Comprehensive molecular phenotyping of ARID1A-deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities.

OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer mortality, with ARID1A being the second most frequently mutated driver gene in GC. We sought to decipher ARID1A-specific GC regulatory networks and examine therapeutic vulnerabilities arising from ARID1A loss. DESIGN: Genomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures of ARID1A inactivation across molecular subtypes. Single-cell transcriptomic profiles of ARID1A-mutated GCs were analysed to examine tumour microenvironmental changes arising from ARID1A loss. Genome-wide ARID1A binding and chromatin profiles (H3K27ac, H3K4me3, H3K4me1, ATAC-seq) were generated to identify gastric-specific epigenetic landscapes regulated by ARID1A. Distinct cancer hallmarks of ARID1A-mutated GCs were converged at the genomic, single-cell and epigenomic level, and targeted by pharmacological inhibition. RESULTS: We observed prevalent ARID1A inactivation across GC molecular subtypes, with distinct mutational signatures and linked to a NFKB-driven proinflammatory tumour microenvironment. ARID1A-depletion caused loss of H3K27ac activation signals at ARID1A-occupied distal enhancers, but unexpectedly gain of H3K27ac at ARID1A-occupied promoters in genes such as NFKB1 and NFKB2. Promoter activation in ARID1A-mutated GCs was associated with enhanced gene expression, increased BRD4 binding, and reduced HDAC1 and CTCF occupancy. Combined targeting of promoter activation and tumour inflammation via bromodomain and NFKB inhibitors confirmed therapeutic synergy specific to ARID1A-genomic status. CONCLUSION: Our results suggest a therapeutic strategy for ARID1A-mutated GCs targeting both tumour-intrinsic (BRD4-assocatiated promoter activation) and extrinsic (NFKB immunomodulation) cancer phenotypes.

Multiancestry genomic and transcriptomic analysis of gastric cancer.

Gastric cancer is among the most common malignancies worldwide, characterized by geographical, epidemiological and histological heterogeneity. Here, we report an extensive, multiancestral landscape of driver events in gastric cancer, involving 1,335 cases. Seventy-seven significantly mutated genes (SMGs) were identified, including ARHGAP5 and TRIM49C. We also identified subtype-specific drivers, including PIGR and SOX9, which were enriched in the diffuse subtype of the disease. SMGs also varied according to Epstein-Barr virus infection status and ancestry. Non-protein-truncating CDH1 mutations, which are characterized by in-frame splicing alterations, targeted localized extracellular domains and uniquely occurred in sporadic diffuse-type cases. In patients with gastric cancer with East Asian ancestry, our data suggested a link between alcohol consumption or metabolism and the development of RHOA mutations. Moreover, mutations with potential roles in immune evasion were identified. Overall, these data provide comprehensive insights into the molecular landscape of gastric cancer across various subtypes and ancestries.

Elective incisional hernia repair: lower risk of postoperative wound infection with laparoscopic versus open repair.

Introduction: The superiority of laparoscopic repair over open repair of incisional hernias (IHs) in the elective setting is still controversial. Our study aimed to compare the postoperative outcomes of laparoscopic and open elective IH repair in an Asian population. Methods: This retrospective study was conducted in an acute general hospital in Singapore between 2010 and 2015. Inclusion criteria were IH repair in an elective setting, IHs with diameter of 3-15 cm, and location at the ventral abdominal wall. We excluded patients who underwent emergency repair, had recurrent hernias or had loss of abdominal wall domain (i.e. hernia sac containing more than 30% of abdominal contents or any solid organs). Postoperative outcomes within a year such as recurrence, pain, infection, haematoma and seroma formation were compared between the two groups. Results: There were 174 eligible patients. The majority were elderly Chinese women who were overweight. Open repair was performed in 49.4% of patients, while 50.6% underwent laparoscopic repair. The mean operation time for open repair was 116 minutes (116 ± 60.6 minutes) and 139 minutes (136 ± 64.1 minutes) for laparoscopic repair (P = 0.079). Within a year after open repair, postoperative wound infection occurred in 15.1% of the patients in the open repair group compared to 1.1% in the laparoscopic group (P = 0.0007). Postoperative pain, recurrence and haematoma/seroma formation were comparable. Conclusion: Elective laparoscopic IH repair has comparable outcomes with open repair and may offer the advantage of reduced postoperative wound infection rates.

