimento del loro impegno quotidiano per la Facoltà.

3)       Assistenza:

Vi ho già parlato del Policlinico Gemelli, una realtà sanitaria di assoluta eccellenza dove si svolge l’attivita’ professionalizzante dei nostri studenti che, unita a una estesa rete formativa di oltre 40 strutture sanitarie del Lazio e 35 in altre Regioni (tra tutte la Fondazione Poliambulanza a Brescia, un’eccellenza della sanità lombarda in cui sono impegnati tanti amici e colleghi, tra tutti 2 nostri straordinari ex docenti: Gennaro Nuzzo e Paolo Magistrelli). Una rete che permette ai nostri specializzandi di completare un percorso in cui la pratica clinica sul malato sia combinata all’apprendimento delle piu’ avanzate tecniche diagnostiche e terapeutiche garantendo la formazione di professionisti pronti per entrare al meglio nel mondo del lavoro.

E ora veniamo alla quarta missione della nostra Facolta’. Quella di cui siamo piu’ fieri perché rappresenta il nostro tratto distintivo: la Solidarieta’.

Un sostantivo indicante una forma di impegno etico-sociale a favore degli altri, una forma di solidarietà sociale in riferimento a staordinarie realta’ Associative con cui abbiamo instaurato rapporti di collaborazione di vario tipo. A tale proposito la Facoltà, col costante sprone del nostro Assistente Spirituale, Sua Eccellenza Claudio Giuliodori, ha recentemente instituito una Commissione Solidarieta’ che ha censito tutte le attività solidali in cui sono impegnati i nostri docenti e studenti.

Attualmente ne abbiamo individuate oltre 100. Da quelle del CESI, centro di Ateneo per la solidarietà internazionale a quelle interne al Campus romano.

Tra tutte quella della Villetta della Misericordia, una casa colonica all’interno del Campus, gestita grazie agli amici della Comunità di Sant’Egidio e dedicata al recupero sanitario, sociale e lavorativo di persone fragili ed emarginate, con patologia spesso associata all’alcol dipendenza. Solo nel 2022 sono state oltre 200 le persone accolte nella Villetta, curate e in oltre il 50% dei casi reinserite nel mondo del lavoro.

Per questa e per tante altre attività di recupero di pazienti fragili ed emarginati permettetemi di ringraziare Sua Eminenza Konrad Krajewsky e Sua Eccellenza Nunzio Galantino che ci hanno cosi tanto supportato in ogni fase di questo progetto. Per questa e per altre iniziative di docenza, ricerca e assistenza dedicate agli ultimi stiamo lavorando per istituire un apposito percorso accademico.

Voglio poi ringraziare:

La Caritas, l’organismo pastorale della CEI oggi rappresentato da don Marco Pagniello e da Giustino Trincia, che con straordinarie attività solidali si adopera per la promozione di una carità ispirata al Vangelo, che si rivolge ai poveri, agli ultimi, agli esclusi, per costruire un mondo basato su giustizia ed amore fraterno, un mondo in cui nessuno sia lasciato indietro.

Il movimento dei Focolari, che ha recentemente realizzato il nuovo centro di accoglienza ed ascolto presso la Chiesa di Santa Maria del Carmine alle Tre Cannelle vicino a Piazza Venezia in cui lavorano nostri docenti e specializzandi.

Altre attività solidali sono realizzate all’estero, come le tante iniziative dell’AUCI coordinate dal suo presidente Giovanni Manganiello o del CUAMM (collegio universitario aspiranti medici missionari), una ONG che si occupa di promozione e tutela della salute della popolazione Africana, oggi rappresentata dal suo direttore don Dante Carraro, che opera in vari paesi dell’Africa centrale per supportare bambini ed adulti colpiti da una malnutrizione feroce.

Un’Africa che, come ci ha recentemente mostrato Sua Santita’ Papa Francesco nel suo emozionante viaggio apostolico in Congo e in Sud Sudan, sta tornando indietro, in silenzio, invisibile, senza voce, troppo spesso dimenticata dai media e dall’informazione.

Com l’AUCI e col CUAMM, in particolare, la nostra Facoltà ha instaurato accordi di collaborazione che hanno gia’ garantito periodi di rotazione di nostri specializzandi in strutture ospedaliere in Africa. Una formazione che ha lasciato una traccia indelebile in chi l’ha vissuta, una traccia che forma medici nuovi nell’anima, piu’ responsabili, piu’ riconoscenti, piu’ consapevoli.

Voglio ricordare poi il progetto riguardante l’Università Cattolica dell’Africa Centrale e il suo Rettore, padre Jean Mbarga, Vescovo metropolita del Camerun, che ha proposto alla nostra Facolta’ la emozionante avventura di supportarli a realizzare la Facolta’ di Medicina e l’annesso Ospedale Universitario a Younde’ in Camerun.

Infine, tengo a ricordare le molteplici attività realizzate dalla fondazione Komen e dal suo instancabile Presidente e nostro docente Riccardo Masetti sia in Italia (maratone Komen e camper della salute con oltre 170.000 ecografie e mammografie fatte in giro per l’italia) che in Ghana con un ospedale da 60 posti letto che si occupa di salute di donne e bambine e che forma sia nostri specializzandi che medici locali, insegnandogli che si può fornire una buona sanitaà anche con risorse limitate.

In tutte queste iniziative saranno impegnati Docenti, Studenti e Specializzandi della nostra Facoltà e, per questi ultimi, i periodi di rotazione saranno obbligatori. Crediamo infatti nel simile valore formativo, sia umano che professionale, che possono garantire lo stare in una sala operatoria ibrida di ultima generazione del Gemelli o in un ambulatorio della Caritas al I binario di Termini o in una corsia di un ospedale africano specializzato in malnutrizione pediatrica o in mutilazioni genitali femminili.

In tante di queste iniziative abbiamo potuto beneficiare del supporto di amici e sostenitori. Tra tutti un grazie speciale alla Fondazione Roma, che ci ha sempre supportato e spronato a realizzare iniziative sanitarie innovative e con le tecnologie piu’ avanzate sia nella Facoltà che nel Policlinico.

Infine, un altro obiettivo della nostra Facoltà per il 2023 sara’ quello di rinsaldare sempre di più i rapporti con gli altri Atenei Romani e Laziali, sia della CRUL, la conferenza dei Rettori delle Università Laziali che saluto affettuosamente e che ci onorano oggi con la loro presenza, che della CRUIPRO, la conferenza dei Rettori delle Universita’ e delle Istituzioni Pontificie.

In particolare, come evidenziato in un recente ed emozionante incontro voluto da Sua Eminenza Angelo De Donatiis nel palazzo apostolico Lateranense tra tutti i Rettori delle Università Laziali, Roma dispone di uno straordinario ecosistema popolato di oltre 350.000 studenti e 25.000 docenti, che propone un’offerta formativa eterogenea e vastissima nell’ambito di un contesto culturale, emotivo e spirituale unico al mondo.

In definitiva, cari Amici, il nostro scopo nel prossimo anno accademico sarà quello di formare medici e professionisti sanitari di eccellenza capaci di affrontare ogni tipologia di paziente e di problematica legata alla salute.

In questo cammino le nostre ragazze e i nostri ragazzi potranno disporre dei più moderni sistemi di didattica, delle migliori tecnologie, di Docenti colti e motivati, di un Campus dotato di uno dei migliori Ospedali del mondo e di una rete di iniziative solidali che gli permetteranno di sperimentare che la salute non e’ solo ipertecnologia, ma è soprattutto presa in carico delle necessità basilari dell’uomo.

Nostro obiettivo finale sarà quello di formare professionisti non solo in grado di curare gli organi malati ma capaci di assumersi il carico integrale della Persona che hanno di fronte, consapevoli dell’importanza di conoscere il contesto in cui è cresciuta, a partire dai primi anni di vita transitando dall’infanzia fino all’adolescenza, quei periodi  così cruciali in cui ci adattiamo all’ambiente esterno.

Un adattamento che ci rende cosi’ diversi uno dall’altro, un adattamento che controlla le funzioni immuno-metaboliche del nostro corpo e tramuta le sofferenze interiori in patologie somatiche. Patologie somatiche in cui anche le piu’ moderne ed innovative terapie possono poco se la presa in carico non e’ della Persona nella sua interezza, fisica e spirituale.

Una totalità spirituale in cui, come afferma Papa Francesco, si armonizzano le dimensioni biologiche e spirituali, culturali e relazionali, progettuali e ambientali dell’essere umano nel percorso della vita.

Il tutto però realizzato con coerenza, quella estrema coerenza che deve contraddistinguere chi cresce nella nostra Comunità della Cattolica. Una coerenza di comportamento che deve combinare merito, trasparenza, onestà, inclusione, sempre nel rispetto dei nostri valori fondanti.

"

Original article on secondotempo.cattolicanews.it

Maria Irene Beiiini, Augusto Lauro, Vito D'Andrea, Ignazio R. Marino

Abstract

Management of benign liver tumors represents still an open debate, with no clear guidelines for patient selection, treatment options, and indications to surgical intervention. Usually, most of these diseases are conservatively treated, in view of their low potential malignancy and incidental diagnosis. However, when the lesions are symptomatic, with a major hepatic parenchyma involvement or life-threatening complications, liver transplant represents the only curative option. The scope of this review is to present an up-to-date state of the art of transplantable benign hepatic neoplasms.

Key words: Hepatic neoplasms, Polycystic liver disease, Transplantation

Introduction

The widespread use of imaging tests, mostly ultrasonography, has led to an increase in the detection of benign liver solid tumors. In the United States, the reported incidence is approximately 20%, exceeding the number of malignant tumors by a 2-to-1 ratio. Most of these benign lesions generally remain asymptomatic over the course of the years; however, they may cause pressure on adjacent structures, leading to abdominal pain, discomfort, and early satiety. Other described symptoms include fever, jaundice, dyspnea, high-output cardiac failure, and hemobilia, with possible compression of the vena cava and biliary structures.

A surgical approach for benign liver lesions accounts for 5% to 10% of patients, with surgery mainly involving either enucleation or resection, due to a better knowledge of liver anatomy, refinements in surgical techniques and minimally invasive surgery, and enhanced postoperative care. As a consequence, today, an increasing number of patients with benign lesions are considered for surgical treatment.

Rarely, benign lesions require orthotopic liver transplant (OLT), as in the case of giant dimension lesions or complete replacement of the hepatic parenchyma. Other indications for OLT include preneoplastic lesions with high risk of malignant transformation, those that have associations with metabolic diseases, and cases of rupture or increased risk of life-threatening complications. A list of the most common benign hepatic tumors treatable with liver transplant is presented in Table 1.

The aim of the present review is to provide the state of the art of indications and long-term results for OLT in cases of benign hepatic lesions, where, in addition to organ donor shortages, there is also the ethical dilemma in which symptom burden is weighed against the risks of long-term immuno­suppression and a complex surgical procedure.

[...]

Read full paper

Global kidney exchange offers an opportunity to expand living donor kidney transplants internationally to patients with immunologic barriers. The concept has been proven to be successful in a limited number of transplants. Mike Rees, the Nobel Laureate Alvin Roth, and I suggest that a systematic application of this innovative tool would offer opportunities to treat thousands of patients worldwide who are presently denied a transplant and often even dialysis access.

I thought to post a few of our scientific manuscripts to share this important innovative procedure that will help thousands of patients suffering from end-stage kidney disease.

September 2020

Global kidney exchange should expand wisely

Alvin E. Roth, Ignazio R. Marino, Obi Ekwenna, Ty B. Dunn, Siegfredo R. Paloyo, Miguel Tan, Ricardo Correa-Rotter, Christian S. Kuhr, Christopher L. Marsh, Jorge Ortiz, Giuliano Testa, Puneet Sindhwani, Dorry L. Segev, Jeffrey Rogers, Jeffrey D. Punch, Rachel C. Forbes, Michael A. Zimmerman, Matthew J. Ellis, Aparna Rege, Laura Basagoitia, Kimberly D. Krawiec, Michael A. Rees

Introduction

We read with great interest and appreciation the careful consideration and analysis by Ambagtsheer et al. of the most critical ethical objections to Global Kidney Exchange (GKE). Ambagtsheer et al. conclude that implementation of GKE is a means to increase access to transplantation ethically and effectively. These conclusions by their European Society of Transplantation (ESOT) committee on Ethical, Legal, and Psychological Aspects of Transplantation (ELPAT) represent a step forward toward a greater understanding and an open, honest debate about GKE. Taken together with the strong endorsement of GKE by Minerva et al. in Lancet and the positive position statement of the American Society of Transplant Surgeons (ASTS), Ambagtsheer et al. successfully dispel previously raised doubts to which we have previously responded.

[Read full article]

June 2022

Criminal, Legal, and Ethical Kidney Donation and Transplantation: A Conceptual Framework to Enable Innovation

Alvin E. Roth, Ignazio R. Marino, Kimberly D. Krawiec and Michael A. Rees

Criminal, legal, and ethical actions are three very different issues: this applies to all human activities, including living kidney donation and transplantation.
Criminal live donor kidney transplantation happens in countries with illegal black markets for organ transplantation. In these countries, surgeons perform the procedure outside regular medical centers, where donors and recipients receive poor surgical care and no postoperative care. Therefore, patients return to traditional medical institutions with no documentation and often with severe and life-threatening opportunistic infections. So far, longstanding efforts to eliminate these markets have failed, despite widespread repugnance to them, and the passage of laws criminalizing payments to donors.
Moeindarbari and Feizi discuss the kidney market in Mashad. In Iran, it is legal to pay kidney donors. Transplants and nephrectomies are conducted in well-qualified transplant centers, which are also responsible for postoperative care of donors and recipients. The vast majority of the world transplant community opposes payments to organ donors, whether legal or illegal. Iranians emphasize the difference between criminal and legal live donor kidney transplantation. Many members of the international transplant community have witnessed that the legal live donor kidney transplantation in Iran is conducted with the highest medical and surgical standards.
We strongly believe that international efforts should concentrate on increasing the availability of ethical high-quality live donor kidney transplantation options in all countries.

[Read full article]

September 2022

The First 52 Global Kidney Exchange Transplants: Overcoming Multiple Barriers to Transplantation

Rees, Michael; Roth, Alvin E.; Marino, Ignazio; Krawiak, Kimberly; Rees, Susan; Sweeeney, Krista; Dunn, Ty; Punch, Jeff; Zimmerman, Michael; Aziz, Feroz; Al Obaidli, Ali Abdul Kareem; Ashlagi, Itai; Whittaker, Vaughn; Rege, Aparna; Forbes, Rachel; Kuhr, Christian; Correa-Rotter, Ricardo; Franco, Citterio; Okwenna, Obi; Paloyo, Siegfredo; Sung, Randall; Leventhall, Joseph; Mor, Eytan; Rogers, Jeffery; Tan, Miguel; Basagoitia, Laura; Ellis, Matthew; Anwar, Siddiq; Romagnoli, Jacopo

Introduction: Many barriers currently stand in the way of achieving international kidney exchange including: financial, regulatory, logistical, cultural, immunological and legal barriers.

Methods: The Alliance for Paired Kidney Donation serves patients in 15 countries. Ten of these countries have participated in Global Kidney Exchange (GKE) transplants in which either living donors, their kidneys or recipients have traveled internationally to achieve successful living donor kidney transplantation (LDKT). In all cases, barriers were present that prevented LKDT in the donor or recipient country of origin.

Results: Between January of 2015 and February of 2022, GKE has produced 11 chains and 4 cycles that has provided LDKT for 17 international patients from 10 countries to be transplanted, as well as 35 LDKT for patients in the United States (US). GKE chains lengths have ranged from 1 to 11; cycles were length 2 or 3. Eight GKE transplants overcame immunologic barriers, 4 financial barriers, and 5 both immunologic and financial barriers. GKE has involved 19 US transplant centers across 18 states and 38% of recipients were minorities. For US recipients 11% had blood type (BT)-A, 57% BT-0, 17% BT-B, and 14% BT-AB; for international recipients 41% had BT-A, 53% BT-O and 6% BT-B. The PRA was 0-20% for 23 patients, 21-79% for 14 and > 80% for 15 (10 international). International pairs were funded by a combination of self-pay, insurance and philanthropy. Transplanting 35 US patients saved US healthcare payers $7-10M vs. dialysis. International recipients have 100% 3-year patient and graft survival and all international donors are alive and have normal creatinine and blood pressure.

Conclusion: GKE overcomes financial and immunological barriers to transplantation. Savings from avoided dialysis offers scalability. Our program ensures transparency of international pair selection, emphasis on donor safety, and assurance of longterm immunosuppression for recipients as prerequisites for sustainability.

[Read full article]

A doctor’s conduct in his clinical activity, his relationship with the patient, not only serve as a role model for new generations but are all elements that make up his way of being a doctor and they are inevitably influenced by his human nature. In this walk of life, whether a person has or doesn’t have a spiritual attitude makes a very significant difference.

23 November 2021
© Springer Nature Switzerland AG 2021 - C. Doria, J. N. Rogart (eds.), Hepato-Pancreato-Biliary Malignancies

Spiritual Thinking and Surgery

Prof. Ignazio Marino - Thomas Jefferson University, Philadelphia, PA, USA - e-mail: ignazio.marino@jefferson.edu

The ways in which patients ask for help from doctors have not changed over the centuries: weakness, fear of pain, and the anguish of losing physical strength remain the same. What has changed radically is the attitude and the role of doctors who once represented an important point of reference for society. Today they appear disoriented and confused in the face of the profound changes to the health system and its organization. Without denying all the progress achieved through the positive aspects of technology and the hyper-specialization of doctors, one should reflect on the gradual loss of the sense of mission that should be a fundamental characteristic of the medical profession.

It is essential to consider the human component which affects the way doctors use their knowledge and training – their way of thinking about life, their spirituality, their faith if they have one – in their efforts to help the patient. Also, doctors must not forget that they have the huge responsibility to train new generations since they necessarily serve as models of inspiration for students and younger practitioners.

This chapter examines the reasons and the engine that has fueled a transformation of the medical profession. From being the sole repository of the knowledge necessary for one’s health, the doctor has become the employee of a highly technological system based on business practices and is asked to follow preestablished protocols and apply procedures that allow a complicated system to function but are often far from what medicine should really be about. The author also considers the role that spirituality and faith might have in the practice of medicine and in the healing process.

Shamans, Scientists, and Hospitals

Entering a sacred place is always a moving experience. It may distress us or induce reflection, but it is never neutral. The objects, the light, the smells, the muted sounds, the songs of the faithful – everything suggests the presence of a divinity (by whatever name you may want to call it). In the church of syncretic rites in San Juan Chamula, during a trip to Chiapas, Mexico, I was fortunate to be present at a healing ceremony conducted by a shaman.

