Hypothermic oxygenated perfusion in extended criteria donor liver transplantation-A randomized clinical trial

Hypothermic Oxygenated Perfusion (HOPE) of the liver can reduce the incidence of early allograft dysfunction (EAD) and failure in extended criteria donors (ECD) grafts, although data from prospective studies are very limited. In this monocentric, open-label study, from December 2018 to January 2021, 110 patients undergoing transplantation of an ECD liver graft were randomized to receive a liver after HOPE or after static cold storage (SCS) alone. The primary endpoint was the incidence of EAD. The secondary endpoints included graft and patient survival, the EASE risk score, and the rate of graft or other graft-related complications. Patients in the HOPE group had a significantly lower rate of EAD (13% vs. 35%, p = .007) and were more frequently allocated to the intermediate or higher risk group according to the EASE score (2% vs. 11%, p = .05). The survival analysis confirmed that patients in the HOPE group were associated with higher graft survival one year after LT (p = .03, log-rank test). In addition, patients in the SCS group had a higher re-admission and overall complication rate at six months, in particular cardio-vascular adverse events (p = .04 and p = .03, respectively). HOPE of ECD grafts compared to the traditional SCS preservation method is associated with lower dysfunction rates and better graft survival

Prognostic Factors for Tumor Recurrence after a 12-Year, Single-Center Experience of Liver Transplantations in Patients with Hepatocellular Carcinoma

Background. Factors affecting outcomes after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) have been extensively studied, but some of them have only recently been discovered or reassessed. Methods. We analyzed classical and more recently emerging variables with a hypothetical impact on recurrence-free survival (RFS) in a single-center series of 283 patients transplanted for HCC between 1997 and 2009. Results. Five-year patient survival and RFS were 75% and 86%, respectively. Thirty-four (12%) patients had HCC recurrence. Elevated preoperative alpha-fetoprotein (AFP) levels, preoperative treatments of HCC, unfulfilled Milan and up-to-seven criteria at final histology, poor tumor differentiation, and tumor microvascular invasion negatively affected RFS by univariate analysis. Milan and up-to-seven criteria applied preoperatively, and the use of m-TOR inhibitors did not reach statistical significance. Cox's proportional hazard model showed that only elevated AFP levels (Odds Ratio = 2.88; 95% C.I. = 1.43–5.80; P = .003), preoperative tumor treatments (Odds Ratio = 4.84; 95% C.I. = 1.42–16.42; P = .01), and microvascular invasion (Odds Ratio = 4.82; 95% C.I. = 1.87–12.41; P = .001) were predictors of lower RFS. Conclusions. Biological aggressiveness and preoperative tumor treatment, rather than traditional and expanded dimensional criteria, conditioned the outcomes in patients transplanted for HCC

Long term results of down-staging and liver transplantation for patients with hepatocellular carcinoma beyond the conventional criteria

The objective of the study is to evaluate 10 years of down-staging strategy for liver transplantation (LT) with a median follow-up of 5 years. Data on long-term results are poor and less information is available for hepatocellular carcinoma (HCC) non-responder patients or those ineligible for down-staging. The outcome of 308 HCC candidates and the long-term results of 231 LTs for HCC performed between 2003 and 2013 were analyzed. HCCs were divided according to tumor stage and response to therapy: 145 patients were T2 (metering Milan Criteria, MC), 43 were T3 successfully down-staged to T2 (Down-Achieved), 20 were T3 not fully down-staged to T2 (Down-not Achieved), and 23 patients were T3 not receiving down-staging treatments (No-Down). The average treatment effect (ATE) of LT for T3 tumors was estimated using the outcome of 535 T3 patients undergoing non-LT therapies, using inverse probability weighting regression adjustment. The 24-month drop-out rate during waiting time was significantly higher in the down-staging groups: 27.6% vs. 9.2%, p < 0.005. After LT, the tumor recurrence rate was significantly different: MC 7.6%, Down-Achieved 20.9%, Down-not Achieved 31.6%, and No-Down 30.4% (p < 0.001). The survival rates at 5 years were: 63% in Down-Achieved, 62% in Down-not Achieved, 63% in No-Down, and 77% in MC (p = n.s.). The only variable related to a better outcome was the effective down-staging to T2 at the histological evaluation of the explanted liver: recurrence rate = 7.8% vs. 26% (p < 0.001) and 5-year patient survival = 76% vs. 67% (p < 0.05). The ATE estimation showed that the mean survival of T3-LT candidates was significantly better than that of T3 patients ineligible for LT [83.3 vs 39.2 months (+44.6 months); p < 0.001]. Long term outcome of T3 down-staged candidates was poorer than that of MC candidates, particularly for cases not achieving down-staging. However, their survival outcome was significantly better than that achieved with non-transplant therapies

Regulatory T cells from patients with end-stage organ disease can be isolated, expanded and cryopreserved according good manufacturing practice improving their function

Background Here, we isolated, expanded and functionally characterized regulatory T cells (Tregs) from patients with end stage kidney and liver disease, waiting for kidney/liver transplantation (KT/LT), with the aim to establish a suitable method to obtain large numbers of immunomodulatory cells for adoptive immunotherapy post-transplantation. Methods We first established a preclinical protocol for expansion/isolation of Tregs from peripheral blood of LT/KT patients. We then scaled up and optimized such protocol according to good manufacturing practice (GMP) to obtain high numbers of purified Tregs which were phenotypically and functionally characterized in vitro and in vivo in a xenogeneic acute graft-versus-host disease (aGVHD) mouse model. Specifically, immunodepressed mice (NOD-SCID-gamma KO mice) received human effector T cells with or without GMP-produced Tregs to prevent the onset of xenogeneic GVHD. Results Our small scale Treg isolation/expansion protocol generated functional Tregs. Interestingly, cryopreservation/thawing did not impair phenotype/function and DNA methylation pattern of FOXP3 gene of the expanded Tregs. Fully functional Tregs were also isolated/expanded from KT and LT patients according to GMP. In the mouse model, GMP Tregs from LT or KT patient proved to be safe and show a trend toward reduced lethality of acute GVHD. Conclusions These data demonstrate that expanded/thawed GMP-Tregs from patients with end-stage organ disease are fully functional in vitro. Moreover, their infusion is safe and results in a trend toward reduced lethality of acute GVHD in vivo, further supporting Tregs-based adoptive immunotherapy in solid organ transplantation

