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A patient with coexistent hemochromatosis and alpha-1-antitrypsin deficiency which led to cirrhosis and death despite adequate therapy for hemochromatosis is reported. Evaluation of the family revealed first degree relatives with iron overload and others with alpha-1-antitrypsin deficiency but none with both conditions. The role of family studies in the early recognition and possible prevention of overt clinical disease in individuals with either of these two genetic diseases is discussed.

Background: The current staging system of hepatocellular carcinoma established by the International Union Against Cancer and the American Joint Committee on Cancer does not necessarily predict the outcomes after hepatic resection or transplantation. Study Design: Various clinical and pathologic risk factors for tumor recurrence were examined on 344 consecutive patients who received hepatic transplantation in the presence of nonfibrolamellar hepatocellular carcinoma to establish a reliable risk scoring system. Results: Multivariate analysis identified three factors as independently significant poor prognosticators: 1) bilobarly distributed tumors, 2) size of the greatest tumor (2 to 5 cm and > 5 cm), and 3) vascular invasion (microscopic and macroscopic). Prognostic risk score (PRS) of each patient was calculated from the relative risks of multivariate analysis. The patients were grouped into five grades of tumor recurrence risk: grade 1: PRS = 0 to 11.0 to 15.0; grade 4: PRS ≥ 15.0; and grade 5: positive node, metastasis, or margin. The proposed PRS system correlated extremely well with tumor-free survival after liver transplantation (100%, 61%, 40%, 5%, and 0%, from grades 1 to 5, respectively, at 5 years), but current pTNM staging did not. Conclusions: 1) Patients with grades 1 and 2 are effectively treated with liver transplantation, 2) patients with grades 4 and 5 are poor candidates for liver transplantation, and 3) patients with grade 1 do not benefit from adjuvant chemotherapy.

Background: This study was designed to review our experience with combined partial hepatectomy and vena caval replacement for primary and metastatic liver tumors. Study Design: The medical records of all the patients who underwent liver resection and excision of the vena cava over a period of 13 years and 4 months at a single institution were analyzed. The types of tumors fell into four categories: 1) metastatic, 2) primary leiomyosarcoma of the inferior vena cava, 3) tumors with direct extension to the liver, and 4) cholangiocarcinoma. Results: The perioperative mortality was 11% related to technical complications and hepatic insufficiency. Other important complications included biliary fistula and liver abscess; patients recovered from these complications without sequalae. Six of nine patients are alive with a followup from 6 months to 156 months (median 66.5 months), and three of them are free of disease. The most common sites of recurrence were lung, liver, and brain. The patients with leiomyosarcoma of the cava and pheochromocytoma who underwent these combined procedures had the longest survival. Conclusions: This small series confirms the feasibility of obtaining longterm survival after excision of tumors that have involved portions of the liver and the vena cava. Innovative variations on the method of vena caval replacement and increased awareness of these complex surgical techniques will expand the indications of hepatic resection.

BACKGROUND The pathologic TNM (pTNM) staging system was designed to aid in determining the prognosis of cancer patients and in planning and evaluating their treatment. The current pTNM classification system was not found to be predictive for patients undergoing orthotopic liver transplantation (OLTx) in the presence of hepatocellular carcinoma (HCC). Therefore, the authors examined the current system to determine whether improvements would allow the development of a more predictive system. METHODS Three hundred seven patients with HCC underwent OLTx between 1981 and 1997. Risk factors for recurrence were identified using the Kaplan–Meier method with the log rank test. The Cox proportional hazards model was used to identify factors independently predictive of recurrence which were then used to create a new staging system. RESULTS There was neither a direct correlation between the current pTNM system and tumor free survival nor homogeneity in outcomes for patients within certain current pTNM categories. Depth of vascular invasion, lobar distribution, lymph node status, and largest tumor size were found to be independent predictors of tumor free survival; tumor number was not found to be significant in multivariate analysis. A new staging system is proposed, which takes into account the results of the multivariate analysis in which tumor free survival correlates directly with stage. CONCLUSIONS The proposed staging system is superior to the current pTNM staging system in predicting tumor free survival following OLTx with HCC. Further studies will determine the appropriateness of this system for staging HCC after subtotal hepatic resection. Cancer 2000;88:538–43. © 2000 American Cancer Society.

Background: Hepatic resection for metastatic colorectal cancer provides excellent longterm results in a substantial proportion of patients. Although various prognostic risk factors have been identified, there has been no dependable staging or prognostic scoring system for metastatic hepatic tumors. Study Design: Various clinical and pathologic risk factors were examined in 305 consecutive patients who underwent primary hepatic resections for metastatic colorectal cancer. Survival rates were estimated by the Cox proportional hazards model using the equation: S ( t )=[ S o ( t )] exp(R−R o ) , where S o (t) is the survival rate of patients with none of the identified risk factors and R o = 0. Results: Preliminary multivariate analysis revealed that independently significant negative prognosticators were: (1) positive surgical margins, (2) extrahepatic tumor involvement including the lymph node(s), (3) tumor number of three or more, (4) bilobar tumors, and (5) time from treatment of the primary tumor to hepatic recurrence of 30 months or less. Because the survival rates of the 62 patients with positive margins or extrahepatic tumor were uniformly very poor, multivariate analysis was repeated in the remaining 243 patients who did not have these lethal risk factors. The reanalysis revealed that independently significant poor prognosticators were: (1) tumor number of three or more, (2) tumor size greater than 8 cm, (3) time to hepatic recurrence of 30 months or less, and (4) bilobar tumors. Risk scores (R) for tumor recurrence of the culled cohort (n = 243) were calculated by summation of coefficients from the multivariate analysis and were divided into five groups: grade 1, no risk factors (R = 0); grade 2, one risk factor (R = 0.3 to 0.7); grade 3, two risk factors (R = 0.7 to 1.1); grade 4, three risk factors (R = 1.2 to 1.6); and grade 5, four risk factors (R > 1.6). Grade 6 consisted of the 62 culled patients with positive margins or extrahepatic tumor. Kaplan-Meier and Cox proportional hazards estimated 5-year survival rates of grade 1 to 6 patients were 48.3% and 48.3%, 36.6% and 33.7%, 19.9% and 17.9%, 11.9% and 6.4%, 0% and 1.1%, and 0% and 0%, respectively (p Conclusions: The proposed risk-score grading predicted the survival differences extremely well. Estimated survival as determined by the Cox proportional hazards model was similar to that determined by the Kaplan-Meier method. Verification and further improvements of the proposed system are awaited by other centers or international collaborative studies.

