PIGA mutations and glycosylphosphatidylinositol anchor dysregulation in polyposis-associated duodenal tumorigenesis.

The pathogenesis of duodenal tumours in the inherited tumour syndromes Familial Adenomatous Polyposis (FAP) and MUTYH-associated Polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumours and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of PIGA in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyses the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA. Implications: PIGA somatic mutation in duodenal tumours from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis.

Chronic Pain as a Complication in Open Inguinal Hernia Repair: A Retrospective Study of Consenting Practice in a Single Centre.

Introduction Inguinal hernia repair is one of the most commonly performed procedures in general surgery in the United Kingdom. Chronic pain as a long-term postoperative complication of this procedure has been extensively documented in the literature. However, this complication is often undisclosed during the consenting process. This omission impairs the patients' informed decision-making process. The Montgomery v Lanarkshire Health Board case, in 2015, changed the way in which patient consent is viewed legally. This has made proper consent practices more important to surgeons undertaking procedures. Aim The objective is to assess if there has been an improvement in consenting practices by comparing consent forms from 2015 (the year of the Montgomery ruling) and 2019, specifically in regard to the risk of chronic groin pain following open inguinal hernia repair with mesh. Methods This was a retrospective review of patients who underwent open inguinal hernia repair using a prosthetic mesh in 2015 and 2019. The medical records were retrieved on the trust's electronic medical record system using the patient's hospital number. The following parameters were obtained: patient demographics, preoperative clinic letters, operation notes and consent forms. The clinic letters and consent forms were systematically reviewed for any mention of chronic groin pain. Results In 2015 and 2019, 163 and 56 open inguinal hernia repairs with mesh were performed, respectively. The median age of patients was 63 (28-88) and 64.5 (19-88) in the respective years. Throughout both years there was a predominance in male patients, and the majority of cases were performed on an elective basis. Consent for chronic pain was present in 60.7% and 62.5% of cases in 2015 and 2019, respectively (p=0.055). Conclusion Despite the importance of adequate consenting practice, we found no significant improvement in consenting practice for chronic pain following open inguinal hernia repair in the four years following the Montgomery ruling.

The impact of COVID-19 pandemic on colorectal cancer patients at an NHS Foundation Trust hospital-A retrospective cohort study.

INTRODUCTION: Current NHS guidelines recommend that treatment of colorectal patients referred through the two-week wait referral system should occur within sixty two days from the date of referral. The COVID-19 pandemic which started in March 2020 has however led to significant delays in the delivery of health services, including colorectal cancer treatments. This study investigates the effects of delayed colorectal cancer treatments during the COVID pandemic on disease progression. METHODS: A retrospective chart review of 107 patients with histologically confirmed diagnosis of colorectal cancer was conducted. The occurrence of cancer upstaging after initial diagnosis was assessed and compared between patients with treatment delays and patients who received treatments within the period recommended by NHS guidelines. A logistic regression was performed to evaluate the association between treatment delays beyond 62 days and cancer upstaging. RESULTS: The median age of the cohort was 71.2 years and 64.5% of the patients were over 65 years. Treatment delays were observed in 53.3% of reviewed patients. Patients with treatment delays received cancer treatments 95.8 (31.0) days on average after referral, compared to 46.3 (11.5) days in patients who experienced no treatment delays (p-value<0.0001). 38.6% of patients with treatment delays experienced cancer upstaging by the time of treatment, compared to 20% in the non-delay group (p-value = 0.036). Patients who received treatment after sixty two days from date of referral were 3.27 times more likely to experience colorectal cancer upstaging compared to those who received timely treatments. CONCLUSION: Although an effective response to the Covid-19 pandemic requires the reallocation of healthcare resources, there is a need to ensure that treatments and health outcomes of patients with chronic diseases such as colorectal cancer continue to be prioritized and delivered in timely fashion.

Prevalence of Carcinoma in Appendectomy Specimens for Patients Presenting With Acute Appendicitis: A Single-Center Study.

