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The transplantation of multiple abdominal viscera, including liver-duodenum-pancreas, liver-stomach-duodenum-pancreas and liver-intestine, is being performed with increasing frequency and success. These procedures and other variations are derived from a seldom used multivisceral operation in which all of the foregoing organs are transplanted en bloc. It is described herein how the full multivisceral transplantation and its less extensive derivatives are based on the same principles of procurement, preservation and postoperative management. With all of these multiple organ permutations and with intestinal transplantation alone, management is complicated by inclusion in the grafts of a large lymphoreticular component that is capable of causing graft versus host disease (GVHD). Because of a systematic error in therapeutic philosophy, past efforts have been directed at altering or damaging the lymphoreticular cells by pretreatment of the donor or of the organs with drugs, irradiation or other means. From recent observations, the alternative approach is suggested of keeping these lymphoid depots intact, which then become the site of two way cell traffic after transplantation. With the use of powerful immunosuppression, such as that provided with FK 506, the donor lymphoreticular cells can circulate in the recipient without causing clinical GVHD, and the lymphoreticular cells in the graft become those of the recipient (local chimerism) without causing rejection. Even with avoidance of rejection and GVHD, metabolic interrelations between the grafted organs, and also between the graft organs and retained recipient viscera can affect the fate of the individual transplanted organs or retained recipient organs. The best delineated of these metabolic influences are mediated by the endogenous splanchnic hepatotrophic factors, of which insulin has been the most completely studied. An understanding of these various immunologic and nonimmunologic factors combined with more potent immunosuppression that is now available is sure to stimulate efforts at transplantation of abdominal organs and particularly of the hollow viscera that have resisted such clinical efforts.

In the Pittsburgh series of 1,000 orthotopic liver transplants (OLTx), from January 1981 to July 1987, the indication for transplantation in five patients consisted of unresectable hepatic metastases arising from endocrine tumors of gastrointestinal origin: glucagonoma, two patients; carcinoid, two, and gastrinoma, one patient. Three patients underwent resection of the primary tumor (two distal pancreatectomies and one ileal resection) at the time of the hepatic transplantation. All patients underwent extensive nodal dissection. Three of the five patients are alive with no evidence of residual disease after a median follow-up study of 12 months. Hepatic transplantation broadens the concept of radical excision of tumor and may be considered as a potential therapeutic approach for some highly selected instances of unresectable hepatic metastases arising from endocrine tumors of the intestine and pancreas.

Methods for combination of donor nephrectomy with donor cardiectomy are outlined. The satisfactory early function of 29 of 34 transplanted kidneys harvested with these techniques supports their wider application and should encourage their wider acceptance.

Ten nondiabetic dogs were submitted to a procedure called splanchnic division which directed the nutrient rich venous return from the intestines into the left lobes of the liver and the hormone rich pancreaticogastroduodenosplenic venous return into the right lobes. Two months later, the right lobes had undergone the expected gross and microscopic hypertrophy. Compared with the abnormal shrunken and glycogen-depleted hepatocytes of the left lobes, the large and otherwise normal hepatocytes of the right lobes had a higher rate of cell division as judged by microscopic examination, measurements of deoxyribonucleic acid synthesis and the results of autoradiography. Both sides had greater cell replication than in the livers of normal unaltered dogs. The dominance of the right lobes following splanchnic division was almost completely eliminated by the prior creation of alloxan-induced diabetes in four dogs and by the performance of total pancreatectomy at the same time as splanchnic division in six dogs. In these ten diabetic dogs, which were treated with subcutaneously administered insulin for the two month period of the post operative study, hepatic lobar and cell size were nearly equal on both sides. By light and electron microscopy, the hepatocytes on both sides had abnormalities, somewhat less pronounced on the right. However, the most active cell division was now transferred to the left lobes. The results with alloxan-induced diabetes were similar to those after total pancreatectomy, except the lipid deposits were less on both liver sides in the alloxan experiments, and the glycogen was selectively reduced in the right lobes. The latter finding presumably was due to the continued action of glucagon in dogs made diabetic with alloxan. Twelve nondiabetic dogs had a procedure called partial portacaval transposition which directed systemic venous blood from the hindquarters, kidneys and adrenal glands into the left lobes of the liver and the total splanchnic venous return into the right lobes. Two months later, the degree of relative hypertrophy and hyperplasia of the glycogen rich right lobes was even greater than after splanchnic division, as was the morphologic damage to the left lobar hepatocytes. The degree of right lobar hypertrophy following partial portacaval transposition was reduced but not eliminated by pre-existing alloxan-induced diabetes in four dogs and by concomitant total pancreatectomy in six more dogs. The dogs were subcutaneously treated with insulin. Structurally, the hepatocytes on the right side after two months were in better condition than were those on the left, although both were abnormal. The dominance of cell division on the right side was reduced, as judged by standard microscopy and by autoradiography, but there was not a shifting of sides. The biochemical analyses reflected the presence or absence of glucagon. These findings are consistent with our earlier multifactorial hypothesis which holds that portal hepatotrophic factors are mainly interreacting hormones generated by splanchnic organs and delivered straight to the liver and that the hormone interrelationships might have augmented significance because of the high concentration of nutritional substrate in the same venous blood. The observations also substantiate by direct testing the suggestion that insulin is the most important hepatotropic factor and that it profoundly affects many aspects of liver cell structure, division and function.

