Real-world experience in treatment of donor-derived Hepatitis C virus in kidney transplant recipients with delayed initiation, shortened course glecaprevir/pibrentasvir versus standard of care.

BACKGROUND: There is limited literature describing the real-world practice of delayed initiation and shortened duration direct-acting antiviral (DAA) in kidney transplant recipients. We compared Hepatitis C virus (HCV) cure rates among kidney transplant recipients who received an HCV nucleic acid test positive (NAT +) kidney and were treated with sofosbuvir/velpatasvir (SOF/VEL) for 12 weeks or glecaprevir/pibrentasvir (G/P) for 8 weeks, a duration that is 4 weeks shorter than the guideline recommendation for treatment delay beyond 1-week post-transplant. METHODS: Retrospective study of HCV-negative adult patients who received a kidney transplant from an HCV NAT+ donor between April 2019 and April 2022 treated with either SOF/VEL for 12 weeks or G/P for 8 weeks. The primary outcome was sustained virologic response 12 weeks after completion of therapy (SVR12). Secondary outcomes included time to DAA initiation, renal function, graft loss, patient death, liver function tests, and opportunistic infections. RESULTS: 102 kidney transplant recipients were included with 36 treated with G/P and 66 treated with SOF/VEL. All 36 (100%) treated with G/P achieved SVR12. One patient in the SOF/VEL group failed to achieve SVR12 but received additional therapy and was cured. Time to DAA initiation was similar with a mean of 4 weeks. There was no difference in AST/ALT > 3x ULN or renal function. One rejection occurred in each group. No patient death or graft loss was observed. There was no difference in cytomegalovirus and BK viremia between groups.  CONCLUSION: Delayed initiation of DAA therapy with 12 weeks of SOF/VEL or 8 weeks of G/P achieves SVR12 in kidney transplant recipients without significant adverse effects.

Outcomes of Nonvariceal Upper Gastrointestinal Bleeding in Patients With Cirrhosis: A National Analysis.

GOALS: We sought to evaluate hospital outcomes of cirrhosis patients with nonvariceal upper gastrointestinal bleeding (NVUGIB). BACKGROUND: NVUGIB is common in patients with cirrhosis. However, national outcome studies of these patients are lacking. STUDY: We utilized the 2014 Nationwide Readmission Database to evaluate NVUGIB in patients with cirrhosis, further stratified as no cirrhosis (NC), compensated cirrhosis (CC), or decompensated cirrhosis (DC). Validated International Classification of Diseases, Ninth Revision, Clinical Modification codes captured diagnoses and interventions. Outcomes included 30-day readmission rates, index admission mortality rates, health care utilization, and predictors of readmission and mortality using multivariable regression analysis. RESULTS: Overall, 13,701 patients with cirrhosis were admitted with NVUGIB. The 30-day readmission rate was 20.8%. Patients with CC were more likely to undergo an esophagogastroduodenoscopy (EGD) within 1 calendar day of admission (74.1%) than patients with DC (67.9%) or NC (69.4%). Patients with DC had longer hospitalizations (4.1 d) and higher costs of care ($11,834). The index admission mortality rate was higher in patients with DC (6.2%) than in patients with CC (1.7%, P <0.001) or NC (1.4%, P <0.001). Predictors of 30-day readmission included performing an EGD >1 calendar day from admission (OR: 1.21; 95% CI, 1.00 to 1.46) and DC (OR: 1.78; 95% CI, 1.54 to 2.06). DC was a predictor of index admission mortality (OR: 3.68; 95% CI, 2.67 to 5.05). CONCLUSIONS: NVUGIB among patients with DC is associated with higher readmission rates, mortality rates, and health care utilization compared with patients with CC and NC. Early EGD is a modifiable variable associated with reduced readmission rates. Early identification of high-risk patients and adherence to guidelines may improve clinical outcomes.

Patients with alcohol-related liver disease hospitalized during the COVID-19 pandemic experienced worse outcomes.

