Ravi, Karthik

ABSTRACT Two major etiologies of hyperbilirubinemia include hemolysis and cholestasis. Although rare, the former can give rise to the latter through the formation of pigment gallstones and subsequent biliary tree obstruction. We report a case of a 57-year-old woman with systemic lupus erythematosus who presented with dyspnea and right upper quadrant abdominal pain. She was found to have hepatolithiasis and choledocholithiasis secondary to warm autoimmune hemolytic anemia in the setting of COVID-19. In patients with symptomatic anemia secondary to acute hemolysis and concomitant right upper quadrant abdominal pain, elevated hepatocellular laboratory results should prompt a high clinical suspicion for biliary tree pigment stones.

AbstractBackground and PurposeIneffective esophageal motility (IEM) is the most frequently diagnosed esophageal motility abnormality and characterized by diminished esophageal peristaltic vigor and frequent weak, absent, and/or fragmented peristalsis on high‐resolution esophageal manometry. Despite its commonplace occurrence, this condition can often provoke uncertainty for both patients and clinicians. Although the diagnostic criteria used to define this condition has generally become more stringent over time, it is unclear whether the updated criteria result in a more precise clinical diagnosis. While IEM is often implicated with symptoms of dysphagia and gastroesophageal reflux disease, the strength of these associations remains unclear. In this review, we share a practical approach to IEM highlighting its definition and evolution over time, commonly associated clinical symptoms, and important management and treatment considerations. We also share the significance of this condition in patients undergoing evaluation for anti‐reflux surgery and consideration for lung transplantation.

SummaryBackgroundPredictive models for eosinophilic oesophagitis (EoE) may not fully rule in the diagnosis.AimTo develop a reverse model that predicts against EoE to eliminate the need for oesophageal biopsies.MethodsIn this two‐centre study, a predictive model was developed (Mayo Clinic) and validated (University of North Carolina [UNC]). Cross‐sectional data from consecutive adult patients without prior EoE who underwent upper enoscopy with oesophageal biopsies were used. EoE cases had ≥15 eosinophils/high‐power field while controls had no eosinophils. Data were collected on patient clinical and endoscopic features. Multiple variable logistic regression was used to identify predictors of non‐EoE status while maintaining specificity ≥95%. A secondary model was developed to predict against the need for endoscopy in patients suspected of having EoE without alarm symptoms.ResultsThe Mayo and UNC cohorts consisted of 345 (EoE = 94, non‐EoE = 251) and 297 patients (EoE = 84, non‐EoE = 213), respectively. A primary model based on clinical and endoscopic features predicted against EoE with c‐statistic 0.92 (95% CI: 0.88–0.96), specificity 95%, and sensitivity 65%. This model was validated (UNC) with c‐statistic 0.87 (95% CI: 0.82–0.92). A simplified scoring system was created and a threshold of ≥12 points excluded EoE with 95% specificity and 50% sensitivity. A secondary model based on clinical characteristics alone predicted against EoE with c‐statistic 0.86 (95% CI: 0.82–0.90), specificity 95% and sensitivity 39% and validated (UNC) with c‐statistic 0.78 (95% CI: 0.71–0.85).ConclusionA simplified scoring system accurately identified a group of patients with a low likelihood of EoE where unnecessary oesophageal biopsies can be avoided, potentially resulting in resource and cost savings.

Abstract Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. Significance: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293

Abstract Bariatric surgeries are often complicated by de-novo gastroesophageal reflux disease (GERD) or worsening of pre-existing GERD. The growing rates of obesity and bariatric surgeries worldwide are paralleled by an increase in the number of patients requiring post-surgical GERD evaluation. However, there is currently no standardized approach for the assessment of GERD in these patients. In this review, we delineate the relationship between GERD and the most common bariatric surgeries: sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB), with a focus on pathophysiology, objective assessment, and underlying anatomical and motility disturbances. We suggest a stepwise algorithm to help diagnose GERD after SG and RYGB, determine the underlying cause, and guide the management and treatment.