Darryn Potosky

Spermine Oxidation Induced by Helicobacter pylori Results in Apoptosis and DNA Damage Implications for Gastric Carcinogenesis

Oxidative stress is linked to carcinogenesis due to its ability to damage DNA. The human gastric pathogen Helicobacter pylori exerts much of its pathogenicity by inducing apoptosis and DNA damage in host gastric epithelial cells. Polyamines are abundant in epithelial cells, and when oxidized by the inducible spermine oxidase SMO(PAOh1) H2O2 is generated. Here, we report that H. pylori up-regulates mRNA expression, promoter activity, and enzyme activity of SMO(PAOh1) in human gastric epithelial cells, resulting in DNA damage and apoptosis. H. pylori-induced H2O2 generation and apoptosis in these cells was equally attenuated by an inhibitor of SMO(PAOh1), by catalase, and by transient transfection with small interfering RNA targeting SMO(PAOh1). Conversely, SMO(PAOh1) overexpression induced apoptosis to the same levels as caused by H. pylori. Importantly, in H. pylori-infected tissues, there was increased expression of SMO(PAOh1) in both human and mouse gastritis. Laser capture microdissection of human gastric epithelial cells demonstrated expression of SMO(PAOh1) that was significantly attenuated by H. pylori eradication. These results identify a pathway for oxidative stress-induced epithelial cell apoptosis and DNA damage due to SMO(PAOh1) activation by H. pylori that may contribute to the pathogenesis of the infection and development of gastric cancer.

Sofosbuvir plus ledispasvir for recurrent hepatitis C in liver transplant recipients.

Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is associated with worse outcomes. The combination of ledipasvir (LDV) and sofosbuvir (SOF) has been approved for HCV treatment after LT, but there are limited data on the effectiveness and safety of LDV/SOF in the “real‐world” setting. This multicenter study is the largest report to date on the effectiveness and safety of LDV/SOF in the post‐LT setting. A total of 204 patients (72% male, 68% Caucasian, 66% genotype [GT] 1a, 21% METAVIR F3‐F4, 49% treatment‐experienced) were treated with LDV/SOF. The mean duration from LT to treatment initiation was 4.8 years. The overall sustained virological response rate 12 weeks after completion of therapy (SVR12) was 96%. Patients treated with 8 or 12 weeks of LDV/SOF without RBV experienced an SVR12 rate of 100% and 96%, respectively. Calcineurin inhibitors were used in 89% of patients, and 32% of patients underwent adjustment in immunosuppression during treatment. One episode of mild rejection, responsive to an increase in immunosuppression dosage, was observed. There was no graft loss attributed to HCV treatment. Four deaths occurred unrelated to HCV treatment, and no significant serious adverse events were documented. In conclusion, SOF and LDV with or without RBV for 8, 12, or 24 weeks in post‐LT patients was effective and safe with a high SVR12 rate across a spectrum of GTs and stages of fibrosis. Liver Transplantation 22 1536–1543 2016 AASLD.

Safety of belatacept bridging immunosuppression in hepatitis C-positive liver transplant recipients with renal dysfunction.

Background Perioperative renal dysfunction in liver transplant recipients complicates maintenance immunosuppressive therapy, particularly in patients with hepatitis C. Calcineurin inhibitors exacerbate renal dysfunction and mammalian target-of-rapamycin inhibitors are generally avoided because of perceived perioperative risks. The authors’ experience with seven liver transplant patients who received belatacept and mycophenolic acid maintenance immunosuppression is reported. Methods A retrospective review of adult liver transplant recipients with hepatitis C receiving belatacept was conducted under Institutional Review Board approval. All patients were Epstein-Barr virus IgG seropositive. The primary endpoint was patient and graft survival, with secondary endpoints including the incidence of acute rejection, degree of renal function recovery, and occurrence of major side effects. Results Between December 19, 2011 and January 25, 2013, seven liver transplant recipients with hepatitis C received belatacept immunosuppression in the perioperative period. The primary indication for belatacept was perioperative renal dysfunction. Belatacept was initiated between 2 and 90 days posttransplant and the duration of belatacept therapy ranged from 19 to 89 days. Patients were transitioned onto calcineurin inhibitor therapy when they reached chronic kidney disease stage 2 or better. Six-month patient and graft survival was 86%. There was one episode of graft rejection on belatacept therapy in a patient who had also had early rejection before initiation of belatacept. Conclusions The results in this initial group of patients suggest that belatacept with mycophenolic acid may be a safe maintenance immunosuppression regimen in hepatitis C–positive liver transplant recipients with renal dysfunction, and that this regimen can serve as an effective bridge to calcineurin inhibitor therapy.