Primary hepatic tumors are epithelial, mesenchymal, or mixed in origin. Of these, epithelial tumors are the most common and include hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocholangiocarcinoma, hepatoblastoma, and a variety of more rare tumors. Hepatocellular carcinoma, also know as hepatoma or malignant hepatoma, is the most common, followed by cholangiocarcinoma. This article discusses these two malignancies.

Background: Because of the rarity of hilar cholangiocarcinoma, its prognostic risk factors have not been sufficiently analyzed. This retrospective study was undertaken to evaluate various pathologic risk factors which influenced survival after curative hepatic resection or transplantation. Methods: Between 1981 and 1996, 72 patients (43 males and 29 females) with hilar cholangiocarcinoma underwent hepatic resection (34 patients) or transplantation (38 patients) with curative intent. Medical records and pathologic specimens were reviewed to examine the various prognostic risk factors. Survival was calculated by the method of Kaplan-Meier using the log rank test with adjustment for the type of operation. Survival statistics were calculated first for each kind of treatment separately, and then combined for the calculation of the final significance value. Results: Survival rates for 1, 3, and 5 years after hepatic resection were 74%, 34%, and 9%, respectively, and those after transplantation were 60%, 32%, and 25%, respectively. Univariate analysis revealed that T-3, positive lymph nodes, positive surgical margins, and pTNM stage III and IV were statistically significant poor prognostic factors. Multivariate analysis revealed that pTNM stage 0, I, and II, negative lymph node, and negative surgical margins were statistically significant good prognostic factors. mFor the patients in pTNM stage 0–II with negative surgical margins, 1-, 3-, and 5-year survivals were 80%, 73%, and 73%, respectively. For patients in pTNM stage IV-A with negative lymph nodes and surgical margins, 1-, 3-, and 5-year survivals were 66%, 37%, and 37%, respectively. Conclusions: Satisfactory longterm survivals can be obtained by curative surgery for hilar cholangiocarcinoma either with hepatic resection or liver transplantation. Redefining pTNM stage III and IV-A is proposed to better define prognosis.

We aimed to determine the most appropriate candidates for liver transplantation based on their survival outcomes. Two hundred and fourteen patients who were transplanted in the presence of hepatocellular carcinoma (HCC) were analyzed. Patient groups were selected as "good risk" candidates for transplantation by our previously developed artificial network model or by the classic pTNM pathological classification system. The survival of the model-selected candidate groups was then compared to the survival of the candidates chosen as "good risk" by the pTNM classification (i.e. , pTNM stages I + II and pTNM stages I + II + III). Suitability for transplantation was judged by long-term survival rates (i.e., 1-10 years post-transplant). By using the neural network prediction model and the subsequent subgroup case analysis, it was possible to generate those combinations of risk factors which predetermined patient survival through HCC recurrence. By applying the developed neural network model to the transplant candidate pool for patients with HCC, it was possible to select the maximum number of suitable candidates for transplantation while minimizing donor organ loss to recurrent HCC.

Fibrolamellar hepatoma (FL-HCC) is an uncommon variant of hepatocellular carcinoma (HCC), distinguished by histo-pathological features suggesting greater differentiation than conventional HCC. However, the optimal treatment and the prognosis of FL-HCC have been controversial. Follow-up studies are available from 1 year to 27 years, after 41 patients with FL-HCC were treated with partial hepatectomy (PHx) (28 patients) or liver transplantation (13 patients). In this retrospective study, the effect on outcome was determined for the pTNM stage and other prognostic factors routinely recorded at the time of surgery. Cumulative survival at 1, 3, 5, and 10 years was 97.6%, 72.3%, 66.2%, and 47.4%. Tumor-free survival at these times was 80.3%, 49.4%, 33%, and 29.3%. The TNM stage was significantly associated with tumor-free survival. Patients with positive nodes had a shorter tumor-free survival than those with negative nodes (P < .015). Patient survival was most adversely affected by the presence of vascular invasion (P < .05). FL-HCC is an indolently growing tumor of the liver, which usually was diagnosed in our patients at a stage too advanced for effective surgical treatment of most conventional HCC. Nevertheless, long-term survival frequently was achieved with aggressive surgical treatment. When a subtotal hepatectomy could not be performed, total hepatectomy (THx) with liver transplantation was a valuable option.

Subtotal hepatic resection was performed in 356 patients; 87 had primary hepatic malignancies, 108 had metastatic tumors, and 161 had benign lesions including 8 traumatic injuries. The global mortality was 4.2%. The experience has elucidated the role of subtotal hepatic resection both for benign and malignant neoplasms.

We have reviewed the long term results of the first 500 liver transplant recipients performed by our group during the cyclosporine era. Three hundred and forty-nine recipients lived (69.8%) more than 1 year and the projected 5 year actuarial survival for this sub-group of patients is 88%. The two most common causes of graft dysfunction after the first year were recurrence of the original disease, usually malignancy, and chronic rejection. Most episodes of rejection can be controlled with medical treatment; however, 16 patients of 34 patients who experienced rejection episodes after the first year required retransplantation. Eleven of these 16 are currently alive and free of jaundice. Another common cause of late graft dysfunction is biliary strictures. The recognized side effects of cyclosporine such as nephrotoxicity and lymphoproliferative disease have been lesser problems as a result of the judicious use of the drug. The quality of life of long term survivors is excellent.

