VO2max as an exercise tolerance endpoint in people with cystic fibrosis: Lessons from a lumacaftor/ivacaftor trial.

BACKGROUND: The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied. METHODS: We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VO2max) during cardiopulmonary exercise testing (CPET) at Week 24. The key secondary endpoint was relative change from baseline in exercise duration during CPET at Week 24. Other secondary endpoints included changes in other indices of exercise tolerance and changes in CF assessments; safety and tolerability were assessed as an endpoint. RESULTS: Seventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VO2max from baseline at Week 24 was -3.2% (95% CI: -9.2, 2.9; P=0.3021); the least-squares mean difference in relative change from baseline in exercise duration at Week 24 was -3.2% (95% CI: -8.0, 1.6). Safety results were consistent with the known lumacaftor/ivacaftor safety profile. CONCLUSIONS: Definitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366.

Adenoma and polyp detection rates during insertion versus withdrawal phase of colonoscopy: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Colonoscopy is the preferred modality for colorectal cancer screening because it has both diagnostic and therapeutic capabilities. Current consensus states that colonoscopy should be performed with initial rapid passage of the instrument to the cecum, followed by thorough evaluation for and removal of all polyps during a deliberate slow withdrawal. Reports have suggested that polyps that are seen but not removed during insertion are sometimes quite difficult to find during withdrawal. METHODS: We performed a comprehensive literature search of several major databases (from inception to March 2020) to identify randomized controlled trials comparing inspection and polypectomy during the insertion phase as opposed to the traditional practice of inspection and polypectomy performed entirely during the withdrawal phase. We examined differences in terms of adenoma detection rate (ADR), polyps detected per patient (PDPP), cecal intubation time (CIT), withdrawal time, and total procedure time. RESULTS: Seven randomized controlled trials, including 3834 patients, were included in our final analysis. The insertion/withdrawal cohort had 1951 patients and the withdrawal-only cohort 1883 patients. Pooled odds of adenoma detection in the insertion/withdrawal cohort was .99 (P = .8). ADR was 47.2% in the insertion/withdrawal cohort and 48.6% in the withdrawal-only cohort. Although total procedure and withdrawal times were shorter in the insertion/withdrawal cohort, PDPP in both cohorts were not statistically significant (1.4 vs 1.5, P = .7). CONCLUSIONS: Additional inspection and polypectomy during the insertion and withdrawal phases of colonoscopy offer no additional benefit in terms of ADR or PDPP.

Clinical efficacy of per-oral endoscopic myotomy (POEM) for spastic esophageal disorders: a systematic review and meta-analysis.

BACKGROUND: POEM has been successfully performed in patients with spastic esophageal disorders (SED), such as diffuse esophageal spasm, jackhammer esophagus, and type 3 achalasia. We performed a systematic review and meta-analysis to evaluate its efficacy in these patients and if total average myotomy length and prior medical or endoscopic treatments affected clinical success. METHODS: PubMed, EMBASE, Google-Scholar, Scopus, and Cochrane Review were searched for studies on POEM in SED from 2008 to September 2018. Clinical success was determined by Eckardt score (≤ 3) at follow-up. Sub-group analysis was performed based on myotomy length and evaluates the effect of prior treatments on clinical success. RESULTS: 9 studies with 210 patients were included in the final analysis. We found that the pooled rate of clinical success for POEM was 89.6% (95% CI 83.5-93.1, 95% PI 83.4-93.7, I2 = 0%). In three studies (50 patients), where total myotomy length was < 10 cm, the pooled rate of clinical success was 91.1% (95% CI 79.5-96.4, I2 = 0%). In six studies (160 patients), the length was > 10 cms and the pooled rate of clinical success was 89.1% (95% CI 83.0-93.2, I2 = 0%). The difference between these results was not statistically significant (p = 0.69). Additionally, a meta-regression analysis showed that prior treatment status did not significantly affect the primary outcome (p = 0.43). CONCLUSIONS: While it is well known that POEM is a safe and effective treatment for spastic esophageal disorders, we conclude that variation in total myotomy length and prior endoscopic or medical treatments did not have a significant effect on clinical success.

Clinical efficacy of gastric per-oral endoscopic myotomy (G-POEM) in the treatment of refractory gastroparesis and predictors of outcomes: a systematic review and meta-analysis using surgical pyloroplasty as a comparator group.