INTRODUCTION AND OBJECTIVES: Psychosocial stressors related to the coronavirus-19 (COVID-19) pandemic increased alcohol consumption. The effect on patients with alcohol-related liver diseases remains unclear. MATERIALS AND METHODS: Hospitalizations at a tertiary care center due to alcohol-related liver disease from March 1 through August 31 in 2019 (pre-pandemic cohort) and 2020 (pandemic cohort) were reviewed retrospectively. Differences in patient demographics, disease features, and outcomes were estimated in patients with alcoholic hepatitis utilizing T-tests, Mann-Whitney tests, Chi-square and Fisher Exact Tests and Anova models and logistic regression models in patients with alcoholic cirrhosis. RESULTS: 146 patients with alcoholic hepatitis and 305 patients with alcoholic cirrhosis were admitted during the pandemic compared to 75 and 396 in the pre-pandemic cohort. Despite similar median Maddrey Scores (41.20 vs. 37.45, p=0.57), patients were 25% less likely to receive steroids during the pandemic. Patients with alcoholic hepatitis admitted during the pandemic were more likely to have hepatic encephalopathy (0.13; 95% CI:0.01, 0.25), variceal hemorrhage (0.14; 95% CI:0.04, 0.25), require oxygen (0.11; 95% CI:0.01, 0.21), vasopressors (OR:3.49; 95% CI:1.27, 12.01) and hemodialysis (OR:3.70; 95% CI:1.22, 15.13). On average, patients with alcoholic cirrhosis had MELD-Na scores 3.77 points higher (95% CI:1.05, 13.46) as compared to the pre-pandemic and had higher odds of experiencing hepatic encephalopathy (OR:1.34; 95% CI:1.04, 1.73), spontaneous bacterial peritonitis (OR:1.88; 95% CI:1.03, 3.43), ascites (OR:1.40, 95% CI:1.10, 1.79), vasopressors (OR:1.68, 95% CI:1.14, 2.46) or inpatient mortality (OR:2.00, 95% CI:1.33, 2.99) than the pre-pandemic. CONCLUSIONS: Patients with alcohol-related liver disease experienced worse outcomes during the pandemic.

Cystic Fibrosis Transmembrane Conductance Regulator Modulator Use Is Associated With Reduced Pancreatitis Hospitalizations in Patients With Cystic Fibrosis.

INTRODUCTION: Acute pancreatitis (AP) occurs among patients with pancreas-sufficient cystic fibrosis (PS-CF) but is reportedly less common among patients with pancreas-insufficient cystic fibrosis (PI-CF). The incidence of AP may be influenced by cystic fibrosis transmembrane conductance regulator (CFTR) modulator use. We hypothesized that CFTR modulators would reduce AP hospitalizations, with the greatest benefit in PS-CF. METHODS: MarketScan (2012-2018) was queried for AP hospitalizations and CFTR modulator use among patients with CF. Multivariable Poisson models that enabled crossover between CFTR modulator treatment groups were used to analyze the rate of AP hospitalizations on and off therapy. Pancreas insufficiency was defined by the use of pancreas enzyme replacement therapy. RESULTS: A total of 10,417 patients with CF were identified, including 1,795 who received a CFTR modulator. AP was more common in PS-CF than PI-CF (2.9% vs 0.9%, P = 0.007). Overall, the observed rate ratio of AP during CFTR modulator use was 0.33 (95% confidence interval [CI] 0.10, 1.11, P = 0.07) for PS-CF and 0.38 (95% CI 0.16, 0.89, P = 0.03) for PI-CF, indicating a 67% and 62% relative reduction in AP hospitalizations, respectively. In a subset analysis of 1,795 patients who all had some CFTR modulator use, the rate ratio of AP during CFTR modulator use was 0.36 (95% CI 0.13, 1.01, P = 0.05) for PS-CF and 0.53 (95% CI 0.18, 1.58, P = 0.26) for PI-CF. DISCUSSION: CFTR modulator use is associated with a reduction in AP hospitalizations among patients with CF. These observational data support the prospective study of CFTR modulators to reduce AP hospitalizations among patients with CF.

Cannabis use may reduce healthcare utilization and improve hospital outcomes in patients with cirrhosis.