The results obtained by liver transplantation (TX) (n = 105) for hepatocellular carcinoma (HCC) were compared with those achieved by hepatic resection (HX) (n = 76). Overall 1- to 5-year survival rates after TX were 66%, 49%, 39%, 36%, and 36%, and those after HX were 71%, 55%, 47%, 37%, and 33%, respectively. The survival rates after TX and HX correlated well with pTNM stages, and the overall survival rates were similar in each stage between the TX and the HX group. However, when HCC was associated with cirrhosis of the liver, the survival rates after TX were significantly higher than those after HX at each stage of pTNM classification. Tumor recurrence rate was high both after TX (43%) and HX (50%), particularly in stage IV-A. Tumor recurrence rate was significantly lower after TX than after HX in HCCs of stages II and III. Liver TX has established its definite role in the treatment of HCC, particularly in the presence of hepatic impairment or cirrhosis of the liver.

Experience with liver transplantation over a period of 11 years at the University of Pittsburgh is presented. The application of liver transplantation to cases of hepatocellular carcinoma has changed considerably over this 11-year period with the sequential introduction of adjuvant and, more recently, neoadjuvant chemotherapy. Results with the combination of chemotherapy plus surgery appear to be better than results with either agent alone. Moreover, the early results with neoadjuvant therapy appear to be better than those achieved with adjuvant therapy. As a result of this experience, conceptual changes in the approach to the problem of hepatic cancer and the role of both chemotherapy and liver transplantation in its management have changed at the University of Pittsburgh. These changes are identified and discussed.

The conventional treatment for hepatocellular carcinoma (HCC) has been surgical resection, typically by segmentectomy, lobectomy, or trisegmentectomy. The large majority of patients, however, cannot have their tumors resected, either because of underlying cirrhosis and liver damage, making resection hazardous, or because of the multifocal or bilobar spread of the hepatoma. In those patients with resectable tumors, the recurrence rates and survival have been found to depend mainly on stage of disease [1,2]. The best results have been with TNM stage I disease, with stage II and resectable stage III disease typically having < 30% survival at 3 years. Factors adversely influencing prognosis have included diffuse disease, multifocal primaries, vascular invasion, and lymph node involvement. Causes of Recurrence After Resection The evidence from liver transplantation specimens indicates that much clinically evident hepatoma is either multifocal or widespread. This suggests that disease that has been diagnosed by angiography, ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) scan consistently underestimates the amount of spread of disease in the liver. Thus, there is a reasonable probability of undetected residual microscopic disease in the remaining liver, which would account for the high recurrence rates.

Seventy-four consecutive pediatric liver transplant recipients were reviewed to assess the effect of the monoclonal anti-T-lymphocyte antibody OKT3 on subsequent viral infection (9 patients were excluded due to postoperative demise during the 1st week). Twenty-two patients received OKT3 in addition to standard cyclosporine-prednisone immunosuppression for either steroid-resistant acute rejection (18) or to facilitate reduction of cyclosporine due to severe renal impairment (4). Invasive infections were diagnosed by histology or culture in tissue biopsies or bronchoalveolar lavage specimens. The overall incidence of viral infection was 58%, half of which was due to cytomegalovirus (CMV). Invasive viral disease was associated with increased mortality (37% vs. 3% p = 0.001). Viral-related deaths were due to CMV (5), disseminated adenovirus (3), disseminated enterovirus (1) and respiratory syncytial viral pneumonia (1). The use of OKT3 was associated with increased viral disease (59% vs. 33% p=0.04) and invasive primary CMV disease (58% vs. 19% p=0.04). Trends were observed toward increased overall viral infection (73% vs. 51 % p=0.08), primary CMV infection (58% vs. 25% p=0.08) and overall mortality (27% vs. 9% p =0.08) following OKT3 therapy. We conclude that pediatric liver transplant recipients who require OKT3 therapy may be at increased risk for invasive viral disease and especially invasive primary CMV disease.

Long-term survival in children with primary hepatic malignancies can not be expected without complete tumor resection. In the last ten years we have treated 21 children with hepatocellular carcinoma (HCC) and 21 children with hepatoblastoma (HEP), with tumor extirpation our surgical goal. Operative treatment included partial hepatectomy ([PH] 20), either primary (10) or delayed (following chemotherapy) (10), total hepatectomy and orthotopic liver transplantation ([OLT] 13), or upper abdominal exenteration and multiple organ transplantation (2). Two patients had both PH and subsequent total hepatectomy and OLT. Overall survival was 48% (20/42), with 9 patients dying of progressive disease prior to removal of their tumor. HEP patient survival was 67% (14/21), including 2 of 6 who underwent primary PH, 7 of 8 who had delayed PH, and 5 of 6 who underwent OLT. Survival for the children with HCC was 29% (6/21), including 1 of 4 after primary PH, 1 of 2 following delayed PH, 3 of 7 following OLT, and 1 of 2 after exenteration and multiple organ transplantation. Preoperative chemotherapy facilitated removal of 10 initially unresectable tumors (8 HEP, 2 HCC) at a second-look procedure. Total hepatectomy and OLT markedly improved survival in patients with disease unresectable by standard methods. Partial hepatectomy, either primary or delayed, should be attempted in all children with hepatic malignancies. Total hepatectomy and OLT appears to be a viable adjunct in the treatment of childhood malignancies, and should be used for otherwise unresectable tumors as part of a carefully planned protocol.

We have come a long way in our understanding of antibodies as effectors of liver graft damage, but we still have much to learn. Animal heterografts provided the first evidence that livers are susceptible to antibody-mediated damage. The pathophysiologic events are similar to those of extrahepatic organ grafts, but the liver is relatively resistant and rapidity of graft destruction is slower, if it occurs at all. Nevertheless, the ABO isoagglutinins can predictably cause human liver allograft failure, often in a quickened, but rarely a hyperacute fashion. The liver is more resistant to lymphocytotoxins, and in many cases will suffer no apparent damage. However, when present, a spectrum of graft pathologic changes can be seen. Early manifestations include hemorrhagic necrosis and lesions mimicking "preservation" injury. Later on, ischemic biliary necrosis and small bile duct loss may be seen. The variability is likely related to a balance between destructive antibody class, specificity, and titers and the ability of the liver to withstand the assault. More precise characterization of lymphocytotoxic antibodies is needed in clinical practice. In addition, antigen distribution in the graft, release of soluble MHC antigens, the role of Kupffer cells and other mechanisms of liver resistance are likely areas of fruitful investigation.