BACKGROUND AND AIMS: Gastric peroral endoscopic myotomy (G-POEM) is a novel minimally invasive technique in endosurgery. Data is limited as to its efficacy, safety, and predictive factors. We conducted this meta-analysis to evaluate the clinical outcomes of G-POEM and used the outcomes of surgical pyloroplasty as a comparator group in the treatment of refractory gastroparesis. METHODS: We searched multiple databases from inception through March 2019 to identify studies that reported on G-POEM and pyloroplasty in gastroparesis. Our primary outcome was to analyze and compare the pooled rates of clinical success, in terms of Gastroparesis Cardinal Symptom Index (GCSI) score and 4-h gastric emptying study (GES) results, with G-POEM and pyloroplasty. RESULTS: Three hundred and thirty-two and 375 patients underwent G-POEM (11 studies) and surgical pyloroplasty (seven studies), respectively. The pooled rate of clinical success, based on the GCSI score, with G-POEM was 75.8% (95% CI 68.1-82.1, I2 = 50) and with surgical pyloroplasty was 77.3% (95% CI 66.4-85.4, I2 = 0), with no significance, p = 0.81. The pooled rate of clinical success, based on the 4-hour GES results, with G-POEM was 85.1% (95% CI 68.9-93.7, I2 = 74) and with surgical pyloroplasty was 84% (95% CI 64.4-93.8, I2 = 81), with no significance, p = 0.91. The overall adverse events were comparable. Based on meta-regression analysis, idiopathic gastroparesis, prior treatment with botulinum toxin and gastric stimulator seemed to predict clinical success with G-POEM. CONCLUSION: G-POEM demonstrates clinical success in treating refractory gastroparesis. Idiopathic gastroparesis, prior treatment with botulinum injections and gastric stimulator appear to have positive predictive effects on the 4-h GES results after G-POEM. Outcomes seem comparable to surgical pyloroplasty.

Jackhammer esophagus with and without esophagogastric junction outflow obstruction demonstrates altered neural control resembling type 3 achalasia.

BACKGROUND: Esophageal hypercontractility can manifest with and without esophagogastric junction (EGJ) outflow obstruction. We investigated clinical presentations and motility patterns in patients with esophageal hypercontractile disorders. METHODS: Esophageal HRM studies fulfilling Chicago Classification 3.0 criteria for jackhammer esophagus (distal contractile integral, DCI >8000 mmHg.cm.s in ≥ 20% swallows) with (n = 30) and without (n = 83) EGJ obstruction (integrated relaxation pressure, IRP > 15 mm Hg) were retrospectively reviewed from five centers (4 in Europe, 1 in US). Single swallows (SS) and multiple rapid swallows (MRS) were analyzed using HRM software tools (IRP, DCI, distal latency, DL); MRS: SS DCI ratio >1 defined contraction reserve. Comparison groups were achalasia type 3 (n = 72, positive control for abnormal inhibition and EGJ obstruction) and healthy controls (n = 18). Symptoms, HRM metrics, and MRS contraction reserve were analyzed within jackhammer subgroups and comparison groups. KEY RESULTS: The esophageal smooth muscle was excessively stimulated at baseline in jackhammer subgroups, with lack of augmentation following MRS identified more often compared with controls (P = .003) and type 3 achalasia (P = .07). Consistently abnormal inhibition was identified in type 3 achalasia (47%), and to a lower extent in jackhammer with obstruction (37%, P = .33), jackhammer esophagus (28%, P = .01), and controls (11%, P < .01 compared with type 3 achalasia). Perceptive symptoms (heartburn, chest pain) were common in jackhammer esophagus (P < .01 compared with type 3 achalasia), while transit symptoms (dysphagia) were more frequent with presence of EGJ obstruction (P ≤ .01 compared with jackhammer without obstruction). CONCLUSIONS AND INFERENCES: The balance of excessive excitation and abnormal inhibition defines clinical and manometric manifestations in esophageal hypercontractile disorders.

Gastrointestinal Bleeding With Left Ventricular Assist Devices (LVAD): Locating the Leak and Identifying Outcomes.

BACKGROUND AND GOALS: Gastrointestinal bleeding (GIB) is a significant complication following left ventricular assist device (LVAD) implantation. We evaluated the incidence, predictors, endoscopic findings, and outcomes of GIB in LVAD recipients. STUDY: Retrospective review of 205 adult patients undergoing HeartMate II LVAD implantation from January 2012 to June 2016. Patients were reviewed and separated into GIB (n=57; 28%) and non-GIB (n=148; 72%) groups. RESULTS: Median time to GIB was 55 (range, 3 to 730) days. The GIB group patients were older (61±12 vs. 56±13, P=0.0042), more often underwent concomitant tricuspid valve (TV) repair (16% vs. 4%, P=0.007), and a higher percentage were assigned for destination therapy (75% vs. 55%, P=0.01). Angioectasia (33%) was the most common identified cause of GIB. Median time to endoscopic intervention was 1 day. The total number of hospital readmissions after LVAD was higher in the GIB group (median of 5 vs. 3, P=0.001), as was the total number of blood products transfused after LVAD (29 vs. 13, P≤0.0001). GIB was associated with an increased risk of death (hazard ratio, 1.94; 95% confidence interval, 1.16-3.25; P=0.01) and the mortality rate during hospitalization for GIB was 11% (P=0.0004). Receiving a heart transplant was associated with a decreased hazard of death (hazard ratio, 0.40; 95% confidence interval, 0.19-0.85; P=0.016). CONCLUSIONS: Older age and destination therapy as implant strategy were found to be associated with an increased risk of GIB, consistent with previous studies. A unique finding in our study is the association of TV repair with a higher incidence of GIB. Further studies are needed to investigate possible mechanisms by which TV repair increases the incidence of GIB.

