The presence of non-hepatic malignancy and its implication in pursuing liver transplantation.

BACKGROUND: Primary extrahepatic malignancy and chronic liver disease co-exist in a considerable number of patients, creating a dilemma both in the aspects of liver transplant candidacy and cancer therapy. In this review, we will explore several aspects and controversies of liver transplantation in patients with non-hepatocellular carcinoma malignancy including risks of cancer recurrence after liver transplantation and the ethical dilemma of the selection of liver transplantation candidates with non-hepatic malignancy. METHODS: We performed a search in several online databases and reviewed published articles and ongoing clinical trials in the topics of transplantation and pre-existing malignancies. RESULTS AND DISCUSSION: Liver transplantation can be safely performed in selected patients with pre-existing extrahepatic malignancies with low recurrence rate if they have an expected 5-year survival rate of at least 50%. The cancer-free period before transplantation depends on the type, stage, and location of cancer. A shorter or no wait-time may be considered in an early stage cancer or carcinoma in situ. The urgency and benefits of liver transplantation should also be taken into consideration when determining a reasonable wait-time. This is particularly important in patients with decompensated cirrhosis who cannot afford to wait a few years before they can undergo liver transplantation.

Hepatocellular carcinoma in patients with no identifiable risk factors.

BACKGROUND: A subset of patients have no risk factors for the development of hepatocellular carcinoma (HCC). We evaluated differences in clinical variables between patients with and without risk factors who underwent surgical resection. METHODS: A prospectively maintained database was queried for patients who underwent R0/R1 resection of HCC between 1992 and 2016. Risk factors included HCV, HBV, hemochromatosis, alcoholic liver disease, or cirrhosis, stage 2 or 3 fibrosis or severe (>66%) steatosis of the non-neoplastic liver. Variables were compared between patients with and without risk factors. RESULTS: There were 416 patients who underwent resection; 276 (66%) had known risk factors while 140 (34%) did not. Patients without risk factors were more likely to be older, female and have hyperlipidemia or coronary artery disease (p < 0.004). These patients had larger tumors and were more likely to undergo major hepatectomy (p < 0.001). There was no difference in OS (5-year, 56% vs 47%, p = 0.335), RFS (27% vs 24%, p = 0.398), or the rates of intrahepatic (HR:1.16 [95%CI:0.95-1.57], p = 0.344) and extrahepatic recurrences (HR:0.72 [95%CI:0.4-1.3], p = 0.261) between groups. CONCLUSION: Patients without risk factors for HCC presented with larger tumors yet had similar outcomes, suggesting these tumors may represent a different disease process, and underlying liver dysfunction can influence overall outcome.

Clinical implications of drug-induced liver injury in early-phase oncology clinical trials.

BACKGROUND: Data on drug-induced liver injury (DILI) and acute liver failure (ALF) in modern phase 1 oncology trials are limited, specifically with respect to the incidence and resolution of DILI and the safety of drug rechallenge. METHODS: This study reviewed all patients who were recruited to phase 1 oncology trials between 2013 and 2017 at Memorial Sloan Kettering Cancer Center. Clinicopathologic data were extracted to characterize DILI, and attribution was assessed on the basis of data prospectively generated during the studies. Logistic regression models were used to explore factors related to DILI and DILI recurrence after drug rechallenge. RESULTS: Among 1670 cases recruited to 85 phase 1 trials, 81 (4.9%) developed DILI. The rate of DILI occurrence was similar for patients in immune-based trials and patients in targeted therapy trials (5.0% vs 4.9%), as was the median time to DILI (5.5 vs 6.5 weeks; P = .48). Two patients (0.12%) met the criteria of Hy's law, although none developed ALF. The DILI resolved in 96% of the patients. Pretreatment factors were not predictive for DILI development. Thirty-six of the 81 patients underwent a drug rechallenge, and 28% of these patients developed DILI recurrence. Peak alanine aminotransferase during the initial DILI was associated with DILI recurrence (odds ratio, 1.04; 95% confidence interval, 1.0-1.09; P = .035). CONCLUSIONS: In modern phase 1 oncology trials, DILI is uncommon, may occur at any time, and often resolves with supportive measures. Rechallenging after DILI is feasible; however, the high rate of DILI recurrence suggests that clinicians should consider the severity of the DILI episode and treatment alternatives.

Safety and Efficacy of Re-treating with Immunotherapy after Immune-Related Adverse Events in Patients with NSCLC.