The growth rates of recurrent hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLTX) were estimated by calculating the tumor doubling time (TDT) in 20 patients. The mean TDT, calculated by multiple measurement of tumor size, was 44.3 +/- 11.3 days (mean +/- standard error) in 12 patients with pulmonary metastasis (range, 10 to 161 days) and 37.6 +/- 8.9 days (range, 7 to 65 days) in 5 patients with liver allograft recurrence. The TDT as estimated by serum alpha-fetoprotein (AFP) levels in 6 patients was 37.3 +/- 10.0 days (range, 12 to 84 days). The mean TDT obtained from 5 control subjects with HCC who were treated with liver resection (without immunosuppression) was 273.8 +/- 79.1 days (range, 82 to 560 days). The disease-free period and survival time after OLTX both correlated well with the TDT (r = 0.546 and r = 0.701, respectively). The patients with fibrolamellar HCC had a greater TDT and a longer survival time than those with nonfibrolamellar HCC. Despite a wide range of TDT in patients who received transplants, their recurrent HCC tumors grew significantly faster than those of patients with the same disease who did not receive transplants. The factors involved in this accelerated growth rate may include the use of immunosuppressive drugs and the consequent suppression of host immunity against the growth of micrometastasis.

From 1976 to 1988, 63 patients received radiation therapy for primary cancers of the extrahepatic biliary system (eight gallbladder and 55 extrahepatic biliary duct). Twelve patients underwent orthotopic liver transplantation. Chemotherapy was administered to 13 patients. Three patients underwent intraluminal brachytherapy alone (range, 28 to 55 Gy). Sixty patients received megavoltage external-beam radiation therapy (range, 5.4 to 61.6 Gy; median, 45 Gy), of whom nine received additional intraluminal brachytherapy (range, 14 to 45 Gy; median, 30 Gy). The median survival of all patients was 7 months. Sixty patients died, all within 39 months of radiation therapy. One patient is alive 11 months after irradiation without surgical resection, and two are alive 50 months after liver transplantation and irradiation. Symptomatic duodenal ulcers developed after radiation therapy in seven patients but were not significantly related to any clinical variable tested. Extrahepatic biliary duct cancers, the absence of metastases, increasing calendar year of treatment, and liver transplantation with postoperative radiation therapy were factors significantly associated with improved survival.

Phenotypic and functional characteristics of tumor-infiltrating lymphocytes (TIL) obtained from human primary and metastatic liver tumors were studied. Lymphocytes isolated from 18 tumors and autologous (A) peripheral blood (6 cases) were phenotyped by 2-color flow cytometry and cloned in a limiting dilution system, which allows virtually all normal T lymphocytes to proliferate; 70-80% of fresh TIL were T cells (i. e., CD3+), and the ratio of CD4+/CD8+ cells was 1.2 in both primary and metastatic liver tumors. TIL contained significantly more CD56+ (NKHI+) cells, half of which were CD3+ CD56+, CD3+ CD25+ cells and CD3+ HLA-DR+ cells, than A-PBL. The frequencies of proliferating T-cell precursors (PTL-p) and cytolytic T-lymphocyte precursors (CTL-p) reactive with K562, allogeneic tumor cells and autologous tumor cells, were determined. Mean PTL-p frequencies for TIL from hepatocellular carcinomas, cholangiocarcinomas and metastatic liver tumors were 0.52 (0.22-0.83), 0.10 (0.05-0.16) and 0.16 (0.01-0.30), respectively. The frequency of CTL-p with natural-killer-like activity was lower in TIL than in A-PBL. The frequency of CTL-p for autologous tumor cells in fresh TIL isolated from primary liver tumors was 0.02-0.13 and 12/81 clones were reactive against autologous tumor. In contrast, only 1/66 TIL clones obtained from colon carcinomas metastatic to liver showed autotumor reactivity. No clones reactive with autologous tumor were obtained from peripheral blood of patients with liver cancer. These data indicate that substantial differences in anti-tumor functions of TIL between primary and metastatic liver tumors exist, which can be detected at a clonal level.

The isolation of mononuclear cells from human liver tissues was achieved by a simple method consisting of enzymatic and mechanical dissociation, density gradient centrifugation, and adherence to plastic. The method was optimized to obtain a nearly complete recovery of different lymphoid subpopulations. The mononuclear cells recovered from "normal" liver tissues consisted of 33 +/- 9% (mean +/- SD) small lymphocytes, 44 +/- 6% large granular lymphocytes, 9 +/- 2% monocytes/macrophages, 9 +/- 3% granulocytes, and 5 +/- 2% other cells as determined by microscopic analysis of May-Grünwald-Giemsa-stained cytocentrifuge smears. Phenotypic analysis of the liver-infiltrating lymphocytes (LIL) by two-color flow cytometry showed that CD3-CD56+ NK cells represented 43 +/- 6% (mean +/- SD), CD3+CD56- T cells, 30 +/- 9%, and CD19+ B cells 3 +/- 1%. The predominant phenotype of the liver-infiltrating NK cells was CD3-CD56+CD16- in contrast to that of circulating NK cells, which are largely CD3-CD56+CD16+. The alpha/beta TCR+ T cells were 42 +/- 14% and gamma/delta T cells were infrequent (4 +/- 4%). The proportions of the three major lymphoid populations (T, NK, and B cells) recovered from liver tissues of 10 patients with different liver diseases were altered. Tissue sections from the same specimens were stained by the immunoperoxidase method to compare the in situ cellular composition with that determined by flow cytometry. LIL recovered from normal (control) and virally infected (non-A, non-B hepatitis) liver tissues had high NK activity (up to 1,000 LU/10(7) cells) as measured against K-562 targets in 4-hr 51Cr-release assays. NK activity was significantly lower (P less than 0.05) in LIL recovered from other liver diseases. LIL had spontaneous cytotoxicity against NK-resistant Daudi targets which was significantly higher (P less than 0.05) in control and virally infected than in other liver tissues. Our results indicated that human LIL recovered from normal and diseased liver tissues contained a high proportion of functionally active NK cells and that NK and lymphokine-activated killer activities but not the percentages of CD56+ cells were decreased in end-stage primary biliary cirrhosis and primary sclerosing cholangitis. In contrast, the proportions of NK cells and NK activity remain high in non-A, non-B hepatitis.