Clinicopathological, Microbiological and Polymerase Chain Reaction Study in a Case of Nocardia Scleritis.

Purpose: To describe the clinicopathological, microbiological and polymerase chain reaction (PCR) study in a case of Nocardia scleritis.Methods: A retrospective chart review.Results: A 32-year old male presented with pain, redness and nodular scleral swelling in the left eye for the past two and a half months following an accidental rice powder injury. He was earlier diagnosed to have tubercular scleritis and treated with oral steroids and anti-tubercular therapy. A repeat scleral biopsy on histopathological examination showed granulomatous inflammation. Microbiological investigations revealed the growth of Gram +ve branching filamentous bacilli in culture suggestive of Nocardia sp. PCR based DNA sequencing identified the bacterium as Nocardia cyriacigeorgica. The patient responded to topical fortified amikacin (2.5%), fortified cefuroxime, oral sulfamethoxazole and trimethoprim with complete healing of scleritis.Conclusions: Nocardia scleritis can be a diagnostic challenge for clinicians. Newer molecular techniques along with histopathological and microbiological investigations can clinch the diagnosis.

Telemedicine takes centre stage during COVID-19 pandemic.

The COVID-19 pandemic continues to spread rapidly and overwhelm health systems around the world. To cope with this unprecedented usage of healthcare resources, increasingly novel solutions are being brought into the fray. Telemedicine has been thrust into the spotlight in the fight against COVID-19 and is being employed in many different ways to better tackle the challenges. Telemedicine will likely have a more permanent place in traditional healthcare delivery long after COVID-19 is over as users and providers recognise its utility.

Microscopically Positive Resection Margins in Laparoscopic Gastric GIST Resection May Not Confer a Poorer Prognosis.

Laparoscopic resection of gastrointestinal stromal tumor (GIST) has increased popularity with studies showing good outcomes for patients with tumors <5 cm, with a shorter hospital stay, lower blood loss, and morbidity. Our study aims to audit the clinical profile and surgical outcomes of GISTs, with an evaluation of laparoscopic versus open surgery and the prognostic role of positive R1 margins. In our retrospective study, 62 GIST patients who underwent surgery were included and further analysis was made for the 48 gastric GISTs patients. In total, 33 patients underwent laparoscopic gastric GIST resection, whereas the rest underwent open resection. There was no difference in operative duration but the blood loss was lesser and length of stay shorter in the laparoscopic group. The laparoscopic group had a higher incidence of R1 resection but none developed recurrence or metastasis during follow-up. Laparoscopic resection in the management of gastric GISTs resulted in higher R1 resection rates but this did not affect recurrence rates or overall survival.

A rare case of bipartite combined tumour of the oesophagus.

BACKGROUND: Bipartite combined oesophageal tumours are an exceedingly rare entity and much less is known about the natural history of these tumours following curative surgery. The authors present a case of a bipartite combined oesophageal tumour comprising of sarcomatoid carcinoma and small cell carcinoma with early postoperative recurrence. CASE PRESENTATION: A 63-year-old Chinese male with a smoking history presents with hemoptysis on a background of dysphagia and odynophagia for 1 month. An endoscopic evaluation found an exophytic oesophageal tumour with contact bleeding for which biopsy of this lesion returned as a malignant high-grade tumour where immunohistochemistry staining was unable to establish the lineage of the tumour. Differential diagnoses include sarcomatoid carcinoma and malignant undifferentiated sarcoma. With the provisional diagnosis of a high-grade oesopheageal sarcoma, the patient underwent minimally invasive McKeown's oesophagectomy. Final histological assessment was pT1bN0 with two histological types of malignancy within a single tumour-70% poorly differentiated spindle cell squamous carcinoma and small cell carcinoma. He was planned for adjuvant chemotherapy in view of the small cell carcinoma component after the resolution of the postoperative infective collections. A computed tomographic scan performed 4 months postoperatively demonstrated metastasis to the lung, pleura, thoracic nodes and liver. Biopsy of the largest lung nodule confirmed small cell neuroendocrine carcinoma with features similar to the small cell carcinoma component in the prior oesophagectomy specimen. He was thereafter initiated on palliative chemotherapy aimed at three weekly carboplatin and etoposide aimed at a total of 4 cycles with peglasta support. Etoposide was stopped during the first cycle due to asymptomatic bradycardia. The regime was then converted to carboplatin with irinotecan for 5 cycles. Repeat computed tomographic scan performed 3 weeks after the completion of chemotherapy showed a complete response of lung and liver metastasis and no evidence of local recurrence or distant metastasis. CONCLUSION: The management of bipartite combined oesophageal tumours should be guided by its more aggressive component. Bipartite combined oesophageal tumours with a small cell carcinoma component are believed to demonstrate aggressive tumour biology likened to that of primary oesophageal small cell carcinoma. Preoperative confirmation of a combined tumour may be challenging, and biopsy results may only yield one of the two components. The more aggressive component is usually a small cell carcinoma, for which the mainstay of therapy is platinum-based chemotherapy rather than surgery.

