Autoimmune hepatitis presenting as acute liver failure: A 20-year retrospective review of North America.

Autoimmune hepatitis is a common cause of acute liver failure. Treatment includes steroids for acute liver injury and liver transplantation in those who fail to respond or develop acute liver failure. The aim of this study is to further characterize acute liver failure secondary to autoimmune hepatitis and identify variables that predict 21-day transplant-free survival. This study included adults hospitalized with acute liver failure enrolled in the Acute Liver Failure Study Group Registry between 1998 and 2019 from 32 centers within the US. The etiology of all cases was reviewed by the Adjudication Committee, and all cases identified as autoimmune hepatitis were included. Acute liver injury was defined as an INR ≥2.0 without encephalopathy and acute liver failure as INR ≥ 1.5 with encephalopathy. Laboratory and clinical data were reviewed. Variables significantly associated with 21-day transplant-free survival were used to develop a multivariable logistic regression model.  A total of 193 cases of acute liver failure secondary to autoimmune hepatitis were identified and reviewed. There were 161 patients (83.4%) diagnosed with acute liver failure on enrollment, and 32 (16.6%) developed acute liver failure during hospitalization. At 21 days, 115 (59.6%) underwent liver transplantation, 28 (14.5%) had transplant-free survival, and 46 (23.8%) died before liver transplantation. Higher admission values of bilirubin, INR, and coma grade were associated with worse outcomes. A prognostic index incorporating bilirubin, INR, coma grade, and platelet count had a concordance statistic of 0.84. Acute liver failure secondary to autoimmune hepatitis is associated with a high short-term mortality. We developed a model specifically for autoimmune hepatitis that may be helpful in predicting 21-day transplant-free survival and early identification of patients in need of expedited liver transplant evaluation.

Facile syntheses of functionalized toll-like receptor 7 agonists.

Protein conjugates of toll-like receptor 7 agonists have been shown to elicit powerful immune responses. In order to facilitate our studies in this area our group has developed efficient syntheses for a number of functionalized derivatives that retain immune stimulatory activity.

Co-targeting androgen receptor and DNA for imaging and molecular radiotherapy of prostate cancer: in vitro studies.

BACKGROUND: The androgen receptor (AR) axis, the key growth and survival pathway in prostate cancer, remains a prime target for drug development. 5-Radioiodo-3'-O-(17ß-succinyl-5α-androstan-3-one)-2'-deoxyuridin-5'-yl phosphate (RISAD-P) is the AR-seeking reagent developed for noninvasive assessment of AR and proliferative status, and for molecular radiotherapy of prostate cancer with Auger electron-emitting radionuclides. METHODS: RISAD-P radiolabeled with 123I, 124I, and 125I were synthesized using a common stannylated precursor. The cellular uptake, subcellular distribution, and radiotoxicity of 123I-, 124I-, and (125) IRISAD-P were measured in LNCaP, DU145, and PC-3 cell lines expressing various levels of AR. RESULTS: The uptake of RISAD-P by prostate cancer cells is proportional to AR levels and independent of the radionuclide. The intracellular accumulation of radioactivity is directly proportional to the extracellular concentration of RISAD-P and the duration of exposure. Initially, RISAD-P is trapped in the cytoplasm. Within 24 hr, radioactivity is associated exclusively with DNA. The RISAD-P radiotoxicity is determined by the radionuclide; however, the cellular responses are directly proportional to the AR expression levels. LNCaP cells expressing high levels of AR are killed at the rate of up to 60% per day after a brief 1 hr RISAD-P treatment. For the first time, the AR expression in PC-3 and DU 145 cells, generally reported as AR-negative, was quantitated by the ultra sensitive RISAD-P-based method. CONCLUSIONS: RISAD-P is a theranostic drug, which targets AR. Its subcellular metabolite participates in DNA synthesis. RISAD-P is a promising candidate for imaging of the AR expression and tumor proliferation as well as molecular radiotherapy of prostate cancer.

Adherence to quality indicators and best practices in surveillance endoscopy of Barrett's esophagus: A video-based assessment.

Background and study aims Adherence to quality indicators (QIs) and best practices (BPs) for endoscopic surveillance of Barrett's esophagus (BE) is low based on clinical documentation which is an inaccurate representation of events occurring during procedures. This study aimed to assess adherence to measurable QI and BP using video evaluation. Methods We performed a single center video-based retrospective review of surveillance endoscopies performed for BE ≥1 cm between March 1, 2018 and October 1, 2020. Adherence to QIs and BPs was assessed through video review and documentation. Videos were evaluated by five gastroenterologists. Interrater variability was determined using 10 videos before reviewing the remaining 128 videos. A generalized linear regression model was used to determine predictors of adherence to QIs and BPs. Results There were 138 endoscopies reviewed. Inspection with virtual chromoendoscopy (VC) occurred in 75 cases (54%) on video review with documentation in 50 of these cases (67%). Adherence to the Seattle protocol (SP) occurred in 74 cases (54%) on video review with documentation in 28 of these cases (38%). Use of VC or the SP was documented but not observed on video review in 16 (12%) and 30 (22%) cases, respectively. Length of BE was associated with increased use of the Prague classification (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.07-1.37) while years in practice was associated with a decreased likelihood of VC use (OR 0.93, 95% CI 0.88-0.99). Conclusions This study validates prior data demonstrating poor adherence to QIs and BPs and highlights discrepancies between clinical documentation and events occurring during procedures.