A rapid technique for multiple organ harvesting is described which allows removal of all the major organs within 30 to 60 minutes after beginning the donor operation. No preliminary dissection of the liver or kidneys is required or necessary since these organs are cooled by infusion of cold solutions in situ and with subsequent rapid dissection in a bloodless field. The incidence of well functioning kidneys, livers and hearts has been better than with the previous methods. The acceptance of this procedure by other personnel has been almost universal.

With the improvements in immunosuppression that have occurred in the last few years, a great increase can be expected in the demand for cadaveric kidneys and other vital organs. Doctor Koop, Surgeon General of the United States, has convened conferences and symposia to examine questions of cadaveric organ solicitation, removal, preservation and deployment. In such discussions, it has been obvious that a uniform procedure should be developed which is flexible enough to allow the excision of various organ combinations without jeopardy to any of the individual grafts. This study was done to report the method which we have used with satisfaction for several years.

All, or nearly all, of the nonhepatic splanchnic viscera were removed in dogs. In most untreated dogs, the liver cells underwent changes similar to those caused by portacaval shunt, including structural deterioration of organelles and fatty metamorphosis. The rate of division of the hepatocytes, as measured by the mitotic index and by autoradiography, was depressed as were deoxyribonucleic acid synthesis and adenylate cyclase activity. These changes were restored to, or toward, normal with the intraportal administration of commercial or purified insulin but not with glucagon or epidermal growth factor. The results of both the pathologic and biochemical studies were consistent, except for an incongruity in some of the dogs in which the colon was retained.

Eighteen patients were treated with primary cadaveric renal transplantation using cyclosporin A therapy, and four more patients undersent cadaveric retransplantation. Eleven of the 22 recipients were conditioned with lymphoid depletion before transplantation, using thoracic duct drainage or lymphapheresis for two to eight and one-half weeks. Cyclosporin A was begun a few hours before grafting. The other 11 patients were pretreated with cyclosporin A for from one day to 18 days. After transplantation, the majority of patients in both subgroups of 11 had rejection develop, but in most, the immunologic process was readily controlled with relatively small dosages of prednisone. After follow-up periods of two to four and one-half months, one patient has died of the complications of a coronary artery reconstruction that was not related to the transplantation. Another graft was lost from rejection, and a third organ was removed because of ureteral necrosis. Nineteen of the original 22 cadaveric kidneys are functioning, including 17 of the 18 kidneys given to patients who were undergoing transplantation for the first time. The only loss in the latter group of 18 patients was in the patient who died after an open heart operation. Results of these studies have shown that cyclosporin A is a superior and safe immunosuppressive drug but that, for optimal use in cadaveric transplantation, it usually should not be given alone. Steroid therapy greatly amplified the value of cyclosporin A. Unless major delayed morbidity develops which is not obvious so far, this drug combination should permit revolutionary advances in the transplantation of all organs. Other adjuncts to the cyclosporin A-steroid combination, including lymphoid depletion techniques, will require further investigation.

This surgical technique has permitted re-entry into the intrahepatic and extrahepatic biliary tree for the purpose of dilatation and the manual propulsion of debris through a ductal anastomosis. The method undoubtedly has other applications in the treatment of complicated biliary duct problems.

