Citations

Background: Pathologic reflux is a common debilitating digestive condition and anti-reflux surgery is an effective treatment option. Depending on the specifics of the procedure, anti-reflux surgery leads to distinct changes in the endoscopic appearance of the esophagogastric junction (EGJ). This American Foregut Society (AFS) white paper develops nomenclature for describing the endoscopic characteristics of the EGJ after commonly performed laparoscopic antireflux operations. Methods: The AFS Anti-Reflux Barrier Collaborative analyzed the anatomic manipulation and corresponding endoscopic appearance of the EGJ after commonly performed anti-reflux surgery including: (1) 360° anterior/posterior (AP) fundoplication (Nissen); (2) posterior partial fundoplication (Toupet); (3) anterior partial fundoplication (Watson, Dor); (4) magnetic sphincter augmentation; and (5) concomitant hiatal hernia repair with transoral fundoplication (cTIF). Results: Characteristics common to the anti-reflux surgery procedures include restoration of intra-abdominal esophageal length and crural diaphragm repair such that the hiatal aperture is no longer visible in the retroflexed endoscopic view. With regard to the geometry of anti-reflux procedures, the Collaborative established that when evaluated endoscopically in retroflection, the surgically constructed valve should be described in reference to the angle of His and the extent of anatomic change described in terms of (1) the depth of the anterior and posterior grooves, (2) the apposition of the valve collar to the endoscope, (3) the length of the valve, and (4) the position of the squamocolumnar junction relative to the lip of the valve. Conclusions: Current anti-reflux operations share much in common but employ varying degrees of valvular reconstruction leading to distinct endoscopic characteristics. Developing a consistent nomenclature for describing the appearance of the post-surgical valve is essential to develop a better understanding of how variables such as the tightness of the hiatal repair, tightness of the valve collar, and length of the valve can impact the outcome of anti-reflux surgery and predict reflux recurrence.

ABSTRACT Lymphoma is one of the leading causes of cancer and cancer deaths and yet has not been amenable to population screening. The role of methylated DNA markers (MDMs) in the detection of lymphoma has not been extensively studied. We aimed to discover, validate, and test tissue–derived MDMs of lymphoma in archival plasma specimens. Reduced representation bisulfite sequencing (RRBS) was performed on a discovery set of frozen tissues. MDMs identified were converted to methylation–specific PCR assays and validated on independent formalin–fixed, paraffin‐embedded (FFPE) tissues. Target enrichment long–probe quantitative‐amplified signal (TELQAS) assays were developed and assayed in plasma–extracted, bisulfite‐converted DNA from independent treatment‐naïve lymphoma patients and healthy controls. Prediction of cancer status was modeled using random forest model with in silico cross‐validation. After discovery and validation in tissue, 16 TELQAS assays ( ZNF503 , VWA5B1 , HOXA9 , GABRG3 , ITGA5 , MAX.chr17.7190 , BNC1 , CDK20 , MAX.chr4.4069 , TPBG , DNAH14 , SYT6 , CACNG8 , FAM110B , ADRA1D , and NRN1 ) were selected for testing in plasma. These detected 78% (95% CI, 74%–82%) of lymphoma cases at 90% specificity. Excluding marginal zone and T‐cell lymphomas, sensitivity increased to 84% (80%–88%). MDMs in plasma show promise to detect lymphoma and are candidates for inclusion in multi‐cancer detection studies.

Objective: This single-arm, pre–post interventional trial (clinicaltrials.gov, NCT04515095) investigates the safety, feasibility, and potential effectiveness of prolonged water-only fasting followed by a whole-plant-food diet in the long-term management of hypertension and other cardiometabolic disorders. Methods: Safety was assessed based on adverse events (AEs) that were recorded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Feasibility was assessed based on retention rate, ability to complete minimal fast length, and intervention acceptability. Twenty-nine participants with stage 1 and 2 hypertension and without type 2 diabetes were enrolled from a residential fasting center. Results: Study retention was 100% at the end of the refeed and 93% at the six-week follow-up visit. Median (range) fasting and refeeding duration were 11 (7–40) and 5 (3–17) days, respectively, and 90% of participants were able to complete at least 7 days of fasting. The majority of AEs were mild (grade 1) and transient and there were no higher-grade or serious AEs. At the end of the intervention, median systolic/diastolic blood pressure had normalized to below 130/80 mmHg, body weight reduced by >5%, and anti-hypertensive medication was completely discontinued. These results were sustained for at least six weeks and potentially up to one year. Conclusions: Our data suggest that the intervention may be a feasible, well-tolerated, low-risk option for lowering and managing high blood pressure, excess body weight, and other cardiometabolic disorders in people with stage 1 and 2 hypertension.