Increased Morbidity and Mortality of Patients with Non-cirrhotic Portal Vein Thrombosis After Abdominal and Pelvic Surgeries: a Study of the National Inpatient Sample 2002 to 2015.

BACKGROUND: A higher rate of postoperative morbidity and mortality in patients with portal hypertension from cirrhosis is well recognized; however, the rate of postoperative morbidity and mortality among patients with portal hypertension from non-cirrhotic portal vein thrombosis (NCPVT) is largely unknown. METHOD: All adults undergoing abdominal and pelvic surgery were identified from the National Inpatient Sample database from 2002 to 2015. Patients were then categorized into three groups: non-cirrhotic non-portal vein thrombosis (NCNPVT), NCPVT, and cirrhotic portal vein thrombosis (CPVT). Inpatient mortality, type of disposition, transfusions, length of stay, postoperative complications, and total charges were compared. Logistic regression and ordinary least squares regression analyses were performed for factors associated with inpatient mortality, transfusions, surgery-related complications, and log length of stay. RESULTS: Patients with NCPVT had significantly higher inpatient mortality rates, surgery-related complications, and longer length of stays compared with patients with NCNPVT (2.64% vs. 0.34%, 10.26% vs. 3.26%, 8 vs. 2 days) but less than patients with CPVT (2.64% vs. 6.31%, 10.26% vs. 17.48%, 8 vs. 11 days). In multiple logistic regression analyses, NCPVT groups remained associated with increased inpatient mortality rate, transfusions, and postoperative complications with odds ratios of 3.71 (1.88, 7.32), 3.43 (2.54, 4.62), and 3.08 (2.16, 4.39), respectively. NCPVT was also associated with 2.4 times increased length of stay. DISCUSSION: Patients with NCPVT had significantly higher risks of postoperative morbidity and mortality than patients with NCNPVT but less than patients with CPVT. Future studies with detail regarding the characteristics of PVTs are needed to confirm the findings in this study.

Endoscopic Approaches to Gastroparesis.

Gastroparesis is a complex syndrome with multiple underlying etiologies and pathophysiologies that can cause significant morbidity for patients. Currently, there are limited effective and durable medical and surgical treatments for patients with gastroparesis. As such, there has been recent innovation and development in minimally invasive endoscopic treatments for gastroparesis. Endoscopic therapies that have been investigated for gastroparesis include enteral feeding tube placement, intrapyloric botulinum toxin injection, transpyloric stenting, gastric peroral endoscopic myotomy, and gastric electrical stimulation. This article aims to assess the effectiveness of current endoscopic therapies, as well as discuss future directions for endoscopic therapies, in the management of gastroparesis.

Ciliated Hepatic Foregut Cyst: A Report of a Case Incidentally Discovered during Transplant Evaluation.

Ciliated hepatic foregut cyst (CHFC) is a rare benign cyst of the liver derived from an embryonic remnant of foregut epithelium. CHFC is typically asymptomatic and is found incidentally. Recent reports of malignant transformation may warrant surgical removal of CHFC. We present the case of a 54-year-old male who was discovered to have a CHFC while undergoing kidney transplant evaluation.

Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy.

Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a lack of effective therapies. Pan-histone deacetylase (HDAC) inhibitors have shown preclinical efficacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic efficacy. However, their use requires identification of the specific HDACs that mediate the therapeutic effects of HDAC inhibitors in PDAC. We determined that the HDAC1/2/3 inhibitor Mocetinostat synergizes with the HDAC4/5/6 inhibitor LMK-235 in a panel of PDAC cell lines. Furthermore, while neither drug alone synergizes with gemcitabine, the combination of Mocetinostat, LMK-235, and gemcitabine showed strong synergy. Using small interfering (si)RNA-mediated knockdown, this synergy was attributed to inhibition of HDACs 1, 2, and 6. Pharmacological inhibition of HDACs 1 and 2 with Romidepsin and HDAC6 with ACY-1215 also potently synergized with gemcitabine in a panel of PDAC cell lines, and this drug combination potentiated the antitumor effects of gemcitabine against PDAC xenografts in vivo. Collectively, our data show that inhibition of multiple HDACs is required for therapeutic effects of HDAC inhibitors and support the development of novel strategies to inhibit HDACs 1, 2, and 6 for PDAC therapy.