Jaideepraj Rao

Whole-genome reconstruction and mutational signatures in gastric cancer

BackgroundGastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability.ResultsIntegrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a common driver event in gastric cancer. We discovered three distinct mutational signatures in gastric cancer - against a genome-wide backdrop of oxidative and microsatellite instability-related mutational signatures, we identified the first exome-specific mutational signature. Further characterization of the impact of these signatures by combining sequencing data from 40 complete gastric cancer exomes and targeted screening of an additional 94 independent gastric tumors uncovered ACVR2A, RPL22 and LMAN1 as recurrently mutated genes in microsatellite instability-positive gastric cancer and PAPPA as a recurrently mutated gene in TP53 wild-type gastric cancer.ConclusionsThese results highlight how whole-genome cancer sequencing can uncover information relevant to tissue-specific carcinogenesis that would otherwise be missed from exome-sequencing data.

Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity

Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H(+) leakage, and the fusion might contribute to invasiveness once a cell is transformed.

Genomic and Epigenomic Profiling of High-Risk Intestinal Metaplasia Reveals Molecular Determinants of Progression to Gastric Cancer

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We performed (epi)genomic profiling of 138 IMs from 148 cancer-free patients, recruited through a 10-year prospective study. Compared with GCs, IMs exhibit low mutational burdens, recurrent mutations in certain tumor suppressors (FBXW7) but not others (TP53, ARID1A), chromosome 8q amplification, and shortened telomeres. Sequencing identified more IM patients with active Helicobacter pylori infection compared with histopathology (11%-27%). Several IMs exhibited hypermethylation at DNA methylation valleys; however, IMs generally lack intragenic hypomethylation signatures of advanced malignancy. IM patients with shortened telomeres and chromosomal alterations were associated with subsequent dysplasia or GC; conversely patients exhibiting normal-like epigenomic patterns were associated with regression.

The Use of Collatamp G, Local Gentamicin-Collagen Sponge, in Reducing Wound Infection

We conducted a retrospective study to examine the role of Collatamp G in reducing postoperative surgical site infection (SSI) in patients with different wound classes. Ninety-two patients (62 men and 30 women; mean age, 58 years; range, 29-88 years) who had undergone surgery between December 2009 and November 2011 in Tan Tock Seng Hospital and who had application of Collatamp G in their wound before closure were included in the study. The primary endpoint was the development of any superficial wound infection within 1 month postoperatively. Of 92 patients studied, 9 (10%) developed a superficial wound infection. Two of 43 patients with clean-contaminated wounds (5%), 2 of 19 with contaminated wounds (11%), and 5 of 30 with dirty-infected wounds (16%) developed infection. Use of the larger size Collatamp G (10 × 10 cm) also appears to have a lower incidence of SSI compared with the smaller Collatamp G (5 × 5 cm); 4% and 12%, respectively. Our data suggest that postoperative SSI was reduced in the group of patients with dirty-infected wound class. SSI appears to be decreased with use of the larger size Collatamp G.

Abdominal schwannomas: case report with literature review.

Schwannomas are rare tumors that arise from Schwann cells in neural sheaths. They are commonly found in the central nervous system, spinal cord, or peripheral nerves of the body. Occasionally, they occur in the gastrointestinal tract, with the stomach being the most common site. However, colorectal and retroperitoneal schwannomas are very rare. Preoperative diagnosis is often difficult and definitive treatment entails surgical excision. We herein present 3 cases of intraabdominal schwannomas.

Abdominal Aortic Pseudoaneurysm Secondary to Melioidosis

Melioidosis is an infective condition which is common in South East Asia. It can present in various forms like cutaneous abscess, pneumonia and severe septicaemia. However, melioidosis causing abdominal aortic pseudoaneurysms is extremely rare and a difficult condition to diagnose and treat. We present our management of two cases of abdominal aortic pseudoaneurysms secondary to melioidosis and their subsequent outcomes.

Enterotomy closure using knotless and barbed suture in laparoscopic upper gastrointestinal surgeries

BackgroundBarbed sutures are recently being employed in intracorporeal suturing in various laparoscopic digestive surgeries. The purpose of this paper was to present our initial experience of enterotomy closure with barbed sutures in upper gastrointestinal and bariatric surgeries, and share optimal technique of using such sutures for enterotomy closure.MethodsFifty patients who underwent laparoscopic closure of enterotomies using barbed sutures were identified in two institutions in Singapore from January 2012 to December 2013. Patient demographics, short-term operative outcomes including anastomotic time, onset of diet, hospital stay, and early post-operative complications are reported.ResultsIn 50 patients a total of 62 anastomotic sites were closed with barbed sutures. The barbed sutures appear to reduce mean anastomotic suturing time of the Roux-en-Y gastrojejunal closure (17.34 vs 44.55 min, p value 0.0001) and jejunojejunal closure (19.46 vs 31.01 min, p value 0.0013) when compared to a subgroup of patients with the same anastomotic sites closed using the standard non-barbed suture. The mean onset to start on diet was 2 ± 1.5 days and mean duration of hospital stay is 7 + 5.3 days. One (1.6 %) anastomotic leak was observed day 3 after a gastric bypass in the series. This leak was the result of a technical error due to inappropriate suturing technique. There were no mortalities, other complications or readmission. While applying traction on the suture brings two tissue edges closer, we observed that pushing the tissues toward each other provided more apposition and prevented unnecessary tearing of tissues that could potentially result in complicationsConclusionsBarbed closure sutures appear to be safe and effective in laparoscopic upper gastrointestinal procedures for closing enterotomies provided appropriate technique is used. The potential benefit is simplifying intracorporeal enterotomy closure.

