Vitamin E treatment in NAFLD patients demonstrates that oxidative stress drives steatosis through upregulation of de-novo lipogenesis.

Oxidative stress (OS) in non-alcoholic fatty liver disease (NAFLD) promotes liver injury and inflammation. Treatment with vitamin E (α-tocopherol, αT), a lipid-soluble antioxidant, improves liver injury but also decreases steatosis, thought to be upstream of OS, through an unknown mechanism. To elucidate the mechanism, we combined a mechanistic human trial interrogating pathways of intrahepatic triglyceride (IHTG) accumulation and in vitro experiments. 50% of NAFLD patients (n = 20) treated with αT (200-800 IU/d) for 24 weeks had a ≥ 25% relative decrease in IHTG by magnetic resonance spectroscopy. Paired liver biopsies at baseline and week 4 of treatment revealed a decrease in markers of hepatic de novo lipogenesis (DNL) that strongly predicted week 24 response. In vitro, using HepG2 cells and primary human hepatocytes, αT inhibited glucose-induced DNL by decreasing SREBP-1 processing and lipogenic gene expression. This mechanism is dependent on the antioxidant capacity of αT, as redox-silenced methoxy-αT is unable to inhibit DNL in vitro. OS by itself was sufficient to increase S2P expression in vitro, and S2P is upregulated in NAFLD livers. In summary, we utilized αT to demonstrate a vicious cycle in which NAFLD generates OS, which feeds back to augment DNL and increases steatosis. Clinicaltrials.gov: NCT01792115.

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies.

BACKGROUND: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01724580 and NCT02974595. FUNDING: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

International multicenter comparative trial of endoscopic ultrasonography-guided gastroenterostomy versus surgical gastrojejunostomy for the treatment of malignant gastric outlet obstruction.

Background and study aims EUS-guided gastroenterostomy (EUS-GE) is a novel procedure that potentially offers long-lasting luminal patency without the risk of tumor ingrowth/overgrowth. This study compared the clinical success, technical success, adverse events (AEs), length of hospital stay (LOHS) and symptom recurrence in EUS-GE versus SGJ. Methods This was a multicenter international retrospective comparative study of EUS-GE and SGJ in patients with malignant gastric outlet obstruction (GOO) who underwent either EUS-GE or SGJ. EUS-GE was performed using lumen apposing metal stents. Results A total of 93 patients with malignant GOO treated with either EUS-GE (n = 30) or SGJ (n = 63) were identified. Peritoneal carcinomatosis was present in 13 (43 %) patients in the EUS-GE group and 7 (11 %) patients in the SGJ group (P < 0.001). Although the technical success rate was significantly higher in the SGJ group as compared to the EUS-GE group (100 % vs. 87 %, P = 0.009), the clinical success rate was not different (90 % vs. 87 %, P = 0.18, OR 0.8, 95 %CI 0.44 - 7.07). The rate of AEs was lower in the EUS-GE group, but the difference was not statistically significant (16 % vs 25 %, P = 0.3). The mean LOHS was similar in the EUS-GE group compared to SGJ (P = 0.35). The rate of recurrent GOO was not different between the two groups (3 % vs. 14 %, P = 0.08). Similarly, the mean time to reintervention was similar (88 days vs. 121 days, P = 0.83). Conclusions EUS-GE is associated with equivalent efficacy and safety as compared to surgical GJ. This is the first comparative trial between both techniques and suggests EUS-GE as a non-inferior but less invasive alter to surgery.

EUS-guided gastroenterostomy is comparable to enteral stenting with fewer re-interventions in malignant gastric outlet obstruction.

BACKGROUND AND AIMS: Endoscopic enteral stenting (ES) in malignant gastric outlet obstruction (GOO) is limited by high rates of stent obstruction. EUS-guided gastroenterostomy (EUS-GE) is a novel procedure that potentially offers sustained patency without tumor ingrowth/overgrowth. The aim of this study is to compare EUS-GE with ES in terms of (1) symptom recurrence and need for re-intervention, (2) technical success (proper stent positioning as determined via endoscopy and fluoroscopy), (3) clinical success (ability to tolerate oral intake without vomiting), and (4) procedure-related adverse events (AEs). METHODS: Multicenter retrospective study of all consecutive patients who underwent either EUS-GE at four centers between 2013 and 2015 or ES at one center between 2008 and 2010. RESULTS: A total of 82 patients (mean age 66-years ± 13.5 and 40.2% female) were identified: 30 in EUS-GE and 52 in ES. Technical and clinical success was not significantly different: 86.7% EUS-GE versus 94.2% ES (p = 0.2) and 83.3% EUS-GE versus 67.3% ES (p = 0.12), respectively. Symptom recurrence and need for re-intervention, however, was significantly lower in the EUS-GE group (4.0 vs. 28.6%, (p = 0.015). Post-procedure mean length of hospitalization was comparable at 11.3 days ± 6.6 for EUS-GE versus 9.5 days ± 8.3 for ES (p = 0.3). Rates and severity of AEs (as per the ASGE lexicon) were also similar (16.7 vs. 11.5%, p = 0.5). On multivariable analysis, ES was independently associated with need for re-intervention (OR 12.8, p = 0.027). CONCLUSION: EUS-GE may be ideal for malignant GOO with comparable effectiveness and safety to ES while being associated with fewer symptom recurrence and requirements for re-intervention.

Enteral stenting versus gastrojejunostomy for palliation of malignant gastric outlet obstruction.

BACKGROUND AND AIMS: Endoscopic placement of enteral self-expandable metallic stents is an alternative to surgical gastrojejunostomy (GJ) for palliation of malignant gastric outlet obstruction (GOO). Factors associated with clinical outcomes are not known. The aims of this study are to compare the overall complication rate and effectiveness (duration of oral intake) between endoscopic stenting (ES) and GJ in patients with GOO and identify predictors of clinical outcomes. PATIENTS AND METHODS: This was a retrospective cohort study at a single tertiary academic center. Patients who underwent ES or GJ for treatment of GOO between 1/2001 and 12/2010 were identified using an institutional claims database. The electronic medical records for each patient were reviewed. Univariate and multivariate logistic regression analyses were performed to study the association of treatment outcomes with patient factors and cancer therapy. RESULTS: 120 patients had ES while 227 had GJ. Technical success was higher for GJ (99 vs. 96 %, p = 0.004). Complication rates were higher in the GJ group (22.10 vs. 11.66 %, p = 0.02). Reintervention was more common with ES [adjusted odds ratio (OR) 9.18, p < 0.0001]. Mean length of hospital stay (LOHS) was shorter (adjusted p = 0.005) in the ES compared with the GJ group. However, mean hospital charges, including reinterventions, were greater in the ES group (US $34,250 vs. US $27,599, p = 0.03). ES and GJ had comparable reintervention-free time in patients who had reintervention (88 vs. 106 days, respectively, p = 0.79). Chemotherapy [adjusted hazard ratio (HR) 3 > 0.57, p = 0.04] and radiation therapy (adjusted HR 0.35, p = 0.03) were associated with significantly longer duration of oral intake after ES or GJ. CONCLUSION: ES is associated with fewer complications, shorter LOHS, but higher reintervention rates and overall charges.