INTRODUCTION AND OBJECTIVES: Previous studies reveal conflicting data on the effect of cannabis use in patients with cirrhosis. This research evaluates the impact of cannabis on hepatic decompensation, health care utilization, and mortality in patients with cirrhosis. MATERIAL AND METHODS: A retrospective analysis of the State Inpatient Database (SID) was performed evaluating patients from Colorado and Washington in 2011 to represent pre-cannabis legalization and 2015 to represent post-cannabis legalization. Multivariable analysis was performed to study the impact of cannabis on the rate of admissions with hepatic decompensations, healthcare utilization, and mortality in patients with cirrhosis. RESULTS: Cannabis use was detected in 370 (2.1%) of 17,520 cirrhotics admitted in 2011 and in 1162 (5.3%) of 21,917 cirrhotics in 2015 (p-value <0.001). On multivariable analysis, cirrhotics utilizing cannabis after its legalization experienced a decreased rate of admissions related to hepatorenal syndrome (Odds Ratio (OR): 0.51; 95% Confidence Interval (CI): 0.34-0.78) and ascites (OR: 0.73; 95% CI: 0.63-0.84). Cirrhotics with an etiology of disease other than alcohol and hepatitis C had a higher risk of admission for hepatic encephalopathy if they utilized cannabis [OR: 1.57; 95% CI: 1.16-2.13]. Decreased length of stay (-1.15 days; 95% CI: -1.62, -0.68), total charges (-$15,852; 95% CI: -$21,009, -$10,694), and inpatient mortality (OR: 0.68; 95% CI: 0.51-0.91) were also observed in cirrhotics utilizing cannabis after legalization compared to cirrhotics not utilizing cannabis or utilizing cannabis prior to legalization. CONCLUSION: Cannabis use in patients with cirrhosis resulted in mixed outcomes regarding hospital admissions with hepatic decompensation. A trend towards decreased hospital utilization and mortality was noted in cannabis users after legalization. These observations need to be confirmed with a longitudinal randomized study.

Outcomes of hepatitis C virus seropositive donors to hepatitis C virus seronegative liver recipients: A large single center analysis.

INTRODUCTION AND OBJECTIVES: The success of direct-acting antivirals (DAA) has transformed the management of hepatitis C virus (HCV) infection and has led to the expansion of the deceased donor organ pool for liver transplantation. MATERIAL AND METHODS: We present a single center retrospective review of liver transplantations performed on HCV-seronegative recipients from HCV-seropositive organs from 11/2017 to 05/2020. HCV nucleic acid testing (NAT) was performed on HCV-seropositive donors to assess active HCV infection. RESULTS: 42 HCV-seronegative recipients underwent a liver transplant from a HCV-seropositive donor, including 21 NAT negative (20 liver, 1 simultaneous liver kidney transplant) and 21 NAT positive liver transplants. Two (9.5%) HCV antibody positive/NAT negative recipients developed HCV viremia and achieved sustained virologic response with DAA therapy. The remaining patients with available data (19 patients) remained polymerase chain reaction (PCR) negative at 6 months. 20 (95%) of HCV antibody positive/NAT positive recipients had a confirmed HCV viremia. 100% of patients with available data (15 patients) achieved SVR. Observed events include 1 mortality and graft loss and equivalent rates of post-transplant complications between NAT positive and NAT negative recipients. CONCLUSIONS: HCV-seropositive organs can be safely transplanted into HCV-seronegative patients with minimal complications post-transplant.

High-grade pancreatic intraepithelial lesions: prevalence and implications in pancreatic neoplasia.