The gross and histopathologic characteristics of 212 nonfibrolamellar hepatocellular carcinomas (HCCs) discovered in native livers removed at the time of liver transplantation were correlated with features of invasive growth and tumor-free survival. The results show that most HCCs begin as small well-differentiated tumors that have an increased proliferation rate and induce neovascularization, compared with the surrounding liver. But at this stage, they maintain a near-normal apoptosis/mitosis ratio and uncommonly show vascular invasion. As tumors enlarge, foci of dedifferentiation appear within the neoplastic nodules, which have a higher proliferation rate and show more pleomorphism than surrounding better-differentiated areas. Vascular invasion, which is the strongest predictor of disease recurrence, correlates significantly with tumor number and size, tumor giant cells and necrosis, the predominant and worst degree of differentiation, and the apoptosis/mitosis ratio. In the absence of macroscopic or large vessel invasion, largest tumor size (P < .006), apoptosis/mitosis ratio (P < .03), and number of tumors (P < .04) were independent predictors of tumor-free survival and none of 24 patients with tumors having an apoptosis/mitosis ratio greater than 7.2 had recurrence. A minority of HCCs (

The aim of this collaborative study was to compare the long term results of hepatic resection (Hx) with those of orthotopic liver transplantation (OLTx) in large numbers of cirrhotic patients with hepatocellular carcinoma (HCC) and to delineate the roles of these two surgical treatments.The databases of the National Cancer Center Hospital in Japan and the University of Pittsburgh Medical Center in the U. S. were exchanged and 294 cirrhotic patients who underwent curative Hx and 270 cirrhotic patients who underwent curative OLTx were selected for comparison.The mortality rate within 30 days and that within 150 days after Hx were significantly lower than those after OLTx (P = 0.001 and P = 0.00007, respectively). Overall survival was similar between the Hx group and the OLTx group (P = 0.40). When compared in the HCC patients without macroscopic vascular invasion and lymph node metastases, the overall survival rate after OLTx was significantly higher than that after Hx (P = 0.006). However, this difference was not significant between the patients with Child-Pugh Grade A tumors in the Hx group and all patients (majority with Child-Pugh Grade C tumors) in the OLTx group (P = 0.25). Tumor free survival after OLTx was significantly higher than that after Hx (P0.0001), particularly in HCCs measuring/=5 cm, unilobarly distributed tumors, and HCCs with either no or only microscopic vascular invasion. In HCCs measuring5 cm and those with macroscopic vascular invasion, the tumor free survival rate was similar between the Hx group and the OLTx group.In the face of organ shortage, HCC developing in a well compensated cirrhotic liver initially may be treated with Hx. However, the authors believe OLTx should be applied selectively to those patients with tumor recurrence and/or progressive hepatic failure.

Objective To analyze a single center's 14-year experience with 62 consecutive patients with hilar (HCCA) and peripheral (PCCA) cholangiocarcinomas. Summary background data Long-term survival after surgical treatment of HCCA and PCCA has been poor. Methods From March 1981 until December 1994, 62 consecutive patients with HCCA (n = 28) and PCCA (n = 34) underwent surgical treatment. The operations were individualized and included local excision of the tumor and suprapancreatic bile duct, lymph node dissection, vascular reconstruction, and subtotal hepatectomy. Clinical and pathologic risk factors were examined for prognostic influence. Results Patients were followed for a median of 25 months (12-102 months). Postoperative morbidity and mortality (at 30 days) were 32% and 14%, respectively, for HCCA and 24% and 6% for PCCA. The survival rates for HCCA and PCCA were 79% (+/-8%) and 67% (+/-8%) at 1 year; 39% (+/-10%) and 40% (+/-9%) at 3 years; and 8% (+/-7%) and 35% (+/-10%) at 5 years, respectively. The median survival was 24 (+/-4) months for HCCA and 19 (+/-8) months for PCCA. The disease-free survival rates for HCCA and PCCA were 85% (+/-10%) and 77% (+/-9%) at 1 year; 18% (+/-11%) and 41% (+/-12%) at 3 years; and 18% (+/-11%) and 41% (+/-12%) at 5 years, respectively. Nearly 80% of these patients had TNM stage IV tumors. With HCCA, no risk factors were associated with patient survival. For PCCA, multiple tumors (relative risk [RR] = 3.5; 95% confidence interval [CI] = 1.2-10.5) and incomplete resection (RR = 8.3; 95% CI = 2.3-29.6) were independently associated with a worse prognosis. For HCCA, there was a trend for lower disease-free survival in females (p = 0.056; log rank test). For PCCA, tumor size >5 cm was the only factor associated with disease recurrence (p = 0.024; log rank test). Conclusions Even though rare, 5-year survival by resection can be achieved in both HCCA and PCCA, but new adjuvant treatments are clearly needed.

