Baig, Muhammad Usman

Summary Achalasia is a motility condition defined by failure of relaxation of the lower esophageal sphincter and loss of peristalsis in the distal esophagus. Per-oral endoscopic myotomy (POEM) is a technique to reduce lower esophageal sphincter pressure. We performed a systematic review and meta-analysis to assess the association between POEM and the clinical outcomes. We performed a systematic review and a meta-analysis (CRD420251052240). Literature search was done on PubMed and Embase (up to 8 June 2025). Original studies involving achalasia patients who underwent esophageal POEM with impedance planimetry using 8-cm balloon at 30 or 40 mL filling volumes with 325 catheter only (not the 322-N catheter) were included. The outcomes of interest were the clinical response groups (responders’ Eckardt score [ES] < 3 and non-responders’ ES > 3), reflux esophagitis, cross-sectional area (CSA), distensibility index (DI), and diameter. Nineteen studies with 1215 patients were included. The responders (ES < 3) showed a statistically significantly greater increase in DI due to POEM (post-op minus pre-op) (mean difference [MD] = 1.92 mm2/mmHg [0.32, 3.53], P = 0.02) as well as a higher postoperative DI (MD = 1.87 mm2/mmHg [0.04, 3.70], P = 0.05) (40 mL). Reflux esophagitis group had statistically significantly higher CSA and diameter values (CSA MD = 15.68 mm2 [6.91, 24.24], P = 0.0005) (diameter MD = 0.96 mm [0.58, 1.33], P < 0.00001) but no statistically significant difference for DI as compared to the non-reflux esophagitis group (DI MD = 0.19 mm2/mmHg [−0.51, 0.89], P = 0.59). In achalasia patients undergoing esophageal POEM, a greater interval increase in the DI as well as a higher post-procedural DI absolute value predicts a favorable clinical response. Higher postoperative CSA and diameter were linked to reflux esophagitis.

ABSTRACT Background Diffuse intrinsic pontine glioma (DIPG) carries a poor prognosis with a median survival of less than 12 months. Key molecular features include histone H3 mutation (K27M) and AKT pathway dysregulation. There is currently no curative treatment. Methods This is a Phase I study of vorinostat and temsirolimus in newly diagnosed (Stratum 1) and progressive (Stratum 2) DIPG (NCT02420613). The primary aims are to determine the safety, maximum tolerated dose (MTD), and toxicities. A modified 3 + 3 design was used to establish the MTD, where the first three patients were assigned the first dose level regardless of stratum. Stratum 1 received radiotherapy with vorinostat, followed by up to 10 cycles of vorinostat and temsirolimus. Stratum 2 received up to 12 cycles of vorinostat and temsirolimus. Vorinostat was administered at a fixed dose of 230 mg/m 2 daily on Days 1–8, and temsirolimus was administered on Days 1 and 8 at 25 mg/m 2 (Dose level 1) or 35 mg/m 2 (Dose level 2). Results Six patients were enrolled, three in each stratum. No dose‐limiting toxicity was observed, and most adverse effects were limited to Grades 1 or 2, including fatigue, myelosuppression, hyperlipidemia, hyperglycemia, elevated creatinine, nausea, vomiting, and headache. One patient experienced Grade 3 leukopenia. In the study, the MTD with acceptable toxicity was vorinostat 230 mg/m 2 and temsirolimus 35 mg/m 2 . Conclusions Overall, the combination of temsirolimus and vorinostat is well‐tolerated and safe, prompting the need for larger studies to investigate its efficacy.

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) carries a poor prognosis with a median survival of less than 12 months. Histone mutation, K27M, and AKT pathway dysregulation play key roles in tumorigenesis. There is no curative treatment with radiation therapy, which currently remains the standard treatment. METHODS This is a phase I study of vorinostat and temsirolimus in newly diagnosed (stratum 1) and progressive (stratum 2) DIPG. The primary aims are to determine the safety, maximum tolerated dose, and toxicities (NCT02420613). Stratum 1 received radiation concurrently with vorinostat, followed by vorinostat and temsirolimus for up to 10 cycles. Stratum 2 received vorinostat and temsirolimus for up to 12 cycles. In stratum 1, vorinostat was administered daily at 230 mg/m2. The maintenance phase (both strata) included concurrent vorinostat 230 mg/m2 daily and temsirolimus 25 or 35 mg/m2 (Days 1 and 8). RESULTS Six patients were enrolled, three in each stratum. Three of the six patients had confirmed H3 K27M mutations. No dose-limiting toxicity was observed, and most adverse effects were limited to grades 1 or 2, including fatigue, nausea, vomiting, myelosuppression, hyperlipidemia, hyperglycemia, elevated liver enzymes, and creatinine. However, one patient experienced grade 3 leukopenia. Two of the three patients in stratum 1 showed evidence of radiographic response after the chemoradiation phase, of whom one patient had progression-free survival of 12 months and completed the 10 maintenance cycles. All patients at stratum 2 had disease progression with no radiographic response. CONCLUSION Overall, the combination of temsirolimus and vorinostat is well tolerated and safe, prompting the need for larger studies to investigate its efficacy. Due to the small number of patients, the study’s findings are limited, and trends in efficacy should be interpreted with caution.