Valery Vilchez

Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. A great effort in developing selective drugs to target components of the β-catenin pathway with anticancer activity is underway but only a few of them have reached phase I clinical trials. We aim to review the role of β-catenin pathway on hepatocarcinogenesis and liver cancer stem cell maintenance. We also evaluated the use of small molecules targeting the Wnt/β-catenin pathway with potential application for treatment of HCC.

Long-term outcome of patients undergoing liver transplantation for mixed hepatocellular carcinoma and cholangiocarcinoma: an analysis of the UNOS database

BACKGROUND Mixed hepatocellular and cholangiocarcinoma (HCC-CC) have been associated with a poor prognosis after liver transplantation (LT). We aimed to evaluate long-term outcomes in patients undergoing LT for HCC-CC versus patients with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC). METHODS Retrospective analysis of the United Network for Organ Sharing (UNOS) database from 1994-2013. Overall survival (OS) in patients with HCC-CC, HCC, and CC, were compared. RESULTS We identified 4049 patients transplanted for primary malignancy (94 HCC-CC; 3515 HCC; 440 CC). Mean age of patients with HCC-CC was 57 ± 10 years, and 77% were male. MELD score did not differ among the groups (p = 0.637). Hepatitis C virus was the most common secondary diagnosis within the HCC-CC (44%) and HCC (36%) cohorts, with primary sclerosing cholangitis in the CC (16%) cohort. OS rates at 1, 3 and 5 years for HCC-CC (82%, 47%, 40%) were similar to CC (79%, 58%, 47%), but significantly worse than HCC (86%, 72%, and 62% p = 0.002). DISCUSSION Patients undergoing LT for HCC had significantly better survival compared to those transplanted for HCC-CC and CC. LT for mixed HCC-CC confers a survival rate similar to selected patients with CC. Efforts should be made to identify HCC-CC patients preoperatively.

Nonalcoholic steatohepatitis is strongly associated with sarcopenic obesity in patients with cirrhosis undergoing liver transplant evaluation.

Sarcopenia is the most common complication of cirrhosis and adversely affects quality of life and outcomes before, during, and after liver transplantation. We studied predictors of sarcopenia and sarcopenic obesity in patients with cirrhosis undergoing liver transplant (LT) evaluation.

Donor positive blood culture is associated with delayed graft function in kidney transplant recipients: a propensity score analysis of the UNOS database

The effect of blood culture positive donor (BCPD) on delayed graft function (DGF) in kidney transplant recipients has not been well established.

Decreased graft survival in liver transplant recipients of donors with positive blood cultures: a review of the United Network for Organ Sharing dataset.

Liver transplantation using blood culture positive donors (BCPD) has allowed a significant expansion of the donor pool. We aimed to characterize BCPD and assess the outcomes of BCPD liver transplant recipients. We retrieved data from the United Network for Organ Sharing (UNOS) registry on all adults who underwent primary, single‐organ deceased‐donor liver transplantation in the USA between 2008 and 2013. Patients were classified into two cohorts: the BCPD cohort and the non‐BCPD cohort. One‐year graft and patient survival were compared between cohorts using Kaplan–Meier estimates and Cox models. A total of 28 961 patients were included. There were 2316 (8.0%) recipients of BCPD. BCPD were more likely to be older, female, black, diabetic, hypertensive, and obese compared to non‐BCPD. Graft survival was significantly lower in BCPD recipients compared to non‐BCPD recipients (Kaplan–Meier, 0.85 vs. 0.87; P = 0.009). Results remained significant in propensity‐matched analysis (P = 0.038). BCPD was independently associated with decreased graft survival (adjusted HR; 1.10, 95% CI 1.01–1.20; P = 0.04). There were no significant differences in patient survival between study groups. BCPD was associated with decreased graft survival in liver transplant recipients. Studies are needed to identify subgroups of BCPD with the highest risk of graft failure and characterize the underlying pathogenic mechanisms.

Liver transplantation for the treatment of neuroendocrine liver metastases

Neuroendocrine neoplasms represent a heterogeneous group of cancers arising from a variety of neuroendocrine cell types. In general, these tumors (NET) are asymptomatic and are discovered late once metastatic disease is present (40-80%). The liver is the most common organ involved when metastases occur (40-93%), followed by bone (12-20%) and lungs (8-10%). A number of different therapeutic options are available for patients with hepatic metastases including surgical resection, transplantation, transarterial chemoembolization, radiofrequency and microwave ablation, radioembolization (Y90), chemotherapy, somatostatin analogues and molecular targeted therapies. Surgical resection is still considered the treatment of choice and provides excellent disease control with an overall survival of 47-92%. Liver transplantation has been advocated in selected patients with bilateral unresectable symptomatic liver metastases. The aim of this study is to review the existing literature emphasizing on the role of transplantation to treat patients with liver metastases from NET.