Background: Recent publications have questioned the role of orthotopic liver transplantation (OLT) in treating advanced or unresectable peripheral cholangiocarcinoma (Ch-Ca). Study Design: We reviewed our experience with Ch-Ca to determine survival rates, recurrence patterns, and risk factors in 54 patients who underwent either hepatic resection or OLT between 1981 and 1994. Liver transplantation was performed in patients with unresectable tumors (n = 12) and in those with advanced cirrhosis (n = 8). There were 33 women (61%) and 21 men (39%), with a mean age of 54.3 years. The median followup period was 6.8 years. Prognostic risk factors were analyzed by univariate and multivariate analyses. Results: Mortality within 30 days was 7.4%. Overall patient and tumor-free survival rates were 64% and 57% at 1 year, 34% and 34% at 3 years, and 26% and 27% at 5 years after operation. Thirty-two patients (59.3%) experienced tumor recurrence. Univariate analysis revealed that multiple tumors, bilobar tumor distribution, regional lymph node involvement, presence of metastasis, positive surgical margins, and advanced pTNM stages were significant negative predictors of both tumor-free and patient survival. Multivariate analysis revealed that positive margins, multiple tumors, and lymph node involvement were independently associated with poor prognosis. When patients with these three negative predictors were excluded, the patient survivals at 1, 3, and 5 years were 74%, 64%, and 62%, respectively. Conclusions: Both hepatic resection and OLT are effective therapies for Ch-Ca when the tumor can be removed with adequate margins, the lesion is singular, and lymph nodes are not involved.

Hepatic epithelioid hemangioendothelioma (PHEHE) is a multifocal, low-grade malignant neoplasia characterized by its epithelial-like appearance and vascular endothelial histogenesis. The outcome of 16 patients treated with orthotopic liver transplantation (OLT) is the subject of this report.A retrospective study of 16 patients with HEHE (7 men, 9 women) with ages ranging from 24 to 58 years (mean 37 +/- 10.6 years). Follow-up intervals ranged from 1 to 15 years (median of 4.5 years).Actual patient survival at 1, 3, and 5 years was 100, 87.5, and 71.3%, respectively. Disease-free survival at 1, 3, and 5 years was 81.3, 68.8, and 60.2%, respectively. The 90-day operative mortality was 0. Involvement of the hilar lymph nodes or vascular invasion did not affect survival. The 5-year survival of HEHE compares favorably with that of hepatocellular carcinoma at the same stage (stage 4A): 71.3 versus 9.8% (p = 0.001)The long-term survival obtained in this series justifies OLT for these tumors even in the presence of limited extrahepatic disease.

Postoperative changes in coagulation parameters, including the abnormal plasma prothrombin level, were studied in 95 patients who underwent liver transplantation, and the results were compared with the clinical outcome. The patients were classified into four groups : Group I had a satisfactory postoperative course, (n=76), Group II suffered graft failure or death at 31 days or more after transplantation (n=9) ; Group III suffered graft failure or death from 8 to 30 days after transplantation (n= 4) ; and Group IV suffered graft failure or death within 7 days of transplantation (n=6). The Normotest, which closely reflected liver graft function, showed an increase immediately after transplantation in Group I, II, and III, but showed a marked decrease in Group IV. In patients with severe acute cellular rejection, the plasma level of abnormal prothrombin (des-gamma-carboxy prothrombin) was compared with the histology of the liver biopsy specimen. When liver graft function was good after orthotopic transplantation, the Normotest value recovered to the normal range of 70% or more. Subsequently, graft function remained good when the des-gamma-carboxy prothrombin level stayed low, whereas acute cellular rejection was indicated by an elevation of des-gamma-carboxy prothrombin. When the Normotest value was lower than 20% for the first 2 days after transplantation, graft failure was likely. Because des-gamma-carboxy prothrombin was not produced by graft with early failure, the des-gamma-carboxy prothrombin level also remained low. Thus, the Normotest value and the des-gamma-carboxy prothrombin level were both useful parameters for assessing hepatic function and rejection after transplantation.

The authors describe the first reported case of spindle cell tumor of the portal vein (SCTPV) surgically excised in a 28-year-old woman. The tumor had caused portal vein obstruction with extensive collaterals. A side-to-side mesocaval shunt was created to reduce portal hypertension. Six months later the SCTPV could be excised. Radiation therapy (4,500 cGY) was given 2 months later. Although the tumor recurred in the liver 4 years later, the patient is alive and free of symptoms 6 years after the initial diagnosis.

Total hepatectomy plus liver transplantation was performed on 105 patients considered unsuitable for liver resection. Postoperative 5-year actuarial survivals correlated with the pathologic stage of the tumor: stage I 75%, stage II 68%, stage III 52,1%, and stage IVA 11%. The overall 5-year survival for all patients was 36%. Nodal disease, bilobar tumor, and macroscopic venous invasion were significant poor-prognosis features. In addition, 12 patients with pT4N1M0 lesions (also stage IVA) had hepatectomy plus more extensive en bloc regional resection (Whipple procedure or cluster resection) plus transplantation in an effort to prevent local recurrence. Only 2 of these 12 patients (16.7%) are alive and free of disease after 2 years. Seven patients (58%) have died from tumor recurrence usually originating from distant metastases an average of 10.6 months after transplantation. Successful transplantation for hepatoma depends on screening programs to identify early stage disease. Successful outcome of transplantation for late stage disease, which includes most of the patients in our series, awaits the development of neoadjuvant therapy to control distant microscopic metastases, which are almost certainly present though not apparent at the time of transplantation.

Uncertainty regarding the liver’s tolerance for resection always occurs whenever there is physical deviation from the norm. A methodical consideration of individual physical characteristics helps to assess the liver accurately. Following are some general guidelines we use to judge the vitality of the liver and its potential for resection.

Objective The purpose of this study was to report the authors' experience with hepatic resection for cystic lesions of the liver. Summary background data Past experience with aspiration, sclerosing therapy, internal drainage, fenestration, and marsupialization are of limited value. Hepatic resection has evolved into a safe operation over the last two decades. Methods A retrospective study of 44 patients with various cystic lesions of the liver (polycystic disease, 2; solitary or multiple congenital cysts, 19; biliary cystadenoma, 6; cystadenocarcinoma, 3; squamous cell carcinoma, 3; Caroli's disease, 5; and hydatid cyst, 6) was performed. Results After 7 trisegmentectomies, 24 lobectomies, 6 left lateral segmentectomies, and 7 nonanatomical hepatic resections, only 1 operative death occurred in a Jehovah's Witness. Symptomatic relief was complete and permanent in all of the patients with benign congenital or parasitic hepatic cysts, except for the two patients with polycystic disease of the liver. One of the 3 patients with adenocarcinoma and 3 patients with squamous cell carcinoma of the cyst wall died of tumor recurrence between 3 and 14 months after hepatic resection. Conclusions Hepatic resection is safe and effective for cystic lesions of the liver. Symptomatic relief is complete and permanent after hepatic resection, except in cases of diffuse polycystic disease of the liver. Liver transplantation should be considered for diffuse polycystic disease of the liver when the symptoms are extremely severe.

