Forrest Dodson

Hepatic Resection for Metastatic Colorectal Adenocarcinoma: A Proposal of a Prognostic Scoring System

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) = [So(t)]exp(R-Ro), where So(t) is the survival rate of patients with none of the identified risk factors and Ro = 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 < 0.0001). 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.

Bone marrow augmentation of donor-cell chimerism in kidney, liver, heart, and pancreas islet transplantation

We have previously postulated that donor cell chimerism in organ transplantation is needed to attain a tolerant state. Here we show that donor cell chimerism can be augmented in organ recipients if they are infused perioperatively with 3 x 10(8) per kg of unmodified donor bone marrow cells and are kept on a conventional immunosuppressive regimen of tacrolimus (FK506) and prednisolone. 36 patients took part, of whom the first 18 patients have good transplanted kidney (n = 10), liver (n = 7), and heart (n = 7) function when followed up between 4 and 16 months. All patients are well. We found persistent multilineage leucocyte chimerism in blood of 17 recipients by flow cytometry and PCR techniques to detect donor alleles or Y chromosomes in female recipients of male organs. The use of the 5-antigben HLA matched same sex donor precluded detection of chimerism in one patient.

Outcome of liver transplantation in hepatitis C virus–infected patients who received hepatitis C virus–infected grafts

BACKGROUND & AIMS The present organ shortage has brought into question the suitability of hepatitis C virus (HCV)-positive grafts. This study reviewed the outcome of such transplantations in our institution. METHODS Twenty-three HCV-positive patients who underwent orthotopic liver transplantation (OLT) for end-stage liver disease with HCV-positive grafts in 1992-1995 were studied. Only patients who survived more than 30 days were included in the analysis. Control group included 169 patients who underwent transplantation for HCV-related cirrhosis and received HCV-negative organs. RESULTS Patients who received HCV-infected organs had a cumulative survival rate of 89% and 72% at 1 and 5 years, respectively, vs. 88% and 73% for the control group (NS). There was no difference in graft survival, incidence of cirrhosis, mean hepatitis activity index score, fibrosis, or mean activity of serum transaminases. There was a trend toward lower incidence of recurrent hepatitis C in the study group compared with control (21% vs. 23% at 1 year and 47% vs. 64% at 5 years; NS). Patients in whom the donor strain became predominant after transplantation had significantly longer disease-free survival than patients who retained their own HCV strain (P < 0.003). CONCLUSIONS HCV-infected livers transplanted into HCV-infected recipients do not appear to convey a worse outcome in the initial years after OLT than HCV-negative grafts.

Liver transplantation for alcoholic cirrhosis: Long term follow-up and impact of disease recurrence

BACKGROUND Alcoholic liver disease has emerged as a leading indication for hepatic transplantation, although it is a controversial use of resources. We aimed to examine all aspects of liver transplantation associated with alcohol abuse. METHODS Retrospective cohort analysis of 123 alcoholic patients with a median of 7 years follow-up at one center. RESULTS In addition to alcohol, 43 (35%) patients had another possible factor contributing to cirrhosis. Actuarial patient and graft survival rates were, respectively, 84% and 81% (1 year); 72% and 66% (5 years); and 63% and 59% (7 years). After transplantation, 18 patients (15%) manifested 21 noncutaneous de novo malignancies, which is significantly more than controls (P=0.0001); upper aerodigestive squamous carcinomas were overrepresented (P=0.03). Thirteen patients had definitely relapsed and three others were suspected to have relapsed. Relapse was predicted by daily ethanol consumption (P=0.0314), but not by duration of pretransplant sobriety or explant histology. No patient had alcoholic hepatitis after transplantation and neither late onset acute nor chronic rejection was significantly increased. Multiple regression analyses for predictors of graft failure identified major biliary/vascular complications (P=0.01), chronic bile duct injury on biopsy (P=0.002), and pericellular fibrosis on biopsy (P=0.05); graft viral hepatitis was marginally significant (P=0.07) on univariate analysis. CONCLUSIONS Alcoholic liver disease is an excellent indication for liver transplantation in those without coexistent conditions. Recurrent alcoholic liver disease alone is not an important cause of graft pathology or failure. Potential recipients should be heavily screened before transplantation for coexistent conditions (e.g., hepatitis C, metabolic diseases) and other target-organ damage, especially aerodigestive malignancy, which are greater causes of morbidity and mortality than is recurrent alcohol liver disease.