While the light from a cool spring morning entered the building’s high windows, the central nave remained in shadows, and there, just a few steps away from what must have been the altar, a tall man with long white hair and arms covered by multicolored ribbons looked intently at the face of a peasant, feeling his pulse to make out its beat and understand what was broken in the balance of nature. According to the tradition of that small community, in fact, a man’s illness is nothing more than the expression of a problem that has befallen an animal in the jungle. That peasant had a sort of twin in the forest, born at the same moment as he, and so creating an indissoluble bond between them.

The shaman, accompanied by several string instruments playing a sweet and repetitive melody, made his diagnosis. Seated on a carpet of aromatic pine needles, drunk with the perfume of incense burnt in huge black chalices among statues and images of Christian saints, and almost hypnotized by the flames of hundreds of candles set out on the floor, I watched the healing rite carried out through formulae that I could not understand: the sacrifice of a chicken, the offer of an egg to the divinity. In a totally natural way, the practice of medicine and religion were intertwined, imbuing the first with a sacred quality that we too have known in a not too-distant past. Before diagnostic tools like the CAT scan or the MRI became part of the normal practice in evaluating pathology, often the only way of making certain that a patient had cancer was to “open him/her up,” that is, to explore the abdomen surgically. Until the 1970s, the figure of the surgeon – always a male – truly resembled that of a priest: he presented himself in the operating room with a long gown down to his calves, hardly ever spoke, and the rare phrases that he pronounced were understandable only by the few faithful assistants who helped him during his surgeries.

Most of the time when he opened a patient’s abdomen to ascertain the presence of a tumor, the only thing he did was to rinse the abdominal cavity with a physiological solution before closing it. In the language of the specialists this procedure was called, without an attempt at irony, “a breath of air.” Miraculously, the patients sometimes felt better after their tumors had taken a breath of air, but quite honestly – no sarcasm intended – the scientific worth of the procedure was not much different than the sacrifice of a chicken.

The important thing was that the patient believed blindly in what the surgeon had decided to do. He did not dare doubt the method and, on the contrary, accepted everything silently, feeling a great sense of gratitude.

Even today, some doctors who specialize in therapies that require highly sophisticated technologies are in a sense surrounded by an aura of sacredness, defined by the exalted term “luminaries.” Often proud and detached, these scientists command a technology that is impenetrable to most people and use terms so complex that they sound like magic formulae to the uninitiated. Even their gestures within the sterile space of an operating room are not so different from those performed by a shaman, and certainly they are just as incomprehensible from the patient’s point of view. When a person goes through radiation therapy, for example, he or she is brought inside a room resembling a white bunker sealed off by a heavy door that blocks the radiation. The contact with the rest of the world occurs only through a thick glass: on the other side, expert hands guide invisible rays. There is no sound, there is nothing to see or hear; a sense of mystery prevails over any other sensation. Nevertheless, there the patient is hit, without having an immediate physical awareness, by extremely potent radiation able to precisely target the point of the body where the tumor has developed, even if it is only a few centimeters in size.

Let us think about another specialty, interventional cardiology. Until a few decades ago, someone with a heart problem either died without any knowledge of the illness or went through a complicated surgical procedure with his/her chest laid open for the replacement of part of the obstructed artery: a procedure with many risks and a long, arduous period of postoperative recovery. Today, for the same sort of problem, the cardiologist merely introduces a thin catheter into the patient’s groin and pushes it along the aorta to the coronary arteries, where he/she inserts a plastic stent that holds open the part of the artery that is narrowing because of cholesterol. In this way, the normal flow of blood to the heart is re-established, and everything is done under fluoroscopic guidance, that is, with an X-ray machine that allows us to follow on a video monitor each small movement of the catheter inside the body. The operation takes at most a couple of hours and is done with a local anesthetic. Patients, along with the doctor, can watch their beating heart on the screen and see the catheter entering the blocked artery, moving rapidly like a cunning snake. In reality, for those patients, the procedure is magical: even if it happens before their eyes, they cannot fully understand what is happening inside their body, so the gestures of the cardiologist, as a miracle worker, are not so unlike those of the shaman in the church of syncretic rites.

The association between spirituality, religion, and medicine in the world and in Western culture can be grasped simply by looking at how patients turn to the doctor with great hope to find relief of their own bodily suffering, not unlike how we ask aid and comfort from a divinity when faced with situations of particular difficulty. The ways in which a sick person asks for help from a doctor have not changed with the passing of years, or even centuries – weakness in the face of sickness has always been the same, accompanied by fear of pain, and the anguish of losing one’s physical strength.

What has changed radically is the attitude and the role of practitioners of medicine, not the “luminaries,” but the thousands of doctors who once upon a time represented an important point of reference for society. Today they seem puzzled, disoriented, and confused in the face of the profound changes to the health system and its organization in the last fifty years.

This chapter examines in depth the reasons for that change and the engine that has fueled this transformation of the medical profession. From being the sole repository of the knowledge necessary for one’s health, the doctor has become the employee of a health care system based on business practices and is asked to follow preestablished protocols and apply procedures that allow a complicated system to function but are often far from what medicine should really be about.

What do you do? What is your profession? Americans often ask. In most cases, a doctor’s answer is very precise: I am an anesthesiologist, a nephrologist, a gynecologist, etc. It is rare to get a generic answer like: I am a doctor. This difference may seem like a linguistic subtlety but, in reality, it implies a clear definition of the role of every doctor within a vast and complex health system where everyone has become a specialist: of a single organ, of a disease, of a function of the human body, or master of a single technique. But the vast technology associated with the organizational needs of the hospital, with its economy, with the need to make plans far in advance to assure the correct functioning of the system – all these elements contribute to the formation of hyper-specialized doctors. The tendency to focus on the specific clouds a vision of the whole to the point that it is not rare these days to run into professionals, expert in extremely complex surgical procedures, like a liver transplantation or a liver resection, who have difficulty with diagnosing something as simple as an inguinal hernia. This process is by now prevalent in American society and culture and is expanding rapidly into a more conservative Europe. Doctors study diseases, evaluate tests, prescribe treatments, operate, and in many cases contribute to the patient’s cure, yet still do not manage to get a complete picture of the person’s problems. Not to mention the now widespread inability to recognize a patient’s global malaise which always has a physical and a psychological component, both present in the moment when one asks a doctor for help. This approach is exactly the opposite of the traditional medicine used widely in all the Asian countries. In Tibetan, Chinese or Ayurvedic medicine, illnesses are considered problems of the whole person, a result of the loss of balance with nature, the lack of harmony with oneself and with the universe, and the loss of symmetry between mind and body.

The Taoist text Lieh Tzu describes Pien Ch’iao, Chinese physician and surgeon (450 BC) replacing diseased hearts with healthy ones. The two patients as Gong Hu 公扈and Qi Ying 齊嬰 had opposite imbalances of qi 氣“breath; lifeforce” and zhi 志“will; intention”. Apparently, they recovered but besides the myth the story tells how surgery and medicine have always been connected with a holistic approach, focusing on a person’s wellness, far beyond just his physical illness.

Without denying all the progress achieved through the positive aspects of technology and the hyper-specialization of doctors, one should reflect on the gradual loss of the sense of mission that should be a fundamental characteristic of the medical profession: to rediscover the passion for a job that is at the same time the choice of a life which doctors can give themselves to, whole heartedly. According to this view, one must also consider the human component which affects the way doctors use their knowledge and training – their way of thinking about life, their spirituality, their faith if they have one – in their efforts to help the patient. And the relationship a doctor establishes with the patient is inevitably bound to reflect all these elements.

Furthermore, doctors must not forget that they have a great responsibility in training new generations, since they necessarily serve as models of inspiration for them. For this reason too, it is not right to sit back and let the example of confused or greedy and disillusioned doctors prevail.

The method of training doctors cannot be based only on a transfer of information. To train someone means above all to assign worth to the students standing before you, to their hopes and goals. This implies making an effort to know them – investing time and energy in motivating and following them – giving them responsibility without abandoning them and being engaged in developing their spirit of observation and selfconfidence. It means recognizing that this role is a priority, a responsibility. In the field of medicine, it means demonstrating with words and actions what it means to be a doctor. The true challenge of this profession is not in learning a theory or executing a technique, but in knowing how to harmonize technique and conduct, cultivating and developing a particular sensibility towards other people.

When I was in medical school, I spent most of my time on books, studying, memorizing the necessary information to pass the exams. But for me and my colleagues in the class, the teachers who inspired us most were not the most illustrious professors – as famous as they were absent from the daily activities of the ward. Rather, we preferred to follow the least-known doctors who spent their days in the hospital, some in the laboratory, some with patients, never complaining and sincerely attached to their profession. It was above all those invisible doctors with no recognition for their dedication who taught us a great deal, allowing us to shadow and observe them, and who were always willing to spend a moment with us students to explain why certain things happened and the reasoning behind clinical decisions.

I remember an assistant in microbiology who “read the plates” every morning, that is, examining the blood or urine cultures to identify the particular bacteria present, and their response to antibiotics. It was not a proper university course and there were no exams to take at the end of the year, but there were many of us who participated in that reading. Many things can be understood about the prescription of therapies thanks to the observation of the behavior of bacteria; but above all, we were drawn to that doctor’s enthusiasm and to his capacity to transmit important information which we would never have found in the textbooks.

Some rethinking in the training methods and in the concept of professionalism is clearly indispensable to give hope to the younger generation, and maybe even to give a new start to our devastated medical practice.

A doctor’s conduct in their clinical activity, their relationship with the patient, not only serve as a role model for new generations but are all elements that make up their way of being a doctor and they are inevitably influenced by their human nature. In this walk of life, whether a person has or does not have a spiritual attitude makes a very significant difference.

Not all medical students are attracted to surgery. When someone enters an operating room for the first time to attend an operation and sees the surgeon cut the skin of an unconscious patient with his scalpel, reactions differ: some people faint, some feel sick, some shudder horrified, others are fascinated and cannot turn their eyes away, and when they leave the operating room, they decide to become surgeons.

When the day comes that you find the scalpel in your own hands, everything changes. The gestures you have seen others make so many times become unexpectedly more difficult, you feel the instrument cutting into the patient’s skin, you must be precise, calculating exactly the weight of your hands in order not to cut too deeply and at the same time you must tie the blood vessels. Stress and tension are at their ultimate height, you do not feel up to the situation’s demands and want only to run away.

Yet with time, when you become an integral part of a surgical team, you cannot do without it. A sort of addiction to the operating room is created through the unique euphoria tied to the surgical act – to the tension, the fear of making a mistake and at the same time the realization that you are doing something indispensable to the health of the patient.

I may be biased because this is my specialty, for I do not believe I am wrong in saying that all surgeons are convinced that theirs is the most wonderful job in the world.

It is an occupation that is part craftsman and part intellectual, characterized by a direct relationship between cause and effect, between what you are doing and the result of your actions [1]. At times this is marvelous, but it can also cause despair according to the outcome of the patient. After a complex surgery, those who intensely experience their profession cannot but mentally repeat every step, every movement of their hands, every stitch, and immediately internalize where complications may arise. This is why one should never make decisions without listening to the opinion of the surgeon who has performed the operation, even though in most cases today postoperative problems are no longer tied to surgical technique but to infection or metabolic disturbances. The surgeon, more than anyone, will know how to anticipate the problem, make a diagnosis, and find the possible solution. In my case, whenever problems arise, I go to the patient’s bed at night when the hospital activities slow down, and stand there alone, searching my thoughts for the intuition that may lead me to the solution of the patient’s problem. This ritual has often enabled me to find a solution. At other times I have agonized, unable to find the right answer. In any case, this bedside visit has been a way for me to renew my bond with the ill person near me and my truest motive for having decided that one day I would become a doctor.

Combining faith in medicine, conceived of as mission, with a spiritual vision of life has both advantages and disadvantages.

“You are more useful to your patients if you spend your time in the intensive care unit rather than praying for them at mass” a friend, a believer in his own way, always told me when I arrived later than usual at the hospital on Sunday morning. For me, however, that small weekly ritual was part of my way of being a doctor. And still today, I am convinced that prayer can have a role in treating a patient. I also believe that it is not possible to speak of a difference between believers and nonbelievers when it comes to equal commitment, preparation, and sincere attachment to patients’ fate, just as faith alone does not provide additional reasons for assisting the sick. The difference is not in the operating room or in a doctor’s excellence but in the interpretation of his or her work and general approach to life. While being a believer does not influence the capacity or commitment that everyone has to their profession, it has a lot of relevance when facing a sick person every day.

Still, the ideals that inspire the believer when faced with diseases are not so different from those of a nonbeliever like Che Guevara, who in the diary he kept as a guerilla fighter wrote: “[. . .] the doctor performs an extraordinary function, not only because he strives to save lives [. . .] but because his task is also to sustain the sick person emotionally and make him feel that there is someone beside him who is striving to alleviate his pain, and that this person will stay beside the wounded or sick so long as he hasn’t been healed or the danger has not passed [2].”

There are many other examples. In Buddhism, the Dalai Lama teaches, quite poetically, that our behavior during life should be marked by love towards everything around us because every living creature – in the cycles of reincarnation – has at some time been our mother and, therefore, for every living being, we must feel the same love that is felt for a mother [3].

Solidarity, love, and compassion are ideas that are repeated in the gospel of the Christians, in the words of Che Guevara, and in the affirmations of the Dalai Lama: different paths, different ethics, but similar conclusions. I am convinced that it may be easier for the believer to adhere to the mission that ought to mark the work of every doctor, because it mirrors an act of faith in the Bible. For a nonbeliever it is a matter of adhering to a scale of values that has become part of his identity. For this reason, once these values are set, they cannot be betrayed without being false to oneself. Although equally committed and dedicated to one’s work and the health of one’s patient, the believer’s path is to some extent easier to follow.

The one real difference between the believer and the nonbeliever is the concept of compensation in the afterlife, something altogether absent from the nonbeliever’s perspective. For the believer, the final judgment on one’s actions, as doctor and human, will be from God, not from other peers. If s/he has acted in the interest of fellow humans and to alleviate the suffering of others, s/he will be rewarded in the afterlife. This is true not only for Christians but for all the religions that link one’s fate in the afterlife to one’s actions during life [4].

In this case, too, one can conclude that though equally committed, the believer is in some way helped while the nonbeliever is supported only by solid personal convictions. Belief in an afterlife represents an important resource for a doctor. While suffering is difficult to accept, death at the end is not only part of the natural biological cycle but represents a moment of passage, or rather the beginning of a new existence, whatever one’s religion. The moment of separation brings great grief to the family, but for those who believe in a monotheistic religion it represents at the same time the hope of rejoining the Father – or for a Buddhist the conclusion of a phase of existence in the cycle of divinity that is in each of us.

In the vision of the nonbeliever, on the other hand, with the end of life everything is over, the cycle is completed and the few remains left on earth will be visible only in the DNA passed to one’s children, or in cases of particularly illustrious men in the ideas or works left behind. For this reason, when medicine fails, the effect of death is even harsher; nothingness and the sensation of defeat cannot be alleviated and are, therefore, unacceptable. Still, there is an element of relief for everyone, even for nonbelievers. When the life of a sick person, forced to enter a hospital, comes to an end, the grief linked to the idea of loss is mixed with a sense of relief from suffering. The family and the doctor themselves are able to begin a new phase, that of mourning and, then, of remembering the positive images of the journey traveled with the departed person.

Finally, an allusion should be made to the role of prayer in relation to medicine [5]. Diverse and in-depth scientific studies have documented significant differences in the journey to healing between patients who trusted in prayer as well as medical care, and patients who did not. The journal Lancet, in June 2005, presented an interesting study, conducted with rigorous scientific methods on the impact of “noetic therapies,” that is therapies that do not resort to drugs, surgery, or other tangible interventions. One of these “therapies” is prayer and, in relation to the impact it can have on the health of a sick person, the study cites an analysis of the data from 393 patients in a heart failure unit [6]. All of them had signed a consent form when they entered the hospital in which it was explained that some of them would be assigned to a group of believers who would pray for their recovery. The patients would not know if in addition to the care of the doctors they were also receiving the prayers, yet in the group which had received them there was a 36% reduction in complications, a result which was certainly surprising but whose mechanisms are unknown to science.

Another scientific analysis, published in 2000, reported that 57% of the studies conducted on this subject demonstrate that prayer plays a role in healing. It does not matter what the religion is: this phenome is observed among Buddhists, Muslims, Christians, Jews, and followers of Confucius. It is a fact that does not have a clear explanation, and the interpretations vary depending on whether the analysis is done by skeptics or believers. In the first case, it is thought that recourse to prayer, to music, or a faith healer can lead to a physiological reaction like vasodilatation which can improve the patient’s health [7]. For someone who believes in God, on the other hand, the benefit is attributed to a plea offered to God and His response in a moment of need, a sign of His immense goodness. As far as I am concerned, when I realize that everything possible has been done to heal a patient, but nothing is working, I always advise family members to pray and do the same myself.

During the three years that I worked in Palermo, Sicily, a young woman in a coma from fulminant hepatitis was admitted to our transplant center. In most of such cases, the only thing that can save the patient’s life is a liver transplant. Requests at the national and European levels were made, so that the first liver available for transplantation would be given to this patient. Alas, the only liver available was that of an 80-year-old man who died falling from a tree. The advanced age of the donor and the trauma he had undergone meant the organ was not ideal for a woman under 30, but the few hours that she had to live did not allow any hesitation. Our team flew to Florence to remove the organ and after a few hours we did the transplant. Unfortunately, the woman developed a severe infection, and the transplanted liver could not function. The clinical picture was critical; despite all our efforts, the woman’s condition continued to worsen. She was in a coma, kept alive by a respirator, dialysis, and a complex machine called an “artificial liver,” in addition to the drugs used to combat the cardiac insufficiency. The grave infection, due to bacteria resistant to most antibiotics, and the lack of function of her transplanted liver, were extinguishing her life. If any of these treatments had been stopped, she would have died in a matter of minutes. There were no scientific guidelines remaining to justify continuing. I knew this, and I saw it in the eyes of Cataldo Doria, the surgeon I have worked with for 15 years and whom I trust the most. The only thing to do, at least for me, was to ask for help with prayer. I no longer pray as I did as a child, but I have established a daily dialogue with God, a higher being who accompanies me during my days and to whom I can turn at any time, to listen, and to also find strength and comfort when I do not find these things inside me. It was in exactly this sort of meditative moment that everything became clear: we had to try a new transplant. Against every expectation, this turned out to be the right choice. After 5 weeks of intensive care, the patient woke up during Christmas week and could finally embrace her five-year-old son. At the beginning of February, she returned home. It may have been luck or sheer coincidence, but for me there was a sign which gave me the determination to go ahead, listening more to my conscience than to what my rational mind was telling me.