Introduction Acute appendicitis is the most common general surgical emergency globally. Its etiology includes the presence of luminal obstruction by faecoliths, lymphoid hyperplasia, impacted stool, and rarely by appendiceal or caecal cancer. Malignancy related to acute appendicitis is usually seen in the older age group. Aim To identify the subset rate of patients operated for acute appendicitis who have appendiceal carcinoma and analyze the outcome of their post-operative management. Material and methods A retrospective study of a cohort of 529 patients aged > 40 diagnosed with acute appendicitis with subsequent appendectomy in the period between 1 January 2014 and 31 December 2019 at Basildon and Thurrock University Hospital, Essex, United Kingdom was conducted. We analyzed the clinical data of the cohort including demographic information, diagnosis, pre-operative imaging, histological diagnosis as well as post-operative management where indicated. Results The median age of patients was 54.5 years (range 40-92). The male to female ratio in the appendicectomy cohort was 1:1.1. About 45% were aged 40-49 years, 24.8% were aged 50-59 and 30.2% were ≥60 years. Post-operative histology revealed acute appendicitis in 82.4% of the group. In 11% of the patients, the histology revealed the presence of other benign pathology as mucocele of the appendix, acute diverticulitis, follicular hyperplasia, and fibrous obliteration. The diagnosis of appendicular malignancy was seen in 1.9%. Conclusion Incidental appendiceal cancers in the resected specimens after acute appendicitis are rare but may be associated with a poor prognosis. It is recommended to consider such diagnosis in particular when dealing with acute appendicitis in older patients with longer symptom history, and in presence of peri-appendicular mass.

Instituting a Green Zone for Elective Surgery During the Second Wave of COVID-19.

Objective Elective surgery came to a standstill during the first wave of COVID-19. The safe resumption of elective surgery with COVID-19 prevalent in the community remains a significant challenge. The aim of this study was to look into the outcomes of elective general surgery in a dedicated 'Green Zone (GZ)' during the second wave of COVID-19 in the United Kingdom. Method A 'Green Zone' pathway, meant to provide a COVID-free environment, was created. A retrospective review of prospectively collected data was done on consecutive patients who underwent an elective general surgical procedure at a single NHS trust over a six-month period (September 1, 2020, to February 28, 2021). The primary outcome was 30-day COVID-19 mortality. Secondary outcomes included 30-day non-COVID-19 mortality, readmissions, and complications. Results The study included 331 patients with a median age of 55 years (interquartile range, IQR, 41-67); 169 (51%) were females. The majority of the patients were American Society of Anaesthesiologists grade 2 (ASA 2; n=177, 53%) followed by ASA 3 (n=76, 23%). Forty-seven patients (14%) had been shielding earlier in the year. Most of the cases were day cases (n=224, 67%). There was no 30-day COVID-19 or non-COVID-19 mortality. One patient developed COVID-19 three weeks after the index operation. Thirty-day readmission and complication rate were 4% (n=14) and 6% (n=21). Most of the complications were Clavien-Dindo grade 2 (n=10, 3%) followed by an equal number of grades 1 and 3b (n=5, 1.5%). Conclusion This study has shown that a dedicated 'Green Zone' elective operating pathway is safe and feasible provided a balanced risk assessment approach is adopted.

Gastric adenomas and their management in familial adenomatous polyposis.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) are at increased risk of developing gastric adenomas. There is limited understanding of their clinical course and no consensus on management. We reviewed the management of gastric adenomas in patients with FAP from two centers. METHODS: Patients with FAP and histologically confirmed gastric adenomas were identified between 1997 and 2018. Patient demographics, adenoma characteristics, and management/surveillance outcomes were collected. RESULTS: Of 726 patients with FAP, 104 (14 %; 49 female) were diagnosed with gastric adenomas at a median age of 47 years (range 19 - 80). The median size of gastric adenomas was 6 mm (range 1.5 - 50); 64 (62 %) patients had adenomas located distally to the incisura. Five patients (5 %) had gastric adenomas demonstrating high-grade dysplasia (HGD) on initial diagnosis, distributed equally within the stomach. The risk of HGD was associated with adenoma size (P = 0.04). Of adenomas > 20 mm, 33 % contained HGD. Two patients had gastric cancer at initial gastric adenoma diagnosis. A total of 63 patients (61 %) underwent endoscopic therapy for gastric adenomas. Complications occurred in three patients (5 %) and two (3 %) had recurrence, all following piecemeal resection of large (30 - 50 mm) lesions. Three patients were diagnosed with gastric cancer at median follow-up of 66 months (range 66 - 115) after initial diagnosis. CONCLUSIONS: We observed gastric adenomas in 14 % of patients with FAP. Of these, 5 % contained HGD; risk of HGD correlated with adenoma size. Endoscopic resection was feasible, with few complications and low recurrence rates, but did not completely eliminate the cancer risk.