Complete diversion of portal blood in dogs caused sustained falls in serum cholesterol and phospholipid concentrations an declines in hepatic cholesterol and triglyceride synthesis. The hepatocytes in these canine livers were deglycogenated, and they atrophied to about half of their original size within two months. At the same time, there was evidence of increased mitoses. Ultrastructurally, the dominant change in the hepatocytes was in the rough endoplasmic reticulum which decreased in amount, underwent marked dilatation, and became depleted of ribosomes. There was also marked loss of glycogen granules, variable mitochondrial abnormalities, and widespread accumulation in the hepatocyte cytoplasm of lipid vacuoles. Bypass of intestinal venous return around the liver through a mesenteric caval shunt did not influence the serum lipid concentrations in dogs and baboons, although cholesterol synthesis was depressed in the canine livers and significant morphologic changes, including atrophy, were produced. In both species, the addition of a second stage central portacaval shunt which diverted venous return from the pancreaticogastroduosplenic area caused declines in serum cholesterol and phospholipid concentrations. After the second operation, hepatic cholesterol synthesis in the dogs was further reduced, and triglyceride synthesis was markedly depressed. The eventual ultrastructural changes were similar to those after one stage portal diversion. In other experiments on dogs, discrete regions of the liver were provided with portal perfusion from different splanchnic sources during a two month period. When the right lobes received pancreatiogastroduodenosplenic venous blood and the left lobes received intestinal venous effluent, in vivo cholesterol and triglyceride synthesis were higher in the hormone-enriched right lobes. This advantage was eliminated with pre-existing alloxan-induced diabetes or by the concomitant performance of total pancreatectomy in dogs that were treated during the ensuing two months with subcutaneously administered insulin. The nutrient-enriched left lobes had the higher lipid synthesis. In a final series of experiments, the right lobes of dogs were given the total splanchnic flow, and the left lobes were perfused with systemic venous blood by anastomosing the left portal vein to the suprarenal vena cava. The right lobar advantage in lipid synthesis could not be eliminated in this preparation with alloxan-induced diabetes or total pancreatectomy. These results indicate that a reduction of hepatic lipid synthesis is an important, although not necessarily the sole, factor in the antilipidemic influence of portacaval shunt. The effects upon synthesis and blood lipids apparently are due more to the diversion of endogenous hormones than to the bypass of intestinal nutrients. The substances in portal venous blood that subserve hepatic lipid metabolism are presumably largely the same as the hepatotropic factors which have been described before as profoundly affecting hepatic structure, function, and the capacity for regeneration. These portal blood factors are multiple and interrelated, but the single most important one seems to be insulin.

A tension mucocele was created in three hepatic homografts by ligating a low-lying cystic duct during transplant cholecystectomy and by incorporating its outflow end into the anastomosis of the common hepatic duct to the recipient common duct or Roux limb of jejunum. The consequent complication of obstruction of the biliary tract that necessitated reoperation and excision of the mucocele in all three patients can be avoided by the simple expedient of completely removing the cystic duct when feasible or providing egress to the secretion of the cystic duct as described.

Whole cadaveric pancreata were transplanted to the pelvic extraperitoneal location in four patients with diabetes who previously had undergone successful cadaveric renal transplantation. One graft was lost within a few hours from venous thrombosis but with patient survival. The other three are providing normal endocrine function after two and a half, 11 and 12 months. The exocrine pancreatic secretions were drained into the recipient jejunum through enteric anastomoses. Because mucosal slough of the graft duodenum and jejunum in two patients caused a protein losing enteropathy and necessitated reoperations, we now do the pancreatic transplantation with only a blister of graft duodenum large enough for side-to-side enteroenterostomy. The spleen has been transplanted with the pancreas mainly for technical reasons, and this technique should have further trials in spite of the fact that delayed graft splenectomy became necessary in two recipients to treat graft induced hematologic complications.

A modified final phase of recipient hepatectomy in orthotopic hepatic transplantation is presented. It involves preservation of the retrohepatic vena cava "in toto" to decrease the risk of injury to the adrenal gland and assure better control of the adrenal vein, as well as the forming of the caval cuffs, for the subsequent implantation of the donor liver.