Role of Transplantation in the Treatment of Benign Solid Tumors of the Liver: A Review of the United Network of Organ Sharing Data Set

IMPORTANCE The role of orthotopic liver transplantation for the treatment of benign solid liver tumors (BSLT) is not well defined. OBJECTIVE To analyze outcomes in the United Network of Organ Sharing data set of patients with a diagnosis of BSLT who underwent transplantation. DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of the United Network of Organ Sharing data set was performed for all (N = 87,280) patients who underwent transplantation for BSLT in the United States from October 1, 1988, through January 31, 2013. MAIN OUTCOMES AND MEASURES Demographics, clinicopathological characteristics, distribution of the procedures by region and state, and overall survival rates. RESULTS During the study period, 147 liver transplants (0.17%) were to treat BSLT. Sixty-two patients (42.2%) had adenomas, 29 (19.7%) had focal nodular hyperplasia, 25 (17.0%) had hemangiomas, 11 (7.5%) had hepatic epithelioid hemangioendotheliomas, and 20 (13.6%) were classified as having unknown benign tumors. The overall 1-, 3-, and 5-year survival rates were 90.9%, 85.2%, and 81.8%, respectively. Using multivariable analysis, we found that age was the only independent factor associated with patient survival. The overall 5-year survival rate for patients older than 50 years was 88% compared with 91% in younger individuals (95% CI, 148-384; P = .005). Region 3 (Alabama, Arkansas, Florida, Georgia, Louisiana, Mississippi, and Puerto Rico) contributed the maximum number (33 [22.4%]) of these transplants. CONCLUSIONS AND RELEVANCE Although liver transplantation cannot be considered a first-line treatment, it is a valid therapeutic option in selected patients who are not amenable to resection. Only 0.17% of the transplants in the United States are performed for this indication, with satisfying long-term results. Age was an independent predictor of patient survival. Further studies are needed to better understand the role of liver transplantation in the treatment of BSLT.

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice

The PI3K/mTOR signaling cascade is fundamental in T‐cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T‐cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T‐cell activities. Substantial adverse effects in long‐term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T‐cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI‐103 and PKI‐587 inhibitors interfered IL‐2‐dependent responses in T‐cells. However, in contrast to the inhibitory effects in non‐Treg T‐cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI‐103, and PKI‐587 targeted different signaling events and induced different metabolic patterns in primary T‐cells. Similar to rapamycin, in vivo administration of PI‐103 and PKI‐587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T‐cells and support their potential as a novel therapeutic option in transplantation.

Liver Cancer Stem Cells: A New Paradigm for Hepatocellular Carcinoma Treatment

Hepatocellular carcinoma (HCC) ranks as fifth most prevalent cancer worldwide. Despite its high prevalence rate the therapeutic options and prognosis of the patients mainly depend on the stage on the presentation. The Cancer Stem Cell (CSC) hypothesis proposes that a small population of cells is responsible for tumour development and disease progression. These cells are characterized by their ability of self-renewal, differentiation, chemo- and radio-resistance. CSC hypothesis could explain HCC heterogeneity within or between masses, its mechanism of recurrence and metastasis, and the poor outcome of current therapies. Due to their role in HCC it might be essential targeting these cells as part of the treatment. Several signaling pathways including RAS/RAF/MAPK, Wnt-β-catenin, PI3K/mTOR, among others; have been implicated in HCC carcinogenesis and their components represent novel molecular therapeutic targets. Because of the heterogeneity of these cancers and the complex process involved in hepatocarcinogenesis, our group and others suggest that combined therapy should be essential in HCC treatment. This review focuses on the current understanding of liver cancer stem cells, their clinical implications, and the rationale for targeting these cells in HCC treatment.

N-Aryl benzenesulfonamide inhibitors of [3H]-thymidine incorporation and β-catenin signaling in human hepatocyte-derived Huh-7 carcinoma cells.

Structure-activity relationships (SAR) in 2,5-dichloro-N-(2-methyl-4-nitrophenyl)benzenesulfonamide (FH535) were examined as part of a program to identify agents that inhibit the Wnt/β-catenin signaling pathway that is frequently upregulated in hepatocellular carcinoma (HCC). FH535 was reported as an inhibitor of both β-catenin in the Wnt signaling pathway and the peroxisome proliferator-activated receptor (PPAR). A β-catenin/T-cell factor (TCF)/Lymphoid-enhancer factor (LEF)-dependent assay (i.e., luciferase-based TOPFlash assay) as well as a [(3)H]-thymidine incorporation assay were used to explore SAR modifications of FH535. Although replacing the 2,5-dichlorophenylsulfonyl substituent in FH535 with a 2,6-dihalogenation pattern generally produced more biologically active analogs than FH535, other SAR modifications led only to FH535 analogs with comparable or slightly improved activity in these two assays. The absence of a clear SAR pattern in activity suggested a multiplicity of target effectors for N-aryl benzenesulfonamides.