The impact of chromoendoscopy for surveillance of the duodenum in patients with MUTYH-associated polyposis and familial adenomatous polyposis.

BACKGROUND AND AIMS: Duodenal polyposis and cancer have become a key issue for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Almost all patients with FAP will develop duodenal adenomas, and 5% will develop cancer. The incidence of duodenal adenomas in MAP appears to be lower than in FAP, but the limited available data suggest a comparable increase in the relative risk and lifetime risk of duodenal cancer. Current surveillance recommendations, however, are the same for FAP and MAP, using the Spigelman score (incorporating polyp number, size, dysplasia, and histology) for risk stratification and determination of surveillance intervals. Previous studies have demonstrated a benefit of enhanced detection rates of adenomas by use of chromoendoscopy both in sporadic colorectal disease and in groups at high risk of colorectal cancer. We aimed to assess the effect of chromoendoscopy on duodenal adenoma detection, to determine the impact on Spigelman stage and to compare this in individuals with known pathogenic mutations in order to determine the difference in duodenal involvement between MAP and FAP. METHODS: A prospective study examined the impact of chromoendoscopy on the assessment of the duodenum in 51 consecutive patients with MAP and FAP in 2 academic centers in the United Kingdom (University Hospital Llandough, Cardiff, and St Mark's Hospital, London) from 2011 to 2014. RESULTS: Enhanced adenoma detection of 3 times the number of adenomas after chromoendoscopy was demonstrated in both MAP (P = .013) and FAP (P = .002), but did not affect adenoma size. In both conditions, there was a significant increase in Spigelman stage after chromoendoscopy compared with endoscopy without dye spray. Spigelman scores and overall adenoma detection was significantly lower in MAP compared with FAP. CONCLUSIONS: Chromoendoscopy improved the diagnostic yield of anomas in MAP and FAP 3-fold, and in both MAP and FAP this resulted in a clinically significant upstaging in Spigelman score. Further studies are required to determine the impact of improved adenoma detection on the management and outcome of duodenal polyposis.

Burden and Profile of Somatic Mutation in Duodenal Adenomas from Patients with Familial Adenomatous- and MUTYH-associated Polyposis.

Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing, and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared with each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006), and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2, and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P = 0.0017).Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease. Clin Cancer Res; 23(21); 6721-32. ©2017 AACR.

Gastric tumours in FAP.

Gastric cancer is not a recognised extra-colonic manifestation of FAP, except in countries with a high prevalence of gastric cancer. Data regarding gastric adenomas in FAP are sparse. The aim of this study was to review the clinical characteristics of gastric tumours occurring within an FAP population from the largest European polyposis registry. All patients that developed a gastric adenoma or carcinoma were identified from a prospectively maintained registry database. The primary outcome measure was the occurrence of gastric adenoma or adenocarcinoma. Secondary outcomes included APC mutation, tumour stage, management and survival. Eight patients developed gastric cancer and 21 an adenoma (median age 52 and 44 years, respectively). Regular oesophagogastroduodenoscopy surveillance was performed in 6/8 patients who developed cancer. Half were advanced T3/4 tumours and 6/8 had nodal or metastatic spread at diagnosis. All cancer cases died within a median of 13.5 months from diagnosis. Gastric adenomas were evenly distributed: 11/21 (52%) in the distal and 10/21 (48%) proximal stomach, whereas 5/8 (63%) cancers were located proximally. An association between gastric tumour and desmoid development was observed; 7/8 (88%) cancer and 11/21 (52%) adenoma cases had a personal or family history of desmoid. It would appear from this small, retrospective study that gastric cancer is not a prominent extra-colonic feature of FAP in the Western world. It seems to present at an advanced stage with a poor prognosis. There may be an association between gastric tumour and desmoid occurrence but a large multicentre cohort is necessary to investigate this further.

Familial adenomatous patients with desmoid tumours show increased expression of miR-34a in serum and high levels in tumours.

