Genomic hallmarks of localized, non-indolent prostate cancer.

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Endoscopic Full-Thickness Resection for Colorectal Lesions: A Systematic Review and Meta-Analysis.

INTRODUCTION: Endoscopic full-thickness resection (EFTR) with an over-the-scope full-thickness resection device is a relatively new technique for the resection of colorectal lesions. Multiple centers have published the results of case series and observational cohorts regarding the use of this technique for managing difficult polyps. This study aims to aggregate the results of these studies to determine the effectiveness and safety of this technique in the resection of these technically challenging colonic lesions. METHODS: MEDLINE, EMBASE, and CENTRAL were searched. Articles were included if they reported technical success rate for EFTR of colonic lesions. The primary outcome was technical success rate and secondary outcomes included rate of R0 resection and overall 30-d morbidity. DerSimonian and Laird random-effects meta-analysis of proportions was used to generate effect sizes for pooled outcomes. RESULTS: From 2211 citations, 21 studies with 1539 patients (mean age 67.2 y, 39.5% female) undergoing 1551 procedures were included. Difficult to resect benign lesions were the most commonly excised lesions (hyperplastic: 35.9%; adenomas: 30.2%), followed by T1 adenocarcinomas (25.6%) and neuroendocrine tumors (6.1%). Technical success rate was 89% (95% confidence interval [CI] 87-92), and R0 resection rate was 79% (95% CI 76-82). Mean procedure time was 53.5 min and mean specimen size was 17.5 mm. Overall 30-d morbidity was 11% (95% CI 7-13), and incidences of perforation and postpolypectomy bleeding were 2% (95% CI 1-2) and 5% (95% CI 3-7), respectively. Lesion recurrence at 3-mo follow-up was 8%. CONCLUSIONS: EFTR requires further large sample size, comparative studies with reporting of long-term oncologic data. However, preliminary findings indicate that it is a safe and effective technique with high rates of technical success and acceptable rates of R0 resection when employed by experienced endoscopists for high-risk colonic lesions.

Venous thromboembolism in emergency general surgery patients: a single-centre retrospective cohort study

Background: There is limited literature on the risk of venous thromboembolism (VTE) in emergency general surgery (EGS) patients. We undertook this study to identify the rate of symptomatic VTE for patients undergoing EGS operations. Methods: We conducted a retrospective cohort study evaluating EGS patients who underwent operative intervention between March and December 2014. Data collected included patient demographics, type of procedure, risk of VTE, VTE prophylaxis, development of symptomatic VTE, and mortality. Results: We included 767 patients in our analysis. The mean age was 53 ± 19.7 years, and 52.2% of patients were female. Eighteen patients (2.3%) experienced VTE in hospital and 12 (1.6%) experienced VTE after discharge. Only 66% of patients received appropriate VTE prophylaxis. High-risk patients had a higher VTE rate (7.4% v. 2.3%, p < 0.001) and higher mortality (17.6% v. 4.0%, p < 0.001) than lowto moderate-risk patients. Conclusion: The risk of VTE in patients requiring EGS is significant and persists after hospital discharge. Further studies on quality improvement with VTE prophylaxis are warranted.

Contexte: La littérature sur le risque de thromboembolie veineuse (TEV) chez les patients soumis à une chirurgie générale urgente est limitée. Nous avons entrepris cette étude afin de mesurer le taux de TEV symptomatique chez les patients ayant subi une intervention urgente en chirurgie générale. Méthodes: Nous avons procédé à une étude de cohorte rétrospective sur les patients qui ont subi une chirurgie générale urgente entre mars et décembre 2014. Parmi les données recueillies, mentionnons données démographiques, type d'intervention, risque de TEV, thromboprophylaxie, apparition d'une TEV symptomatique et mortalité. Résultats: Nous avons inclus 767 patients dans notre analyse. L'âge moyen était de 53 ± 19,7 ans et 52,2 % des patients étaient de sexe féminin. Dix-huit patients (2,3 %) ont présenté une TEV en cours d'hospitalisation et 12 (1,6 %) après leur congé. Seulement 66 % des patients ont reçu une thromboprophylaxie adéquate. Les patients à haut risque ont présenté des taux de TEV (7,4 % c. 2,3 %, p < 0,001) et de mortalité (17,6 % c. 4,0 %, p < 0,001) plus élevés que les patients présentant un risque faible à modéré. Conclusion: Le risque de TEV chez les patients soumis à une chirurgie générale urgente est significatif et persiste après le congé hospitalier. Il faudra mener des études plus approfondies sur l'amélioration de la qualité de la thromboprophylaxie.