Now, several years later, I still get regular news from that woman who has resumed a normal life, forgetting as time passes how she had almost died. She was certainly helped by the perseverance and tenacity of the doctors, but I do not exclude the possibility that her guardian angel also played a part.

Conclusion

In surgery, when performing the complex procedures described in this book, the surgeon should also bring his/her faith – whatever that might be. It always helped me. 

References

1. Gawande A. Complications: A Surgeon’s Notes on an Imperfect Science, Picador USA; 2003
2. Che Guevara. Radical Writings on Guerrilla Warfare, Politics and Revolution, Filiquarian Publishing; 2006
3. Dalai Lama, An Open Heart, Little Brown and Company, Boston, New York, London; 2001.
4. Pope John Paul II, Evangelium Vitae: The Gospel of Life, Pauline Books & Media, Vatican City; 1995.
5. Roberts L, Ahmed I, Hall S, Sargent C. Intercessory prayer for the alleviation of ill health. Cochrane Database Syst Rev. 2000;2:CD 000368.
6. Byrd RC. Positive therapeutic effects of intercessory prayer in a coronary care unit population. South Med J. 1988;81:826–829.
7. Krucoff MW, Crater SW, Gallup D, Blankeship JC, Cuffe M, Guarneri M, Krieger RA, Kshettry VR, Morris K, Oz M, Pichard A, Sketch MH Jr, Koenig HG, Mark D, Lee KL. Music, imagery, touch, and prayer as adjuncts to interventional cardiac care: the Monitoring and Actualisation of Noetic Trainings (MANTRA) II randomised study. Lancet. 2005;366:211–217

30 years ago the first baboon-to-human transplant, with my mentor T. E. Starzl. I would like to recall this historic article in the journal "The Lancet" of 9 January 1993

Our ability to control both the cellular and humoral components of xenograft rejection in laboratory experiments, together with an organ shortage that has placed limits on clinical transplantation services, prompted us to undertake a liver transplantation from a baboon to a 35-year-old man with B virus-associated chronic active hepatitis and human immunodeficiency virus infection.
Liver replacement was performed according to conventional surgical techniques. Immunosuppression was with the FK 506-prednisone-prostaglandin regimen used routinely for hepatic allotransplantation, to which a daily non-myelotoxic dose of cyclophosphamide was added. During 70 days of survival, there was little evidence of hepatic rejection by biochemical monitoring or histopathological examination. Products of hepatic synthesis, including clotting factors, became those of the baboon liver with no obvious adverse effects.
Death followed a cerebral and subarachnoid haemorrhage that was caused by an angioinvasive aspergillus infection. However, the underlying cause of death was widespread biliary sludge that formed in the biliary tree despite a seemingly satisfactory choledochojejunostomy. During life and in necropsy samples, there was evidence of the chimerism that we believe is integral to the acceptance of both xenografts and allografts. Our experience has shown the feasibility of controlling the rejection of the baboon liver xenograft in a human recipient. The biliary stasis that was the beginning of lethal infectious complications may be correctable by modifications of surgical technique. In further trials, the error of over-immunosuppression should be avoidable.

Introduction

Previous attempts to transplant seven baboon kidneys and two hearts resulted in graft loss or patient death between 0 and 60 days after transplantation. A common difficulty was uncontrolled cellular rejection, together with antibody-mediated occlusive endotheliolitis of graft microvasculature and parenchymal necrosis. Recent laboratory investigations have shown that the presumably humoral component of xenograft rejection could be diminished by a short course of antimetabolite therapy, such as cyclophosphamide, which targeted the B-cell proliferative response. By overcoming this antibody barrier, the value of maintenance therapy with T-celldirected immunosuppressants was unmasked.
We now describe a baboon-to-human liver xenotransplantation in which FK 506 and cyclophosphamide were given as immunosuppressants, together with prednisone and prostaglandin, both of which help to mitigate preformed antigraft antibody syndromes and cellular rejection.

[...]

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Cities under Climate Threat. 

Understanding the Impact of Climate Change: Policies, Urban Design, Economics, Environment and Population Health

Panel I: Thursday, October 20, 2022, 12PM-2:00PM

Panel II: Friday, October 21, 2022, 12PM – 2:00PM

Location: ZOOM

The institute of Smart and Healthy Cities at Thomas Jefferson and the Università Iuav di Venezia, Italy and AARP PA present the joint Symposium Smart and Healthy Cities 2022, “Cities under Climate Threat”. The Symposium will focus on the interrelationship between climate change and urbanization, technological innovation, demographic trends, and population health. It will look at how cities can better prepare for future global crises. The Symposium will be attended by academics, scientists, entrepreneurs, and leaders in architecture, engineering, population health, and city government. 

The American Association of Retired People AARP PA supports this Symposium. 

Panel I: Thursday, October 20, 2022, 12PM-2:00PM

Virtual Flyer - Click Here

Understand the impact of climate change on cities: Policies, Economics, Big Data, Environment, and Population.

Opening remarks: Barbara Klinkhammer, Dean College of Architecture and the Build Environment, Thomas Jefferson University

Speaker 1: Dr. Stephan Al, Professor Virginia Tech and Columbia University: "Adapting Cities to Sea Level Rise: Multi-functional Flood Management Solutions for Costal Cities"

Speaker 2: Yocasta Lora, AARP American Association of Retired People: “The Effects of Climate Change on Senior Citizens.”

Speaker 3: Dr. Kathleen Miller, Research Applications Program, National Center for Atmospheric Research in Boulder:” The economic and social impacts of climate change”

Speaker 4: Vittore Negretto, PhD, Università Iuav di Venezia, Dipartimento di Culture del Progetto: “Resilience Systems in Urban Design and Planning”

Speaker 5: Dario Trabucco, PhD, Associate Professor in Building Technology, IUAV: “Tall Buildings: Is Site Specificity and Adaptation to Local Climate Enough?”

Moderator: 

Dr. Francesco Musco, Professor of Urban Planning - Deputy Director for Research at Università Iuav di Venezia

Dr. Edgar Stach, Director, Institute of Smart and Healthy Cities, Thomas Jefferson University

Panel II: October 21, 2022, 12PM – 2:00PM

Virtual Flyer - Click Here

Drivers for change - mediate the effects of climate change: Population Health, Technological Innovation, Making Buildings, Entrepreneurs

Opening remarks: 

Ignazio R. Marino, MD. Professor of Surgery, Sidney Kimmel Medical College, TJU, Executive Vice President for International Innovative Strategic Ventures, Thomas Jefferson University and Jefferson Health

Executive Director, Jefferson Italy Center, Former Mayor of Rome 

Speaker 1: Francesco Musco, PhD Professor of Urban Planning, IUAV: “Planning Climate Resilient Cities, a European Viewpoint”

Speaker 2: Dr. Steffen Lehmann, Professor of Architecture and Urbanism at the University of Nevada: ”The next-generation City”

Speaker 3: Luke Leung, Principal SOM: "Post Carbon and Pandemic World”

Speaker 4: Dr. Leah Schinasi, Assistant Professor of Environmental and Occupational Health at Drexel University’s Dornsife School of Public Health: "The Nexus of Climate Change and Environmental Health Justice"

Speaker 5: Mattia Bertin, Università Iuav di Venezia, Dipartimento di Culture del Progetto: "When the Unexpected Becomes Frequent"

Moderator: 

Katie DiSantis, PhD, MPH, Associate Professor, College of Population Health, Thomas Jefferson University

Carlo Federico dall'Omo, Università Iuav di Venezia, Dipartimento di Culture del Progetto: “Mediterranean Cities at the Age of Climate Change. The Role of Climate Adaptation Planning.”

Sponsor / co-host

Yocasta Lora, American Association of Retired People AARP Pennsylvania

FREE TICKETS

Today I went back to Via dei Fori Imperiali to experience an exceptional experiment patented by Invisible Cities: a bus that uses a very sophisticated technology (not yet on the market) to travel around the iconic sites of ancient Rome, bringing them to life and reconstructing them before our eyes, on the windows/screens, showing us the city as it once was and even letting us experience its scents. 

An incredible experience that I hope will soon be available to all Romans and tourists and visitors who come to the most beautiful city in the world every day from every corner of the globe.

Congratulations to the Invisible Cities team, and sincere thanks to the far-sightedness of the Sovrintendenza Capitolina ai Beni Culturali, which has encouraged the development of this brilliant example of private enterprise.

Prof. Ignazio Marino

Combining questions about a person’s health with data from smartwatch sensors, a new app developed using research at Princeton University can predict within minutes whether someone is infected with COVID-19.

This new breed of diagnostic tool stems from research led by Niraj Jha, a professor of electrical and computer engineering at Princeton University. His team is developing artificial intelligence (AI) technology for COVID-19 detection, as well as diagnosis and monitoring of chronic conditions including depression, bipolar disorder, schizophrenia, diabetes and sickle cell disease.

NeuTigers, a company founded to commercialize Jha’s work, applied to the U.S. FDA, under the agency’s provision for “software as a medical device,” for clearance for its CovidDeep product. Shayan Hassantabar, a Ph.D. student in Jha’s group, is the lead author of a paper in IEEE Transactions on Consumer Electronics describing the development and testing of CovidDeep. The software integrates smartwatch sensor readings of heart rate, skin temperature and galvanic skin response with blood pressure and oxygen saturation levels, as well as a questionnaire on COVID symptoms.

Jha’s research group at Princeton has long focused on adapting a type of AI called deep learning, which is typically energy-intensive, to function on low-power electronic devices such as phones and watches instead of centralized cloud computing centers. This approach, known as edge AI, has the added benefit of helping to preserve users’ privacy and increase security. A key innovation is pared-down neural networks  (the “neu” of NeuTigers) that mimic human brain development.

“It’s a very generalizable framework,” said Jha. “Smart health care is just one application. We are also applying it to cybersecurity and other internet-of-things applications.” Similar to preventive medical interventions, machine learning models could spot aberrant patterns and help fix software vulnerabilities before a cyberattack ever occurs, he said.

In recent years, Jha’s team has explored edge AI for health care applications such as noninvasive detection of diabetes and mental health disorders from smartwatch and smartphone sensor data.

In fall 2017, former pharmaceutical executive Adel Laoui  audited Jha’s class on “Machine Learning for Predictive Data Analytics” and was intrigued by the technology. Laoui, who had experience developing and deploying new technologies for disease management, approached Jha after the course ended. After further discussions with Jha’s Ph.D. students, they launched NeuTigers in June 2018.

“We saw a lot of intersections in our interests,” said Jha. “Smart health care with the help of edge AI was taking off, so it was an opportune moment for a startup in this area. Adel had a lot of connections with angel investors, and so it ramped up very quickly.”

Several patented technologies from Jha’s lab have been licensed to NeuTigers, including methods for diagnosis of diabetes and mental health conditions, and for security vulnerability detection in internet-of-things systems.

When the COVID-19 pandemic was declared in March 2020, Jha wondered whether his team’s deep learning approaches could be used to diagnose the virus — especially in people with the potential to spread COVID-19 with no apparent symptoms, a major problem for controlling the disease.

“The hypothesis was that the disease leaves a unique signature on the physiological signals emanating from our body,” said Jha. “This hypothesis seems to have been true, at least for the few diseases we had looked at, so my idea was to see if we could diagnose COVID-19 this way.”

Jha and Laoui got in touch with Ignazio Marino, a professor of surgery at Thomas Jefferson University in Philadelphia and the executive director of the Jefferson Italy Center.

In May 2020, at the tail end of northern Italy’s initial cluster of COVID-19 in Europe, NeuTigers CTO Vishu Ghanakota traveled to Pavia, Italy, to deliver medical-grade smartwatches, software applications and training materials to Marino’s colleagues at San Matteo Hospital. The clinical researchers collected data from 87 individuals, 30 of whom had tested negative for COVID by PCR; another 30 tested positive and were symptomatic, and 27 tested positive and were asymptomatic.

The data included 60 minutes of smartwatch sensor readings on heart rate, skin temperature and galvanic skin response (a measure of sweat gland activity), divided into 15-second intervals. Separately, the clinicians measured participants’ blood pressure and oxygen saturation levels, and answered a questionnaire indicating whether each participant had shortness of breath, cough, fever or any of eight other symptoms.

The Princeton researchers, led by Ph.D. student Hassantabar, used a subset of this data to train neural network models to predict a patient’s COVID-19 status, and another subset to test the resulting models. The team found that their models were 98.1% accurate at detecting COVID-19.

One method Hassantabar used to boost the models’ accuracy was the addition of synthetic data obtained based on the probability distribution of the real data — a broadly applicable technique that Jha’s group first used for other applications. Another method he used was based on the grow-and-prune neural network synthesis paradigm developed in Jha’s group.

The researchers have since validated the method with a larger field trial in France, and health organizations in the United States and Algeria have piloted CovidDeep among their staff. To enable more widespread adoption of CovidDeep, NeuTigers is working to make it compatible with some types of Samsung, Fitbit and Apple smartwatches, which will also integrate blood pressure and pulse oximeter measurements.

Manually entering clinical data into a smartphone app could be another useful screening approach in many settings, especially since smartphones are far more common worldwide than smartwatches, said Marino, who oversaw clinical data collection for the study. On the other hand, said Laoui, using a smartwatch alone may be preferable for many users, and the researchers are also working to adapt the neural network models to function with a smartwatch’s more limited computing power.

“I think this could be far superior [to rapid antigen tests], because the accuracy of a rapid test that you do by yourself at home is limited,” said Marino. “Pushing the swab up in the nose is obviously a discomfort, and I don’t know if people are going to do that as accurately as they need to. But if you have a device on your wrist that is not invasive and is totally independent from a physical human maneuver, I think that is much better.”

Marino also expressed hope that the technology could improve early diagnosis of widespread conditions such as diabetes. “There are millions of people in the United States that have early diabetes that probably is very treatable, and they don’t know,” he said. Having new information that leads to early diagnosis could lead to “a very successful treatment,” he added.

Laoui is interested in exploring the methods’ use for diagnosis and monitoring of other diseases such as cardiovascular disorders and sepsis infections, both increasing problems for the world’s aging population.

“We’re going to have a library of disease models embedded in the watch, and from time to time we’re going to run the sensors’ information through these disease models, which will be personalized,” said Laoui. “If there is something wrong or something unusual, we are going to inform you in a meaningful way. I believe this new era of smart health care will be powered by edge AI applications and will redefine healthcare delivery and consumer well-being.”

Original article on princeton.edu

One day in 1979, as I was leaving the hospital after my shift in the operating room, I saw two young men on a motorcycle snatch the purse of an elderly woman who fell violently against the edge of the sidewalk and died of head trauma. I learned that the snatching was related to drug use and since then I began to question myself, as a doctor and as a citizen, about that lost life and the dramas that accompany the use and distribution of drugs. Years afterwards, when in addition to my work as a surgeon, I had the responsibility of chairing the Health Commission of the Senate of the Italian Republic, I tried in every way to introduce rationality instead of ideologies and scientific data instead of clichés in the debate.
As a doctor has a personal responsibility in improving the life of his patient, so should a parliamentarian contribute to making citizens’ lives better with useful laws.

In 2014, when I was Mayor of Rome, I reaffirmed my belief that it was necessary to implement what the people indicated in the 1993 referendum, when 37 million Italians went to vote and the majority of them declared themselves in favor of the liberalization of cannabis for therapeutic or personal use. I had no doubt that I would have fueled controversy. I was even accused of negligence, because I dedicated a reflection to topics considered far from Rome and the Romans.

Those who criticized me had probably never studied the data on cannabis consumption, for example in Roman schools, and how much the illegality of marijuana favors criminal activities.
We live in a time when a reform of drug laws is necessary on a national and international level and the debate on legalization must be evaluated on the basis of scientific data, rather than slogans.

Prohibitionist policies have not been able to solve the problem of the high diffusion of drugs, let alone the problem of organized crime, which manages the national and international drug trade.

The legalization of cannabis is an urgent and necessary initiative to take an important market away from criminal associations.
Today, cannabis regulations are evolving throughout the world and there are many virtuous examples of a total legalization process: such as Canada or Colorado, which have initiated a process of legalization of marijuana for recreational purposes, followed by more than 20 U.S. states and some other countries such as Uruguay.

The figures in the World Drug Report need no comment: approximately 275 million people worldwide (or 5.6% of the world's population aged 15-64) have used drugs at least once.
However, the amount of cannabis seized worldwide decreased by 22% from previous years, to a total of 4,682 tonnes, the lowest level recorded since 2000, and it is interesting that the decline was particularly marked in North America, where cannabis use has been legalized for recreational purposes in several states.

One of my biggest concerns as a physician is the practice by drug cartels in recent years of genetically modifying plants for the criminal purpose of creating a highly addictive product, almost on par with so-called "hard drugs".

Cannabis includes different species, which vary in the percentage of THC and other cannabinoids such as CBD, CBN, CBC, THCV depending on which one has a different physiological and psychotropic effect. The genetic modifications of cannabis enhance its dangerousness.
According to recent studies, the THC content of marijuana available in the main Italian markets has almost doubled in the last 15 years, reaching 10%, while cannabidiol, the non-psychoactive principle, is almost completely absent.

In other words, organized crime creates increasingly dangerous products, and it becomes impossible to monitor the risk to which unsuspecting consumers are subjected.
The mafia covers up knowledge in order to profit from health. Making cannabis legal for recreational consumption would make people more aware of the health risks as well as avoid financing drug cartels.

Another reason for me to reiterate as a physician my position in favor of legal cannabis is the possibility of promoting the use of a vaporizer rather than a joint. With a capsule inserted in a vaporizer you know exactly which chemical characteristics and dosage you consume, thanks to the control of health authorities, and thus prevent the risk of cancer linked to cigarette combustion.
The participation of science in the health debate should always be encouraged and sought after. Instead, institutions in Italy tend to ignore science and the voice of citizens, pretending to forget that 37 million Italians expressed themselves in favor of cannabis for recreational use in the referendum a third of a century ago.

