Small bowel hemorrhage from check point inhibitor enteritis: a case report.

BACKGROUND: There is rising utilization of immune checkpoint inhibitors (ICI) for a growing number of metastatic malignancies. While gastrointestinal side effects of ICI are common, isolated ICI-induced enteritis leading to small bowel hemorrhage is rare. CASE PRESENTATION: A 71-year-old man with a previously resected right colon adenocarcinoma on atezolizumab and recently treated Clostridioides difficile presented with acute on chronic abdominal pain and non-bloody diarrhea. A CT scan revealed enteritis of the duodenum and jejunum without colitis. Initial endoscopic work-up revealed many clean-based non-bleeding duodenal ulcers to the third portion of the duodenum and normal rectosigmoid mucosa. The patient initially improved on steroids but was readmitted on day after discharge with hematochezia and hemorrhagic shock. Repeat CT showed improvement in enteritis; however, repeat push enteroscopy revealed multiple duodenal and jejunal ulcers, two with visible vessels requiring endoscopic intervention. He continued to have significant hemorrhage requiring transfusions despite IV methylprednisolone. Conventional angiogram revealed multiple sites of active extravasation, and he underwent small bowel resection and subsequent IR embolization due to persistent bleeding. He was then started on infliximab 10 mg/kg with resolution of his small bowel hemorrhage and diarrhea. CONCLUSIONS: Severe isolated ICI-enteritis is rare and can lead to clinically significant gastrointestinal hemorrhage. Patients with severe ICI-enteritis on endoscopy should be carefully monitored for steroid refractory disease for consideration of step-up therapy such as infliximab.

Lower Likelihood of Post-transplant Graft Failure, Death, and Retransplantation in the Era of Direct-Acting Antivirals.

BACKGROUND: Direct-acting antivirals (DAAs) are expected to improve outcomes for patients with hepatitis C virus (HCV) infection after liver transplantation (LT). We aim to evaluate trends in post-LT outcomes with availability of DAAs. METHODS: We retrospectively evaluated US adults transplanted from January 1, 2002, to March 31, 2018, using the United Network for Organ Sharing Registry, stratified by pre-DAA (January 1, 2002- to December 31, 2013) vs. post-DAA (January 1, 2014-, to March 31, 2018) eras. Adjusted multivariate Cox regression analyses and competing risk models evaluated likelihood of graft failure, death, and retransplantation (re-LT). RESULTS: Among 97,147 patients, 30.2% had HCV infection and 19.4% had hepatocellular carcinoma (HCC). Of all patients, 31.9% experienced graft failure, 27.1% died after LT, and 4.7% underwent re-LT. The post-DAA era experienced lower likelihood of graft failure (hazard ratio [HR] = 0.69, p < 0.001). Although patients with HCV infection (HR = 1.18, p < 0.001) and HCC (HR = 1.11, p < 0.001) had higher likelihood of graft failure in the pre-DAA era, no differences were seen in the post-DAA era. Although patients with HCV infection (HR = 1.20, p < 0.001) and HCC (HR = 1.17, p < 0.001) had higher likelihood of death after LT in the pre-DAA era, no differences were seen in the post-DAA era. The post-DAA era had lower likelihood of post-LT death when stratified by non-HCC (HR = 0.70, p < 0.001) and HCC cohorts (HR = 0.67, p < 0.001) or by non-HCV (HR = 0.73, p < 0.001) and HCV (HR = 0.58, p < 0.001) cohorts. CONCLUSION: Although patients with HCV infection and HCC had higher risk of post-LT graft failure and death in the pre-DAA era, the disparity disappeared in the post-DAA era independently of each other. This likely reflects impact of DAAs on improving post-LT outcomes among patients with HCV infection and improved selection of patients with HCC for LT after 2014.

Improved liver transplant waitlist mortality and lower risk of disease progression among chronic hepatitis C patients awaiting liver transplantation after the introduction of direct-acting antiviral therapies in the United States.

Direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection achieve high cure rates, reducing HCV-related disease progression to cirrhosis and hepatocellular carcinoma. We aim to evaluate the impact of DAAs on US liver transplant (LT) waitlist outcomes. We retrospectively evaluated US adults (age ≥18) with and without chronic HCV listed for LT before and after the widespread use of sofosbuvir, allowing a 6-month period after approval (Era 1: 1/1/2002-5/31/2014 vs Era 2: 6/1/2014-12/31/2016) using the United Network for Organ Sharing registry. Overall, LT waitlist survival and likelihood of receiving LT were evaluated with multivariate Cox regression models. From 2002 to 2016, 158 045 patients were listed for LT. While the number of patients listed for HCV has been decreasing since 2012, the proportion of HCV patients with concurrent HCC is increasing by 3.33% per year (R2 : 0.99, P < 0.001 by simple linear regression). While there was no difference in likelihood of LT between HCV and non-HCV patients, those listed in Era 2 had lower likelihood of LT (HR: 0.91, P < 0.001), more pronounced in the HCV cohort (HR: 0.83, P < 0.001) compared to the non-HCV cohort (HR: 0.93, P < 0.001). Compared to non-HCV patients, higher waitlist mortality was seen in HCV patients in Era 1 (HR: 1.08, P < 0.001) but not in Era 2 (HR: 1.02, P = 0.75). Since the introduction of DAAs for HCV treatment, number of patients with HCV listed for LT has declined. In the post-DAA era, HCV patients on the LT waitlist had improved waitlist mortality.

Lower rates of receiving model for end-stage liver disease exception and longer time to transplant among nonalcoholic steatohepatitis hepatocellular carcinoma.