Roux-en-Y or Billroth II Reconstruction After Radical Distal Gastrectomy for Gastric Cancer: A Multicenter Randomized Controlled Trial

Objective: The aim of the study was to compare the clinical symptoms between Billroth II (B-II) and Roux-en-Y (R-Y) reconstruction after distal subtotal gastrectomy (DG) for gastric cancer. Background: Surgery is the mainstay of curative treatment for gastric cancer. The technique for reconstruction after DG remains controversial. Both B-II and R-Y are popular methods. Methods: This is a prospective multicenter randomized controlled trial. From October 2008 to October 2014, 162 patients who underwent DG were randomly allocated to B-II (n = 81) and R-Y (n = 81) groups. The primary endpoint is Gastrointestinal (GI) Symptoms Score 1 year after surgery. We also compared the nutritional status, extent of gastritis on endoscopy, and quality of life after surgery between the 2 procedures at 1 year. Results: Operative time was significantly shorter for B-II than for R-Y [mean difference 21.5 minutes, 95% confidence interval (95% CI) 3.8–39.3, P = 0.019]. The B-II and R-Y groups had a peri-operative morbidity of 28.4% and 33.8%, respectively (P = 0.500) and a 30-day mortality of 2.5% and 1.2%, respectively (P = 0.500). GI symptoms score did not differ between R-Y versus B-II reconstruction (mean difference -0.45, 95% CI -1.21 to 0.31, P = 0.232). R-Y resulted in a lower median endoscopic grade for gastritis versus B-II (mean difference -1.32, 95% CI -1.67 to -0.98, P < 0.001). We noted no difference in nutritional status (R-Y versus B-II mean difference -0.31, 95% CI -3.27 to 2.65, P = 0.837) and quality of life at 1 year between the 2 groups too. Conclusion: Although BII is associated with a higher incidence of heartburn symptom and higher median endoscopic grade for gastritis, BII and RY are similar in terms of overall GI symptom score and nutritional status at 1 year after distal gastrectomy.

Patient-reported Urinary Continence (Third-party Interview): Results of Post-radical Retropubic Prostatectomy in Singaporeans

OBJECTIVE To determine the patient-reported urinary continence rate after retropubic radical prostatectomy (RRP) for prostate carcinoma through a third-party interview and to grade the severity of incontinence. METHODS Between 1997 and 1999, 34 patients were evaluated through an independent third party about the degree of continence as well as the quality of life after RRP. Patients were interviewed either in person or over the telephone. Urinary continence was defined as wearing no diapers, pads or tissue paper. RESULTS Of the 34 patients, 44% achieved immediate continence. Urinary incontinence gradually improved with time after surgery and 82% (n = 28) were fully continent at 12 months. Using the quality-of-life index, 91% of patients characterized their urinary incontinence as not or minimally bothersome. There was no significant difference between urologist- and patient-reported continence rates after RRP. CONCLUSION Based on our grading system, urinary continence gradually improved with time and was 82% at 1 year.

Goal-directed program after sleeve gastrectomy improves weight loss.

BACKGROUND The aim of our study is to determine if a goal-directed program improves weight loss after sleeve gastrectomy. METHODS Our goal-directed program involves setting excess weight loss targets at fixed intervals after sleeve gastrectomy. We identified patients in 3 bariatric centers between April 2010 and July 2013 and compared the center that has a goal-directed weight loss program (goal-directed program) with the other 2 centers (standard program). RESULTS A total of 211 patients were included, with 129 patients in the goal-directed weight loss program. The 2 groups were similar in terms of gender distribution, ethnicity distribution, age, and preoperative weight, preoperative body mass index, and surgical technique. The follow-up rates at 3, 6, 9, and 12 months for patients in the goal-directed program was 84.5%, 75.2%, 59.7%, and 82.2%, respectively, compared with 65.9%, 68.3%, 51.2%, and 68.3% for the standard program. The percentage total weight loss at 3, 6, 9, and 12 months was 17.1%, 23.3%, 26.8%, and 28.6%, respectively, for the goal-directed program, compared with 15.3%, 21.8%, 24.4%, and 25.4%, respectively, for the standard program. The mean excess weight loss at 3, 6, 9, and 12 months were 40%, 54%, 62%, and 67%, respectively, for the goal-directed program group, and 36%, 50%, 54%, and 55%, respectively, for the standard program, where statistical significance (P<.005) was achieved at 12 months. CONCLUSION Our results suggest that a goal-directed protocol may improve weight loss outcomes after laparoscopic sleeve gastrectomy.