Laparoscopic adjustable gastric band revisional surgery: a single surgeon series.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is a safe and proven surgical option for morbid obesity; however, the need for revisional surgery is being increasingly reported. This study reports outcomes and incidence for a large cohort of patients requiring revisional LAGB surgery for various indications. METHODS: A retrospective review of prospectively collected data for 1524 primary LAGB placed between 2003 and 2013 by a single surgeon at a single institution was performed, analysing data for all patients in this cohort requiring revisional LAGB surgery. RESULTS: A total of 434 revisions were performed on 349 patients. A total of 278 patients had a single revision, with 71 patients having two or more revisions. Revisions amounting to 213 were band repositions, 68 were band removal only and 153 were band removal with conversion to another bariatric procedure, mostly Roux-en-Y gastric bypass (n = 143). A total of 47 (35.1%) 'band-to-band' revision patients were lost to follow-up. Patients undergoing 'band-to-band' revision for a slipped band, patient intolerance and mechanical band failure had mean excess weight loss (EWL) at 4 years of 49.9% (n = 35), 38.6% (n = 10) and 67.4% (n = 6), respectively. Port or tubing revisions were not included. Mean follow-up for 'band-to-band' revision patients was 33.4 months (standard deviation 26.4 months). 22.9% of patients required one or more band revision procedures by 2013, increased from 13% in 2008. CONCLUSION: Continued EWL is achieved with repositioning or replacement of a LAGB. However, a significant and increasing rate of re-operation over time exists.

An audit study of the sensitivity and specificity of ultrasound, fine needle aspiration cytology and frozen section in the evaluation of thyroid malignancies in a tertiary institution.

INTRODUCTION: The aim of this study was to conduct an audit of the sensitivity and specificity of ultrasound, fi ne needle aspiration cytology (FNAC) and frozen section in the evaluation of thyroid malignancies in our practice. MATERIALS AND METHODS: The medical records of all the patients who underwent thyroid surgery in a tertiary institution's General Surgery Department between January 2005 and December 2007 were retrospectively reviewed using a standardised data collection template. Results of the ultrasounds, FNACs and frozen sections were compared with the fi nal histological diagnosis. RESULTS: A total of 112 patients underwent thyroid surgery in the 3-year study period. Thyroid malignancy constituted 34 (30%) of all patients who underwent thyroid surgery. The most popular diagnostic tools used were ultrasound (81%), FNAC (69%) and frozen section (59%). The sensitivity of ultrasound, FNAC and frozen section were 41.4%, 86.4% and 68.8%, respectively. FNAC was shown to be a superior diagnostic test in detecting malignancy compared to ultrasound. FNAC was able to pick up 53% of thyroid cancers missed by ultrasound. Frozen section was able to pick up 33% of thyroid cancers that were missed by both ultrasound and FNAC. CONCLUSION: FNAC is the most reliable tool in detecting malignancies and ought to form the mainstay for investigation of thyroid nodules. The utilisation of ultrasonographic features in the evaluation of thyroid nodules might not necessary improve the detection rate of thyroid malignancy. Frozen section helps to improve the detection rate of thyroid malignancy but further studies into its cost-effectiveness ought to be performed.