From 1980 to 1989,76 patients with hepatocellular carcinoma were treated by subtotal hepatic resection (HX) and 105 by orthotopic liver transplantation (TX). The overall 1 to 5 year survival rates of the HX group were 71.1%, 55.0%, 47.2%, 37.2% and 32.9% respectively, and those of the TX group were 65.7%, 49.0%, 39.2%, 35.6% and 35.6%, respectively. The survival was similar stage by stage in both groups and correlated well with the pTNM classification. Tumor recurrence was high in both groups after HX (50%) and TX (43%) particularly in stages IV-A (≥ 60%). Twelve patients after HX and 13 patients after TX lived more than 5 years.

Two new human cholangiocarcinoma (CC) cell lines (CC-SW-I and CC-LP-I) were established and maintained in culture for 2 years. Histologically, both original liver tumors were adenocarcinomas, and the cell lines exhibited morphologic features of moderately differentiated adenocarcinoma. Immunohistochemistry showed that both cell lines were strongly positive for cytokeratin AEI but negative for carbohydrate tumor-associated antigen, CA19-9. Ultrastructural analysis of both cell lines showed the presence of tight junctional complexes and focally formed microvilli. Both CC cell lines were tumorigenic in nude mice. Cytogenetic analysis showed that both cell lines expressed highly aneuploid karyotypes with numerous structural and numerical deviations. CC-SW-I was hypodiploid with numerous chromosome losses and structural rearrangements, while CC-LP-I was hyperdiploid and displayed multiple additional chromosomes. Doubling times for the CC-SW-I and CC-LP-I cell lines in the presence of 15% fetal bovine serum were 72 hr and 180 hr, respectively. Growth of the CC-SW-I cell line was significantly stimulated in the presence of insulin, while that of the CC-LP-I cell line was significantly augmented by epidermal growth factor (EGF). In contrast, dexamethasone strongly inhibited proliferation of both cell lines in a dose-dependent manner. Among various recombinant cytokines examined for effects on growth or surface antigen expression on CC cell lines, only interleukin I-beta (ILI-beta) strongly inhibited growth of the CC-LP-I cell line, while interferons (IFNs) or tumor necrosis factor-alpha (TNF-alpha) were mildly inhibitory. Both tumor cell lines were resistant to natural killer (NK) cells but sensitive to lymphokine-activated killer (LAK) cells. Preincubation of tumor cells with IFN-gamma, IFN-alpha or TNF-alpha significantly decreased the susceptibility of each tumor cell line to lysis by LAK cells, and the change in sensitivity did not correlate with the expression of HLA antigens or intercellular adhesion molecule-I (ICAM-I) on the surface of tumor cells. These 2 CC cell lines are expected to provide valuable information about cell biology of human CC.

The vast majority of patients who require liver transplants have significant portal venous hypertension, and their liver replacement is specifically aimed to treat three major complications of portal hypertension, namely, bleeding oesophageal varices, refractory ascites and encephalopathy (liver failure). Variceal haemorrhage and ascites can be treated effectively by various types of portal decompression surgery, but these procedures invariably decrease hepatic blood flow and hence worsen the function of an already compromised liver. The enthusiasm for treating oesophageal varices and ascites with non-selective portosystemic shunting started to wane more than two decades ago when it became apparent that the price of preventing haemorrhage from oesophageal varices and intractable ascites in this manner was dehumanizing encephalopathy and progressive hepatic dysfunction (Jackson et al, 1971; Resnick et al, 1974). With the development of potent and specific diuretic drugs, truly intractable ascites is extremely uncommon. When it does occur, more appropriate therapy than portosystemic shunt will often be a peritoneojugular shunt. Chronic hepatic encephalopathy can rarely be managed by medical means, and it is effectively treated only with liver transplantation. Thus, the principal problem in portal hypertension for which therapeutic planning must be done is the haemorrhage from oesophageal varices. Prophylactic and therapeutic uses of anti-P-adrenergic agents and endoscopic sclerotherapy play a significant role in the management of oesophageal varices. Various types of portosystemicvenous shunting have been evaluated as to their efficacy in preventing both haemorrhage from varices and accelerated decline of hepatic function. In our centre, where there is a chronic shortage of organs, Child’s A patients who have had variceal bleeding are systemically screened for selective splenorenal shunts, performed electively. The procedure is being used on a trial basis because it is attended by a lower incidence of encephalopathy than is seen after non-selective shunts. Forty patients have been entered with no perioperative deaths but longer follow-up will be necessary to assess the validity of this approach. Five of the 40 have come to successful transplantation during the first 12 months after their Warren

Twenty‐six adult patients with preformed IgG donor lymphocytotoxic antibodies received primary liver allografts under FK 506 immunosuppression. The effect of the crossmatch‐positive state on early graft function and on the immunopathological and histopathological findings was compared with that of 52 crossmatch‐negative control recipients. The presensitized (crossmatch‐positive) patients had prolongation of early graft dysfunction, underwent more clinically indicated biopsies and had a higher incidence of cellular rejection, both overall (p < 0.05) and within 10 days of transplantation (p < 0.01). They also had a higher incidence of graft failure in the first 180 days (p < 0.01). Hyperacute rejection with necrotizing or neutrophilic arteritis was not seen in the crossmatchpositive grafts. However, histological findings associated with presensitization included platelet margination in central veins and sinusoids in biopsy specimens 60 to 90 min after graft revascularization. Later biopsy specimens had neutrophilic portal venulitis followed by cholangiolar proliferation, acute cholangiolitis and centrilobular hepatocyte swelling that mimicked preservation injury, endothelial activation of arteries with medial changes and relapsing episodes of acute cellular rejection. These clinicopathological observations suggest that lymphocytotoxic antibodies can have a deleterious effect on liver allograft function and survival, even if they do not precipitate immediate or hyperacute rejection. (HEPATOLOGY 1992;16:671–681.) Copyright © 1992 American Association for the Study of Liver Diseases