Strategies to improve function of marginal grafts and to recover discharged grafts in liver and kidney transplantation

The discrepancy between the number of transplant procedures and the patients in waiting list is linked to the scarcity of suitable donors. Dynamic perfusion of marginal grafts seems to be promising in their recovery. Twenty discarded kidneys were used to perform a preclinical study with a new hypothermic oxygenate machine perfusion. Encouraging preclinical results allowed us to perform a clinical trial, in whom 10 extended criteria donors (ECD) livers and 10 ECD kidneys were perfused with the new machine and then transplanted, and compared with control groups (30 ECD liver transplant and 30 ECD kidney transplant preserved in cold storage). Overall graft dysfunction was 10% in study groups, compared to 31.6% in control group (P < 0.001). The peak of aspartate aminotransferase within 7-days post liver transplant was 637 U/L in control group compared to 344 U/L of liver study group (P = 0.006). Patients receiving a kidney graft with more than 2 hours of hypothermic oxygenate perfusion treatment had lower rate of delayed graft function than control group (0% vs. 40%, p = 0.04). Preclinical analyses demonstrated the absence of damage at histological examination, the improved metabolic activity and a diminished expression of genes related to ischemia/reperfusion injury, especially in case of hyperbarism application during perfusion. Further studies are needed to confirm this hypothesis. On the other hand, the clinical phase of present study documented the safety and efficacy of a new type of machine perfusion, which is low-cost and, unlike the already present in commerce, was effective and safe in both liver and kidney transplantation settings

Can Positive Resection Margin of Intra-hepatic Cholangiocarcinoma Still Provide a Survival Benefit over Systemic Chemotherapy?

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Peritoneal seeding from appendiceal carcinoma: A case report and review of the literature

Non-carcinoid appendiceal malignancies are rare entities, representing less than 0.5% of all gastrointestinal malignancies. Because of their rarity and particular biological behavior, a substantial number of patients affected by these neoplasms do not receive appropriate surgical resection. In this report, we describe a rare case of primary signet-ring cell carcinoma of the appendix with peritoneal seeding which occurred in a 40-year old man admitted at the Emergency Surgery Department with the clinical suspicion of acute appendicitis. After a surgical debulking and right hemicolectomy, the patient had systemic chemotherapy according to FOLFOX protocol. After completion of the latter, the patient underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy. This report offers a brief review of the literature and suggests an algorithm for the management of non-carcinoid appendiceal tumors with peritoneal dissemination

Comments to â\u80\u9cLong-Term Survival Benefit and Potential for Cure After R1 Resection for Colorectal Liver Metastasesâ\u80\u9d

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17. Other Malignant Primary Tumors of the Liver

\u2022 The most common malignant hepatic tumor is by far hepatocellular carcinoma, followed by intrahepatic cholangiocarcinoma. However, other primary malignancies can occur and require specific approaches. \u2022 Cystadenocarcinoma is a cystic tumor that usually develops from hepatic biliary cystadenoma. In both cases, radical surgical resection is the treatment of choice. \u2022 Primary hepatic lymphomas are very rare (contrary to the frequent secondary involvement of the liver in disseminated non-Hodgkin lymphoma) and frequently associated with hepatitis C virus infection. Chemotherapy is efficient for most tumors and surgical resection indicated for complete resection of limited tumors or to reduce tumor burden before systemic therapy. \u2022 Most cases of hepatoblastoma occur in childhood. Prognosis in adults is much poorer due to late diagnosis. Treatment is based on complete surgical resection. \u2022 Hepatic epithelioid hemangioendothelioma is a rare vascular tumor with variable degrees of aggressiveness. Surgical resection (including liver transplantation) is the best approach when no extrahepatic involvement is present. \u2022 Angiosarcoma, the most common primary hepatic sarcoma, represents up to 2% of primary liver malignancies, occurs more frequently in aged patients, and carries a very poor prognosis. Surgical resection is the best option in resectable cases, although recurrence is very common. Chemotherapy and trans-arterial therapy are used alone (to prevent bleeding and avoid tumor growth) or in combination with surgery

Retransplantation (causes, outcome)

Orthotopic liver transplantation (OLT) has been established as the definitive therapy for all types of end-stage liver failure. In spite of the steady improvement in survival of OLT recipients over the past two decades, a proportion of those patients experience graft failure and require retransplantation (re-OLT). Over the last 10 years, the reported waitlist admission for re-OLT varied between 5.5 and 14 % [1\u20133]. Re-OLT indications can be divided into \u201cearly\u201d and \u201clate\u201d causes. Causes of early graft failure are: \u2022 Primary non-function (PNF) \u2022 Vascular complications (hepatic artery thrombosis, portal thrombosis, hepatic vein thrombosis) \u2022 Acute rejection Causes of late graft failure include: \u2022 Recurrence of liver disease (viral infection, autoimmune diseases) \u2022 Chronic rejectio