Abstract Background Glioblastoma (GBM) has a median survival of <2 years. Pexidartinib (PLX3397) is a small-molecule inhibitor of CSF1R, KIT, and oncogenic FTL3, which are implicated in GBM treatment resistance. Results from glioma models indicate that combining radiation therapy (RT) and pexidartinib reduces radiation resistance. We added pexidartinib to standard-of-care RT/temozolomide (TMZ) in patients with newly diagnosed GBM to assess the therapeutic benefit of altering the tumor microenvironment with pexidartinib. Methods In this open-label, dose-escalation, multicenter, Phase 1b/2 trial, pexidartinib was administered in combination with RT/TMZ followed by adjuvant pexidartinib + TMZ. During Phase 1b, pexidartinib was given 5 or 7 days/week at multiple dosing levels. The primary Phase 1b endpoint was the recommended Phase 2 dose (RP2D). Phase 2 patients received the RP2D with the primary endpoint of median progression-free survival (mPFS). Secondary objectives were median overall survival (mOS), pharmacokinetics, and safety. Results The RP2D of pexidartinib was 800 mg/day for 5 days/week during RT/TMZ, followed by 800 mg/day for 7 days/week with adjuvant TMZ. mPFS was 6.7 months (90% CI: 4.5, 11.5) for the modified intention-to-treat population. The actual mOS was 13.1 months (90% CI: 11.5, 24.5), and the mOS corrected for comparison with matched historical controls was 18.8 months (95% CI: 12.6, 28.0). Conclusions This trial established the RP2D of pexidartinib in combination with RT/TMZ and adjuvant TMZ. Pexidartinib was generally safe and well tolerated. Although the study regimen with pexidartinib was not efficacious, pharmacodynamic studies showed modulation of systemic markers that could lead to alteration of the tumor microenvironment.

Abstract Background In BRAF-mutated high-risk melanoma, targeted therapy (BRAF/MEK inhibitors) and checkpoint inhibitor (CPI) immunotherapy have durable benefits as first-line (1L) adjuvant therapy. Based on differing action mechanisms of BRAF/MEK inhibitors and CPI immunotherapies, there is interest in evaluating the activity of 2L adjuvant targeted therapy in decreasing the risk of subsequent recurrence after repeat resection following relapse on/after 1L adjuvant CPI. Patients and methods This was a retrospective review of BRAF V600-mutated resected stage III/IV melanoma patients in the United States, Australia, and The Netherlands who received 1L adjuvant CPI immunotherapy, relapsed locoregionally/distantly, were again resected to no evidence of disease, and received dabrafenib/trametinib (dab/tram) as 2L adjuvant therapy. The primary endpoint was relapse-free survival (RFS) from initiation of 2L adjuvant dab/tram (RFS-2), analyzed via Kaplan-Meier methods. Results Thirty-eight patients were included (median age 50 years, 63% male, 87% stage III, median follow-up 19 months from 2L dab/tram initiation). Median dab/tram duration was 10.1 months (range: 1 day–22.7 months), with half discontinuing due to progression or adverse events. Median (95% CI) RFS-2 was 18.9 (14.9–28.1) months, with 91%, 81%, and 58% remaining relapse-free at 6, 12, and 18 months, respectively. Most patients remained distant metastasis-free at 6, 12, and 18 months (97%, 85%, and 71%, respectively). Two patients were deceased at the last follow-up, with 97% alive at 18 months. Conclusions Over 80% of patients remained relapse- and metastasis-free at 12 months after 2L dab/tram initiation, with only 2 deaths observed. Dab/tram appears to have activity in the 2L adjuvant setting, although more follow-up is required.