Refractory Hepatic Hydrothorax in the Absence of Ascites as a First Sign of Cirrhosis.

Hepatic hydrothorax (HH) occurs in 5-10 percent of patients with cirrhosis and usually develops in conjunction with ascites. We report a case of refractory right sided pleural effusion which turned out to be HH in the absence of ascites or previous history of cirrhosis. HH is thought to occur in isolation due to the superior absorptive capacity of the peritoneum as compared to the pleura. Diagnosis is usually clinical but can be confirmed by scintigraphic studies. The treatment is similar to that for ascites with transjugular intrahepatic portosystemic shunt (TIPS) being the most effective but it is associated with high rate of complications.

Use of Endoscopic Ultrasound in a Diagnostic Dilemma: Metastatic Breast Cancer to the Stomach.

A 55-year-old woman presented with persistent nausea, vomiting, and weight loss previously attributed to Ménétrier's disease. On further workup, she was found to have metastatic lobular breast carcinoma causing gastric outlet obstruction, diagnosed by endoscopic ultrasound with fine needle aspiration after previous gastric mucosal biopsies were unremarkable. In most reported cases of gastric metastasis from breast cancer, a diagnosis was established by mucosal biopsy. This case is an important reminder that mucosal biopsies can be negative in about 20% of patients with gastric metastasis, which may lead to a delay in diagnosis and treatment. Gastroenterologists should be diligent in taking deeper biopsies if there is a suspicion for gastric metastasis.

Castleman's Disease and Posttransplant Lymphoproliferative Disorder after Liver Transplant: 3-Year Follow-Up.

A 59-year-old male with a history of hepatitis C cirrhosis and history of hepatitis B exposure presented 8 months after orthotopic liver transplant (LT) with fever, fatigue, myalgia, night sweats, nonproductive cough, and shortness of breath. Bone marrow biopsy for pancytopenia was positive for Epstein-Barr virus (EBV) DNA. Lymph node biopsy for lymphadenopathy on imaging showed human herpes virus 8 (HHV8) associated Castleman's disease. Treatment included valganciclovir, rituximab, and prednisone taper with eventual discontinuation. Quantitative HHV8 DNA was initially 611,000 DNA copies/mL and was later undetectable at 6 months following treatment and remained undetectable at 3-year follow-up.

Needle-Knife Fistulotomy for the Rescue: An Unusual Cause of Iatrogenic Extrahepatic Biliary Obstruction.

A 71-year-old male presented to our institution with cholestatic hepatitis after having recently undergone upper endoscopy for treatment of gastrointestinal bleeding. Further investigation with endoscopic retrograde cholangiopancreatography revealed a hemostatic clip on the ampulla of Vater. After initial attempts at cannulation of the common bile duct were unsuccessful, biliary decompression was achieved by use of needle-knife fistulotomy. A common bile duct stent was placed and the liver function tests improved prior to discharge.

A Case of Hepatotoxicity Related to Kombucha Tea Consumption.

The use of herbal and dietary supplements (HDSs) is widespread and growing due to the popular notion that these products are of natural origins and safe. Kombucha (or "mushroom") tea is one HDS that is consumed by people for various perceived health benefits. Kombucha tea is a well-known health beverage made by fermenting sweet black tea with a round, flat, gray fungus for a week or longer. There is concern, however, from the evidence of a few case reports currently available, that it may pose life-threatening and/or adverse effects for users.

The Effect of Ramelteon on Heartburn Symptoms of Patients With Gastroesophageal Reflux Disease and Chronic Insomnia: A Pilot Study.