Considering retreatment following recovery from an immune-related adverse event (irAE) is a common clinical scenario, but the safety and benefit of retreatment is unknown. We identified patients with advanced non-small cell lung cancer (NSCLC) treated with anti-PD-(L)1 who had treatment held due to irAEs and divided them into two groups: those retreated with anti-PD-(L)1 (retreatment cohort) or those who had treatment stopped (discontinuation cohort). Out of 482 NSCLC patients treated with anti-PD-(L)1, 68 (14%) developed a serious irAE requiring treatment interruption. Of these, 38 (56%) were retreated and 30 (44%) had treatment discontinued. In the retreatment cohort, 18 (48%) patients had no subsequent irAEs, 10 (26%) had recurrence of the initial irAE, and 10 (26%) had a new irAE. Most recurrent/new irAEs were mild (58% grade 1-2) and manageable (84% resolved or improved to grade 1). Two treatment-related deaths occurred. Recurrent/new irAEs were more likely if the initial irAE required hospitalization, but the initial grade and time to retreatment did not influence risk. Among those with no observed partial responses prior to the irAE, progression-free survival (PFS) and overall survival (OS) were longer in the retreatment cohort. Conversely, for those with objective responses prior to the irAE, PFS and OS were similar in the retreatment and discontinuation cohorts. Among patients with early objective responses prior to a serious irAE, outcomes were similar, whether or not they were retreated. Together, data suggest that benefit may occur with retreatment in patients with irAEs who had no treatment response prior to irAE onset. Cancer Immunol Res; 6(9); 1093-9. ©2018 AACR.

High prevalence of colon adenomas in end-stage kidney disease patients on hemodialysis undergoing renal transplant evaluation.

The aim of this study was to determine whether patients with end-stage kidney disease (ESKD) on hemodialysis (HD) undergoing kidney transplant evaluation are at higher risk for colonic neoplasia than the general population. This is a retrospective cohort study of patients with ESKD who underwent a first screening colonoscopy while undergoing kidney transplant evaluation. Data were collected on the prevalence of adenomatous polyps and advanced adenomas in 70 patients with ESKD and 70 controls, undergoing their first screening colonoscopy, matched for age, gender, and endoscopist. At the time of the colonoscopy, an average time on HD was 3.2 ± 2.9 yr. The prevalence of adenomatous polyps was significantly higher in ESKD on HD (54.3% vs. 32.9%, p = 0.008) than in controls. In a multivariate analysis controlling for other factors, ESKD on HD remained a risk factor for the presence of adenomas (OR 3.06, 95% CI 1.21, 7.73). No colonoscopy-related complications were reported in the patients with ESKD on HD. We demonstrate a significantly higher prevalence of adenomatous polyps in patients with ESKD undergoing a first screening colonoscopy as part of kidney transplant evaluation. In addition, colonoscopy can be safely performed in this population.

FibroSURE as a noninvasive marker of liver fibrosis and inflammation in chronic hepatitis B.

BACKGROUND: Noninvasive markers of liver fibrosis have not been extensively studied in patients with chronic hepatitis B virus (HBV) infection. Our aim was to evaluate the capacity of FibroSURE, one of the two noninvasive fibrosis indices commercially available in the United States, to identify HBV infected patients with moderate to severe fibrosis. METHODS: Forty-five patients who underwent liver biopsy at a single tertiary care center were prospectively enrolled and had FibroSURE performed within an average interval of 11 days of the biopsy. RESULTS: Of the 45 patients, 40% were Asian, 40% were African American, and 13% were Caucasian; 27% were co-infected with HIV and 67% had no or mild fibrosis. We found FibroSURE to have moderate capacity to discriminate between patients with moderate to high fibrosis and those with no to mild fibrosis (area under receiver operating characteristic [AUROC] curve = 0.77; 95% confidence interval [CI] [0.61, 0.92]). When we combined the fibrosis score determined by FibroSURE with aspartate aminotransferase (AST) measurements and HIV co-infection status, the discriminatory ability significantly improved reaching an AUROC of 0.90 (95% CI [0.80, 1.00]). FibroSURE also had a good ability to differentiate patients with no or mild from those with moderate to high inflammation (AUROC = 0.83; 95% CI [0.71, 0.95]). CONCLUSIONS: FibroSURE in combination with AST levels has an excellent capacity to identify moderate to high fibrosis stages in chronic HBV-infected patients. These data suggest that FibroSURE may be a useful substitute for liver biopsy in chronic HBV infection.

Viral hepatitis, non-alcoholic fatty liver disease and alcohol as risk factors for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common cancer worldwide, with significant increase in the incidence observed in the past two decades in the United States. Majority of cases of HCC are due to chronic viral hepatitis B and C infections; however non-alcoholic fatty liver disease, associated with obesity and diabetes emerges as an important risk factor for HCC, in particular in the developed countries. Here we will review viral characteristics associated with increased risk for development of HCC and role of antiviral therapy in decreasing risk of HCC in those with viral hepatitis and cirrhosis. Association of alcoholic cirrhosis and non-alcoholic fatty liver disease with liver cancer will be reviewed as well as possible measures to decrease the risk of HCC in these highly prevalent populations.

Advances in the treatment of hepatitis C virus infection.