BACKGROUND: High-grade pancreatic intraepithelial neoplasia (PanIN-3), a precursor of pancreatic ductal adenocarcinoma (PDAC), is not universally detected in resected pancreatic neoplasms. We sought to determine the prevalence and prognostic relevance of PanIN-3 lesions in primary surgical resections of PDACs and intraductal papillary mucinous neoplasms (IPMNs). METHODS: A retrospective review of a tertiary care center pathology database (1/2000-6/2014) was performed. Demographics, imaging, pathology, disease-recurrence, and survival data were reviewed. RESULTS: A total of 458 patients who underwent primary pancreatic resection were included. "PanIN-3" lesions were found in 74 (16.2%) patients who either had PDAC (n=67) or main duct (MD)-IPMN (n=7). Among IPMN-MDs, PanIN-3 lesions were exclusively found in those with pathological evidence of chronic pancreatitis. For PDACs, the median overall survival (OS) for pancreata with PanIN-3 lesions was significantly better than those without (OS 1.12 years, inter-quartile range [IQR] 0.72, 2.05 years vs OS 0.86 years, IQR 0.64, 1.60 years respectively; P=0.04). Multivariate Cox regression analysis demonstrated that the presence of PanIN-3 lesions was associated with a reduced risk of death (HR=0.43; 95% CI: 0.23-0.82; P=0.01). CONCLUSIONS: Following primary resection of pancreatic adenocarcinoma, the lower survival observed in patients without PanIN-3 lesions might suggest a state of complete or accelerated transformation. Further investigations are necessary to validate these findings that might impact disease prognosis and management.

Impact of social vulnerability index on patients with alcohol-related liver disease.

INTRODUCTION: Alcohol related liver disease (ALD) affects diverse communities with individual and social characteristics that can impact outcomes. The social vulnerability index (SVI) assigns a score between 0 and 1, where higher scores represent an increased risk of social vulnerability. We sought to assess the impact of SVI on outcomes of patients hospitalized with ALD with access to social support services. METHODS AND MATERIALS: Hospitalizations for ALD at our institution between March and August 2019 were reviewed. All patients were assigned an SVI score based on their residential census tract. Per our standard practice, patients were screened by care coordinators to identify needs for rehabilitation counseling, and care coordination after discharge. Demographics, hepatic decompensation, critical care needs, readmission, and mortality were compared. RESULTS: Among 73 patients admitted for alcoholic hepatitis, 32 had a low SVI and 42 had a high SVI. African American patients were more likely to have a higher SVI (35% vs 0%, p=<0.001). No significant difference in outcomes based on SVI was noted. There were 393 patients admitted for alcoholic cirrhosis including 166 with a low SVI and 227 with a high SVI. Patients that were African American (23.6% vs 5.5%, p=<0.001) or disabled (41.4% vs 29.5%, p = 0.008) had a higher SVI. No significant difference in outcomes based on SVI was noted. CONCLUSION: Most patients admitted for ALD had a high SVI; however, SVI did not impact hospitalization outcomes.

Treatment of children with diffuse intrinsic pontine gliomas with chemoradiotherapy followed by a combination of temozolomide, irinotecan, and bevacizumab.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) are inoperable and highly resistant tumors to chemotherapy and irradiation. DIPG has the worst prognosis among all pediatric brain tumors and the overwhelming majority of patients die within 6-18 months after diagnosis. METHODS: We retrospectively reviewed the charts of six DIPG patients treated with chemoradiotherapy (daily carboplatin and oral etoposide in five patients and temozolomide in one patient) followed by maintenance chemotherapy consisting of irinotecan, temozolomide, and bevacizumab at our institution between January 2007 until December 2007. RESULTS: Event-free survival (EFS) and overall survival (OS) were 10.4 ± 3.08 and 14.6 ± 3.55 months, respectively. Side effects in the patients included hypertension in two, abdominal cramping and diarrhea in four, and neutropenia in five patients. CONCLUSIONS: This augmented regimen was associated with increased but tolerable toxicity and a modest increase in EFS and OS when compared with published literature in patients with DIPG (median EFS and OS of 6.1 and 9.6 months, respectively). More effective therapies are desperately needed.