Familial adenomatous polyposis (FAP) is rare affecting 1 in 10,000 people and a subset (10%) are at risk of myofibroblastic desmoid tumours (DTs) after colectomy to prevent cancer. DTs are a major cause of morbidity and mortality. The absence of markers to monitor progression and a lack of treatment options are significant limitations to clinical management. We investigated microRNAs (miRNA) levels in DTs and serum using expression array analysis on two independent cohorts of FAP patients (total, n=24). Each comprised equal numbers of patients who had formed DTs (cases) and those who had not (controls). All controls had absence of DTs confirmed by clinical and radiological assessment over at least three years post- colectomy. Technical qPCR validation was performed using an expanded cohort (29 FAP patients; 16 cases and 13 controls). The most significant elevated serum miRNA marker of DTs was miR-34a-5p and in-situ hybridisation (ISH) showed most DTs analysed (5/6) expressed miRNA-34a-5p. Exome sequencing of tumour and matched germline DNA did not detect mutations within the miR-34a-5p transcript sites or 3'-UTR of target genes that would alter functional miRNA activity. In conclusion, miR-34a-5p is a potential circulatory marker and therapy target. A large prospective world-wide multi-centre study is now warranted.

Frequency and Features of Duodenal Adenomas in Patients With MUTYH-Associated Polyposis.

BACKGROUND & AIMS: MUTYH-associated polyposis (MAP) is similar to familial adenomatous polyposis (FAP), in that it increases the risk for duodenal adenomas and cancer. Almost all patients with FAP develop duodenal adenomas and 5% develop duodenal cancer. Little is known about the prevalence of duodenal adenomas and cancer in patients with MAP, but current surveillance recommendations are the same for patients with FAP-they should begin surveillance when they are 25 years old. We aimed to assess the prevalence, extent, and progression of duodenal adenomas in patients with MAP and evaluate upper gastrointestinal tract surveillance recommendations. METHODS: In a retrospective study, we collected data on all patients (n = 92) with MAP undergoing surveillance esophagogastroduodenoscopy from registries at St Mark's Hospital (London, UK) and the Academic Medical Center (Amsterdam, The Netherlands) from 2002 through 2014. We collected information on adenoma development, age at adenoma detection, interventions, and disease progression. RESULTS: Duodenal adenomas were detected in 31 patients (34%), at a median age of 50 years. When duodenal polyposis first was detected, it was Spigelman stages I or II in 84% of patients; most had few small polyps, without high-grade dysplasia or villous features. Subsequent esophagogastroduodenoscopy evaluation of 18 of these patients found that 14 (78%) had Spigelman stages 0 to II disease (median follow-up period, 7.8 y). Disease progressed in stage in 6 patients, over 9.5 years, because of lesion size or villous features (2 reached stage IV disease). Adenomas were down-staged in 8 patients after biopsy or polypectomy analyses, and were unchanged for 3 patients. CONCLUSIONS: In a data analysis from 92 patients with MAP, duodenal polyposis seemed to develop less frequently than in patients with FAP, and developed at a later age. Increasing lesion size and villous change appear to promote adenoma progression, rather than polyp number or dysplasia. It may be time to consider a new staging system for patients with MAP, to better determine disease severity and surveillance strategies.

Medical student experience in surgery influences their career choices: a systematic review of the literature.

OBJECTIVES: Student experiences during surgical rotations may dictate interest in future surgical careers. The objective of this study was to systematically examine the effect of surgical experience (SE) on student attitudes toward surgical careers and also to identify variables influencing the educational value of SE. METHODS: A systematic review of the available literature was conducted by 2 independent researchers searching Medline, EMBASE, Google Scholar, and Cochrane databases, in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses recommendations. Studies assessing SE during the students' surgical rotations were identified. The quality of the included studies was assessed using a validated quality index. Factors affecting student surgical rotation experience and perceptions of surgical careers were recorded. RESULTS: Overall, 204 studies were identified; 20 unique studies met the inclusion criteria with a median cohort size of 169 (interquartile range: 107-262) respondents. Most were cross-sectional surveys (n = 16/20) and administered to clinical students (n = 16/20). All studies investigating the effect of SE on career choices (n = 8) found that positive experiences during the surgical placement were associated with an increased interest in surgical careers. The operating theater experience was identified as a defining feature of overall SE. Involvement in operative procedures, a welcoming environment, and avoidance of syncopal events positively influenced the SE, particularly in those who actively sought educational opportunities. Study limitations included single-center and single-year cohort designs (70%) with the use of nonvalidated research tools (95%). CONCLUSIONS: A systematic review of the literature highlights a number of factors associated with a positive surgical rotation, which may lead to more students deciding to pursue a career in surgery. Understanding the factors that contribute to these decisions through multicenter studies using validated research tools may lead to more effective surgical rotations, ultimately improving the delivery of the surgical education.