Prof. Ignazio Marino

Un giorno del 1979, mentre uscivo dall’Ospedale dopo il mio lavoro in sala operatoria, vidi due giovani in moto strappare la borsa a una donna anziana che cadde urtando violentemente lo spigolo del marciapiede e morì per il trauma cranico. Appresi che lo scippo era legato al consumo di droga e da allora iniziai a interrogarmi, come medico e come cittadino, su quella vita perduta e sui drammi che si accompagnano al consumo e allo spaccio della droga. Così negli anni in cui oltre al mio mestiere di chirurgo ebbi la responsabilità di presiedere la Commissione Sanità del Senato della Repubblica Italiana cercai in ogni modo di introdurre razionalità al posto delle ideologie e dati scientifici al posto dei luoghi comuni.
Come un medico ha una responsabilità personale nel migliorare la vita del proprio paziente, così un parlamentare può contribuire al miglioramento delle condizioni di vita di molti con una legge utile ai cittadini.

Nel 2014 riaffermai la mia convinzione che fosse necessario attuare quanto indicato dal popolo con il referendum del 1993, quando 37 milioni di Italiani si recarono a votare e la maggioranza di essi si dichiarò favorevole alla liberalizzazione della cannabis per uso terapeutico o personale. Non avevo dubbi che avrei alimentato polemiche. Fui addirittura accusato di negligenza nel mio lavoro da Sindaco, perché dedicavo una riflessione ad argomenti giudicati lontani da Roma e dai Romani.

Chi mi criticava probabilmente non aveva mai studiato i dati sul consumo di cannabis, ad esempio nelle scuole di Roma, e quanto l’illegalità della marijuana favorisca le attività criminali.
Viviamo in un epoca in cui una riforma delle leggi sulle droghe è necessaria a livello nazionale e internazionale e il dibattito sulla legalizzazione deve essere valutato sulla base di dati scientifici, piuttosto che di slogan.

Le politiche proibizioniste non sono state in grado di risolvere il problema dell’alta diffusione della droga, né tantomeno quello della criminalità organizzata, che ne gestisce il traffico nazionale e internazionale.

La legalizzazione della cannabis è una urgente e necessaria iniziativa per sottrarre un mercato importante alle associazioni criminali.
Oggi le norme sulla cannabis sono in evoluzione in tutto il mondo e sono molti gli esempi virtuosi di un processo di legalizzazione totale: come il Canada o il Colorado che hanno dato il via a un processo di legalizzazione della marijuana a scopo ricreativo, seguiti da oltre 20 Stati USA e alcuni altri Paesi come l'Uruguay.

I dati del World Drug Report non hanno necessità di commenti: circa 275 milioni di persone in tutto il mondo (pari al 5,6% della popolazione mondiale di età compresa tra i 15 e i 64 anni) hanno fatto uso di droghe almeno una volta.
La quantità di cannabis sequestrata a livello mondiale è tuttavia diminuita del 22% rispetto agli anni precedenti, per un totale di 4.682 tonnellate, il livello più basso registrato dal 2000, ed è interessante che il declino è stato particolarmente marcato in Nord America, dove in diversi Stati il consumo di cannabis è stato legalizzato a fini ricreativi.

Una delle mie più grandi preoccupazioni da medico è la prassi messa in atto dai cartelli della droga negli ultimi anni di modificare geneticamente le piante, con il fine criminale di creare un prodotto in grado di determinare una forte dipendenza, quasi alla pari delle cosiddette “droghe pesanti”.

La cannabis comprende diverse specie, che variano per percentuale di THC e di altri cannabinoidi come CBD, CBN, CBC, THCV a seconda dei quali si ha un effetto fisiologico e psicotropo differente. Le modificazioni genetiche della cannabis ne potenziano la pericolosità.
Secondo studi recenti il tasso di THC della marijuana da spaccio reperibile nelle principali piazze italiane è quasi raddoppiato negli ultimi 15 anni e arriva fino al 10%, a fronte di una quasi totale assenza del cannabidiolo, il principio non psicoattivo.

In altre parole, la criminalità organizzata crea prodotti sempre più pericolosi, e diventa così impossibile monitorare il rischio a cui sono sottoposti, ignari, i consumatori.
La mafia insabbia la conoscenza, per lucrare sulla salute. Rendere legale la cannabis per il consumo ricreativo renderebbe le persone maggiormente consapevoli dei rischi per la salute oltre ad evitare il finanziamento ai cartelli della droga.

Un’altra ragione che mi spinge a ribadire come medico la mia posizione a favore della cannabis legale è la possibilità di promuovere l’uso del vaporizzatore piuttosto che di uno spinello. Con una capsula inserita in un vaporizzatore si conoscono esattamente le caratteristiche chimiche e il dosaggio di ciò che si consuma, grazie al controllo delle autorità sanitarie, e si previene così il rischio di cancro legato alla combustione della sigaretta.
La partecipazione della scienza al dibattito sulla salute dovrebbe sempre essere incoraggiato e ricercato. Invece, le istituzioni in Italia tendono a ignorare la scienza e la voce dei cittadini, fingendo di dimenticare che 37 milioni di Italiani si espressero a favore della cannabis per uso ricreativo con il referendum di un terzo di secolo fa.
 

Prof. Ignazio Marino

L'Italia non è tra i 21 Paesi del mondo che possono vantare una piena democrazia.

L'Italia si posiziona al 31esimo posto: non solo dopo tutti i Paesi Scandinavi e ad alcuni Paesi anglosassoni come l'Australia, il Canada e la Nuova Zelanda, ma anche dietro a Uruguay, Mauritius, Costa Rica, Corea del Sud, Taiwan e Botswana.
La classifica è stilata tenendo conto di indicatori come, tra gli altri, i diritti civili, la partecipazione alla vita politica dei cittadini e i sistemi elettorali.

Vorrei fare una riflessione su quest'ultimo, il sistema elettorale. Secondo me il punteggio che viene attribuito all'Italia è troppo benevolo.

È vero che gli italiani possono accedere a elezioni in cui è garantita la pluralità di partecipazione e la certezza dei dati.
Ma è anche vero che le diverse leggi elettorali negli ultimi 15 anni hanno di fatto garantito ai leader di partito la scelta dei candidati alle elezioni e, soprattutto, la scelta di coloro che si vedono garantita l'elezione.

Questo significa che la scelta dei membri del Parlamento è di fatto controllata da 7-8 leader di partito e non dal popolo elettore.

Questo ha determinato un progressivo cambiamento che ha portato i Parlamentari a sentirsi vincolati non agli elettori ma alle persone che hanno il potere di comporre le liste elettorali. In questo modo la democrazia reale in Italia è significativamente inferiore a quella già deludente di questa classifica.

Ignazio Marino

I took part in a global health forum organised by Jefferson medical students to talk about how Italy has dealt with and managed the pandemic crisis, from the first official case recorded in Codogno, to the present day.

Undoubtedly, the population density in Lombardy, one of the most productive areas in Europe, contributed greatly to the spread of Covid in our country at the end of March 2020.
In fact, in the first few months, official reports counted 7,593 deaths associated with COVID-19 in Lombardy and 44,773 infected, respectively 57.7% and 40.5% of all Italian cases.

I also addressed the delicate issue of lockdown and how a balance can be maintained between the economy, society and the management of the healthcare system in such a complicated period.

Prof. Ignazio Marino

Ecco il podcast della mia intervista per Radio Popolare sul tema del primo trapianto con cuore di maiale geneticamente modificato eseguito dai chirurghi dell’University of Maryland Medical Center a Baltimora

When we tell a woman how she should dress, that is violence

When in the back of our minds when we think about an episode of violence such as a rape, we wonder where that woman was, what time of day or night, if she had had a drink or smoked a joint, that is violence

If we think that we have to say "well done" to a man who helps out at home, cooperates, and fully shares the household commitments, that is violence

Everything that discriminates women from men, that considers them different as human beings, with different goals, purposes, lives, that is violence.

Feminicide and domestic violence are children of this way of thinking, not just another emergency to face now. They are part of a culture that we carry with us and that we must win, delete, with daily work.

Much depends on us "males", but a lot is also up to women, because how they raise their children, their male children is very important, how they make them perceive from the beginning that we are all equal, without differences and that we must remember this not only today, November 25 -the Day Against Violence Against Women.

Major project result of fundraising efforts by former Rome mayor Ignazio Marino.

A project is underway that will change the landscape of Trajan’s Forum in the heart of Rome.

The Basilica Ulpia, built by the architect Apollodorus of Damascus at the behest of the Emperor Trajan between 106 and 113 AD, is to receive a new lease of life thanks to a €1.5 million donation from an Uzbekistan businessman.

The patron was convinced to donate the funds for this purpose by the former mayor of Rome, Ignazio Marino, who announced the news on social media with the message: “Today is truly a very beautiful day.”

Interview with former Rome mayor Ignazio Marino

Marino recalled that after having pedestrianised Via dei Fori Imperiali in 2013 he oversaw the raising of seven columns at the Temple of Peace and opened excavations at Via Alessandrina, in addition to introducing a new lighting system and launching popular light shows at night in the Forum of Augustus and the Forum of Caesar.

Seven years later, the latest project dating from the Marino era will see the Basilica Ulpia revived using anastylosis, a reconstruction technique whereby the ruins are restored using the original architectural elements to the greatest degree possible.

The effect will add a whole new dimension to the ancient site – once dedicated to the administration of justice and commerce – granting visitors a better grasp of the vast scale of the building which collapsed in the mediaeval era, its ruins pillaged for construction material.

[...]

Full article nemo.guide

Today is really a beautiful day: work has begun on the Basilica Ulpia in the Forum of Trajan!

After pedestrianizing the Imperial Fora in 2013, I committed myself to enhancing them.

In a few months of government, in 2014-2015, we realized the night shows of Piero Angela in the Forum of Augustus and the Forum of Caesar, the night lighting designed by Vittorio Storaro. We raised seven columns of the Temple of Peace, sought philanthropists to resume excavations in Via Alessandrina and carried out the anastylosis of two orders of columns of the Basilica Ulpia in the Forum of Trajan.

It is an honor to continue to witness the opening of the sites we designed and financed in the service of Rome.

Rome and Philadelphia are more than 7 thousand kilometers apart, but former Mayor Ignazio Marino still thinks about the Capital: "In 2014 I obtained from a philanthropist 2 million euro to restore two orders of columns in the Forum of Trajan. I left project and money. If Gualtieri realized it, that would remain in history."

What is your opinion of Roberto Gualtieri's council? Have the currents weighed in?

The council reveals a careful evaluation of the currents of the PD and of the coalitions with other forces that will have to support it. Characters have been nominated that have been militating in parties opposed to the left as the UDC. One of them has professional relationships with a gentleman that in Rome they call Er Faina (“the Weasel”). These things make me first smile, then sad. The president of the City Council (Virginia Celli, ed.) is an astute politician: elected in 2013 in the "Marino" list, she then went to the notary to bring down the mayor and devised a list called "Roma torna Roma". Each of the Roman masterminds got their share. It is no coincidence that Gualtieri and Enrico Letta said that they do not fear betrayal or tripping. All legitimate, but I believe that the city needed new energy. Instead, the same names keep coming up, even if behind different desks. This way it is impossible to change Rome.

Should Gualtieri have been more autonomous?

Autonomy for a mayor, as for any other leader or manager, should not be seen as a source of unreliability.

Do you see your "stabbers" in the PD in the Municipality?

Years have passed and that event has lost all personal value for me. I have suffered a lot but my pain does not count. I don't know what the 700,000 Romans think who had elected the mayor and saw 19 Dems go joyfully to a notary public to trash their vote. Instead, the thought of the PD is clear. It has protected them by offering them positions that guarantee them a salary. With very few exceptions, they live off politics. I have no feelings towards them. I am sorry that Rome cannot have a different ruling class.

Michetti did not want to enter the Council, Calenda did after a change of heart.

Every time I have run for a position, I have done so believing in it to the end. To this day, I am the only member of parliament who resigned, renouncing his senatorial seat and salary, even before knowing whether I had won or lost the Municipal elections. I wanted to run for mayor without reserve seats. The current mayor resigned as a congressman two weeks after being elected to the City Council. I respect Gualtieri, who has integrity, but his way of thinking is different from mine. The presence of Carlo Calenda in the City Council is positive, it will raise the level of debate. His list has obtained the highest percentage of votes in Rome, so it is right that it is well represented in the Council.

Gualtieri wants to clean up the city by December. How can he accomplish that?

The challenge is not to clean up by December, but to keep Rome clean by transforming AMA, the waste management company. When I closed the Malagrotta landfill in 2013, I did it with a strategic plan that I hope will be implemented. It was based on three lines: plant autonomy, cost reduction with increased productivity and increased separate collection. We would have realized "ecodistricts" for the transformation of all waste into industrial product also thanks to over 300 million euros of investment. I want to give a piece of advice to the mayor: put back in operation the shredder that I bought. It is located in Ostia but should be moved back to Rocca Cencia. Governor Zingaretti authorized the use of the private one owned by Mr. Cerroni and not the one I bought with public money. It can treat 300 tons a day: certainly a help. Moreover, with the guidance of a great servant of the State, we had identified an area where we could build a service dump and produce energy from waste. I'm ready to make that documentation available to Gualtieri.

Is a new stadium needed?

Rome has missed an opportunity for all citizens and soccer fans. The project that we voted for in 2014 guaranteed the public interest, thanks to the obligation of the private entrepreneur to invest hundreds of millions of euros in works that would protect the territory and improve the lives of citizens before being able to use the stadium. The private proposer was required to enhance rail transport, build a new bridge, mitigate the hydrogeological risk, build a public park. Interventions that Rome had demanded in exchange for the construction of the stadium. The debate has been clouded by ignorance, bad faith or worse.

Source ilfattoquotidiano.it

Tra Roma e Philadelphia ci sono oltre 7mila chilometri di distanza, ma l’ex sindaco Ignazio Marino pensa ancora alla Capitale: “Nel 2014 ottenni da un filantropo 2 milioni per restaurare due ordini di colonne  nel Foro di Traiano. Ho lasciato progetto e soldi. Se Gualtieri lo realizzasse rimarrebbe nella storia”.

Che giudizio dà della giunta di Roberto Gualtieri?  Le correnti hanno pesato?

La giunta rivela un’attenta valutazione delle correnti del Pd e delle coalizioni con altre forze che dovranno sostenerla. Sono stati nominati personaggi che hanno militato in partiti opposti alla sinistra come l’Udc. Uno di essi ha rapporti professionali con un signore che a Roma chiamano Er Faina. Fatti che mi fanno prima sorridere e poi rattristare. La presidente del Consiglio Comunale (Virginia Celli, ndr) è un’astuta politica: eletta nel 2013 nella lista “Marino”, poi andò dal notaio per far cadere il sindaco e ideò una lista chiamata “Roma torna Roma”. Ognuno dei capibastone romani ha avuto la sua quota. Non a caso Gualtieri ed Enrico Letta hanno affermato di non temere tradimenti o sgambetti. Tutto legittimo, ma credo che la città avesse bisogno di energie nuove. Invece, girano sempre gli stessi nomi anche se dietro scrivanie diverse. Così è impossibile cambiare Roma.

Gualtieri doveva essere più autonomo?

L’autonomia per un sindaco, come per ogni altro leader o manager, non dovrebbe essere vista come fonte di inaffidabilità.

Vede i suoi “accoltellatori” nel Pd in Comune?

Sono passati anni e quella vicenda ha perso ogni valenza personale per me. Ne ho molto sofferto ma il mio dolore non conta. Non so cosa pensino i 700mila romani che avevano eletto il sindaco e videro 19 dem andare festosi da un notaio per cestinare il loro voto. È chiaro invece il pensiero del Pd. Li ha protetti ricandidandoli oppure offrendo loro posizioni che garantiscano un salario. Con l’esclusione di pochissime eccezioni, vivono di politica. Nei loro confronti non provo alcun sentimento. Mi dispiace che Roma non possa avere una classe dirigente diversa.

Michetti non ha voluto entrare in Consiglio, Calenda dopo un ripensamento sì.

Ogni volta che ho corso per una posizione, l’ho fatto credendoci fino in fondo. Ad oggi resto l’unico parlamentare che si è dimesso rinunciando al seggio di senatore e allo stipendio, prima ancora di sapere se avrei vinto o perso le Comunali. Volevo correre da sindaco senza poltrone di riserva. L’attuale sindaco ha cessato le funzioni da deputato due settimane dopo l’elezione in Comune. Rispetto Gualtieri, di indole integra, ma è un modo di pensare diverso dal mio. La presenza di Carlo Calenda in Aula è positiva, alzerà il livello del dibattito. La sua lista ha ottenuto la percentuale di voti più alta a Roma, quindi è giusto che sia ben rappresentata in Consiglio.

Gualtieri vuole ripulire la città entro dicembre. Come può riuscirci?

La sfida non è ripulire entro dicembre, ma mantenere Roma pulita, trasformando Ama, l’azienda che gestisce i rifiuti. Quando chiusi la discarica di Malagrotta nel 2013, lo feci con un piano strategico che mi auguro venga attuato. Si basava su tre linee: autonomia degli impianti, riduzione dei costi con incremento della produttività e aumento della raccolta differenziata. Avremmo realizzato degli “ecodistretti” per la trasformazione di tutti i rifiuti in prodotto industriale anche grazie a oltre 300 milioni di euro di investimenti. Voglio dare un consiglio al sindaco: rimetta in funzione il tritovagliatore che acquistai. Si trova ad Ostia ma andrebbe spostato nuovamente a Rocca Cencia. Il governatore Zingaretti autorizzò l’uso di quello di proprietà dell’avvocato Cerroni e non di quello che acquistai con i soldi pubblici. Può trattare 300 tonnellate al giorno: certamente un aiuto. Inoltre, con la guida di un grande servitore dello Stato, individuammo un’area dove realizzare una discarica di servizio e produrre energia dai rifiuti. Sono pronto a mettere quella documentazione a disposizione di Gualtieri.

Un nuovo stadio serve?

Roma ha perso una occasione per tutti i cittadini e per i tifosi. Il progetto che votammo nel 2014 garantiva l’interesse pubblico, grazie all’obbligo del privato, prima di poter utilizzare lo stadio, di investire centinaia di milioni di euro in opere che avrebbero tutelato il territorio e migliorato la vita dei cittadini. Il proponente privato era tenuto a potenziare i trasporti su ferro, a realizzare un nuovo ponte, a mitigare il rischio idrogeologico, a costruire un parco. Interventi che Roma aveva preteso in cambio della costruzione dello stadio. Il dibattito è stato offuscato da ignoranza, malafede o peggio ancora. 

Articolo originale su ilfattoquotidiano.it

By Marco Venturini

What are your views about the recent electoral campaign for the mayor of Rome and what is your opinion about the winner, Roberto Gualtieri?