BACKGROUND: There is a bidirectional relationship between gastroesophageal reflux disease (GERD) and sleep. It has been demonstrated that antireflux treatment can improve sleep quality in GERD patients with nighttime reflux. MATERIALS AND METHODS: Patients with heartburn and/or regurgitation ≥3 times/week and insomnia for ≥3 months were included. Patients were assessed at baseline with the demographic, GERD symptom assessment scale, Epworth sleepiness scale, Berlin sleep apnea, Pittsburgh sleep quality index, and the Insomnia severity index questionnaires. Subjects underwent an upper endoscopy followed by pH testing. Subsequently, subjects were randomized, in a double-blind, placebo-controlled trial, to receive either ramelteon 8 mg or placebo before bedtime for 4 weeks. During the last week of treatment, subjects completed a daily GERD symptom and sleep diary and underwent actigraphy. RESULTS: Sixteen patients completed the study, 8 in each arm (mean age and M/F were 48.5 vs. 57.8 y, and 8/0 vs. 6/2, respectively). Patients who received ramelteon demonstrated a statistically significant decrease in symptom score as compared with those who received placebo for daytime heartburn (-42% vs. -29%), nighttime heartburn (-42% vs. 78%), 24-hour heartburn (-42% vs. -3%), and 24-hour acid regurgitation (-26% vs. 19%) (all P<0.05). Insomnia severity index score was significantly reduced in patients receiving ramelteon as compared with placebo (-46% vs. -5%, P<0.05). Ramelteon group also demonstrated a significant improvement in sleep efficiency and sleep latency, as compared with placebo, P<0.05). No significant adverse events were observed with ramelteon. CONCLUSIONS: Ramelteon significantly improved symptoms in patients with GERD. In addition, ramelteon significantly improved patients' sleep experience. Further studies are needed in the future (NCT01128582).

Naps are associated more commonly with gastroesophageal reflux, compared with nocturnal sleep.

BACKGROUND & AIMS: Acid reflux during nighttime sleep has been associated with more severe gastroesophageal reflux disease (GERD). Napping is common, especially after lunch time, in many cultures. We aimed to compare reflux characteristics between nighttime sleep and naps in patients with GERD. METHODS: We performed a study of 15 patients (mean age, 58.5 ± 18.4 y; 10 men) with heartburn and/or regurgitation at least 3 times/week for the past 3 months, who experienced a nap in addition to regular nighttime sleep. All were evaluated using the demographics and GERD Symptoms Checklist questionnaires. Patients underwent pH testing concomitantly with actigraphy when they were not receiving antireflux treatment; only patients with abnormal results from pH tests were included in the study. Raw data from actigraphy analyses were superimposed over those collected from pH monitoring, matched by time. Integrative software was used to determine recumbent-awake, recumbent-asleep, and naps alongside pH monitoring data. RESULTS: The mean duration of nocturnal sleep time and nap time were 446.0 ± 100.7 minutes and 61.9 ± 51.8 minutes, respectively. The mean number of reflux events per hour was significantly greater during nap than nocturnal sleep time (40.1 ± 69.9/h vs 3.5 ± 4.2/h; P < .05). The mean duration of reflux events was longer during nap than nocturnal sleep time (1.9 ± 2.8 min vs 1.5 ± 2.7 min). The percentage of time spent at a pH less than 4 was significantly greater during naptime than nocturnal sleep time (36.2% ± 38.8% vs 8.9% ± 11.6%; P < .05). Arousals from naps were rare, compared with nocturnal sleep (mean, 0.7 ± 1.1 vs 4.2 ± 2.9; P < .05). Patients also experienced more acid reflux associated with symptoms during nap than nocturnal sleep (mean, 8.08% vs 0.45%; P < .05). CONCLUSIONS: We associated naps with significantly greater numbers of, and duration of, esophageal acid exposure and symptoms, compared with nocturnal sleep. Naps therefore might have important effects on disease severity.

The relationship between type 2 diabetes mellitus and failure to proton pump inhibitor treatment in gastroesophageal reflux disease.

BACKGROUND: There is limited information regarding the contribution of diabetes mellitus (DM) to proton pump inhibitor (PPI) failure in gastroesophageal reflux disease (GERD) patients. AIM: To determine whether type 2 DM is a risk factor for PPI failure and the potential predictive factors for PPI failure among type 2 DM patients with GERD. DESIGN: A case-control study was performed using hospital medical records of GERD patients treated with a PPI. The prevalence of type 2 DM and other risk factors (established >1 y before study enrollment) was determined in the PPI failure (treatment with more than once daily PPI) as compared with PPI responders. RESULTS: A total of 732 GERD patients receiving PPI therapy, including 285 who failed PPI treatment, were included. The overall prevalence of PPI failure was significantly higher in diabetic versus nondiabetic patients. The relationship between PPI failure and type 2 DM depended on body mass index. Only in obese patients the odds ratio of PPI failure was significantly higher in type 2 DM as compared with non-DM patients. In the subgroup of GERD patients with type 2 DM (n=349), PPI failure was significantly associated with female sex, the presence of general comorbidities, and adequate DM control. Duration of DM, type of antidiabetic medication prescribed, and DM-associated complications were not associated with PPI failure. CONCLUSIONS: PPI failure was significantly associated with type 2 DM in obese patients. Among GERD patients with type 2 DM, failure of PPI treatment was significantly associated with female sex and the presence of general comorbidities.