Hedgehog transcriptional effector GLI mediates mTOR-Induced PD-L1 expression in gastric cancer organoids.

Tumors evade immune surveillance by expressing Programmed Death-Ligand 1 (PD-L1), subsequently inhibiting CD8+ cytotoxic T lymphocyte function. Response of gastric cancer to immunotherapy is relatively low. Our laboratory has reported that Helicobacter pylori-induced PD-L1 expression within the gastric epithelium is mediated by the Hedgehog (Hh) signaling pathway. The PI3K/AKT/mTOR pathway is activated in gastric cancer and may have immunomodulatory potential. We hypothesize that Hh signaling mediates mTOR-induced PD-L1 expression. Patient-derived organoids (PDOs) were generated from gastric biopsies and resected tumor tissues. Autologous organoid/immune cell co-cultures were used to study the immunosuppressive function of MDSCs. NanoString Digital Spatial Profiling (DSP) of immune-related protein markers using FFPE slide-mounted tissues from gastric cancer patients was performed. DSP analysis showed infiltration of immunosuppressive MDSCs expressing Arg1, CD66b, VISTA and IDO1 within cancer tissues. Orthotopic transplantation of patient derived organoids (PDOs) resulted in the engraftment of organoids and the development of histology similar to that observed in the patient's tumor tissue. PDO/immune cell co-cultures revealed that PD-L1-expressing organoids were unresponsive to nivolumab in vitro in the presence of PMN-MDSCs. Depletion of PMN-MDSCs within these co-cultures sensitized the organoids to anti-PD-1/PD-L1-induced cancer cell death. Rapamycin decreased phosphorylated S6K, Gli2 and PD-L1 expression in PDO/immune cell co-cultures. Transcriptional regulation of PD-L1 by GLI1 and GLI2 was blocked by rapamycin. In conclusion, the PDO/immune cell co-cultures may be used to study immunosuppressive MDSC function within the gastric tumor microenvironment. The mTOR signaling pathway mediates GLI-induced PD-L1 expression in gastric cancer.

Metabolic outcomes after revisional bariatric surgery: a systematic review and meta-analysis.

BACKGROUND: It has been well-established that primary bariatric surgery is effective in inducing improvement of diabetes and other associated co-morbidities in patients with obesity. Evidence demonstrating the influence of revisional bariatric surgery on this trajectory, however, is lacking. OBJECTIVES: We performed a systematic review and meta-analysis to examine the impact of revisional bariatric surgery on obesity-related metabolic outcomes. SETTING: University Hospital, Singapore METHODS: We examined outcomes of remission and improvement of diabetes, hypertension, hyperlipidemia, and obstructive sleep apnea. Revisional surgeries included sleeve gastrectomy, Roux-en-Y gastric bypass, pouch revision, duodenal switch, and minigastric bypass. RESULTS: Our search identified 33 relevant studies including a total of 1593 patients. Meta-analysis of proportions demonstrated a 92% improvement in diabetes with 50% achieving remission after revisional bariatric surgery. Of patients, 81% achieved improvement of hypertension with 33% achieving complete remission. In both groups, the highest proportion of improvement was observed after revisional duodenal switch. Although reported by fewer studies, a remission of hyperlipidemia was reported in 37% of patients and improvement of obstructive sleep apnea was seen in 86% of patients. CONCLUSIONS: Revisional bariatric surgery improves the outcomes of obesity-related co-morbidities and should be considered in patients with persistent metabolic disease after primary bariatric surgery.

Totally extra-peritoneal repair for acute incarcerated femoral hernia with intestinal obstruction.

INTRODUCTION: Femoral hernias frequently present with incarceration, resulting in obstruction and strangulation. Laparoscopic groin hernia repairs have been shown in the elective setting to be an effective alternative to open repair. Acute incarceration of groin hernia with obstruction, though previously seen as a relative contraindication, has been increasingly repaired with minimally invasive techniques, with the potential benefit of avoiding the morbidity associated with a laparotomy. PRESENTATION OF CASE AND DISCUSSION: We describe a case of an acutely incarcerated femoral hernia with intestinal obstruction that was repaired using the totally extra-peritoneal approach. A releasing incision was performed to facilitate reduction of hernia prior to mesh repair. Diagnostic laparoscopy through a separate incision was then performed. CONCLUSION: This modification of the TEP repair technique for the acutely incarcerated and obstructed femoral hernia serves to minimise potential contamination by keeping the pre-peritoneal plane strictly separate from the intra-peritoneal space.

In vivo diagnosis of gastric cancer using Raman endoscopy and ant colony optimization techniques.

This study aims to evaluate the clinical utility of image-guided Raman endoscopy for in vivo diagnosis of neoplastic lesions in the stomach at gastroscopy. A rapid-acquisition image-guided Raman endoscopy system with 785-nm excitation has been developed to acquire in vivo gastric tissue Raman spectra within 0.5 sec during clinical gastroscopic examinations. A total of 1,063 in vivo Raman spectra were acquired from 238 tissue sites of 67 gastric patients, in which 934 Raman spectra were from normal tissue whereas 129 Raman spectra were from neoplastic gastric tissue. The swarm intelligence-based algorithm (i.e., ant colony optimization (ACO) integrated with linear discriminant analysis (LDA)) was developed for spectral variables selection to identify the biochemical important Raman bands for differentiation between normal and neoplastic gastric tissue. The ACO-LDA algorithms together with the leave-one tissue site-out, cross validation method identified seven diagnostically important Raman bands in the regions of 850-875, 1,090-1,110, 1,120-1,130, 1,170-1,190, 1,320-1,340, 1,655-1,665 and 1,730-1,745 cm(-1) related to proteins, nucleic acids and lipids of tissue and provided a diagnostic sensitivity of 94.6% and specificity of 94.6% for distinction of gastric neoplasia. The predictive sensitivity of 89.3% and specificity of 97.8% were also achieved for an independent test validation dataset (20% of total dataset). This work demonstrates for the first time that the real-time image-guided Raman endoscopy associated with ACO-LDA diagnostic algorithms has potential for the noninvasive, in vivo diagnosis and detection of gastric neoplasia during clinical gastroscopy.