I followed the electoral campaign from abroad, and criticised the general vagueness of the candidates. A few weeks before the vote, with the sole exception of Carlo Calenda [leader of the liberal centrist Azione party], they only had generic programmes lacking in detail.

Another serious shortcoming was the public debate between the candidates. At the end of September, a Rome newspaper published a letter from me to the candidates in which I listed what, for me, remain the five priorities for building the Rome of the future. Six years after the end of my time as mayor, it was interesting to read how almost all of the aspiring mayors were in full agreement with my programme for the city.

Unfortunately, many in the election campaign make promises that they don't keep. In 2013, when I was elected mayor with a large majority, 64 per cent of the votes, I was committed to consistently implementing everything I had proposed, starting with the pedestrianisation of many central areas (Fori Imperiali and Piazza di Spagna), the closure of the landfill at Malagrotta, and doubling the amount of recycled  waste collection in the city.

As for a judgment on the newly elected mayor, I think it is right and necessary to wait at least six months to evaluate his work. I hope that he thinks about the good of the citizens and the  competance of the councillors.

Recently the outgoing mayor Virginia Raggi apologised for some comments she  made about you when she was mayor. What do you think about this and what is your opinion on the outgoing administration?

I sincerely appreciate the public and repeated apologies of Virginia Raggi. This step of hers, by no means taken for granted, means that we can open a dialogue. She is a strong woman who has accumulated considerable experience after five years as mayor. I was the first to criticise many of her choices in the city government (for example the management of municipal pharmacies, her choice in terms of the Olympics, the wrong assignments for the heads of the administration), but I appreciate her gesture and I wish her well.

[...]

Read more on wantedinrome.com

In occasione della prima visita ufficiale della nuova Console Generale d'Italia a Philadelphia, Cristiana Mele, ho avuto il piacere di accompagnarla presso la sede della AugustaWestland.
Guidati dall’esperto manager, dott. Vittorio Della Bella, abbiamo potuto osservare negli hangar le diverse fasi di costruzioni di queste sofisticate macchine. L’amministratore delegato Della Bella ha espresso l’interesse dell’Agusta a “fare sistema” e sostenere collaborazione con centri accademici come la Thomas Jefferson University.

Abbiamo anche appreso che l’Agusta da tre anni consecutivi ha strappato il primato mondiale alla compagnia americana Bell nella qualità e la cura degli elicotteri.
Le capacità degli ingegneri e tecnici Italiani sono così apprezzate che da qualche tempo è stato aperto negli USA un servizio di riparazione delle pale degli elicotteri  a cui fanno riferimento anche le compagnie di altri Paesi.
 

Incredibile, poi, il livello tecnologico dell' “AW609” metà elicottero e metà aereo. Decolla verticalmente, sposta i rotori, e in meno di 4 secondi diviene un aereo a tutti gli effetti.
Da medico ho subito pensato all’uso che se ne potrà fare per salvare vite umane perché ha la flessibilità di un elicottero ma la capacità di volare con ogni condizione atmosferica per l’altitudine che può raggiungere. È sempre bello conoscere realtà imprenditoriali che rappresentano l’eccellenza italiana nel mondo.

AugustaWestland è leader mondiale nel settore elicotteristico, opera attraverso 5 Divisioni e un network internazionale di aziende sussidiarie e joint venture pur mantenendo il  suo quartier generale a Samerate, in provincia di Varese.

Ignazio Marino

Da Philadelphia, dove dal 2016 è tornato a occuparsi di trapianti alla Thomas Jefferson University, parla il chirurgo, ex presidente della commissione Sanità del Senato ed ex sindaco di Roma, Ignazio Marino: “Un Paese che non investe in ricerca, che non premia i propri giovani migliori, che non li sostiene e che li lascia partire dopo averli formati è un Paese che svende il proprio futuro”.

di Lorenzo Sommella
(da panoramasanita.it del 03/05/2021)

“Nel 2020 nessuno nel mondo industrializzato era preparato ad affrontare decessi così numerosi legati a una malattia infettiva. A livello globale abbiamo dovuto confrontarci con le stesse paure, incertezze, la stessa impreparazione che ci ha colpito l’ultima volta cento anni fa, coinvolgendo tutti i continenti e tutti i ceti sociali”. Così Ignazio Marino, dal 2016 Executive Vice President della Thomas Jefferson University di Philadelphia, in questo colloquio a tutto campo. Dal suo osservatorio privilegiato, Marino ha accettato di dare a Panorama della Sanità il suo punto di vista su tutto quello che sta avvenendo nel nostro Paese e negli Usa evidenziando numerose differenze.

Qual è la situazione attuale negli Stati Uniti? E qual è l’atteggiamento degli americani rispetto alla pandemia e alla campagna vaccinale? Puoi evidenziare le diversità tra l’approccio alla pandemia tra Usa e Italia?

Negli Usa, abbiamo vissuto i mesi più drammatici del 2020 fra aprile e giugno, un po’ in ritardo rispetto all’Europa, quindi anche all’Italia. Alla mia università, la Thomas Jefferson University di Philadelphia, nei suoi quattordici ospedali, abbiamo operato due scelte strategiche, che io ho fortemente sostenuto: accettare ogni paziente, anche quelli trasferiti da altri Stati (assistendo, ad oggi, oltre ventimila persone colpite dal Covid-19), e non licenziare nessuno, nonostante la consistente perdita economica legata alla pandemia (su un bilancio di 6 miliardi di dollari, nel 2020 abbiamo perso 290 milioni di dollari). Il tempo è un fattore determinante per affrontare una malattia come il Covid-19. A Jefferson abbiamo avuto modo di acquisire maggiori informazioni sul virus e la gestione è stata più efficace. Faccio un esempio.

Quando la pandemia ha coinvolto la Pennsylvania, lo Stato dove risiedo e lavoro, mi sono confrontato con gli specialisti italiani che avevano trattato i primi pazienti Covid in Italia. Attraverso una serie di videoconferenze con il prof. Raffaele Bruno dell’Università di Pavia, abbiamo appreso che spesso il decesso non era causato dalla polmonite, ma dalla coagulazione intravascolare disseminata che si poteva prevenire con la somministrazione di eparina. Grazie a questo dato scientifico abbiamo immediatamente inserito questo farmaco nei nostri protocolli Covid. L’Italia, fatalmente colpita in modo così drammatico, è stata all’inizio della pandemia un modello esemplare di gestione sanitaria. Tuttavia, con il trascorrere dei mesi, certe misure sono state allentate incautamente, lasciando maggiore spazio ai decisori politici piuttosto che agli esperti di malattie infettive. Inoltre, i contratti dei ventisette Paesi dell’Unione europea con l’industria farmaceutica sono stati firmati con ritardo e con gravi lacune. Lacune che a livello organizzativo e gestionale oggi rendono la campagna vaccinale troppo lenta. Gli Usa, al contrario, hanno affrontato male le prime fasi della pandemia, a causa del negazionismo del presidente Trump, ma hanno poi recuperato rapidamente e ad oggi più della metà della popolazione è stata vaccinata, mentre l’Italia non ha vaccinato neanche un quinto dei cittadini.

Leggi l’intervista integrale di Lorenzo Sommella* a Ignazio Marino su PANORAMA DELLA SANITÀ n.5 maggio 2021

*Direttore Sanitario Policlinico Universitario Campus Bio-Medico di Roma

È ormai assodato che tra le caratteristiche che devono contraddistinguere chi decide di intraprendere la professione medica un ruolo centrale lo debba ricoprire l’empatia. La presenza di personale sanitario empatico influenza positivamente il decorso e l’esito della malattia e, infatti, in alcuni percorsi formativi, come ad esempio quello infermieristico, esiste una forte componente didattica basata sulle capacità umane e relazionali.

Ne scrivo perché qualche giorno fa lo stesso Presidente della Thomas Jefferson University, dove insegno ed esercito, si è dichiarato a favore di un nuovo possibile criterio di selezione degli studenti di medicina basato sull’empatia. D’altronde è proprio dal puntuale lavoro della nostra Università che è nata la Jefferson Scale of Phisician Empathy (JSE), dalla quale sono poi scaturiti numerose ricerche tra le quali l’ultima del Center for Research Medical Education and Health Care volta ad esaminare l’empatia nelle professioni sanitarie.

La sopracitata scala di valutazione ha rilevato che sono le donne a dimostrare maggiore empatia nel trattamento dei pazienti (dato confermato anche dalla Balanced Emotional Empaty Scale – BEES). Inoltre, la scoperta dei neuroni a specchio da parte del neuroscienziato italiano Giacomo Rizzolatti ha dimostrato che questa caratteristica risiede nel nostro corredo genetico. Ciò non toglie che la stessa può essere anche insegnata e valorizzata, fatto che mi auguro avvenga in futuro nel maggior numero possibile di Facoltà di Medicina e Chirurgia, in ogni parte del mondo.
Già nel 2012 l’Università degli studi del Piemonte Orientale Amedeo Avogadro ha sottoposto i suoi studenti di Infermieristica alla BEES, attraverso il feedback a 30 affermazioni per individuare chi ha maggiore empatia nei confronti dei vissuti emozionali altrui. “La sua peculiarità, rispetto ad altri strumenti che rilevano il fenomeno empatico, è quella di essere in grado di analizzare e misurare in modo specifico la condivisione affettiva e di considerare situazioni caratterizzate oltre che da emozioni negative anche da emozioni positive”.

Da un altro studio, condotto dalla University of Central Lancashire di Preston, si è poi notato che a seconda delle facoltà universitarie esiste un differente grado di empatia. Infermieristica e Farmacia, ad esempio, registrano in media risultati più alti rispetto a Giurisprudenza. Ma mentre per Farmacia il livello aumentava con il progredire degli anni scolastici, per quanto riguarda Infermieristica il trend risultava essere inverso[1].

Ancora più significativo è un recente studio della Fondazione Giancarlo Quarta Onlus condotto in collaborazione con l’Università di Udine e con la Clinica psichiatrica Asuiud Santa Maria della Misericordia. La Functional Imaging of Reinforcement Effects (Fiore) è stata presentata lo scorso anno a Milano ed è riuscita a mettere in relazione diversi stili comunicativi di un comunicatore con le rispettive aree cerebrali della sfera di apprendimento del relativo ascoltatore, arrivando a dichiarare che “questa evidenza esperienziale, indagata dalla psicologia comportamentale, ha una sostanza neuroscientifica".

La stessa Fondazione è stata capace di sviluppare un modello relazionale chiamato Ippocrates che si basa su 5 punti corrispondenti a 5 aree di bisogno del malato, che a loro volta vengono associate a precisi stili comunicativi indicati nel trattamento. Grazie a questo modello si è scoperto che un iniziale “bisogno di comprensione” da parte del paziente richiede spiegazioni razionali del medico. Successivamente, il paziente ha “bisogno di rassicurazioni”. È, quindi, necessario “uno stile comunicativo improntato sulla continuità”. Il “bisogno di rassicurazione” richiede una condivisione di emozioni e una manifestazione di disponibilità da parte del medico che aiutino la persona ammalata nell’accettazione della diagnosi. Si passa quindi al “bisogno di attenzione”, che richiede una “valorizzazione delle specifiche istanze del paziente”, per arrivare, infine, alla decisione terapeutica vera e propria, che necessita da parte del medico di una capacità di dialogo che sappia comprendere suggerimenti, indicazioni, proposte e soluzioni.

Tornando alla ricerca Fiore, invece, tali modalità argomentative sono state analizzate con la  Risonanza Magnetica Funzionale (neuroimaging) e correlate a specifiche attivazioni cerebrali. Si è così scoperto che “comportamenti di valorizzazione attivano la sfera sensoriale e in particolare la corteccia visiva", mentre "comportamenti di influenzamento stimolano le regioni del cervello collegate alla teoria della mente che, tra le altre cose, si traduce nell'acquisizione di comportamenti da parte della persona". Ne consegue che un medico in grado di comunicare bene, orientando il paziente nelle decisioni, favorisce la reiterazione del suo comportamento virtuoso e riduce significativamente degenza e malattia.

Fabio Sambataro, Professore di Psichiatria dell’Università degli Studi di Udine, ha aggiunto che “servirebbe invece una prova pratica di empatia", in quanto i corsi di psicologia clinica si risolvono in una mera presentazione di slides e non sono assolutamente sufficienti alla formazione del giovane medico. "Tra gli anni '50 e '70 c'è stata una rivoluzione della medicina che ci ha permesso di diventare sempre più tecnici e molto meno orientati verso il paziente, con un processo che si chiama 'de-umanizzazione'. Qualcuno pensa che il distacco sia d'aiuto al malato. In realtà, se è vero che il 'sentire' la stessa cosa che sente il paziente non è utile, il 'capire' quello che sente è fondamentale", ha poi concluso. È sempre il Prof. Sambataro, poi, ad aggiungere come negli Stati Uniti questa pratica sia molto più consolidata, tanto che “nel processo di accreditamento del medico esiste questo 'clinical skill' e quindi nella prova clinica pratica si testa anche la comunicazione camice bianco-paziente. È parte dell'esame”.

C’è un netto dislivello percettivo tra quanto ritengono di fare i medici e quanto avvertono i pazienti. Già in uno studio di 15 anni fa il 75% dei chirurghi ortopedici statunitensi dichiararono di aver avuto un buon feeling con i pazienti; di contro, soltanto il 21% dei loro pazienti riferirono di aver raggiunto un sufficiente livello di empatia.

Sono numeri che debbono essere migliorati attraverso training, feedback dei pazienti e diversi altri strumenti capaci di trasmettere le basi neurobiologiche dell’empatia, così da far percepire l’importanza di migliorare la relazione medico-paziente[2].

Il primo passo consiste sempre nell’ascolto, base di ogni rapporto umano ed elemento imprescindibile nel rapporto medico-paziente. Proprio per questo motivo condivido fortemente l’appello per un test di accesso alla Facoltà di Medicina e Chirurgia incentrato sulla capacità empatica dello studente, negli Stati Uniti ma anche in Italia e in tutti gli altri paesi.

Di recente ho partecipato a un podcast curato da The Visible Voice e organizzato per commentare il film Syndrome K[1]. Questa pellicola è incentrata su una vicenda avvenuta a Roma nella Seconda Guerra Mondiale (più precisamente ci troviamo nell’ottobre del 1943). Una vicenda che ha riguardato la comunità scientifica e la drammatica realtà delle deportazioni razziali.

Per chi non fosse a conoscenza di questa incredibile storia ospedaliera di resistenza e di umanità, il Morbo K è stata una tremenda epidemia scoppiata all’interno di un padiglione del Fatebenefratelli di Roma nel 1943. La curiosità è che questa malattia estremamente contagiosa è stata una completa invenzione del medico antifascista Adriano Ossicini che, anche per questo motivo, fu imprigionato e torturato da nazisti e fascisti.

Nell’anno in cui avvenne il maggior numero di deportazioni razziali, infatti, il Fatebenefratelli, un complesso ospedaliero situato sull’isola Tiberina fu lo scenario di una delle più straordinarie iniziative di solidarietà da parte di un gruppo di militanti antifascisti romani: i “congiurati” dell’isola Tiberina, che dopo il rastrellamento del 16 ottobre ai piedi del teatro di Marcello e del Portico di Ottavia si attivarono per salvare il maggior numero di ebrei dalla morte nelle camere a gas. Addirittura, la scelta del nome rappresenta un forte simbolo di rivalsa, avendo utilizzato la lettera K in riferimento agli ufficiali nazisti Kesselring e Kappler[2].

“Ricordo ancora”, dichiarò lo stesso Adriano Ossicini in riferimento all’accaduto, “lo straziante grido di una madre in quell’alba, a via della Reginella, che urlava al figlio piccolo ‘Scappa via, bello de mamma, scappa!’”. Dopo essersi recato di corsa verso l’ingresso dell’Ospedale assieme ad un altro medico riuscirono a nascondere una ventina di cittadini al suo interno, ricoverandoli in un reparto isolato grazie alla collaborazione del primario Giovanni Borromeo. Fu allora che ad un giovane medico, anch’egli ebreo, venne l’idea di inserire nella cartella clinica la Sindrome di K, diventata poi nell’accezione comune Morbo K, “per distinguerli dagli altri pazienti e per sintetizzare il morbo di Kesserling, nome dell’ufficiale nazista, razzista e persecutore”[3].

Si è trattato di un’operazione talmente importante che la Fondazione internazionale Raoul Wallenberg, patrocinata dalla Comunità ebraica di Roma e dalla Fondazione museo della Shoah, nel 2016 è arrivata a premiare il complesso ospedaliero capitolino con il titolo di Casa di Vita. Che io sappia, quindi, si tratta della prima premiazione di una struttura sanitaria per aver avuto il merito di inventarsi una falsa epidemia.

“Bisogna sempre cercare di essere dalla parte giusta”, dichiarò lo stesso Adriano Ossicini in una recente intervista rilasciata prima del suo decesso, avvenuto nel 2019, raccontando di come insieme a Borromeo e con la collaborazione dei suoi colleghi “scrisse sulle cartelle cliniche, altrettanto false, dei pazienti che erano affetti da una malattia molto contagiosa, il Morbo di K. Questo scoraggiò i nazisti al controllo dei nomi dei pazienti. Nel frattempo, nei sotterranei una radio clandestina permetteva di comunicare con i partigiani, mentre nell’ospedale trovavano rifugio molti romani”.

Le false generalità delle cartelle cliniche non furono mai scoperte proprio perché l’entourage medico isolò tutti i finti pazienti all’interno di uno stesso reparto. I nazisti decisero di non entrare in quel reparto perché terrorizzati dal possibile contagio con una malattia mortale. Durante i giorni di degenza nel padiglione, quindi, i cittadini di origine ebraica avevano il tempo di farsi preparare i falsi documenti di identità grazie ai quali fuggire dopo una finta dichiarazione di morte a causa dello stesso Morbo K.

Nel 2007, il figlio del Dott. Borromeo svelò nel dettaglio come il padre un giorno avesse sventato un blitz delle SS che occuparono l’intero ospedale per un rastrellamento di massa, spiegando loro in tedesco la gravità e l’altissima contagiosità della malattia fino ad aggiungere approfondimenti dettagliati “sugli effetti devastanti cui sarebbero stati esposti entrando nel reparto K”. La descrisse come una malattia neurodegenerativa, che si manifestava in un’iniziale fase di convulsioni e demenza fino a portare alla graduale paralisi degli arti e alla conseguente morte per asfissia[4]. Questa descrizione allontanò definitivamente le truppe dal reparto.