During the 11 1/2 year period ending 13 months ago, 93 consecutive patients were treated with orthotopic liver transplantation. Fifty-six of the recipients were 18 years old or younger, and the other 37 were adults. The most common indications for operation were biliary atresia, primary hepatic malignant tumor, chronic aggressive hepatitis and alcoholic cirrhosis. There has been a gradual improvement in results throughout the period of study, although to a satisfactory level. Twenty-seven of the 93 patients survived for at least one year after liver replacement with a maximum of six years, and 16 are still alive after 13 to 71 months. The 11 late deaths after one to six years were caused by chronic rejection, biliary obstruction, recurrence of hepatoma, systemic infection or hepatitis of the homograft. Rejection of the liver as judged by classical histopathologic criteria played a surprisingly small role in the heavy over-all mortality, accounting for less than 10 per cent of the deaths. Technical or mechanical problems, especially those of biliary duct reconstruction, were a far greater cause of failure, as were systemic infections. Six of the 37 adult recipients had lethal cerebrovascular accidents during, or just after, operation. When abnormalities of liver function developed in the postoperative period, the nearly automatic diagnosis of homograft rejection, in retrospect, proved to have been wrong in most instances. Further development of liver transplantation depends upon two kinds of progress. There must be reduction of operative and early postoperative accidents and complications by more discriminating patient selection, purely technical improvement and better standardization of biliary duct reconstruction. The second area will be in sharpening the criteria for the differnetial diagnosis of postoperative hepatic malfunction, including the liberal use of transhepatic cholangiography and needle biopsy. Only then can better decisions be made about changes in medication or about the need for secondary corrective surgical procedures.

We investigated the fate of the cadaver renal transplant done with cyclosporine and prednisone immunosuppression into a recipient who had suffered the loss of at least two prior allografts. Nineteen cadaver renal allografts were transplanted into 18 recipients. All 18 recipients had previously rejected at least two prior allografts. One of these rejected an allograft done at our institution with cyclosporine and prednisone and was included a second time in this series when a fourth allograft was received. Nine of 19 allografts were successfully transplanted. Average follow-up time was 39 months. Eight allografts were rejected. One graft was lost to technical complications. In one instance, the recipient died with a functioning graft. Duration of function of previous allografts was not found to be a critical determinant of third or fourth graft survival. Human leukocyte antigen matching was not a statistically significant determinant. Panel reactive antibody was higher in those who rejected the third or fourth allograft, but not with statistical significance. Recipients with the blood type A were less likely to enjoy successful third or fourth cadaver renal transplantation. We concluded that the "two time loser" renal allograft recipient should not be systematically denied subsequent transplantation.

Thoracic duct drainage was added to conventional immunosuppression with azathioprine, prednisone and, sometimes, antilymphocyte globulin in 83 patients given cadaveric kidneys, including 65 primary graft recipients. The most effective use of thoracic duct drainage was for pretreatment. Optimal conditioning was at least four weeks duration, and when lymph drainage was this long, the incidence of rejection during the first three postoperative months was reduced to 4.5 per cent. Shorter pretreatment or institution of thoracic duct drainage contemporaneous with transplantation were less effective, but the one year results were still better than those with conventional immunosuppression alone. However, the advantage gained with thoracic duct drainage during the first year was diminished in all the treatment groups by graft losses in the second postoperative year. It was concluded that, without better maintenance therapy, the full value of temporary early lymphoid depletion procedures cannot be fully exploited.

From nine to 18 months ago, 66 patients were given 67 randomly matched cadaveric kidneys with cyclosporin A and steroid therapy. Nine of the recipients were undergoing retransplantation. The over-all kidney survival rate to date has been 77.6 per cent, and 78.8 per cent of the recipients are dialysis-free. The patient mortality in this learning phase was 13.3 per cent. Nephrotoxicity, hepatotoxicity and other side-effects of cyclosporin A could usually be dealt with by dosage adjustments, making feasible the chronic use of this agent. One B-cell immunoblastic sarcoma was encountered which was monoclonal. It was not responsible for death. Another patient had a perforation of the intestine from a lympho-proliferative reaction in which the B cells were polyclonal. After jejunal resection a year ago, there were no further complications. This lesion was not classified as a lymphoma. Both lympho-proliferative lesions were associated with a rise in antibody to viral capsid antigen of Epstein-Barr virus. Results of this study have verified the effectiveness and relative safety of cyclosporin A with steroids for immunosuppression in human recipients of cadaveric kidneys.