Cystic fibrosis patients on cystic fibrosis transmembrane conductance regulator modulators have a reduced incidence of cirrhosis.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators significantly improve pulmonary function in patients with cystic fibrosis (CF) but the effect on hepatobiliary outcomes remains unknown. We hypothesized that CF patients on CFTR modulators would have a decreased incidence of cirrhosis compared to patients not on CFTR modulators or on ursodiol. AIM: To investigate the effect of CFTR modulators on the development of cirrhosis in patients with CF. METHODS: A retrospective analysis was performed using Truven MarketScan from January 2012 through December 2017 including all patients with a diagnosis of CF. Patients were excluded if they underwent a liver transplantation or if they had other etiologies of liver disease including viral hepatitis or alcohol use. Subjects were grouped by use of CFTR modulators, ursodiol, dual therapy, or no therapy. The primary outcome was development of cirrhosis. Kaplan-Meier curves estimated the incidence of cirrhosis and log-rank tests compared incidence curves between treatment groups. RESULTS: A total of 7201 patients were included, of which 955 (12.6%) used a CFTR modulator, 529 (7.0%) used ursodiol, 105 (1.4%) used combination therapy, and 5612 (74.3%) used neither therapy. The incidence of cirrhosis was 0.1% at 1 year and 0.7% at 4 years in untreated patients, 5.9% and 10.1% in the Ursodiol group, and 1.0% and 1.0% in patients who received both therapies. No patient treated with CFTR modulators alone developed cirrhosis. Patients on CFTR modulators alone had lower cirrhosis incidence than untreated patients (P = 0.05), patients on Ursodiol (P < 0.001), and patients on dual therapy (P = 0.003). The highest incidence of cirrhosis was found among patients treated with Ursodiol alone, compared to untreated patients (P < 0.001) or patients on Ursodiol and CFTR modulators (P = 0.01). CONCLUSION: CFTR modulators are associated with a reduction in the incidence of cirrhosis compared to other therapies in patients with CF.

Modulatory effect of curcumin on survival of irradiated human intestinal microvascular endothelial cells: role of Akt/mTOR and NF-{kappa}B.

Radiation therapy is an essential modality in the treatment of colorectal cancers. Radiation exerts an antiangiogenic effect on tumors, inhibiting endothelial proliferation and survival in the tumor microvasculature. However, damage from low levels of irradiation can induce a paradoxical effect, stimulating survival in endothelial cells. We used human intestinal microvascular endothelial cells (HIMEC) to define effects of radiation on these gut-specific endothelial cells. Low-level irradiation (1-5 Gy) activates NF-kappaB and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is involved in cell cycle reentry and cell survival in HIMEC. A downstream target of PI3K/Akt is mammalian target of rapamycin (mTOR), which contributes to endothelial proliferation and angiogenesis. The aim of this study was to investigate the signaling molecules involved in the radiosensitizing effects of curcumin on HIMEC subjected to low levels of irradiation. We have demonstrated that exposure of HIMEC to low levels of irradiation induced Akt and mTOR phosphorylation, which was attenuated by curcumin, rapamycin, LY294002, and mTOR small interference RNA (siRNA). Activation of NF-kappaB by low levels of irradiation was inhibited by curcumin, SN-50, and mTOR siRNA. Curcumin also induced apoptosis by induction of caspase-3 cleavage in irradiated HIMEC. In conclusion, curcumin significantly inhibited NF-kappaB and attenuated the effect of irradiation-induced prosurvival signaling through the PI3K/Akt/mTOR and NF-kappaB pathways in these gut-specific endothelial cells. Curcumin may be a potential radiosensitizing agent for enhanced antiangiogenic effect in colorectal cancer radiation therapy.

Rare cause of dysphagia after esophageal variceal banding: A case report.

BACKGROUND: Esophageal varices are a result of progressive liver disease and portal hypertension. Treatment can be performed with band ligation versus non-selective beta blockers depending on the size of varices, ability to tolerate medications and history of variceal bleeding. Band ligation is an effective intervention with rare but serious complications including bleeding, ulcers and rarely obstruction. Few cases of esophageal obstruction and necrosis caused by banding have been reported, each with varied management from conservative treatment to band removal. CASE SUMMARY: An 89 years old woman with a past medical history of nonalcoholic steatohepatitis cirrhosis presented to the hospital with an inability to swallow one day after screening esophagogastroduodenoscopy where band ligation of esophageal varices was performed for primary prophylaxis. The patient was not able to tolerate her oral secretions. Initial blood work revealed a Model of End Organ Liver Disease score of 7. She was treated with sublingual nitroglycerin for esophageal spasm, a known complication after esophageal banding. When she failed to improve, esophagogastroduodenoscopy was performed and revealed the mucosa surrounding the banded varix was necrosed and blocking the lumen of the esophagus. The band was purposefully dislodged, revealing distal ulceration and stricturing. Within 72 h after band removal, she was tolerating an oral diet. Endoscopy performed 2 wk later revealed an intrinsic stenosis, measuring 8 mm in diameter by 1 cm in length, which was dilated. CONCLUSION: Esophageal obstruction is a complication of variceal banding that should be considered in patients with inability to tolerate oral diet after banding.

Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): role of PKC, MAPKs, and NF-kappaB.

Human esophageal epithelial cells play a key role in esophageal inflammation in response to acidic pH during gastroesophageal reflux disease (GERD), increasing secretion of IL-6 and IL-8. The mechanisms underlying IL-6 and IL-8 expression and secretion in esophageal epithelial cells after acid stimulation are not well characterized. We investigated the role of PKC, MAPK, and NF-kappaB signaling pathways and transcriptional regulation of IL-6 and IL-8 expression in HET-1A cells exposed to acid. Exposure of HET-1A cells to pH 4.5 induced NF-kappaB activity and enhanced IL-6 and IL-8 secretion and mRNA and protein expression. Acid stimulation of HET-1A cells also resulted in activation of MAPKs and PKC (alpha and epsilon). Curcumin, as well as inhibitors of NF-kappaB (SN-50), PKC (chelerythrine), and p44/42 MAPK (PD-098059) abolished the acid-induced expression of IL-6 and IL-8. The JNK inhibitor SP-600125 blocked expression/secretion of IL-6 but only partially attenuated IL-8 expression. The p38 MAPK inhibitor SB-203580 did not inhibit IL-6 expression but exerted a stronger inhibitory effect on IL-8 expression. Together, these data demonstrate that 1) acid is a potent inducer of IL-6 and IL-8 production in HET-1A cells; 2) MAPK and PKC signaling play a key regulatory role in acid-mediated IL-6 and IL-8 expression via NF-kappaB activation; and 3) the anti-inflammatory plant compound curcumin inhibits esophageal activation in response to acid. Thus IL-6 and IL-8 expression by acid may contribute to the pathobiology of mucosal injury in GERD, and inhibition of the NF-kappaB/proinflammatory cytokine pathways may emerge as important therapeutic targets for treatment of esophageal inflammation.

Role of MutS homolog 2 (MSH2) in intestinal myofibroblast proliferation during Crohn's disease stricture formation.

Tissue remodeling and mesenchymal cell accumulation accompanies chronic inflammatory disorders involving joints, lung, vasculature, and bowel. Chronic inflammation may alter DNA-mismatch repair (MMR) systems in mesenchymal cells, but is not defined in Crohn's disease (CD) and its associated intestinal remodeling and stricture formation. We determined whether DNA-MMR alteration plays a role in the pathogenesis of CD tissue remodeling. Control and CD bowel tissues were used to generate primary cultures of muscularis mucosa myofibroblasts, which were assessed directly or following stimulation with TNF-alpha/LPS or H2O2. MutS homolog (MSH)2, MSH3, and MSH6 expression in tissues and myofibroblasts was determined. Immunohistochemical staining revealed an increased expression of MSH2 in CD muscularis mucosa and submucosal tissues compared with controls or uninvolved CD tissue, and MSH2 expression was increased in CD myofibroblasts compared with control cells. TNF-alpha/LPS and H2O2 further enhanced MSH2 expression in both control and CD cells, which were decreased by simvastatin. There were no significant changes in MSH3 and MSH6 expression. Proliferating cell nuclear antigen and Ki67 staining of CD tissue revealed increased proliferation in the muscularis mucosa and submucosa of chronically inflamed tissues, and enhanced proliferation was seen in CD myofibroblasts compared with controls. Simvastatin reversed the effects of inflammatory stress on the DNA-MMR and inhibited proliferation of control and CD myofibroblasts. Gene silencing with MSH2 siRNA selectively decreased CD myofibroblast proliferation. These data demonstrate a potential role for MSH2 in the pathogenesis of nonneoplastic mesenchymal cell accumulation and intestinal remodeling in CD chronic inflammation.