R Robles

Spanish Experience in Liver Transplantation for Hilar and Peripheral Cholangiocarcinoma

Objective:To assess the real utility of orthotopic liver transplantation (OLT) in patients with cholangiocarcinoma, we need series with large numbers of cases and long follow-ups. The aim of this paper is to review the Spanish experience in OLT for hilar and peripheral cholangiocarcinoma and to try to identify the prognostic factors that could influence survival. Summary Background Data:Palliative treatment of nondisseminated irresectable cholangiocarcinoma carries a zero 5-year survival rate. The role of OLT in these patients is controversial, due to the fact that the survival rate is lower than with other indications for transplantation and due to the lack of organs. Methods:We retrospectively reviewed 59 patients undergoing OLT in Spain for cholangiocarcinoma (36 hilar and 23 peripheral) over a period of 13 years. We present the results and prognostic factors that influence survival. Results:The actuarial survival rate for hilar cholangiocarcinoma at 1, 3, and 5 years was 82%, 53%, and 30%, and for peripheral cholangiocarcinoma 77%, 65%, and 42%. The main cause of death, with both types of cholangiocarcinoma, was tumor recurrence (present in 53% and 35% of patients, respectively). Poor prognosis factors were vascular invasion (P < 0.01) and IUAC classification stages III–IVA (P < 0.01) for hilar cholangiocarcinoma and perineural invasion (P < 0.05) and stages III-IVA (P < 0.05) for peripheral cholangiocarcinoma. Conclusions:OLT for nondisseminated irresectable cholangiocarcinoma has higher survival rates at 3 and 5 years than palliative treatments, especially with tumors in their initial stages, which means that more information is needed to help better select cholangiocarcinoma patients for transplantation.

Life-supporting human complement regulator decay accelerating factor transgenic pig liver xenograft maintains the metabolic function and coagulation in the nonhuman primate for up to 8 days

Background. It is not known whether the pig liver is capable of functioning efficiently when transplanted into a primate, neither is there experience in transplanting a liver from a transgenic pigs expressing the human complement regulator human complement regulator decay accelerating factor (h-DAF) into a baboon. The objective of this study was to determine whether the porcine liver would support the metabolic functions of non-human primates and to establish the effect of hDAF expression in the prevention of hyperacute rejection of porcine livers transplanted into primates. Methods. Five orthotopic liver xenotransplants from pig to baboon were carried out: three from unmodified pigs and two using livers from h-DAF transgenic pigs. Findings. The three control animals transplanted with livers from unmodified pigs survived for less than 12 hr. Baboons transplanted with livers from h-DAF transgenic pigs survived for 4 and 8 days. Hyperacute rejection was not detected in the baboons transplanted with hDAF transgenic pig livers; however, it was demonstrated in the three transplants from unmodified pigs. Baboons transplanted with livers from h-DAF transgenic pigs were extubated at postoperative day 1 and were awake and able to eat and drink. In the recipients of hDAF transgenic pig livers the clotting parameters reached nearly normal levels at day 2 after transplantation and remained normal up to the end of the experiments. In these hDAF liver recipients, porcine fibrinogen was first detected in the baboon plasma 2 hr postreperfusion, and was present up to the end of the experiments. One animal was euthanized at day 8 after development of sepsis and coagulopathy, the other animal arrested at day 4, after an episode of vomiting and aspiration. The postmortem examination of the hDAF transgenic liver xenografts did not demonstrate rejection. Interpretation. The livers from h-DAF transgenic pigs did not undergo hyperacute rejection after orthotopic xenotransplantation in baboons. When HAR is abrogated, the porcine liver maintains sufficient coagulation and protein levels in the baboon up to 8 days after OLT.

FoxP3 in peripheral blood is associated with operational tolerance in liver transplant patients during immunosuppression withdrawal.

Background. Human liver allografts do sometimes survive in a recipient after withdrawal of immunosuppression (IS), commonly referred to as “operational tolerance.” Preliminary clinical data have suggested an increase in the frequency of regulatory T cells (Treg) CD4+CD25high and FoxP3 expression in operationally tolerant liver transplant recipients (Gr-T). In the context of human liver transplantation, the dynamics of Treg have not been studied. We designed a prospective study to ascertain the profile of the Treg population and FoxP3 expression during IS withdrawal. Methods. To identify such parameters, we analyzed peripheral blood mononuclear cell populations and FoxP3 mRNA expression in 12 liver allograft recipients under cyclosporine A-based IS, who showed stable function of the allograft for more than 2 years. Results. An increase was observed in the frequency of CD4+CD25high cells when the IS was withdrawn in Gr-T patients (n=5). These patients exhibited a 3.5-fold increase for relative mRNA FoxP3 expression before the complete IS withdrawal and this continued when IS therapy was stopped. In patients who suffered rejection (n=7) there was no increase in the CD4+CD25high cells or FoxP3 expression. Conclusions. With the present study, the first evidence is provided that the increase of CD4+CD25high T cells and FoxP3 transcripts is associated with operational tolerance in liver transplanted patients during IS withdrawal.