ShatterProof: operational detection and quantification of chromothripsis.

BACKGROUND: Chromothripsis, a newly discovered type of complex genomic rearrangement, has been implicated in the evolution of several types of cancers. To date, it has been described in bone cancer, SHH-medulloblastoma and acute myeloid leukemia, amongst others, however there are still no formal or automated methods for detecting or annotating it in high throughput sequencing data. As such, findings of chromothripsis are difficult to compare and many cases likely escape detection altogether. RESULTS: We introduce ShatterProof, a software tool for detecting and quantifying chromothriptic events. ShatterProof takes structural variation calls (translocations, copy-number variations, short insertions and loss of heterozygosity) produced by any algorithm and using an operational definition of chromothripsis performs robust statistical tests to accurately predict the presence and location of chromothriptic events. Validation of our tool was conducted using clinical data sets including matched normal, prostate cancer samples in addition to the colorectal cancer and SCLC data sets used in the original description of chromothripsis. CONCLUSIONS: ShatterProof is computationally efficient, having low memory requirements and near linear computation time. This allows it to become a standard component of sequencing analysis pipelines, enabling researchers to routinely and accurately assess samples for chromothripsis. Source code and documentation can be found at http://search.cpan.org/~sgovind/Shatterproof.

Geographic Variation in Appendiceal Perforation Rates in Canada: a Population-Based Cohort Study.

BACKGROUND: We hypothesized that patients living in rural neighborhoods experience delayed access to surgical services manifesting in increased appendiceal perforation rates in cases of appendicitis. METHODS: This population-based cohort study included adult patients with acute appendicitis in Canada (excluding Quebec) between April 2008 and March 2015. The main outcome of interest was rate of perforation. Predictors of interest included socioeconomic, geographic, and individual predictors of perforation. Spatial analysis was used to analyze spatial clustering of perforation. RESULTS: We identified 143,195 patients throughout the course of the study. The average perforation rate across our study was 35.9% (n = 51,456). Cluster analysis identified 286 (24%) neighborhoods with perforation rates greater than the average. Rural neighborhoods had a 1.89 times higher odds of being in a high perforation cluster (95% CI 1.08-3.08, p = 0.024). Compared to neighborhoods > 75 km from the admitting hospital, closer neighborhoods were less likely to be in a high perforation cluster (0-35 km OR 0.64, 95% CI 0.38-0.98, p = 0.049; 36-75 km OR 0.60, 95% CI 0.37-0.92, p = 0.019). Patients admitted to small community hospitals had a 0.51 times lower odds of perforation than those admitted to academic centers (95% CI 0.47-0.54, p < 0.001) and those who lived in high perforation clusters had a 1.42 times higher odds of perforation (95% CI 1.39-1.46, p < 0.001). CONCLUSION: Neighborhoods located far from hospitals have increased appendiceal perforation rates. Also, patients with appendicitis treated at small community hospitals have significantly lower odds of perforation. From a policy point of view, patients with symptoms of appendicitis can be safely treated at the nearest hospital.

Gastric necrosis in a term infant treated with near-total gastrectomy and delayed reconstruction with a Hunt-Lawrence pouch.

The creation of an intestinal pouch following total gastrectomy is exceedingly rare in infants. We present the case of a term infant who underwent a near-total gastrectomy on day 2 of life for diffuse gastric necrosis with perforation due to severe hypoxemia from an intrapartum nuchal cord. Gastrointestinal continuity was restored at 5 months of age with a Hunt-Lawrence pouch. The child is now 3 years old and has achieved a weight in the 47th percentile despite challenges with micronutrient deficiencies, reduced caloric intake and renal insufficiency requiring 8 months of intermittent haemodialysis.

A 15 year cohort review of in-hospital pediatric trauma center mortality: A catalyst for injury prevention programming.

