Malay Shah

The evaluation of the safety and tolerability of two formulations of cyclosporine: neoral and sandimmune. A meta-analysis.

BACKGROUND Neoral, a microemulsion formulation of cyclosporine, was approved for use in the United States in 1995. Many studies comparing Neoral and Sandimmune have been conducted, and although most state that Neoral is the superior cyclosporine formulation, results have failed to conclusively demonstrate this claim. The aim of this meta-analysis was to compare the safety and efficacy of Neoral and Sandimmune. METHODS Publications comparing the use of Neoral and Sandimmune were reviewed for demographic variables, adverse events, rejection incidence, graft losses, and serum creatinine. Neoral and Sandimmune were compared in all patients and in the following subgroups: (1) age (adult or pediatric), (2) transplant type (kidney, liver, or heart), (3) indication (de novo or stable), and (4) study design (randomized prospective trials versus nonrandomized, blinded versus open-labeled studies). RESULTS The rate of graft loss was similar when comparing Neoral and Sandimmune in all analyses. The incidence of rejection was lower in Neoral-treated de novo renal, liver, and cardiac transplants (P<0.05). There were significantly more adverse events in Sandimmune-treated de novo liver transplants than Neoral-treated de novo liver transplants (P<0.00001). When considering only randomized prospective trials, the incidence of rejection was lower in Neoral-treated de novo and stable patients (P<0.05). However, there were more adverse events in Neoral-treated stable patients (P<0.00001). When considering only blinded studies, there were more adverse events in Neoral-treated patients (P<0.05), whereas in open-labeled studies there was no difference in adverse events comparing Neoral and Sandimmune (P=NS). CONCLUSIONS Considering all published trials, the data seem to indicate that Neoral therapy is preferred because of a lower rejection incidence, with a trend toward less adverse events. However, when limiting the analysis to only randomized prospective trials, and specifically assessing blinded studies, the data become less clear. Neoral use was associated with more adverse events in blinded studies, and Sandimmune use was associated with more adverse events in open-labeled studies. Careful individual consideration must be given in choosing the best possible cyclosporine formulation.

Targeting the Wnt/β-Catenin Signaling Pathway in Liver Cancer Stem Cells and Hepatocellular Carcinoma Cell Lines with FH535

Activation of the Wnt/β-catenin pathway has been observed in at least 1/3 of hepatocellular carcinomas (HCC), and a significant number of these have mutations in the β-catenin gene. Therefore, effective inhibition of this pathway could provide a novel method to treat HCC. The purposed of this study was to determine whether FH535, which was previously shown to block the β-catenin pathway, could inhibit β-catenin activation of target genes and inhibit proliferation of Liver Cancer Stem Cells (LCSC) and HCC cell lines. Using β-catenin responsive reporter genes, our data indicates that FH535 can inhibit target gene activation by endogenous and exogenously expressed β-catenin, including the constitutively active form of β-catenin that contains a Serine37Alanine mutation. Our data also indicate that proliferation of LCSC and HCC lines is inhibited by FH535 in a dose-dependent manner, and that this correlates with a decrease in the percentage of cells in S phase. Finally, we also show that expression of two well-characterized targets of β-catenin, Cyclin D1 and Survivin, is reduced by FH535. Taken together, this data indicates that FH535 has potential therapeutic value in treatment of liver cancer. Importantly, these results suggest that this therapy may be effective at several levels by targeting both HCC and LCSC.

Gold nanoparticles: various methods of synthesis and antibacterial applications.

Colloidal gold is very attractive for several applications in biotechnology because of its unique physical and chemical properties. Many different synthesis methods have been developed to generate gold nanoparticles (AuNPs). Here, we will introduce these methods and discuss the differences between fabrication techniques. We will also discuss ecofriendly synthesis methods being developed to efficiently generate AuNPs without the use of toxic substrates. Finally, we will discuss the medical applications for AuNPs by highlighting the potential use of intact or functionalized AuNPs in combating bacterial infections.

Simeprevir and sofosbuvir with or without ribavirin to treat recurrent genotype 1 hepatitis C virus infection after orthotopic liver transplantation

Although combination simeprevir (SIM) plus sofosbuvir (SOF) is an approved regimen for genotype 1 chronic hepatitis C virus (HCV), data regarding its safety and efficacy in liver transplant recipients remain limited. A multicenter retrospective study was performed to determine the efficacy and tolerability of a 12‐week regimen of SIM/SOF with or without ribavirin (RBV) in 56 consecutive liver transplant recipients in 2014; 79% of patients had genotype 1a, 14% had cirrhosis, and 73% were treatment experienced. Sustained virological response at 12 weeks (SVR12) was 88% by intention to treat analysis (95% confidence interval, 84%‐90%). Four patients relapsed, but no on‐treatment virological failures occurred. The Q80K polymorphism did not impact SVR12, but there was a trend toward decreased sustained virological response with advanced fibrosis (P = 0.18). HCV RNA was detectable at treatment week 4 in 21% of patients, and those who had detectable levels were less likely to achieve SVR12 (58% versus 95%; P = 0.003). Five patients had baseline Child‐Pugh class B cirrhosis, and 2 of them died (1 following early discontinuation of therapy). An additional discontinuation resulted from a severe photosensitivity reaction in a patient on concomitant cyclosporine. Seven patients receiving RBV developed progressive anemia requiring intervention. Immunosuppression dose modifications were minimal. SIM/SOF for 12 weeks was effective and well tolerated by compensated liver transplant recipients especially when administered without concomitant RBV or cyclosporine. SIM/SOF appears to have a niche as the only 12‐week RBV‐free treatment regimen currently recommended by guidelines for compensated transplant recipients. However, 12 weeks may not be the optimal duration of therapy for those with detectable virus at week 4 or possibly for those with cirrhosis. These data require confirmation by prospective randomized clinical trials. Liver Transplantation 22 635‐643 2016 AASLD.

PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation

BACKGROUND Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells). MATERIALS AND METHODS Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways. RESULTS Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 (P < 0.001). Interestingly, HuH7 cells were more sensitive to sorafenib than LCSC or PLC cells. Additionally, combination therapy with PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 μM (P < 0.001; n = 12) and 67% by PKI-587 at 0.1 μM (P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% (P = 0.002; n = 12). CONCLUSIONS LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro. The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation.

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.

Peri-operative challenges and long-term outcomes in liver transplantation for polycystic liver disease.

BACKGROUND The purpose of this study was to determine peri-operative mortality and long-term outcomes in patients undergoing liver transplantation in the US using the United Network for Organ Sharing (UNOS) database. METHODS This study is a retrospective review of liver transplantations (LT) recorded in the UNOS database performed between 1988 and 2010. In total, 107 411 LT were performed in the US, 357 (0.3%) were for adult polycystic liver disease (PLD). A random group of 9416 adult patients transplanted for other diagnoses was created for comparison (10% of the adult non-PLD database). RESULTS Two hundred and seventy-one patients in the adult PLD group were females (75.9%), the mean age was 52.3 ± 8.2 [standard deviation (SD)] years. The median length of transplantation hospital stay was 11 days (interquartile range 8-21). Patients from the PLD group versus the comparison group (9416 patients) consisted of more females, lower Model for End-Stage Liver Disease (MELD) scores (17 versus 21 points), more multi-organ transplants (41% versus 4 %), chronic renal failure (creatinine 2.7 versus 1.5) and fewer patients with chronic hepatitis C (1.4% versus 32%). Peri-operative mortality (≤30 days) was 9% in the PLD versus 6% in the comparison group; however, at 1 year PLD survival was similar (85% versus 85%) to other diagnoses and better at 3 (81% versus 77%) and 5 years (77% versus 71%, overall Log Rank P = 0.006). A similar PLD survival advantage was observed in isolated initial transplants (P = 0.019). CONCLUSION In spite of early technical challenges and mortality, transplantation should be considered an option for selected patients with PLD as excellent long-term outcomes can be achieved.

Liver transplantation for fibrolamellar hepatocellular carcinoma: A national perspective

Fibrolamellar Hepatocellular Carcinoma (FL‐HCC) is a rare primary liver tumor that usually presents in younger patients without underlying liver disease.

Combined liver–kidney transplantation for polycystic liver and kidney disease: analysis from the United Network for Organ Sharing dataset

The purpose of this study was to evaluate predictors of outcomes in combined liver–kidney transplants for polycystic liver and kidney disease.

A randomized, phase 2 study of ASP0113, a DNA-based vaccine, for the prevention of CMV in CMV-seronegative kidney transplant recipients receiving a kidney from a CMV-seropositive donor

Cytomegalovirus (CMV) is a latent infection in most infected individuals, but can be pathogenic in immunocompromised kidney transplant recipients. ASP0113 is a DNA‐based vaccine for the prevention of CMV‐related mortality and end‐organ disease in transplant recipients. The efficacy, safety, and immunogenicity of ASP0113 was assessed in a phase 2, double‐blind, placebo‐controlled study in CMV‐seronegative kidney transplant recipients receiving a kidney from a CMV‐seropositive donor. Transplant recipients were randomized (1:1) to receive 5 doses of ASP0113 (5 mg; n = 75) or placebo (n = 74) on Days 30/60/90/120/180 posttransplant, and they received prophylactic valganciclovir/ganciclovir 10‐100 days posttransplant. The primary endpoint was the proportion of transplant recipients with CMV viremia ≥1000 IU/mL from Day 100 through to 1 year after the first study vaccine injection. There was no statistically significant difference in the primary endpoint between the ASP0113 and placebo groups (odds ratio 0.79, 95% confidence interval 0.43‐1.47; P = .307). There were similar numbers of transplant recipients with treatment‐emergent adverse events between groups; however, more transplant recipients reported injection site pain in the ASP0113 group compared with placebo. ASP0113 did not demonstrate efficacy in the prevention of CMV viremia in this CMV‐seronegative kidney transplant population, but demonstrated a safety profile similar to placebo. ClinicalTrials.gov registration number: NCT01974206.