Subtotal colectomy vs. intraoperative colonic irrigation in the management of obstructed left colon carcinoma

PURPOSE: Whether primary anastomosis should be performed after segmental resection with intraoperative colonic irrigation or subtotal colectomy is not yet established in the surgical treatment of obstructive left colon carcinoma. In this prospective, nonrandomized study, we present the results of 66 patients undergoing one-stage surgery for obstructed left colon carcinoma. PATIENTS AND METHODS: We compared two techniques, subtotal colectomy (35 patients) and intraoperative colonic irrigation with segmental resection and immediate anastomosis (31 patients). RESULTS: The mortality rate was similar in both groups, 8.5 percent in the subtotal colectomy group and 3.2 percent in the intraoperative colonic irrigation group. The surgical complication rate was significantly higher in the intraoperative colonic irrigation group (41.9 percent) than in the subtotal colectomy group (14.2 percent;P<0.05). Mean operating time was significantly lower in the subtotal colectomy group than in the intraoperative colonic irrigation group (P<0.05). Both groups had a similar mean duration of hospital stay. Ten patients who underwent subtotal colectomy (31.2 percent) presented with diarrhea in the immediate postoperative period, which disappeared spontaneously or with antidiarrheal medication; a disabling diarrhea persisted in two patients only (6.2 percent). CONCLUSION: We believe that subtotal colectomy is the treatment of choice for obstructed left-sided colonic carcinoma. Segmental resection with intraoperative colonic irrigation is more appropriate than subtotal colectomy only in patients with carcinomas of the rectosigmoid junction or with previous anal incontinence to avoid the appearance of postoperative diarrhea.

Endothelial cell chimerism does not influence allograft tolerance in liver transplant patients after withdrawal of immunosuppression.

Background. Human liver allografts sometimes show self-induced permanent tolerance without immunosuppression. It has recently been proposed that the replacement of liver donor endothelial cells by recipient cells could confer a survival advantage. The aim of this study was to analyze liver endothelial cell replacement in relation to the response (tolerance or rejection) after withdrawal of immunosuppression in liver transplant patients. Methods. Nine liver recipient patients were entered into a program of immunosuppressive drug withdrawal. The authors studied liver endothelial cell chimerism in five of these patients who received a liver from a donor of the opposite sex by in situ hybridization for X and Y chromosomes. Results. Three patients (33%) achieved complete withdrawal of immunosuppression. The authors’ data show similar endothelial cell chimerism in both the tolerant and nontolerant patients analyzed. Conclusions. Endothelial cell chimerism has nothing to do with the induction of clinical tolerance in liver transplant patients after withdrawal of immunosuppression.

Tourniquet modification of the associating liver partition and portal ligation for staged hepatectomy procedure

In staged liver resections, associating liver partition and portal ligation for staged hepatectomy (ALPPS) achieves sufficient hypertrophy of the future liver remnant (FLR) in 7 days. This is based on portal vein ligation and transection, and on occlusion of intrahepatic collaterals. This article presents a new surgical technique for achieving rapid hypertrophy of the FLR, which also involves adding intrahepatic collateral occlusion to portal vein transection.

Eversion thromboendovenectomy in organized portal vein thrombosis during liver transplantation

Portal thrombosis is no longer considered a contraindication for transplantation because of the technical experience acquired in the field of liver transplantation and the development of various surgical techniques. All the same, the results obtained in portal thrombosis patients are at times suboptimal, and the surgical technique used (thromboendovenectomy or veno‐venous bypass) is also controversial.