Is selection bias toward super obese patients in the rationing of metabolic surgery justified?--A pilot study from the United Kingdom.

BACKGROUND: Recent evidence suggests that National Health Service (NHS) rationing of bariatric surgery is biased toward super-obese patients without scientific basis. The aim of this study was to compare health, quality of life, and employment outcomes in morbidly obese (MO) versus super-obese (SO) patients after laparoscopic Roux-en-Y gastric bypass (LRYGB) to provide a basis for rationing. METHODS: Consecutive patients undergoing LRYGB from January 2008-September 2009, with baseline body mass index (BMI)<45 kg/m(2) (MO) and BMI>60 kg/m(2) (SO) were identified from a prospective database. Seventy-six eligible patients were invited to complete a questionnaire comprising BAROS (bariatric analysis and reporting outcome system), EQ-5D (EuroQol-5D), EQVAS (Euro-QoL visual analog score), and employment status preoperatively and postoperatively. Anthropometric, demographic, and clinical data were recorded. RESULTS: Fifty-one patients responded: 23 MO and 28 SO. Groups were matched for demographic characteristics and co-morbidities. The MO group had significantly higher percentage excess weight loss (%EWL) (82% versus 53%; t test: P<.001) and mean BAROS score (5.47 versus 4.21; t test: P = .025) than the SO group. EQ-5D improved significantly for both groups in 3 domains (self care, anxiety/depression, and pain/discomfort); there was no significant difference in improvement between groups. EQVAS was significantly higher for the MO group (90 versus 70; Mann-Whitney U: P = .001). Employment status changed for 8 patients postoperatively, but there was no significant difference between groups. CONCLUSION: These results suggest that MO patients appear to benefit more than SO patients from LRYGB and yet seem to be disadvantaged in some NHS Trusts in the United Kingdom for access to bariatric surgery. This study provides a baseline framework for further research to generate evidence for more scientific rationing of bariatric surgery.

Abnormal expression of pRb, p16, and cyclin D1 in gastric adenocarcinoma and its lymph node metastases: relationship with pathological features and survival.

The retinoblastoma (Rb) pathway controls the G1-S checkpoint of the cell cycle. Inactivating mutations and deletions of p16 and Rb and up-regulation of cyclin D1 disrupt this pathway and occur in many cancers. However, the concurrent expression of these genes in primary and metastatic gastric cancer is unknown, and the prognostic value of their expression is unclear. In this study, the expression of cyclin D1, retinoblastoma protein (pRb), and p16 in 67 resected gastric adenocarcinomas, and of pRb and p16 in 40 associated lymph node metastases, was determined using a streptavidin-biotin-peroxidase immunohistochemical method. Relationships with clinical and pathological features were analyzed. Cyclin D1 overexpression (>/=5% expression) was seen in 55% of cancers; pRb loss (<20% expression), in 33%; p16 loss (<10% expression), in 49%; and at least 1 of these abnormalities, in 92.5%. Cyclin D1 overexpression was associated with poor differentiation (P = 0.027) and signet ring cell type (P = 0.029). pRb expression was lower in lymph node metastases than in the corresponding primary tumors (P <0.001). Univariate and multivariate survival analysis (minimum follow-up 72 months or until death) revealed that <20% pRb expression, <30% pRb expression, and International Union Against Cancer stage >2 were associated with worse overall survival. The results suggest that Rb pathway disturbances play an important role in gastric carcinogenesis. The poor prognosis of cancers with low pRb expression and the reduced pRb expression in lymph node metastases raise the possibility that Rb and related genes also influence progression.