“È vietato l’accesso ai non addetti” fu il cartello che Ossicini, futuro Ministro per la famiglia e la solidarietà sociale, affisse all’ingresso del reparto per autenticare la sua bugia e allo stesso tempo salvare le centinaia di vite destinate ai campi di concentramento nazisti.

Come si legge dalle ricostruzioni storiche, tutta l’operazione fu talmente ben strutturata che proseguì “nonostante la prigionia del dottor Adriano Ossicini”[5].

Ho voluto ricordare questa storia per ribadire come non può esserci medicina senza etica.

La pandemia da COVID-19 non si limita a minacciare la vita dei pazienti che contraggono il virus, o l’economia dei vari Paesi costretti ad attuare misure stringenti per arginare i contagi, ma colpisce particolarmente le fasce sociali più deboli.

Una di queste ripercussioni, forse la più pericolosa, è sicuramente la sospensione delle campagne di vaccinazione che venivano attuate con regolarità prima del propagarsi della pandemia. Come ci conferma il New York Times è passato pochissimo tempo, infatti, e già assistiamo a un aumento dei casi di morbillo e poliomielite.

Chiusura dei laboratori, interruzione della catena di distribuzione dei farmaci e riduzione dei richiami sono stati tutti fattori che hanno diminuito l’efficacia di questo indispensabile strumento di prevenzione sanitaria. Le conseguenze di tutto ciò si sono tradotte, purtroppo, in “un incremento delle infezioni di colera in Cameron, Mozambico, Bangladesh, Yemen e Sud Sudan; la nascita di focolai di difterite in Nepal, Pakistan e Bangladesh e la diffusione di un ceppo mutato del virus della poliomielite in decine di Paesi, mentre in Congo è emerso un nuovo focolaio di Ebola” e in Europa sono tornati a crescere i casi di morbillo[1].

A sottolineare la gravità della situazione ci ha pensato anche il presidente di Medici Senza Frontiere in Africa Centrale Chibuzo Okonta, che ha affermato come ci sia un alto rischio che “un’epidemia in pochi paesi uccida più bambini del Covid-19”, dal momento che su 29 Stati che hanno sospeso le campagne di vaccini a causa della pandemia sono stati addirittura 18 quelli in cui si sono registrati dei focolai epidemici. Un esempio? In Pakistan e Afghanistan si sono registrati 61 casi di poliovirus di tipo 1, mentre in Ciad, Ghana e Etiopia è comparso il poliovirus di tipo 2.

Alcuni paesi si stanno adesso attrezzando per fronteggiare questa nuova emergenza, come l’Uganda, che ha dotato gli operatori sanitari di motociclette per distribuire i farmaci, e il Brasile, che invece ha offerto vaccinazioni mediante l’impiego di auto. Tuttavia, la situazione è così grave da essere ben fotografata dall’allarme internazionale di GAVI (Global Polio Eradication Initiative), che ha fatto una stima per la quale “se la pandemia finisse entro 3 mesi [ci si potrebbe rimettere] al passo con le vaccinazioni entro un anno e mezzo”[2]. È evidente che ci troviamo di fronte ad un altro enorme problema di carattere sanitario[3].

Fanno sicuramente riflettere anche le parole di Seth Berkley, direttore di GAVI, che ammonisce tutti sul fatto che “se trascuriamo le catene di approvvigionamento e le infrastrutture di immunizzazione, rischiamo anche di ostacolare la nostra capacità di far arrivare i vaccini (quando saranno disponibili, n.d.r.) per il COVID-19, che rappresentano la nostra migliore speranza di sconfiggere questa pandemia, quando saranno pronti”[4].

Cercando di quantificare i numeri di questa nuova emergenza, il lavoro combinato dell’Organizzazione Mondiale della Sanità, dell’UNICEF, di GAVI e del Sabin Vaccine Institute ha rilevato che al momento ci sono 80 milioni di bambini sotto il primo anno di vita esposti a malattie infettive gravi come quelle citate, e che il problema riguarda in maniera sostanziale 68 Paesi del mondo (il 53% di quelli che hanno reso disponibili i dati)[5].

Tedros Adhanom Ghebreyesus, direttore generale dell’OMS, ha recentemente ribadito che proprio perché “l’immunizzazione è uno dei più potenti e fondamentali strumenti di prevenzione delle malattie nella storia della salute pubblica, [...] il COVID-19 minaccia di compromettere i servizi di immunizzazione in tutto il mondo, ciò significa che decine di milioni di bambini, che vivono in paesi sia ricchi sia poveri, sono a rischio di malattie come la difterite, il morbillo e la polmonite”[6].

È stata poi l’UNICEF a rilevare che, oltre ai problemi logistici interni ai singoli Paesi, c’è stato anche un “importante ritardo nella consegna di vaccini a causa delle misure di lockdown e la conseguente riduzione di voli commerciali e la limitata disponibilità dei voli charters”. Tanto che la stessa GAVI ha ritenuto utile firmare un accordo con l’UNICEF per coprire finanziariamente i maggiori costi di trasporto dei farmaci[7].

Henrietta Fore, direttore esecutivo dell’UNICEF, ha saggiamente affermato che “non possiamo lasciare che la lotta contro una malattia vada a scapito dei progressi a lungo termine nella lotta contro altre malattie”, invitando quindi a riprendere il prima possibile le vaccinazioni per non creare altri focolai mortali[8].

I vaccini sono lo strumento più efficace per prevenire molte malattie in passato mortali, ma è sufficiente un piccolo passo indietro per annientare i progressi sanitari raggiunti con il lavoro di anni.

Ignazio Marino

Shayan Hassantabar, Novati Stefano, Vishweshwar Ghanakota, Alessandra Ferrari, Gregory N. Nicola, Raffaele Bruno, Ignazio R. Marino, Niraj K. Jha

The novel coronavirus (SARS-CoV-2) has led to a pandemic. Due to its highly contagious nature, it has spread rapidly, resulting in major disruption to public health. In addition, it has also had a severe negative impact on the world economy. As a result, it is widely recognized now that widespread testing is key to containing the spread of the disease and opening up the economy. However, the current testing regime has been unable to keep up with testing demands. Hence, there is a need for an alternative approach for repeated large-scale testing of COVID-19. The emergence of wearable medical sensors (WMSs) and novel machine learning methods, such as deep neural networks (DNNs), points to a promising approach to address this challenge. WMSs enable continuous and user-transparent monitoring of the physiological signals. However, disease detection based on WMSs/DNNs and their deployment on resource-constrained edge devices remain challenging problems. In this work, we propose CovidDeep, a framework that combines efficient DNNs with commercially available WMSs for pervasive testing of the coronavirus. We collected data from 87 individuals, spanning four cohorts including healthy, asymptomatic (but SARS-CoV-2-positive) as well as moderately and severely symptomatic COVID-19 patients. We trained DNNs on various subsets of the features extracted from six WMS and questionnaire categories to perform ablation studies to determine which subsets are most efficacious in terms of test accuracy for a four-way classification. The highest test accuracy obtained was 99.6%. Since different WMS subsets may be more accessible (in terms of cost, availability, etc.) to different sets of people, we hope these DNN models will provide users with ample flexibility. The resultant DNNs can be easily deployed on edge devices, e.g., smartwatch or smartphone, which also has the benefit of preserving patient privacy.

INTRODUCTION

SARS-COV-2, also known as novel coronavirus, emerged in China and soon after spread across the globe. The World Health Organization (WHO) named the resultant disease COVID-19. COVID-19 was declared a pandemic on March 11, 2020 [1]. In its early stages, the symptoms of COVID-19 include fever, cough, fatigue, and myalgia. However, in more serious cases, it can lead to shortness of breath, pneumonia, severe acute respiratory disorder, and heart problems, and may lead to death [2]. It is of paramount importance to detect which individuals are infected at as early a stage as possible in order to limit the spread of
disease through quarantine and contact tracing. In response to COVID-19, governments around the world have issued social distancing and self-isolation orders. This has led to a significant increase in unemployment across diverse economic sectors. As a result, COVID-19 has triggered an economic recession in a large number of countries [3].

Reverse Transcription-Polymerase Chain Reaction (RTPCR) is currently the gold standard for SARS-CoV-2 detection [4]. This test is based on viral nucleic acid detection in sputum or nasopharyngeal swab. Although it has high specificity, it has several drawbacks. The RT-PCR test is invasive and uncomfortable, and non-reusable testing kits have led to significant supply chain deficiencies. SARS-CoV-2 infection can also be assessed with an antibody test [5]. However, antibody titers are only detectable from the second week of illness onwards and persist for an uncertain length of time.  The antibody test is also invasive, requiring venipuncture which, in combination with a several-day processing time, makes it less ideal for rapid mass screening. In the current economic and social situation, there is a great need for an alternative SARS-CoV-2/COVID-19 detection method that is easily accessible to the public for repeated testing with high accuracy.

To address the above issues, researchers have begun to explore the use of artificial intelligence (AI) algorithms to detect COVID-19 [6]. Initial work concentrated on CT scans and X-ray images [4], [7]–[21]. A survey of such datasets can be found in [22], [23]. These methods often rely on transfer learning of a convolutional neural network (CNN) architecture, pre-trained on large image datasets, on a smaller COVID-19 image dataset. However, such an imagebased AI approach faces several challenges that include lack of large datasets and inapplicability outside the clinic or hospital. In addition, other work [24] shows that it is difficult to distinguish COVID-19 pneumonia from influenza virus pneumonia in a clinical setting using CT scans. Thus, the work in this area is not mature yet.

CORD-19 [25] is an assembly of 59000 scholarly articles on COVID-19. It can be used with natural language processing methods to distill useful information on COVID-19-related topics.

AI4COVID-19 [26] performs a preliminary diagnosis of COVID-19 through cough sample recordings with a smartphone application. However, since coughing is a common symptom of two dozen non-COVID-19 medical conditions, this is an extremely difficult task. Nonetheless, AI4COVID-19 shows promising results and opens the door for COVID-19 diagnosis through a smartphone.

The emergence of wearable medical sensors (WMSs) offers a promising way to tackle these challenges. WMSs can continuously sense physiological signals throughout the day [27]. Hence, they enable constant monitoring of the user’s health status. Training AI algorithms with data produced by WMSs can enable pervasive health condition tracking and disease onset detection [28]. This approach exploits the knowledge distillation capability of machine learning algorithms to directly extract information from physiological signals. Thus, it is not limited to disease detection in the clinical scenarios.

We propose a framework called CovidDeep for daily detection of SARS-CoV-2/COVID-19 based on off-the-shelf WMSs and compact deep neural networks (DNNs). It bypasses manual feature engineering and directly distills information from the raw signals captured by available WMSs. It addresses the problem posed by small COVID-19 datasets by relying on intelligent synthetic data generation from the same probability distribution as the training data [29]. These synthetic data are used to pre-train the DNN architecture in order to impose a prior on the network weights. To cut down on the computation and storage costs of the model without any loss in accuracy, CovidDeep leverages the grow-and-prune DNN synthesis paradigm [30], [31]. This not only improves accuracy, but also shrinks model size and reduces the computation costs of the inference process.

The major contributions of this article are as follows:

• We propose CovidDeep, an easy-to-use, accurate, and pervasive SARS-CoV-2/COVID-19 detection framework. It combines features extracted from physiological signals using WMSs and simple-to-answer questions in a smartphone application-based questionnaire with efficient DNNs.
• It uses an intelligent synthetic data generation module to obtain a synthetic dataset [29], labeled by decision rules. The synthetic dataset is used to pre-train the weights of the DNN architecture.
• It uses a grow-and-prune DNN synthesis paradigm that learns both an efficient architecture and weights of the DNN at the same time [30], [31].
• It provides a solution to the daily SARS-CoV-2/COVID-19 detection problem. It captures all the required physiological signals non-invasively through comfortably-worn WMSs that are commercially available.

The rest of the article is organized as follows. Section 2 reviews background material. Section 3 describes the CovidDeep framework. Section 4 provides implementation details. Section 5 presents experimental results. Section 6 provides a short discussion on CovidDeep and possible directions for future research. Finally, Section 7 concludes the article.

[...]

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Nonostante in questi ultimi mesi l’attenzione di tutti si sia concentrata sulla pandemia CoVid-19 e su quanto abbia stravolto il nostro modo di vivere e, purtroppo, anche di morire, abbiamo comunque l’obbligo di mantenere alta la guardia su quello che è uno dei temi in assoluto più importanti per il futuro della Terra: l’impegno per ridurre il Global Warming.

Vorrei utilizzare questo spazio per sottoscrivere e promuovere l’appello che ha recentemente lanciato il fondatore del movimento di cittadini europei sullo sviluppo sostenibile EUMANS, nonché tesoriere dell’Associazione Luca Coscioni, Marco Cappato, per il quale “è tempo di agire, ne va della salute di tutti e della sopravvivenza della Terra”.

L’occasione è stata il lancio della petizione Stop Global Warming, un’iniziativa nata in corrispondenza della cinquantesima Giornata della Terra che ha come obiettivo il raggiungimento di 1 milione di firme da presentare poi alla Commissione Europea per sollecitare una legge volta alla tassazione delle emissioni di Co2. A sostegno dell’iniziativa partecipano ben 27 premi Nobel e 5227 scienziati.

“Siamo di fronte a un bivio. La crisi del Coronavirus rischia di spazzare via i risultati in questi anni contro i cambiamenti climatici, con risultati devastanti per il pianeta” ha dichiarato lo stesso Marco Cappato, aggiungendo come sia “possibile che la nuova consapevolezza della nostra fragilità ci faccia compiere le scelte necessarie proprio ora che saranno messi in campo investimenti pubblici senza precedenti. Ora [...] l’Iniziativa dei Cittadini Europei www.stopglobalwarming.eu rappresenta l’unica occasione di partecipazione democratica per spingere l’Europa a dare l’esempio su scala mondiale, rilanciando il Green deal annunciato dalla Commissione Europea”[1].

Già durante il recente periodo di lockdown l’organizzazione Fridays For Future Italia aveva tentato di mantenere alta la guardia, aggiornando settimanalmente il blog #QuarantenaForFuture. Al suo interno, infatti, si potevano leggere tutti gli sconcertanti dati che riguardano questa emergenza globale: dal numero di morti dovuti al surriscaldamento globale alla rilevazione delle temperature terrestri, che secondo il Gruppo Intergovernativo sul Cambiamento Climatico (Ipcc) si sono alzate di più di un grado centigrado nell’ultimo secolo, contribuendo al parziale scioglimento dei poli e a tutte le conseguenze a cui assistiamo oggi.

Tra queste vi è sicuramente l’incremento di malattie cardiovascolari e respiratorie (“aumento del 3,4% della mortalità cardiovascolare, [...] del 3,6% della mortalità respiratoria e [...] dell’1,4% della mortalità cerebrovascolare”[2]), con una statistica che andrà sicuramente peggiorando se si realizzerà ciò che denuncia la stessa Organizzazione Mondiale della Sanità (OMS), lo stabilizzarsi di 250 giorni di afa alla fine di questo secolo. Per non parlare della salute mentale: l’associazione degli psichiatri degli Stati Uniti ritiene che l’aumento di disturbi di ansia e di suicidi è strettamente collegato al tema del surriscaldamento globale. Saranno direttamente proporzionali anche l’incremento di malattie oncologiche, infettive, obesità, endocrine e malattie della riproduzione. La tropicalizzazione del clima, poi, si porta sicuramente dietro una scia di effetti secondari, tra i quali “il proliferare di specie tropicali e di patogeni tropicali” quali lo Zika, il Dengue e il West Nile trasportate dalla zanzara tigre (specie che più delle altre ha beneficiato dell’innalzamento climatico).

Un altro pericolo è dato dalla risposta dell’ambiente a questo aumento di temperature, come ad esempio il triplicarsi di inondazioni e di calamità naturali, che sicuramente in contesti urbani come quelli odierni causerebbero ingenti perdite di vite umane, oltre che danni al tessuto socioeconomico cittadino. Sembrano previsioni catastrofiste, ma è sufficiente considerare che già oggi l’inquinamento atmosferico (concausa del Global Warming) soltanto in Italia si traduce in oltre 80mila morti l’anno[3].

I costi del riscaldamento globale, anche in termini economici e finanziari, sono stati calcolati da The Lancet Countdown 2019: Tracking Progress on Health and Climate Change, un report stilato da 120 esperti che hanno cooperato a livello internazionale lo scorso novembre e presentato in Italia dalla Fondazione CMCC e dall’Università Ca’ Foscari a Venezia. Grazie a questo report scopriamo che, ad esempio, nel solo 2018, 831 eventi climatici hanno causato perdite economiche per 166 miliardi di dollari.

Stando a quanto enunciato dalla ricercatrice dell’University College di Londra Marina Romanello, co-autrice del sopracitato report, l’Italia sarà tra i Paesi che maggiormente accuseranno l’evolversi di questo problema, “probabilmente a causa dell’alta porzione di anziani che vivono nelle aree urbane in queste regioni: si tratta di una fascia di popolazione particolarmente vulnerabile a ictus e problemi renali legati ai colpi di calore perché maggiormente affetta da malattie croniche”.

Concentrandoci invece sulle ripercussioni economiche, secondo tale analisi nel solo 2017 sono state 1,7 milioni le ore di lavoro perse a causa dell’esposizione alle alte temperature, soprattutto nel settore dell’agricoltura. Come ha stimato Shouro Dasgupta, ricercatore della Ca’ Foscari, entro il 2080 andremo incontro ad un calo dell’11,2% all’interno della filiera dell’agricoltura e dell’8,3% nel settore industriale. “Gli impatti sull’Italia sono anche maggiori, con una riduzione rispettivamente del 13,3 per cento e dell’11,5 per cento. È importante sottolineare che i cambiamenti climatici, oltre a danneggiare l’economia italiana con un calo del PIL dell’8,5 per cento al 2080, aumenteranno anche le disparità di reddito interne al paese, aggravando il divario Nord-Sud: tutto ciò avrà implicazioni significative per la salute”, ha poi aggiunto.[4]

Tornando al focus, la salute, è interessante (e preoccupante allo stesso tempo) dare uno sguardo anche allo studio pubblicato dal British Medical Journal a firma di Renee Salas e Ashish Jha dell’Harvard Global Health Institute, per i quali il Global Warming rischia seriamente di compromettere il raggiungimento dell’Universal Health Coverage (UHC – assistenza sanitaria universale), tema centrale per l’Agenda 2030 delle Nazioni Unite e di altri enti internazionali.