BACKGROUND: The objective of our study was to identify the most common mechanisms of injury leading to death in our pediatric population. METHODS: A retrospective cohort of fatally injured children 0-17 years old treated at our trauma center during 2000-2015. RESULTS: The mortality rate in our population was 8% (n = 103). Fifty-five percent were male. The majority (76%) of fatal injuries were blunt. Overall, motor vehicle collisions (MVCs) were the most common mechanism of injury (61%), followed by assault/abuse (9%). Of the deaths caused by MVCs, 37 (59%) were occupants, 11 (17%) were pedestrians, and 6 (10%) were cyclists. In the infant sub-population, assault/abuse was the most common mechanism of injury. CONCLUSION: MVCs were the leading cause of death in this population. In the infant subpopulation (<1 year), abusive head trauma emerged as the leading mechanism. Injury prevention programming should target abusive head trauma in infants and teen road safety.

Hepato-bronchial fistula secondary to perforated sigmoid diverticulitis: a case report.

BACKGROUND: Patients with diverticulitis are predisposed to hepatic abscesses via seeding through the portal circulation. Hepatic abscesses are well-documented sequelae of diverticulitis, however instances of progression to hepato-bronchial fistulization are rare. We present a case of diverticulitis associated with hepatic abscess leading to hepato-bronchial fistulization, which represents a novel disease course not yet reported in the literature. CASE PRESENTATION: A 61-year-old Caucasian man presented with a history of unintentional weight loss and dyspnea both at rest and with exertion. He had a significant tobacco and alcohol misuse history. A massive right-sided pleural effusion was found on chest X-ray, which responded partially to chest tube insertion. A computed tomography scan of his thorax confirmed the presence of innumerable lung abscesses as well as a complex pleural effusion. An indeterminate tiny air pocket at the dome of the liver was also noted. A follow-up computed tomography scan of his abdomen revealed a decompressed hepatic abscess extending into the right pleural space and the right lower lobe. A sigmoid-rectal fistula was also revealed with focal colonic thickening, presumed to be the sequelae of remote or chronic diverticulitis. An interventional radiologist inserted a percutaneous drain into the decompressed hepatic abscess and the instillation of contrast revealed immediate filling of the right pleural space, lung parenchyma, and bronchial tree, confirming a hepato-bronchial fistula. After two concurrent chest tube insertions failed to drain the remaining pleural effusion completely, surgical lung decortication was conducted. Markedly thickened pleura were seen and a significant amount of gelatinous inflammatory material was debrided from the lower thoracic cavity. He recovered well and was discharged 10 days post-thoracotomy on oral antibiotics. The percutaneous liver abscess tube was removed 3 weeks post-discharge from hospital after the drain check revealed that the fistula and abscess had entirely resolved. CONCLUSIONS: Refractory right-sided pleural effusion combined with constitutional symptoms should alert clinicians to search for possible hepatic abscess, especially in the context of diverticulitis. The rupture of an untreated hepatic abscess could lead to death from profound sepsis or rarely, as in this case, a hepato-bronchial fistula. Timely investigation and a multidisciplinary treatment approach can lead to improved patient outcomes.

Spatial genomic heterogeneity within localized, multifocal prostate cancer.

Herein we provide a detailed molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer to delineate new oncogenes or tumor suppressors. We initially determined the copy number aberration (CNA) profiles of 74 patients with index tumors of Gleason score 7. Of these, 5 patients were subjected to whole-genome sequencing using DNA quantities achievable in diagnostic biopsies, with detailed spatial sampling of 23 distinct tumor regions to assess intraprostatic heterogeneity in focal genomics. Multifocal tumors are highly heterogeneous for single-nucleotide variants (SNVs), CNAs and genomic rearrangements. We identified and validated a new recurrent amplification of MYCL, which is associated with TP53 deletion and unique profiles of DNA damage and transcriptional dysregulation. Moreover, we demonstrate divergent tumor evolution in multifocal cancer and, in some cases, tumors of independent clonal origin. These data represent the first systematic relation of intraprostatic genomic heterogeneity to predicted clinical outcome and inform the development of novel biomarkers that reflect individual prognosis.