Liver transplantation with cavoportal hemitransposition in the presence of diffuse portal, vein thrombosis

BACKGROUND Orthotopic liver transplantation is possible even in the presence of recipient portal vein thrombosis, provided that hepatopetal portal flow to the graft can be restored. On rare occasions this is not possible due to diffuse thrombosis of the portal venous system. In these cases, successful liver transplantation has been considered impossible. Portocaval transposition was introduced in the pretransplantation era to study the effect of systemic venous flow on the liver and has been used in three patients for the treatment of glycogen storage disease. We used portocaval hemitransposition (portal perfusion with inflow from the inferior vena cava) in liver transplantation when portal inflow to the graft was not feasible. We are reporting the collective experience of nine patients from four liver transplant centers. METHODS Cavoportal hemitransposition was used in nine patients. In seven of these cases, the technique was used during the original transplant (primary group). In two cases, it was used after the portal inflow to the first transplant had clotted (secondary group). RESULTS Five of seven patients in the primary group are alive after intervals of 6-11 months. The two patients in the rescue group died. In the successful cases, liver function and histology were indistinguishable from those of conventional liver transplantation. Ascites disappeared within 3-4 months and the patients were able to return to their normal activities. Postoperative variceal bleeding necessitated splenectomy and gastric devascularization in one case and splenic artery embolization in another case. Bleeding was controlled in both these cases. Splenectomy and gastric devascularization were performed prophylactically in one patient with a history of variceal bleeding in order to prevent this complication after transplantation. CONCLUSION Portocaval hemitransposition maybe useful in liver transplantation when hepatopetal flow to the liver graft cannot be established by other techniques. Rescue after failure of conventional technique was not possible in two patients.

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.

Impact of anti-hepatitis Bc-positive grafts on the outcome of liver transplantation for HBV-related cirrhosis.

Background. The present scarcity of organ donors requires consideration of grafts from sources not previously used. Several studies have addressed the use of grafts from donors who have antibodies to the hepatitis B core antigen (anti-HBc+). The aim of this study was to evaluate the impact of the use of anti-HBc+ grafts in patients transplanted for hepatitis B virus (HBV)-related cirrhosis. Methods. Recipients of first hepatic transplants from donors with antibodies to HBV were identified retrospectively. All patients who had serology suggestive of active HBV and were negative for hepatitis C and D were included in the analysis. The Kaplan-Meier method was used to assess the actuarial recurrence-free survival on patients with graft survival longer than 1.5 months. The stepwise Cox regression model was used to identify independent predictors of HBV recurrence. Results. One thousand seven hundred seventeen first liver transplants were performed at the Thomas E. Starzl Transplantation Institute from September 1, 1990, to December 31, 1999. HBV was the cause of cirrhosis in 112 patients (6.5%). Thirty-three patients had coexistent viral infection (23 HCV and 10 HDV). Fourteen donors (17.2%) were positive for HBV markers, with nine anti-HBc+ and with five both anti-HBc+ and anti-HB surface-positive; of these, 13 anti-HBc+ organ recipients had long-term survival. Nine (69.2%) of these cases were reinfected versus 20 (35.7%) in the group that received grafts from HBV− donors (P <0.05, Fisher’s exact test). The mean time to reinfection was shorter in the anti-HBc+ group (2.9 yr vs. 6.4 yr, P <0.005). There were no statistical differences in graft or patient survival between the two groups. HBV prophylaxis with combined lamivudine and hepatitis B immunoglobulin (HBIG) significantly reduced the reinfection rate (P <0.03). Hepatitis Be (Hbe) antigen-positive recipients trended to faster reinfection (not significant). Cox regression analysis revealed that both anti-HBc graft donor status (RR, 2.796;P =0.020) and combination of lamivudine/HBIG (RR, 0.249;P =0.021) are independently associated with reinfection. Conclusions. The use of anti-HBc+ liver grafts does not affect graft or patient survival. However, patients who receive these organs are 2.5 times more likely to develop HBV recurrence. Lamivudine and HBIG combination decreases HBV recurrence 4-fold.

A Prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone and mycophenolate mofetil in primary adult liver transplantation: a single center report

BACKGROUND Tacrolimus (TAC) and mycophenolate mofetil (MMF) are currently approved immunosuppressants for prevention of rejection in liver transplantation (LTx). They have different modes of action and toxicity profiles, but the efficacy and safety of MMF in primary liver transplantation with TAC has not been determined. METHODS An Institutional Review Board-approved, open-label, single-center, prospective randomized trial was initiated to study the efficacy and toxicity of TAC and steroids (double-drug therapy (D)) versus TAC, steroids, and MMF (triple-drug therapy (T)) in primary adult LTx recipients. Both groups of patients were started on the same doses of TAC and steroids. Patients randomized to T also received 1 gm MMF twice a day. RESULTS Between August 1995 and May 1998, 350 patients were enrolled at a single center-175 in the D and 175 in the T groups. All patients were followed until May 1998, with a mean follow-up of 33.8+/-9.1 months. Using an intention-to-treat analysis, the 1-, 2-, 3-, and 4-year patient survival was 85.1%, 81.6%, 78.6%, and 75.8%, respectively, for D and 87.4%, 85.4%, 81.3%, and 79.9%, respectively, for T. The 4-year graft survival was 70% for D and 72.1% for T. Although the rate of acute rejection in the first 3 months was significantly lower for T than for D (28% for triple vs. 38.9% for double, P=0.03), the overall rate of rejection for T at the end of 1 year was not significantly lower than for the D (38.9% triple vs. 45.2% double). The median time to the first episode of rejection was 14 days for D versus 24 days for T (P=0.008). During the study period, 38 of 175 patients in D received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 103 patients in the T discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. The need for corticosteroids was less after 6 months for T and the perioperative need for dialysis was lower with use of MMF. CONCLUSION This final report confirms similar patient survival and graft survival up to 4 years with a trend towards fewer episodes of rejection, lower need for steroids, and better perioperative renal function. However, the complex nature of LTx patients and their posttransplantation course prevents the routine application of MMF.

Infusion of donor leukocytes to induce tolerance in organ allograft recipients.

To further enhance chimerism, 229 primary allograft recipients have received perioperative intravenous infusion of a single dose of 3 to 6 × 108 unmodified donor bone marrow (BM) cells/kg body weight. In addition, 42 patients have been accrued in a concurrent protocol involving multiple (up to three) sequential perioperative infusions of 2 × 108 BM cells/kg/day from day 0–2 posttransplantation (PTx). Organ recipients (n = 133) for whom BM was not available were monitored as controls. The infusion of BM was safe and except for 50 (18%), all study patients have optimal graft function. Of the control patients, allografts in 30 (23%) have been lost during the course of follow‐up. The cumulative risk of acute cellular rejection (ACR) was statistically lower in the study patients compared with that of controls. It is interesting that, 62% of BM‐augmented heart recipients were free of ACR (Grade ≥ 3A) in the first 6 months PTx compared to controls. The incidence of obliterative bronchiolitis was also statistically lower in study lung recipients (3.8%) compared with the contemporaneously acquired controls (31%). The levels of donor cell chimerism were at least a log higher in the peripheral blood of majority of the study patients compared with that of controls. The incidence of donor‐specific hyporeactivity, as determined by one‐way mixed leukocyte reaction, was also higher in those BM‐augmented liver, kidney, and lung recipients that could be evaluated compared to controls. J. Leukoc. Biol. 66: 310–314; 1999.

Three years of follow-up of bone marrow-augmented organ transplant recipients: The impact on donor-specific immune modulation ☆

The discovery of the presence of previously unsuspected microchimerism in successful longterm liver and kidney transplant recipients prompted us to postulate that these cells are essential for graft acceptance and the induction of donor-specific hyporeactivity.1–3 This observation provided the basis for the initiation of a new therapeutic strategy which involved infusion of donor bone marrow (BM) cells under conventional immunosuppressive treatment with tacrolimus and prednisolone.4 The initial outcome of sequential in vitro immunologic evaluations performed to determine the development of donor-specific hyporeactivity in the first 15 BM-augmented and 16 contemporaneous controls has been described previously.5,6 We report here the immune profile of 102 BM-augmented and 57 control patients who were at least 6 months posttransplantation.