A questo studio si aggiunge la stima della stessa Organizzazione Mondiale della Sanità, per la quale i cambiamenti climatici causeranno oltre 250.000 decessi annui entro il 2030 dovuti alla malnutrizione, alla malaria, alla diarrea, al Dengue (tutte malattie legate alla carenza di acqua e cibo) e alle ondate di calore[5].

Le conseguenze del nostro disinteresse nei confronti della Terra sono sotto gli occhi di tutti, come denunciano giustamente i più giovani che prima della pandemia hanno riempito le piazze e le strade di tutto il mondo rivendicando il loro diritto ad avere un futuro. Non possiamo più permetterci di essere miopi ed è tempo che tutti si attivino per invertire un percorso che se non verrà fermato condurrà ad una catastrofe epocale.

Ignazio Marino

Come ho scritto sui miei social networks poco tempo fa, alla Thomas Jefferson University riteniamo imprescindibili le attività umanistiche all’interno del percorso formativo degli studenti in Medicina. Per questo attraverso Jefferson Humanities & Health proponiamo una serie di progetti durante il corso di laurea. Tra questi spicca un workshop di medicina narrativa virtuale volto a promuovere l’empatia, il team building e un approccio olistico ai percorsi di cura[1].

Il termine Narrative Medicine (NBM) si riferisce ad una metodologia clinico-assistenziale che poggia sulla capacità comunicativa, un aspetto della cura che ha sempre fatto parte della Medicina ma che oggi, a causa della tecnologia, si rischia di perdere. Tale metodologia, infatti, presuppone la narrazione come strumento essenziale all’acquisizione, alla comprensione e alla sincronizzazione di differenti punti di vista circa il manifestarsi di sintomi o l’approcciarsi alle rispettive cure, il tutto con l’obiettivo unico di realizzare una “storia di cura”, una costruzione condivisa del percorso che accompagnerà il paziente alla guarigione[2].

Il nucleo di questo metodo è dunque il processo narrativo, dove per narrazione, stando alla definizione di Barbara Herrnstein Smith, intendiamo semplicemente il “discorso in cui qualcuno dice a qualcun altro che qualcosa è accaduto”. Il racconto della malattia diventa in questo senso centrale: un concetto apparentemente semplice ma assai più rilevante della raccolta di dati impersonali nella cartella clinica[3].

Questa metodologia non prescinde da quella che viene definita Evidence-Based Medicine (EBM), ma viene utilizzata a livello complementare al fine di perseguire l’estrema completezza, personalizzazione ed efficacia delle decisioni clinico-assistenziali. Quello che si ricerca, quindi, è la “partecipazione attiva dei soggetti coinvolti nelle scelte. Le persone, attraverso le loro storie, diventano protagoniste del processo di cura”, come è stato affermato durante la Conferenza di consenso Linee di indirizzo per l’utilizzo della Medicina Narrativa in ambito clinico assistenziale per le malattie rare e cronico-degenerative, svoltasi dall’11 al 13 luglio del 2014 durante il Second International Congress Narrative Medicine And Rare Diseases[4].

Tutto questo è orientato verso l’unico obiettivo importante dal punto di vista clinico-assistenziale: comprendere il paziente, la sua malattia e facilitare la relazione umana tra la persona ammalata e il suo medico curante[5].

Riprendendo la definizione della direttora del programma di Medicina Narrativa alla Columbia University, Rita Charon, possiamo, in sintesi, utilizzare questa dizione: “riconoscere, assorbire, metabolizzare, interpretare ed essere sensibilizzati dalle storie della malattia: aiuta medici, infermieri, operatori sociali e terapisti a migliorare l'efficacia di cura attraverso lo sviluppo della capacità di attenzione, riflessione, rappresentazione e affiliazione con i pazienti e i colleghi”.

Ed è in gran parte grazie al lavoro di Rita Charon e di un’altra studiosa, Rachel Naomi Remen, che a partire dalla fine degli anni Novanta abbiamo una definizione scientifica di questa area della medicina. Le due esperte, infatti, sono state tra le prime a definire i contorni di questa tecnica e a utilizzarla per migliorare la cura del paziente. In un’epoca in cui medici e infermieri si affidano sempre di più all’aiuto di sofisticate attrezzature, le due ricercatrici si sono attivate per sollecitare l’adozione di un approccio d’insieme nei confronti del paziente con un maggiore coinvolgimento umano del medico nel percorso di cura. L’empatia che ne scaturisce, come dimostrarono, avrebbe favorito l’ottimizzazione della cura offrendo “all’operatore una metodica per la rilevazione del vissuto soggettivo di malattia”.

Studiando la sua genesi scopriamo che tale modello era stato precedentemente sviluppato presso la Harvard Medical School da Byron J. Good, che ne aveva previsto anche un approfondimento qualitativo basato sulla raccolta dei dati sentimentali del paziente stesso. Annotando, ad esempio, gli stati di tristezza, solitudine, dolore o sconforto, oppure registrando le reazioni che egli provava nei confronti del suo vissuto nell’ambiente di cura. Questo a conferma del fatto che la descrizione dei sintomi va oltre la valutazione della qualità delle cure ma si estende a tutta l’esperienza del paziente nel suo complesso.

Per un medico tendere l’orecchio al racconto del paziente e invogliarlo ad estenderlo anche alle vicende e al contesto in cui esso si pronuncia diventa una pratica fondamentale per ricostruire in modo critico una serie di particolari solitamente messi in secondo piano. Come afferma la stessa Società Italiana di Medicina Narrativa (SIMeN) solo in questo modo “il soggetto e la sua famiglia entrano a pieno titolo come protagonisti e co-autori del percorso di cura”[6].

“La malattia raccontata dal paziente è [quindi] illness e sickness, non solo disease”[7].

In Italia l’ospedale Fatebenefratelli della Provincia Lombardo Veneta utilizza da tempo la NMB come un cardine organizzativo della pratica medica, arrivando addirittura a spiegare (sulla pagina web dell’ospedale) come attraverso questa metodologia “la persona condivide sentimenti, emozioni, paure e preoccupazioni con altri individui, ripercorrendo l’immaginario vissuto e condividendo una personale fase della sua vita”, e che tale approccio “allevia la sofferenza e permette alle persone malate di creare una connessione con altre persone che hanno vissuto la stessa esperienza o che vogliono co-partecipare e dare conforto al paziente”.

Lo scopo è quello di umanizzare l’assistenza e la cura integrale della persona[8].

Un’altra iniziativa degna di nota è stata intrapresa dalla stessa SIMeN, che durante l’emergenza sanitaria dovuta all’epidemia di COVID-19 ha lanciato il progetto R-Esistere, un portale aperto ai contributi di tutti coloro i quali hanno sentito il bisogno di raccontare l’esperienza vissuta sulla propria pelle. Uno spazio di ascolto rivolto ai pazienti, ai familiari e a tutti gli operatori sanitari che nell’arco di questi mesi hanno contrastato, quotidianamente, l’aggressività di un nuovo terribile virus.
“In questi ultimi mesi ci è mancato l’ossigeno, a ognuno in maniera diversa: siamo testimoni involontari di un tempo sospeso, ci siamo sentiti lontani dal nostro passato, non abbiamo più visto il futuro” ha dichiarato la Presidente della società Stefania Polvani, aggiungendo poi come si sia sentito il bisogno di “confrontarci direttamente con le nostre emozioni ed è in questi momenti, tra paura e coraggio, eroismo e isolamento, che il progetto R-Esistere vuole provare a dar voce ai sentimenti contrastanti di disperazione e speranza che ci hanno accompagnato in questo momento di distanza sociale durante questa pandemia, e che continueremo probabilmente a vivere”[9].

Il progetto è nato, dunque, per aiutare anche gli operatori sanitari, “offrendo percorsi inaspettati su mondi che sembravano irraggiungibili o lontanissimi”, per citare le parole di Ubaldo Sagripanti, psichiatra del Dipartimento di Salute Mentale dell’Ospedale San Claudio di Corridonia (MC)[10].

In conclusione, è fondamentale riportare all’interno della cura valori essenziali come il dialogo, l’ascolto e quell’empatia necessaria affinché la persona ammalata percepisca che chi lo sta curando non solo è competente ma rimarrà umanamente accanto sino a quando il pericolo non sarà passato. Questa è la vera essenza del mestiere del medico.

Ignazio Marino

Con più di 9mila trapianti eseguiti dal 1990 a oggi, il Piemonte continua a confermarsi la Regione leader in Italia (per la quale la Città della Salute di Torino ne rappresenta il centro più attivo), anche se il 2019 con le sue 435 operazioni ha registrato un leggero calo nei confronti dell’anno precedente dove, invece, ne erano state praticate 468. Tra questi sono stati 232 quelli di rene, 148 di fegato, 25 di cuore, 23 di polmone e 6 di pancreas.

Allo stesso modo si registra un aumento qualitativo per ciò che concerne i risultati clinici dei trapianti combinati e di quelli da donatore vivente, fattori che hanno permesso un aumento dell’aspettativa di vita a cinque anni dagli interventi[1].

Il centro torinese lo scorso anno ha ospitato 8 trapianti combinati di rene e fegato, 4 di rene e pancreas, uno di fegato e pancreas, uno di cuore e polmoni e addirittura uno combinato di fegato, polmoni e pancreas[2]. In Piemonte si registra anche un’alta percentuale di donazioni (137 nel 2019), “il terzo miglior risultato degli ultimi 10 anni”, un traguardo dovuto soprattutto alla netta diminuzione di chi, tra i familiari della persona deceduta, si oppone alla donazione degli organi. Ma dobbiamo anche ricordare il fatto che in Piemonte ben 976 Comuni della Regione[3] offrono la possibilità ai residenti di esprimere la propria volontà in relazione alla donazione degli organi dopo la morte. Un tema che non deve essere sottovalutato e, personalmente, sono orgoglioso di aver introdotto questa possibilità all’Anagrafe di Roma dove oggi ogni cittadino può esprimere le proprie indicazioni al momento del rinnovo della carta di identità.

Questa maggiore disponibilità degli Italiani nei confronti delle donazioni si evince anche da un recente fatto di cronaca. Nell’ospedale San Marco di Catania è stato realizzato il primo prelievo multiorgano su un paziente di 75 anni deceduto nel reparto di rianimazione in seguito ad un sanguinamento intracranico. “Spero che il nostro gesto serva per sensibilizzare la gente a donare”, è stato il commento di uno dei figli del donatore, che ha visto destinare il fegato prelevato dai medici dell’Ismett di Palermo ad un paziente di una struttura in Lombardia, mentre le cornee sono state destinate alla banca degli organi di Catania[4]. Tutto questo si è reso possibile grazie al lavoro sinergico di diverse figure, prima su tutte il Dott. Alessandro Conti, referente per il San Marco del Coordinamento locale dei trapianti dell’Azienda Ospedaliera Universitaria di Catania, che si è occupato di parlare con i familiari e di coinvolgere la Direzione Medica di Presidio e tutti gli specialisti[5].

Un altro dato positivo ci viene dalla Sardegna, una Regione che ha registrato una crescita delle segnalazioni dei donatori addirittura del 30%, passando da 70 nel 2018 a 92 nello scorso anno, e attestandosi al quarto posto di questa importante classifica della generosità italiana. La Sardegna ha anche ottimi risultati per quanto riguarda l’attesa per un organo dei pazienti, con una media di 63 giorni per ciò che riguarda il trapianto di fegato (a fronte dei 150 giorni di media nazionale), 85 giorni per il cuore (360 di media in Italia), 240 per il rene (750, in questo caso, la media nazionale)[6].

Numeri che hanno spinto l’assessore alla Sanità Mario Nieddu, in occasione del report su donazioni e trapianti del 2019 enunciato alla fine di gennaio 2020 a Cagliari assieme al coordinatore del Centro regionale trapianti, Lorenzo D’Antonio, a dichiarare come “l’attività di donazione e trapianti ha registrato nel 2019 numeri positivi sul nostro territorio, con una considerevole inversione di tendenza rispetto all’anno precedente. Un aspetto che testimonia il grande potenziale di un ambito che in Sardegna esprime eccellenze e grandi professionalità”.

Ovviamente uno dei fattori più importanti è quello dell’informazione da parte delle Istituzioni che non deve essere occasionale o episodica.

Un impegno, questo, che Il Centro Regionale Trapianti della Sardegna ha assunto con particolare vigore: sono infatti stati realizzati diversi incontri che, a partire dalla facoltà di Scienze infermieristiche dell’Università di Cagliari, dall’Ordine delle Professioni infermieristiche di Cagliari e dal personale dell’Anagrafe dei Comuni della Sardegna, hanno coinvolto gli studenti delle scuole superiori e le Forze Armate, con l’obiettivo di divulgare la cultura della donazione mediante il progetto chiamato Una scelta in Comune[7].

Un’altra Regione particolarmente virtuosa sul tema si conferma essere il Friuli-Venezia Giulia, come ha dichiarato anche il vicepresidente con delega alla Salute Riccardo Riccardi in occasione della Giornata della Riconoscenza, organizzata a Udine dall’Ado Fvg “e rivolta alle 272 famiglie provenienti da tutta la regione che nel 2018 hanno scelto di donare gli organi di un loro congiunto”. Durante l’incontro è stato dichiarato un incremento del 10% dei trapianti di organo. Dal 1999, anno in cui è nato il Centro di Coordinamento Regionale, si sono contati ben 2.381 trapianti e un’impennata dalle 700 alle attuali 1.700 donazioni annue. E se fa ovviamente piacere ascoltare da Riccardi che “il 97 per cento dei Comuni è abilitato a recepire la dichiarazione di volontà del donatore al momento del rinnovo della carta di identità, un'adesione che ha portato da 48mila a 103mila le persone disponibili a donare”, però, le parole che ho più apprezzato riguardano la sua esortazione ad una “cultura della gratitudine, che va recuperata assieme al tema estremamente attuale della riconoscenza”.

“Non c'è valore più alto che questa società possa esprimere nella capacità di donare ad altri la vita nel momento in cui si sta perdendo quella di chi ci è più caro al mondo”, sono tutte parole che sottoscrivo[8].

Bisogna ribadire l’importanza di questa consapevolezza, che dovrà sicuramente passare attraverso la volontà delle istituzioni nell’organizzare frequenti campagne di informazione arrivando a coinvolgere un numero sempre più grande di cittadini e che non potrà esimersi da una revisione degli squilibri tuttora presenti sul territorio nazionale.

Come ha spiegato il Direttore del Centro Nazionale Trapianti, Massimo Cardillo, in un’intervista di qualche tempo fa all’Avvenire, infatti, “i tassi di donazione sono soddisfacenti in alcune regioni ma non in tutte: c'è ancora divario tra le regioni del Nord e quelle del Sud, che va colmato. Bisogna incardinare la donazione all'interno dei percorsi consolidati dell'ospedale: la segnalazione di un potenziale donatore non deve essere legata soltanto alla buona volontà dei professionisti ma seguire procedure consolidate e strutturate. Esistono figure di riferimento per la donazione, sia negli ospedali sia nei coordinamenti regionali, ma spesso queste strutture non sono messe in grado di operare con risorse adeguate". Uno strumento che potrà rivelarsi utile, dunque, sarà il Piano Nazionale per le Donazioni che mi auguro venga inserito il prima possibile all’interno del rinnovato Patto per la salute[9].

Ignazio Marino

A causa della pandemia, che ci vede tutti coinvolti e uniti verso la comune ricerca di una soluzione, è cresciuta l’attenzione relativa agli investimenti sulla salute e sul Servizio Sanitario Nazionale.

È stata anche l’occasione di ribadire e sottolineare temi che alcuni, come me, cercano di sollevare da diversi anni: l’incredibile sproporzione tra ciò che lo Stato ritiene giusto spendere per la Difesa e per gli armamenti e quello che concede alla sanità. Tra l’altro, con una Costituzione che all’articolo 11 ripudia la guerra e all’articolo 32 stabilisce il diritto alle cure per tutti. Abbiamo il dovere di esaminare le priorità del Paese e delle persone, e dobbiamo avere la coerenza di fondare le nostre decisioni di bilancio sui principi della nostra Costituzione.

Personalmente provo sofferenza e disagio nel leggere gli ultimi dati registrati dalla Fondazione GIMBE – Gruppo Italiano per la Medicina Basata sulle Evidenze – che da un lato rivelano per la spesa sanitaria di quest’anno una contrazione sul PIL dello 0,5% e dall’altro attestano come per quella militare la tendenza sia opposta, arrivata ormai ad occupare stabilmente l’1,40% del prodotto interno lordo nazionale. Anche l’Osservatorio Mil€x condivide gli stessi risultati[1], confermando come nel 2019 siano stati investiti in Difesa circa 25 miliardi di euro (che quest’anno sono diventati 26), comprendendo in essi sia gli importi per le missioni all’estero (1,3 miliardi annui) sia quelli per il procurement militare, ossia gli acquisti di armamenti, tra i quali vi sono 6 miliardi per le fregate FREMM e altre esigenze della marina militare, soldi per bombe e missili e 15 miliardi per l’acquisto degli F-35. Ma la lista non è finita: approfondendo l’analisi notiamo come a questa spesa si aggiungono anche 7 miliardi di euro sbloccati dalla Difesa e dal MISE per i mezzi blindati e per gli accordi siglati con Leonardo.

Tantissimi soldi, soprattutto se consideriamo che nello stesso periodo il settore sanitario assisteva a una riduzione di oltre 43.000 risorse umane con una riduzione dei finanziamenti per la salute di oltre 37 miliardi di euro in 10 anni. È sufficiente un dato del quale i telegiornali ogni giorno, negli ultimi due mesi, hanno sottolineato l’importanza: la carenza dei posti letto. A causa dei tagli alla sanità l’Italia è scesa molto al di sotto della media europea di posti letto ogni 1.000 abitanti (3,2 a fronte di una media europea di 5).

In tutto questo siamo incredibilmente sempre più legati ad accordi internazionali, come dimostra una recente dichiarazione del Presidente USA Donald Trump che imponeva ai Paesi membri della Nato di spendere ogni anno non meno del 2% del loro PIL in armamenti. Per l’Italia significa aumentare ulteriormente di circa 10 miliardi di euro l’anno le spese militari.

Per dare un’immagine chiara delle proporzioni dei due diversi investimenti, basti pensare che in questa inedita e storica situazione di emergenza sanitaria il Governo italiano si è sforzato di mettere in campo 25 miliardi di euro attraverso il decreto Cura Italia. Questa stessa cifra è il corrispettivo di ogni anno di Bilancio della Difesa[2].