Evaluating a Collaborative Approach to Improve Prior Authorization Efficiency in the Treatment of Hepatitis C Virus

Objective:A team-based approach to obtaining prior authorization approval was implemented utilizing a specialty pharmacy, a clinic-based pharmacy technician specialist, and a registered nurse to work with providers to obtain approval for medications for hepatitis C virus (HCV) infection. The objective of this study was to evaluate the time to approval for prescribed treatment of HCV infection. Methods:A retrospective observational study was conducted including patients treated for HCV infection by clinic providers who received at least 1 oral direct-acting antiviral HCV medication. Patients were divided into 2 groups, based on whether they were treated before or after the implementation of the team-based approach. Student t tests were used to compare average wait times before and after the intervention. Results:The sample included 180 patients, 68 treated before the intervention and 112 patients who initiated therapy after. All patients sampled required prior authorization approval by a third-party payer to begin therapy. There was a statistically significant reduction (P = .02) in average wait time in the postintervention group (15.6 ± 12.1 days) once adjusted using dates of approval. Conclusions:Pharmacy collaboration may provide increases in efficiency in provider prior authorization practices and reduced wait time for patients to begin treatment.

Massive Hematochezia from Ascending Colonic Varices.

A 54-year-old man with a history of alcohol use presented with hematochezia and syncope. Upon arrival to the hospital, his bleeding had stopped. He was hemodynamically stable with hemoglobin of 11g/dL, international normalized ratio of 1.8 and platelets of 37K/mcL. Nasogastric aspirate found bilious gastric contents without blood. Esophagogastroduodenoscopy revealed mild gastritis without evidence of bleeding. Colonoscopy discovered a purple-colored semi-circumferential ascending colon lesion that inflated and deflated spontaneously, without arterial pulsation. The lesion would disappear completely upon deflation, except for a visible fibrin plug, indicative of recent bleeding. Computed tomography further delineated the structure as varices, surrounding the right colon (Figure). Nearly 36 hours after presentation, the patient developed recurrent substantial hematochezia. He required intubation and massive transfusion for a hemoglobin nadir of 5g/dL. During emergent transjugular intrahepatic portosystemic shunt (TIPS) placement, large ascending colonic varices feeding from the superior mesenteric vein were confirmed and embolized. Bleeding ceased and he was ultimately discharged to alcohol rehabilitation. Figure Computed tomography, axial view. Arrows indicate varices. Esophageal and gastric varices are frequent complications of advanced liver disease. Ectopic varices (ECV), those not found in the esophagus and stomach, are less common; reported locations of ECV include the small bowel, gallbladder, colon, and rectum.1 Non-cirrhotic causes of ECV include congenital venous anomalies, splenic vein thrombosis, superior mesenteric vein obstruction and congestive heart failure.2 Given their often-obscure location, ECV can be difficult to identify. Once located, the ideal therapeutic intervention is unknown. Endoscopic options include band ligation and injection of tissue adhesives.1 TIPS with angiographic variceal embolization represents another approach for portal decompression in the setting of hemorrhage. Although scarcely reported in the literature, ECV should be considered a source of gastrointestinal bleeding, especially in a patient with liver disease. As seen in this case, colonic varices can cause profound hemorrhage, requiring prompt evaluation and intervention.

Pharmacokinetics and Tolerability of Intravenous Sildenafil in Two Subjects with Child–Turcotte–Pugh Class C Cirrhosis and Renal Dysfunction

Phosphodiesterase-5 (PDE-5) inhibitors have been used successfully in patients with cirrhosis to treat porto-pulmonary hypertension. Additionally, in cirrhosis, PDE-5 inhibitors can potentially improve portal hypertension and renal hemodynamics. No pharmacokinetics and tolerability studies of intravenous (IV) sildenafil have been conducted in Child-Turcotte-Pugh (CTP) class C cirrhosis and renal dysfunction. We report two subjects with CTP class C cirrhosis and estimated glomerular filtration rate of 25.8 and 22.4 ml/min/1.73m2 treated with a single-dose, IV bolus injection of 2.5 mg sildenafil. Both subjects had diuretic-refractory ascites with model for end-stage liver disease scores of 25 and 35. Both subjects tolerated IV Sildenafil without side effects. The observed maximum concentrations of plasma sildenafil were 35 and 20.6 ng/ml, with modeled pharmacokinetic estimates for clearance (11.9 and 14.9 L/hr), volumes of distribution (72.8 and 77.3 L) and half-life (4.2 and 3.6 hrs). N-desmethyl sildenafil concentrations ranged from 3 to 40% of the parent concentrations. Our results showed that in CTP class C cirrhosis and renal dysfunction, IV bolus injection of 2.5 mg sildenafil is safe and tolerable.

Diaphragmatic herniation due to massive hepatomegaly in a patient with pulmonary arterial hypertension.

A 56-year-old woman with severe pulmonary arterial hypertension (PAH) presented with right upper quadrant abdominal pain. The patient was diagnosed with PAH 5 years prior and started on oral therapy, but due to worsening pulmonary haemodynamics and symptoms, intravenous treprostinil was initiated. Imaging studies demonstrated hepatomegaly and a liver biopsy showed hepatic venous outflow obstruction and findings consistent with nodular regenerative hyperplasia. There was no evidence of …