Therapy for chronic hepatitis C virus (HCV) infection with pegylated interferon α and ribavirin leads to suboptimal rates of viral eradication in patients with genotype 1 HCV, the most common viral strain in the United States and many other countries. Recent advances in the study of viral kinetics, host factors that predict response to antiviral therapy, and viral protein structure have established the foundation of a new era in the treatment of HCV infection. The HCV NS3/4A protease inhibitors boceprevir and telaprevir, the first 2 agents in a new and promising generation of direct-acting antiviral agents to have completed phase III studies, were approved by the US Food and Drug Administration in May 2011. The addition of these HCV protease inhibitors to standard therapy has been demonstrated to dramatically improve sustained virologic response rates, both in treatment-naïve patients and in prior relapsers and nonresponders. These novel agents represent only the beginning of a revolution in HCV therapy, which will include additional protease inhibitors as well as other classes of drugs currently under investigation, such as polymerase inhibitors, NS5A inhibitors, and host factor inhibitors such as cyclophilin antagonists. The future of HCV therapy holds promise for significantly higher sustained virologic response rates with shorter treatment durations, as well as the intriguing potential to achieve virologic cure with interferon-free combination therapy regimens.

Resistance-associated variants in chronic hepatitis C patients treated with protease inhibitors.

Direct-acting antiviral agents in combination with pegylated interferon (PEG-IFN) and ribavirin (RBV) significantly improve sustained virologic response rate and reduce duration of therapy among both treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C. One of the most important considerations with both boceprevir and telaprevir is the potential development of resistant variants with therapy. Patients with poor intrinsic responsiveness to interferon, and those with incomplete virological suppression on protease inhibitor therapy, appear to be at higher risk for resistance. In this article we will define antiviral resistance and review the data on both in vitro and in vivo resistance to protease inhibitors, concentrating on data on boceprevir and telaprevir. We will also explore the significance of resistant variants present at the baseline, as well as the fate of the resistant variants and the ways to minimize the development of resistance to protease inhibitors.

Hepatitis B in pregnancy.

In countries with a high prevalence of chronic hepatitis B, perinatal transmission from mother to infant accounts for the majority of cases of chronic hepatitis B. Passive-active immunoprophylaxis with hepatitis B immunoglobulin and hepatitis B vaccine at birth is 95% efficacious in reducing the risk of HBV transmission but is less effective in HBeAg-positive mothers with very high serum HBV DNA levels. In the last 4 weeks of pregnancy lamivudine may provide additional protection in pregnant women who have high-level viremia. Further studies are needed to evaluate the use of nucleos(t)ide analogues to treat chronic hepatitis B during pregnancy.

Prevalence of nonalcoholic fatty liver disease in women with polycystic ovary syndrome.

BACKGROUND & AIMS: Insulin resistance has been implicated in the pathogenesis of both nonalcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS). We hypothesized that NAFLD would be common in both obese and nonobese women with PCOS. The aim of this study was to estimate the prevalence of and identify associated factors for hepatic steatosis in women with PCOS. METHODS: This is a retrospective study of 88 consecutive premenopausal women with PCOS. Clinical history, height, weight, and laboratory values were obtained. Fasting measurements of serum glucose and insulin were used to calculate homeostasis model assessment of insulin resistance (HOMA-IR). Abdominal ultrasonography was used to determine the presence and severity of hepatic steatosis. RESULTS: Of the 88 women (median age, 31.4 years), 48 (55%) had steatosis; 15 (39%) of them were lean women. The presence of steatosis was associated with a greater body mass index (BMI) (P = .005) and HOMA-IR (P = .033), a lower fasting high-density lipoprotein (P = .003), and a greater prevalence of impaired fasting glucose, impaired glucose tolerance, and diabetes mellitus (P = .013). Only 7 (15%) subjects with hepatic steatosis had abnormal liver chemistries. CONCLUSIONS: Fatty liver was identified in 55% of subjects with PCOS, nearly 40% of whom were lean women. High BMI and insulin resistance appeared to be important associated factors. Early recognition of NAFLD in this group of young patients is warranted, and further investigation including liver biopsy might be indicated.

Cancer history and other personal factors affect quality of life in patients with hepatitis C.

BACKGROUND: Although patients with chronic hepatitis C (CHC) have been found to have reduced quality of life, little is known about how other characteristics affect their quality of life. The purpose of this study was to investigate the effect of other characteristics, including history of cancer, on quality of life in patients with CHC. METHODS: One hundred forty patients from clinics at three hospitals in New York City completed a detailed epidemiologic interview about demographic and lifestyle characteristics and the SF-36 measuring health-related quality of life. We compared results from our patients to normative data using t-tests of differences between means. We used multivariate analyses to determine other personal and health-related factors associated with quality of life outcomes. RESULTS: Compared to normative data, these patients had reduced quality of life, particularly on physical functioning. The summary Physical Component Score (PCS) was 45.4 +/- 10.6 and the Mental Component Score (MCS) was 48.2 +/- 11.1, vs norms of 50 +/- 10.0; p-values were < 0.0001 and < 0.05, respectively. In multivariate analyses, the PCS was significantly lower among those with cancer history, > or = 2 other chronic conditions, less education, low physical activity, and higher alanine aminotransferase (ALT) levels. Cancer was more important for men, while other chronic conditions were more important for women. On the MCS, history of depression, low physical activity, alcohol use, and female gender were independently associated with poorer scores. CONCLUSION: Several health and lifestyle factors independently influence quality of life in CHC patients. Different factors are important for men and women.