Addentrandoci ancora di più nel documento dell’Osservatorio Mil€x, che basandosi sulla definizione di spesa militare fornita dall’istituto di ricerca SIPRI di Stoccolma, afferma che si registra un “fortissimo aumento di oltre 1,5 miliardi di euro pari ad oltre il 6% in più su base annua, sia per la crescita diretta del bilancio proprio del Ministero della Difesa sia per il mantenimento di alti livelli di spesa di natura militare anche su altri Dicasteri”. Approfondendo tale report, “continua ad essere in crescita la quota di investimento per nuovi sistemi d’arma proveniente dal Ministero per lo Sviluppo Economico (ormai arrivata a quasi tre miliardi) ma è soprattutto la decisa risalita degli investimenti per armi allocati sul bilancio della Difesa (circa 2,8 miliardi con un +40% rispetto al 2019) a portare i fondi a disposizione per acquisti di nuove armi ad un livello forse record di quasi 6 miliardi”[3].

Alla luce di tutte queste cifre è utile sottolineare quanto dichiarato dalle due associazioni sopracitate, che auspicano per l’Italia l’attuazione di una “conversione dal militare al civile” in quanto per “nessun Governo nell’ultimo decennio la sanità ha mai rappresentato una priorità politica”. È estremamente frustrante, infatti, constatare come ogni volta che l’economia si trovi in una situazione di stagnazione “la sanità si trasforma inesorabilmente in un ‘bancomat’ mentre in caso di crescita economica i benefici per il SSN non sono proporzionali, rendendo di fatto impossibile il rilancio del finanziamento pubblico”[4].

Fatti che disorientano. Con amarezza viene da scrivere che non avevamo, quando erano indispensabili, respiratori e posti letto per tutti gli ammalati, ma abbiamo sempre avuto in tutto questo frangente la certezza che grazie agli F-35 saremmo stati in grado di bombardare qualunque luogo nel raggio di 1.000 km dall’Italia.

Una riflessione per il Parlamento e per un Governo sostenuto da forze politiche che a parole aborrono la guerra e gli armamenti, come dimostrava la volontà dello stesso Beppe Grillo che sul suo blog, prima dell’ascesa del M5S a Palazzo Chigi, annunciava un imminente taglio di 10 miliardi alle spese militari[5], o come l’allora Ministro Trenta che addirittura dichiarava a nome di tutto il Movimento “non compreremo nuovi caccia e, alla luce dei contratti in essere già siglati dal precedente esecutivo, stiamo portando avanti un’attenta valutazione che tenga esclusivamente conto dell’interesse nazionale"[6], ma che poi nei fatti confermano e, se possibile, addirittura incrementano quello che a parere mio e di molti altri è nient’altro che una scelta sbagliata. E l’attuale Ministro della Difesa ha confermato l’impegno economico per gli F-35: affermando, anche durante la pandemia in atto, che sia un errore contrapporre gli investimenti della Difesa a quelli della Salute. Personalmente, sono convinto che se si potessero esprimere i cittadini italiani non condividerebbero questa visione e preferirebbero investire in strumenti per proteggere la salute piuttosto che in cacciabombardieri.

In Italia vi è la necessità di ripensare il Servizio Sanitario Nazionale restituendo alla medicina territoriale il suo ruolo, che è quello di soggetto indispensabile volto alla cura delle malattie croniche, al coordinamento della salute delle persone e al primo soccorso medico.

Tutti abbiamo assistito, tristemente, alle grida di allarme pervenute in queste settimane di emergenza sanitaria da parte del personale medico di tutta Italia, che ha ripetutamente denunciato come i posti a disposizione per i ricoveri urgenti fossero già da tempo al collasso.

È per lo stesso motivo che molte delle proposte giunte da chi lavora nel campo medico su come gestire la situazione post-emergenziale si sono concentrate sull’esigenza di ridare centralità alla medicina generale e alla prima assistenza territoriale, condizioni che sicuramente contribuiscono a prevenire la nascita di nuovi focolai e la confusione dei pazienti.

Ovviamente in una situazione straordinaria come quella che stiamo vivendo schierare i medici generali nel contrasto al COVID-19 non può prescindere dall’adozione di tutte le precauzioni volte ad evitare che lo stesso professionista venga contagiato.

Purtroppo, non possiamo pensare che tutto si digitalizzi automaticamente. Immaginare in Italia una simile rivoluzione operativa nell’immediato non è realistico.

Nonostante quindi il dibattito politico si sia trasformato in uno scontro tra chi ritiene la medicina di prossimità inutile, come nel caso della Regione Lombardia, e chi, invece, la ritiene completamente digitalizzabile, non possiamo non considerare che il rapporto personale tra un paziente e il suo medico dovrà continuare ad esistere se vogliamo una medicina umana. È indispensabile fin da subito agire per programmare ogni possibile protezione idonea, analizzando la distribuzione della medicina di prossimità nel Paese[1].

Soltanto attraverso una valorizzazione attenta e capillare dei medici di base saremo in grado di intercettare tutte le necessità dei pazienti. Come ha recentemente affermato anche il viceministro alla Salute Pierpaolo Sileri: “la medicina territoriale va sicuramente potenziata. Non si può programmare una riapertura senza avere certezza dei servizi sanitari territoriali dei medici di medicina generale e dei medici competenti in sanità pubblica, e dell’utilizzo dei tamponi”. Per poi aggiungere come “nella fase 2 dovrebbero essere i medici di base a eseguire i tamponi: è necessario che il territorio risponda ma che gli vengano anche dati gli strumenti per farlo”[2].

Ridurre il ruolo della medicina di prossimità significa ridurre drasticamente le possibilità diagnostiche e questo aumenta la pericolosità di una malattia, specialmente in una situazione di emergenza.

D’altronde sarebbe sufficiente affidarsi alle osservazioni di tutti quei professionisti che stanno curando gli ammalati di Coronavirus. Ho trovato infatti prezioso il contributo che hanno voluto dare 70 medici generali della Lombardia che hanno redatto un vero e proprio manifesto operativo volto alla gestione del COVID-19. Il loro documento sottolinea con chiarezza come soltanto mediante un alleggerimento dell’attuale sistema sanitario “ospedalecentrico” si possa efficacemente affrontare e superare una pandemia.

“La soluzione per convivere e avviare una Fase 2 nella sanità è individuare ospedali di piccole medie dimensioni da adibire totalmente al servizio per i pazienti infettivi, con i diversi livelli assistenziali relativi e personale volontario e comandato che sia residente nella struttura, con percorsi e passaggi obbligati e con tutti i dispositivi di protezione personale per la sicurezza dei lavoratori” hanno affermato. Inoltre, si dovrebbe ampliare l’assistenza territoriale così da ridurre quel 24,7% dei contagi, registrato dall’Istituto Superiore di Sanità, avvenuti in ambito familiare a causa dell’aver delegato l’assistenza ai soli familiari[3].

I presupposti ci sono, e si possono già vedere realizzati in alcuni territori virtuosi che per primi, negli anni passati, hanno attuato una riorganizzazione sanitaria basata sulla prossimità.

Come ad esempio l’Usl Umbria 2, che negli anni passati ha istituito “le Usca, Unità Speciali di Continuità Assistenziale, oggi presenti in tutti i distretti sociosanitari di Terni, Foligno, Narni-Amelia, Spoleto, Orvieto e Valnerina, affiancandole al prezioso lavoro dei medici di medicina generale, ai servizi di prevenzione e alle attività di sorveglianza attiva e domiciliare”. Si tratta di “un’attività di monitoraggio capillare nei territori di 12 ore al giorno, sette giorni su sette, a cui hanno aderito molti professionisti neolaureati che con grande passione per il proprio lavoro e generosità sono parte attiva di questa difficile sfida”, come spiega il commissario straordinario dell’Azienda, attività, che sono indispensabili alla prevenzione e al contenimento del contagio[4].

La strategia migliore per intervenire sul contenimento della pandemia e quindi su una sua più lungimirante gestione, dunque, sembra essere la stessa che ha indicato anche un recente comunicato inviato dalla Fimmg (Federazione Italiana Medici di Famiglia) al Ministro Roberto Speranza. All’interno di questo documento, infatti, si può leggere come nel prossimo futuro bisognerà concentrarsi su “prossimità̀ e pro-attività̀ per modificare l’attuale paradigma assistenziale, troppo centrato su una prospettiva specialistica e ospedalo-centrica e rendendolo più sostenibile”. Nel documento si augura lo sviluppo di un “Piano Nazionale che sappia coordinare gli interventi in maniera efficace, evitando che iniziative eccessivamente localistiche e non coordinate possano compromettere i grandi sforzi e sacrifici che tutta la Comunità Nazionale ai vari livelli sta compiendo”, una vera e propria rivoluzione nella distribuzione e nel monitoraggio dei fondi destinati alle varie realtà nazionali[5].

Bisogna insistere sul rafforzare il rapporto tra medico e paziente, potenziandone di conseguenza il livello di cure e di assistenza fino a ristabilire quel ciclo di fiducia che è proprio della medicina generale e che ne rappresenta lo strumento più efficace.

Ignazio Marino

È di qualche giorno fa, in piena emergenza CoVid-19, la dichiarazione dell’assessore al Welfare della Regione Lombardia Giulio Gallera che consigliava agli over 65 anni di rimanere a casa in quanto individui più a rischio. Neanche un giorno dopo, lo stesso annunciava la volontà di richiamare in servizio medici e infermieri in pensione a causa della mancanza di personale sufficiente.

A tali parole si contrapponevano quelle di Carlo Palermo, segretario di Anaao Assomed, sindacato dei medici, che evidenziava come “sarebbe meglio assorbire forze fresche per il Sistema Sanitario Nazionale, già carente e stressato di per sè e ancor di più messo a dura prova dall’epidemia da Coronavirus”, per renderci conto di essere davanti a un enorme problema nazionale che la recente emergenza sanitaria ha solo riportato all’attenzione di tutti[1].

Io stesso ne avevo scritto tempo fa, su questo stesso blog, di come potessimo pensare “che l’utilizzo di camici bianchi militari o già pensionati possano risolvere una crisi che è sistemica”, ma la mia era stata solo una voce tra tante. Tante voci inascoltate da anni: istituzioni e governi non hanno fatto nulla per invertire la rotta[2].

A queste riflessioni ne andavano aggiunte due: il 10% degli individui risultati positivi al virus è proprio composto dal personale medico: medici, tecnici e infermieri che da quando è iniziata l’emergenza hanno esteso i loro turni per poter fronteggiare la maggior parte delle esigenze nazionali. Come commentare il fatto che quattromila laureandi lo scorso 28 febbraio avrebbero dovuto sostenere l’esame di Stato per l’abilitazione all’esercizio e, invece, sono rimasti in “panchina”. Chiedete a qualunque medico se l’esame di stato ha aggiunto qualcosa alla sua preparazione. Tutti vi risponderanno che non ha aggiunto nulla. Parliamo di quattromila giovani medici che, a tirocinio già terminato, si trovavano in attesa che il Ministero comunicasse loro una data possibile per effettuare il test a crocette per l’ingresso all’albo. Giovani come F.M. di 24 anni, neolaureato in medicina e chirurgia a ottobre scorso, che giudicava questa situazione (paradossalmente causata dallo stesso virus) offensiva e umiliante. “Siamo in tanti e saremmo pronti a dare una mano. Invece ci lasciano qui nel limbo e richiamano i pensionati. Poi si domandano perché i giovani se ne vanno all’estero”, come dichiarava in una recente intervista a L’Espresso.

Sarebbe così laborioso per il Parlamento votare in un giorno una legge di un singolo articolo che dica: “Al fine di fronteggiare l’emergenza sanitaria in atto a tutti i laureati è consentita l’iscrizione all’Albo senza dover sostenere l’esame di stato”? Questa la domanda che mi ponevo continuamente.

In una situazione come quella attuale tenere queste risorse bloccate rappresentava un’assurdità. “Tenerci fermi è un paradosso, io sono di Milano e tanti miei colleghi lombardi, veneti, emiliani, siamo medici e sappiamo di avere le competenze per poter dare un contributo importante in questa emergenza. Invece c’è solo la frustrazione di non poter far nulla”, continua lo stesso F.M. nella stessa intervista.

Una situazione che si faceva sempre più frustrante, per loro e per chi ha realmente bisogno del contributo che potrebbero immediatamente dare, aggravata oltretutto dalla quantità di medici e ricercatori che hanno già salutato questo Paese in cerca del meritato riconoscimento estero.

Come ad esempio la dottoressa in immunologia L. S. dell’Istituto Pasteur che, intervistata, ha confermato come sia “straziante assistere a questa emergenza e sapere che il nostro contributo, la nostra presenza sul campo, lì negli ospedali, avrebbe contribuito a combattere questo virus con più forza”. Ancora più interessante è ciò che aggiunge, denunciando come non si comprendano “le reali motivazioni di questo allontanamento, nonostante il fenomeno dell’espatrio dei neolaureati, scienziati e medici sia sotto gli occhi di tutti. C’è chi pensa di poterci richiamare con uno sgravio fiscale, ma non è una questione di soldi”.

Durante l’incontro Italiani all’estero: intelligenze senza confini sono stati diffusi dati davvero allarmanti. Ogni anno il 15% dei nuovi medici specialisti espatria, per un totale di oltre 10.000 risorse emigrate nell’ultimo decennio. Tra le mete preferite in grado di riconoscere il giusto merito e compenso a queste figure vi sono sicuramente la Svizzera e il Regno Unito. Parliamo di professionisti per ognuno dei quali l’Italia ha speso circa 500.000 Euro per formarli (dalle elementari alla specializzazione sono almeno ventiquattro anni di studio). E cosa fa l’Italia dopo aver investito così tanto in capitale umano? Crea le condizioni di impiego peggiori e li spinge a scegliere di lavorare in altri Paesi che non hanno investito un Euro nella loro formazione.

E qual è la situazione italiana nel frattempo? “Una voragine di 56mila medici che mancano all’appello” che si vuole colmare “puntando sui pensionati e richiamando specialisti da Paesi dove le condizioni di lavoro sono più arretrate delle nostre, come l’Est Europa o il Pakistan”.

È questo il giudizio severo rilasciato alla più prestigiosa rivista europea di medicina, The Lancet, dall’anestesista L.L.C.; un giudizio che condividevo in pieno. Il giovane laureato in medicina al San Raffaele di Milano, e poi specializzato in Anestesia e Rianimazione all’Università di Parma, lavora oggi alla Duke University del North Carolina e dichiara di riconoscersi nei principi del Servizio Sanitario Nazionale italiano ma che esso “è diventato anacronistico e va svecchiato, riformato”[3]. Non parliamo della semplice (seppur fondamentale) questione salariale, ma di una più generale mancanza di valorizzazione del capitale umano, in termini di riconoscimenti e potere contrattuale.

Possiamo infatti essere orgogliosi ma non certo felici di fronte alle diverse fotografie, diventate ormai virali, che ritraggono il personale medico, dottori e infermieri, stremati nei reparti da turni interminabili per assistere il numero crescente di pazienti colpiti dal Coronavirus.

“Ciao dall'inferno. Qui è veramente pesante e dura. Siamo allo stremo ma resistiamo. Vi chiedo un favore per noi e soprattutto per gli infermieri che sono oltre l'eroismo. Aiutateci stando a casa, non siamo quasi più in grado di assistere oltre” è stato uno dei messaggi pervenuti da un medico del Sacco di Milano. Lo stesso medico proseguiva spiegando come i bisognosi di soccorso aumenteranno “ancora ma noi siamo sempre gli stessi. Convincete amici e conoscenti a resistere 15-20 giorni rispettando le regole. Altrimenti sarà un bagno di sangue”.

Ed è stato lo stesso direttore del Sacco Emanuele Catena ad aggiungere che “gli infermieri hanno turni di otto ore, i medici di 12-14 ore, e dopo il turno escono stremati, perché passano gran parte tempo sotto le tute protettive, con un lavoro duro su pazienti molto complessi, pericolosi, delicati, che richiedono anche variazioni di postura per poter essere curati al meglio”[4].

Insomma, una situazione che evidenziava come una gestione più lungimirante delle nostre risorse umane avrebbe potuto aiutare adesso e in futuro.

Fortunatamente sembra che questa esigenza sia definitivamente emersa anche per i vertici di Palazzo Chigi, dove con l’ultimo Decreto finalmente lo strumento dell’esame di Stato in medicina è stato abolito così da far diventare la laurea abilitante a tutti gli effetti.

Dopo le decise pressioni che il Ministero dell’Università e Ricerca ha esercitato sull’esecutivo, infatti, questa misura è stata definitivamente inserita all’interno dell’ultimo Decreto legislativo per fronteggiare l’emergenza da CoVid-19. Nero su bianco, quindi, si dice che “per gli studenti che alla data di entrata in vigore del presente decreto risultino già iscritti al predetto Corso di laurea magistrale, resta ferma la facoltà di concludere gli studi, secondo l’ordinamento didattico previgente, con il conseguimento del solo titolo accademico”[5].

E così, dopo tanto tempo, pare che finalmente sia stato riscritto il percorso finale della formazione dei giovani medici e chirurghi che non dovranno più, al termine della sessione di laurea e del tirocinio valutativo di quattro settimane sostenere la formalità della parte teorica dell’Esame di Stato (il sopracitato test d’abilitazione). Una misura che era già in parte stata proposta dall’ex Ministro dell’Istruzione Valeria Fedeli all’interno del Decreto Calabria che ora, visto il contesto, prende definitivamente piede.

Sembra una piccola modifica, ma non lo è. Prendiamo il caso dei circa 4 mila giovani laureati che attendevano questa seconda sessione del 2019, che era prevista per il 28 febbraio, e che di fatto hanno atteso 8 mesi senza, nel frattempo, poter esercitare. Grazie a questo Decreto, quindi, sono divenuti una preziosa risorsa per l’Italia.

Un deciso passo in avanti, tanto che d’ora in poi l’abilitazione verrà raggiunta soltanto con il titolo accademico e il superamento del tirocinio. Come si legge nella relazione illustrata, infatti, “la proposta è finalizzata a superare, a regime, il meccanismo dell’abilitazione all’esercizio professionale per i laureati in medicina e chirurgia attraverso l’esame di Stato”[6].

Che altro dire? Sono contento che si sia raggiunto questo importante. Mi dispiace, ovviamente, che quella che sembrava a tutti gli effetti una decisione logica e di buon senso sia stata attuata soltanto in occasione di una delle più grandi emergenze nazionali e internazionali che abbiamo mai avuto il compito di affrontare. Questo non deve rappresentare un punto di arrivo ma soltanto un primo passo per far sì che le nostre risorse rimangano ad esercitare in Italia con il giusto riconoscimento, umano, economico e professionale.

Ignazio Marino