Does the standard vs piggyback surgical technique affect the development of early acute renal failure after orthotopic liver transplantation

The objective of this study was to evaluate the effect of the surgical technique on postoperative renal function during the first week after liver transplantation (OLT). We performed a retrospective study of 184 consecutive OLT. Criteria for acute renal failure were: serum creatinine >1.5 mg/dL, an increase by 50% in the baseline serum creatinine, or oliguria requiring renal replacement therapy. The distribution of patients according to the surgical technique was: standard (n=84), venovenous bypass (n=20), and piggyback (n=80). Other variables analyzed were: intraoperative requirement for blood products, treatment with adrenergic agonists, intraoperative complications, and postreperfusion syndrome. Univariate analysis showed the following parameters to be significantly related to postoperative renal failure: intraoperative fresh frozen plasma and cryoprecipitate requirements, intraoperative complications, postreperfusion syndrome, need for noradrenaline or dobutamine, standard surgical technique versus piggyback (39% vs 18%, P<.01) and venovenous vs piggyback (50% vs 18%, P<.01). Logistic regression analysis identified the following variables as having independent prognostic value: (1) Standard surgical technique vs piggyback (OR=3.3, P=.01); (2) venovenous vs piggyback (OR=4.7, P=.02); and (3) >20 U cryoprecipitate requirement (OR=1.04, P=.01). In conclusion, compared with the piggyback technique, the standard surgical technique appears to be an independent risk factor for postoperative acute renal failure. When venovenous bypass is used in patients who do not tolerate trial clamping of inferior vena cava, it does not reduce the incidence of postoperative renal failure. Finally, the piggyback technique significantly reduces the probability of acute renal failure after liver transplantation.

Can we expand the indications for liver transplantation among hepatocellular carcinoma patients with increased tumor size

INTRODUCTION Due to the scarcity of donors and the fact that size is the main prognostic factor, Milan criteria have been used since 1996 to select hepatocellular carcinoma (HCC) patients for liver transplantation. In 2001 UCSF criteria showed that including layer tumors did not reduce the survival results. The objective of this paper was to evaluate whether HCC tumor sizes exceeding the Milan criteria adversely influence survival rates. PATIENTS AND METHODS Between May 1988 and July 2001, 53 patients were transplanted due to HCC and cirrhosis. The etiology of cirrhosis was HCV in 23 cases and HBV in 6. In 11 cases the HCC were incidental by discovered namely, a mean/ diameter of 1.8 cm (versus 2.6 cm in nonincidental HCC). Sixty-two percent of tumors met the Milan criteria, and 68% the USCF criteria. RESULTS The actuarial survival was 79% at 1 year and 62% at 5 years. The survival of patients with incidental HCC was 82% at 1 year and 82% at 5 years, which is better than the survival of those with nonincidental HCC (78% at 1 year and 57% at 5 years, P<.05). According to Milan criteria, the survival patients with early tumors was 82% at 1 year and 68% at 5 years, and for advanced tumors (NS), 75% and 54%, respectively. Comparison of early versus advanced tumors according to UCSF criteria showed survivals of 84% versus 64% at 1 year (P<.05) and 67% versus 48% at 5 years (P<.05), respectively. CONCLUSION Increasing the HCC size among LT according to the California criteria did not reduce survival rates compared with the Milan criteria.

Immunosuppression withdrawal improves long-term metabolic parameters, cardiovascular risk factors and renal function in liver transplant patients

Abstract:  After liver transplantation, long‐term immunosuppression (IS) administration is commonly complicated by renal dysfunction and cardiovascular complications. Twenty liver transplant patients on cyclosporine (CyA)‐based IS were followed up prospectively after IS withdrawal. They consisted of 10 electively weaned patients and 10 either forcibly or incidentally weaned patients. Liver biochemical tests, blood pressure, serum creatinine, serum urea, serum uric acid, triglycerides, cholesterol and glucose were monitored after the start of weaning. Eight of the 20 patients (40%) were IS therapy free for a mean period of 61 ± 39 months (range: 10–132 months). Of the remaining 12 patients, mild or moderate acute rejection occurred in six patients (30%), and mixed inflammatory portal tract infiltrate was seen in another six patients (30%). At the end of the study, mean (SD) serum creatinine had fallen by 0.28 (0.10) mg/dL (p < 0.001) in operationally tolerant (T) patients whereas the serum creatinine level increased in IS‐dependent patients [+0.35 (0.35) mg/dL] (p = 0.005). In T patients, serum cholesterol, serum uric acid, fasting glucose and diastolic arterial pressure values significantly decreased. IS withdrawal can be achieved in selected liver transplant patients, and can improve not only kidney function, but also other CyA‐associated side effects, such as hypercholesterolemia, hyperuricemia, hypertension and diabetes.