Extensive hepatocellular adenomatosis (HA) and focal nodular hyperplasia (FNH) represent a proliferation of hepatic cells that occurs most frequently in women. These lesions are uncommon in the pediatric age group, accounting for 2 % of pediatric hepatic tumors, and are extremely rare in males. The etiology of HA and FNH has been correlated with the use of oral contraceptives. We report to the best of our knowledge the first series of patients treated with OLTx for HA and FNH (five cases). All these patients had lesions involving at least 90 % of the hepatic parenchyma and all underwent major hepatic surgery before OLTx because of life threatening complications. One patient died in the immediate postoperative period following retransplantation for primary non-function of the first OLTx. Four out of five patients are currently alive from 4.1 to 9.6 years after OLTx. Our results justify the use of OLTx for symptomatic patients with HA and FNH who cannot be treated with conventional hepatic resections.

Tumor-infiltrating lymphocytes (TIL) were isolated from 22 human primary and metastatic liver tumors, and expanded in vitro in the presence of either interleukin-2 (IL-2, 100 U/ml) plus tumor necrosis factor alpha (TNF alpha, 1000 U/ml), IL-2 (1000 U/ml) plus IL-4 (1000 U/ml) or IL-2 (1000 U/ml) alone. TIL proliferated in culture in 20/22 cases. Among different cytoline combination, TNF alpha and IL-2 were most effective in promoting the outgrowth of CD3+CD8+T lymphocytes (mean +/- SEM: 90% +/- 5) in the cultures of TIL from primary liver tumors. Cytotoxicity against autologous tumor cells was demonstrated in all early cultures of TIL from primary liver cancers in the presence of IL-2 plus TNF alpha. In contrast, cultures of TIL derived from colon cancer metastatic to liver had significantly lower levels of autotumor cytotoxicity and proportions of CD3+CD8+ cells (40% +/- 13) than those of TIL from primary liver tumors. The addition on day 0 of interferons (alpha or gamma) to TIL cultured in the presence of TNF alpha and IL-2, significantly augmented cytotoxicity against autologous tumor. In contrast, incubation of TIL in the presence of IL-4 and IL-2 did not result in increased autotumor responses in the cultures of TIL from primary liver tumors. The expansion (-fold) of TIL (day 30) cultured in the presence of IL-2 alone compared to that in the presence of TNF alpha and IL-2 was significantly greater for hepatocellular carcinoma (median, 280 vs 260) than for autologous peripheral blood lymphocytes (36 vs 27), cholangiocarcinoma (42 vs 51) or TIL from metastatic colon cancer (39 vs 30). Outgrowth of TIL in IL-2 plus TNF alpha offers an opportunity for in vitro enrichment in cells with autotumor cytotoxicity in primary liver tumors. However, this cytokine combination was unable to promote and sustain growth of autotumor effectors from TIL in metastatic liver cancer.

• We evaluated the efficacy of reconstruction of the hepatic artery for intraoperative or postoperative thrombosis in orthotopic liver transplantation. Of 37 grafts with artery thrombosis, 13 (35.1%, 6 intraoperative and 7 postoperative) underwent reconstruction of the hepatic artery. The arterial flow was reestablished and maintained in 5 (38.5%) of the 13. Recurrent thrombosis in the other 8 grafts developed 2 to 24 days (mean, 13.8 days) after transplantation. Reconstruction was successful in 50% (4/8) of the adults, compared with only 20% (1/5) of the children. Satisfactory results were obtained when a definitive cause of thrombosis could be identified. We conclude that early recognition and correction of the cause of hepatic artery thrombosis during or after orthotopic liver transplantation, especially in adults, is often a graft-saving and lifesaving procedure worthy of consideration. ( Arch Surg . 1990;125:628-631)

Objective: To evaluate the frequency and outcome of liver transplantation for symptomatic, unresectable, benign hepatic neoplasms. Design: Retrospective study. Setting: Presbyterian University Hospital, a tertiary care referral center for liver transplantation affiliated with the University of Pittsburgh (Pa). Patients: All 3239 liver transplant recipients at the University of Pittsburgh from January 1981 until January 1993. Results: Twelve (0.37%) of 3239 patients required liver transplantation for benign, highly symptomatic hepatic neoplasms that were unresectable. Origins included adenoma (n=6), mesenchymal hamartoma (n=2), massive hepatic lymphangiomatosis (n=l), hilar fibrous angiodysplasia (n=1), focal nodular hyperplasia (n=1), and hemangioma (n=l). There were three perioperative deaths and two late deaths at 56 and 84 months. The remaining patients are alive, with follow-up ranging from 36 to 145 months. Median survival for the nine patients who survived the perioperative period is 88 months. The early deaths were attributable to hemorrhagic complications (n=2) and necrotizing pancreatitis (n=1). The two late deaths were due to disseminated aspergillosis and hepatitis-associated cirrhosis. Conclusion: Patients with severe symptoms from benign hepatic neoplasms that are not resectable can be treated by total hepatectomy and orthotopic liver transplantation, with the expectation of good long-term results. (Arch Surg. 1995;130:153-156)

OKT3 monoclonal antibody therapy was added to preexisting baseline immunosuppressive treatment with ciclosporin and steroids to treat rejection in 52 recipients of cadaveric livers and 10 recipients of cadaveric kidneys. Rejection was controlled in 75% of patients treated, often after high-dose steroid therapy had failed. Rejection recurred during the 17-month follow-up period, after completion of OKT3, in only 25% of the patients who had responded. The safety and effectiveness of this monoclonal therapy, added to ciclosporin and steroids, has been established in this study.