Receiving Model for End-Stage Liver Disease (MELD) exception status for hepatocellular carcinoma (HCC) improves wait-list survival and probability of liver transplantation (LT). We aim to evaluate etiology-specific disparities in MELD exception, LT wait-list times, and post-LT outcomes among patients with HCC listed for LT. Using United Network for Organ Sharing 2004-2013 data, we evaluated adults (age > 18 years) with HCC secondary to hepatitis C virus (HCV), nonalcoholic steatohepatitis (NASH), alcoholic cirrhosis (EtOH), hepatitis B virus (HBV), combined EtOH/HCV, and combined HBV/HCV. Multivariate regression models evaluated etiology-specific odds of active exception, probability of receiving LT, and post-LT survival. In total, 10,887 HCC patients were listed for LT from 2004 to 2013. Compared with HCV-HCC patients (86.8%), patients with NASH-HCC (67.7%), and EtOH-HCC (64.4%) had a lower proportion with active MELD exception (P < 0.001). On multivariate regression, NASH-HCC and EtOH-HCC patients had significantly lower odds of active MELD exception compared with HCV-HCC (NASH-HCC-odds ratio [OR], 0.73; 95% confidence interval [CI], 0.58-0.93; P = 0.01; EtOH-HCC-OR, 0.72; 95% CI, 0.59-0.89; P = 0.002). Compared with HCV-HCC patients, NASH-HCC (HR, 0.83; 95% CI 0.76-0.90; P < 0.001), EtOH-HCC (HR, 0.88; 95% CI 0.81-0.96; P = 0.002), and EtOH/HCV-HCC (HR, 0.92; 95% CI 0.85-0.99; P = 0.03) were less likely to receive LT if they had active exception. Without active exception, these discrepancies were more significant (NASH-HCC-HR, 0.22; 95% CI, 0.18-0.27; P < 0.001; EtOH-HCC-HR, 0.22; 95% CI, 0.18-0.26; P < 0.001; EtOH/HCV-HCC-HR, 0.26; 95% CI, 0.22-0.32; P < 0.001). In conclusion, among US adults with HCC listed for LT, patients with NASH-HCC, EtOH-HCC, and EtOH/HCV-HCC were significantly less likely to have active MELD exception compared with HCV-HCC, and those without active exception had a lower likelihood of receiving LT. More research is needed to explore why NASH-HCC patients were less likely to have active MELD exception. Liver Transplantation 22 1356-1366 2016 AASLD.

Implications of discordant findings between hepatic angiography and cross-sectional imaging in transplant candidates with hepatocellular carcinoma.

The goal of this study was to determine whether the detection of discordant numbers of hypervascular foci at hepatic angiography versus contrast-enhanced (CE) cross-sectional imaging [computed tomography (CT) or magnetic resonance imaging (MRI)] is associated with adverse clinical outcomes in patients with hepatocellular carcinoma (HCC) who are listed for liver transplantation. We retrospectively reviewed the records of 218 consecutive patients with HCC who were listed for a liver transplant and who underwent transarterial chemoembolization at our institution between January 1, 2006 and December 31, 2010. Patients were grouped into 3 categories: (1) the number of nodules at CT/MRI was concordant with the number of hypervascular foci detected at angiography (n=136), (2) the number of nodules at CT/MRI was greater than the number of hypervascular foci at angiography (n=45), and (3) the number of nodules at CT/MRI was fewer than the number of hypervascular foci at angiography (n=37). The study outcomes were liver transplantation and tumor recurrence after transplantation. The detection of at least 3 more hypervascular foci at angiography versus the number of HCC nodules on CT/MRI was associated with a significantly lower rate of transplantation [multivariate subhazard ratio (SHR), 0.39; 95% confidence interval (CI), 0.17-0.92]. The detection of fewer hypervascular foci at angiography versus the number of HCC nodules on CT/MRI was associated with a significantly higher rate of tumor recurrence after transplantation (multivariate SHR, 3.49; 95% CI, 1.27-9.56). In conclusion, liver transplant candidates with HCC who demonstrate discordant findings between angiography and CE CT or MRI may be at a higher risk for dropout from the transplant list and for tumor recurrence after transplantation.

Chemical genetics analysis of an aniline mustard anticancer agent reveals complex I of the electron transport chain as a target.

The antitumor agent 11ß (CAS 865070-37-7), consisting of a DNA-damaging aniline mustard linked to an androgen receptor (AR) ligand, is known to form covalent DNA adducts and to induce apoptosis potently in AR-positive prostate cancer cells in vitro; it also strongly prevents growth of LNCaP xenografts in mice. The present study describes the unexpectedly strong activity of 11ß against the AR-negative HeLa cells, both in cell culture and tumor xenografts, and uncovers a new mechanism of action that likely explains this activity. Cellular fractionation experiments indicated that mitochondria are the major intracellular sink for 11ß; flow cytometry studies showed that 11ß exposure rapidly induced oxidative stress, mitochondria being an important source of reactive oxygen species (ROS). Additionally, 11ß inhibited oxygen consumption both in intact HeLa cells and in isolated mitochondria. Specifically, 11ß blocked uncoupled oxygen consumption when mitochondria were incubated with complex I substrates, but it had no effect on oxygen consumption driven by substrates acting downstream of complex I in the mitochondrial electron transport chain. Moreover, 11ß enhanced ROS generation in isolated mitochondria, suggesting that complex I inhibition is responsible for ROS production. At the cellular level, the presence of antioxidants (N-acetylcysteine or vitamin E) significantly reduced the toxicity of 11ß, implicating ROS production as an important contributor to cytotoxicity. Collectively, our findings establish complex I inhibition and ROS generation as a new mechanism of action for 11ß, which supplements conventional DNA adduct formation to promote cancer cell death.