The postoperative convalescence period was analyzed for 42 consecutive patients who had cadaveric renal transplantation under therapy with cyclosporin A and steroids. Twenty-two of the patients underwent transplantation for the first time, and the other 20 had retransplantation. None of the recipients has died. With follow-up period of two to eight months, the survival rate of grafts is 96 per cent after first transplantation and 85 per cent after retransplantation. Immunosuppression with a standard regimen was used for all patients at the outset. Early convalescence was highly variable, often necessitating adjustments of cyclosporin A and steroid dosage to accommodate the possibilities of rejection or cyclosporin A nephrotoxicity, or both, simultaneously. Management problems were more frequent and complex in patients undergoing retransplantation. From the results, a classification of convalescence patterns was evolved, with recommendations about how standardized initial therapy should be adjusted if the renal graft does not function promptly or deteriorates later.

Fourteen patients with fibrolamellar hepatoma were treated with radical excision. In eight, a subtotal hepatic resection was performed from 16 months to more than 16 years ago. None of the patients have died and recurrences have been seen in only one patient. Six other patients had total hepatectomy and hepatic replacement. Two of these six patients have died of metastases and a third is living with recurrent tumor. This experience has Justified the continuing use of quite aggressive extirpative procedures for the treatment of fibrolamellar hepatoma.

The influence of portal blood factors on canine liver regeneration was studied with graded nonhepatic splanchnic evisceration, coupled with 44 and 72 per cent hepatectomies. In one type of experiment, the pancreas was retained while the rest of the intra-abdominal gastrointestinal tract was removed. In a second variety, total pancreatectomy was performed with preservation of the intra-abdominal organs. In a third kind of experiment, total nonhepatic splanchnic evisceration was performed. Liver regeneration after hepatectomy was decreased by all three kinds of viscera removed as judged by deoxyribonucleic acid synthesis, autoradiography and mitotic index. Pancreatectomy and nonpancreatic splanchnic evisceration caused almost equal decreases in the regenerative response. Total nonhepatic splanchnic evisceration essentially halted regeneration during the first three postoperative days and intraportal infusions of insulin or glucagon, or both together, did not reverse this effect. The decrease in liver membrane bound adenyl cyclase activity and biphasic change in liver cyclic 3', 5' -adenosine monophosphate concentrations normally seen after partial hepatectomy were disrupted after the various eviscerations. Adenyl cyclase activity and cyclic 3', 5' -adenosine monophosphate concentrations tended to be higher than normal in the eviscerated dogs. These observations provide more support for our previously proposed hypothesis that control of liver regeneration is by multiple factors. Pancreatic hormones are important modifiers of this response but, by no means, exercise exclusive control. Other substances of gastrointestinal origin, presumably including hormones and nutrient supply apparently play important specific roles. The volume of portal flow is a secondary and nonspecific, but possibly significant, factor.

A method has been described for establishing shunt patency by determining the difference in postprandial plasma glucose levels between a peripheral vein and the inferior vena cava at or near the site of the portal-systemic anastomosis. This tet was evaluated both in the laboratory with normal dogs before and after Eck fistula formation as well as cirrhotic patients with and without shunts. The results indicate that this test is reliable and has the advantages of safety, specificity, and ease of performance.

Dogs in which livers have been replaced with hepatic homografts usually die in 5 to 10 days. Liver metabolism is not detectably abnormal at first, but gradual deterioration of function commences on the fourth or fifth day. There was histologic evidence of rejection in all dogs dying after 4 days. This ranged from minimal mononuclear infiltration to almost complete destruction of parenchyma. In the longest survivor, 20 1/2 days, histologic changes were less profound than in many animals dying earlier. Widespread histologic changes were found in host reticuloendothelial system, involving the bone marrow, kidneys, lungs, lymph nodes, and other tissues. These consisted of fixed tissue proliferation and infiltration of mononuclear cells, principally plasma cells. These changes were thought to be due to a general host reticuloendothelial response to the antigenic stimulus of the homograft.