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Supplementary methods

Summary of all validated variants identified by exome sequencing. Patterned shading indicates duplicate adenomas.

Pre- and Post-validation protein altering somatic variants identified by whole exome sequencing.

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.

Summary of the 62 recurrently mutated genes in the exome dataset (supplementary table 2) and the number of mutations identified in each gene. Total numbers of variants in each gene take into account any mutations identified in duplicate adenomas.

Database of somatic APC mutations reported in FAP and MAP duodenal and colorectal adenomas. NA, Not available. NI, Not identified

Histogram showing number of validated protein changing somatic variants identified per adenoma.

This article explores ways in which material changes engendered by World War I influenced ideas about Cape Town and its people. For the city's middle classes, these conditions – including a rise in the cost of living, increased urbanization, the growth of factory work for women and the notable presence of soldiers in the city – heightened the sense that Cape Town was a place of increased moral corruption. In particular, females were portrayed as pivotal to the upholding of the moral and racial integrity of the city, nation and empire. Yet the perceived race and class of different Capetonian women influenced the expectations (and accordant condemnations) of their behaviour. This linked to white middle-class anxieties about miscegenation and urban order. As such, discourses around female behaviour during the war represented a nexus between issues of health, race and morality within the South African urban context.

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

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

Trove opens possibilities for collaborative, transnational and comparative research from scholars in the Global South, who often work with limited financial resources. Indeed, Trove has been indispensable for the South African-based historians in the International Studies Group, who would otherwise face difficulties accessing Australian primary sources. It also enables Australian perspectives to be incorporated into African histories, fostering the emergence of new historical insights. However, mass digitisation has the potential to create an unevenness in transnational history by privileging certain connections, particularly between British settler colonies. These reflections will offer crucial perspectives from a network of early career historians outside Australia.

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.

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.

Aim Nutrition is an important aspect in the patient’s road to recovery after any surgical procedure. Often there is a communication gap which is not beneficial for the patient. The aim of this audit was to evaluate the communication regarding patient nutrition requirements. Method All consecutive patients on a General surgical morning ward round were included. Four communication points were reviewed: Data was collected prospectively on a predesigned proforma. Results First Cycle: Second Cycle: Conclusion Nutrition in surgical patients is very important. It is proven that patients on ERAS programme have fewer complications, more rapid return to function and shorter hospital stay. Emphasis and education about the importance of nutrition is the way forward.

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.

Although duodenal adenomas and cancer appear to occur significantly less frequently in autosomal recessive MUTYH-associated polyposis (MAP) than in autosomal dominant familial adenomatous polyposis (FAP),1 current guidelines recommend similar endoscopic surveillance for both disorders.2-4 This involves gastro-duodenoscopy starting at 25 to 35 years of age and repeated at intervals determined by Spigelman staging based on the number, size, histological type and degree of dysplasia of adenomas, and by ampullary staging. Case reports of duodenal cancers in MAP suggest that they may develop in the absence of advanced Spigelman stage benign disease and even without coexisting adenomas.1 Recent molecular analyses suggest thatMAPduodenal adenomashave a higher mutational burden than FAP adenomas and are more likely to harbor oncogenic drivermutations, such as those in KRAS.5 These apparent differences in the biology and natural history of duodenal polyposis in FAP and MAP challenge the assumption that the same surveillance should be applied in both conditions.

The aim of this retrospective cohort study was to review urological complication rates arising from familial adenomatous polyposis associated desmoid tumours and their management. All patients over a 35-year period were identified from a prospectively maintained polyposis registry database and had an intra-abdominal desmoid tumour. Those without ureteric complications (n = 118, group A) were compared to those that developed ureteric obstruction (n = 40, group B) for demographics, treatment interventions and survival outcomes. 158 (56% female) patients were identified. Median age at diagnosis was 31 years and desmoids typically occurred 3.6 years after colectomy for familial adenomatous polyposis. Ureteric obstruction secondary to tumour growth occurred in 25% of cases. There was no significant difference in gender distribution or overall age at desmoid diagnosis between the two groups. In group B, the median age at desmoid diagnosis was significantly younger in women compared to men (25 and 43 years, respectively) (p = 0.01). Thirty-eight percent of patients already had ureteric obstruction at desmoid diagnosis, the remainder occurred after 48.6 months, but 20 years in two cases. Seventy-three percent (29/40) had ureteric stenting, a long-term requirement for most. Permanent renal injury occurred in six cases but survival between the two groups was not significantly different. Ureteric obstruction occurs frequently in patients with familial adenomatous polyposis and an intra-abdominal desmoid tumour. Those most at risk are the young following colectomy. Clinicians should actively survey the renal tract at regular intervals after a diagnosis of an intra-abdominal desmoid tumour as complications can arise insidiously, at any stage.

This article reflects on my experiences making the film documentary Those Dying Days (South Africa, 2012). The documentary itself explores the question of personal and public remembrance of World War Two in Cape Town. It speaks not only to the fluid and adaptive nature of memory, but also to the relative silence regarding the war in terms of public commemoration. The article discusses the challenges and rewards of film as a medium for historical argument and information and argues for an affinity between film and oral history. It provides the thinking behind the choices made in the construction of argument in a non-written discourse (film) and reveals the methods adopted in an attempt to create a complicated historical account which recognises the contingent nature of history and one which allows for a multiplicity of perspectives and voices to be heard. After discussing the making of the documentary, the article concludes that film is more than capable of creating nuanced and complicated historic...

Background and Aims\ud \ud 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, with 5% developing 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.\ud \ud \ud Methods\ud \ud 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.\ud \ud \ud Results\ud \ud Enhanced adenoma detection of 3 times the number of adenomas after chromoendoscopy was demonstrated in both MAP (p=0.013) and FAP (p=0.002), 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.\ud \ud \ud Conclusions\ud \ud Chromoendoscopy improved the diagnostic yield of adenomas 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.

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.

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.

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.

Colorectal cancer (CRC) development depends upon complex interaction between genetic predisposition and environment. Most tumours occur by chance, and environmental factors are thought largely responsible. Familial CRC arises in individuals where genetics plays a more influential role. This group may be categorised into low, moderate or high risk for CRC. This risk is higher in families with more relatives affected by cancer, and when tumours arise at a young age. About 5 % of CRC falls into the high-risk group, where genotype plays a fundamental role in the inheritance of bowel cancer. Lynch syndrome and polyposis syndromes fall into this group.

Spontaneous rectal rupture with subsequent transanal evisceration is an unusual phenomenon that has been rarely reported in the literature. Owing to its infrequent occurrence, little is known about the aetiology of this event although a weakening of the anterior rectal wall has been proposed. This article describes the first reported case of spontaneous transanal evisceration occurring in a patient with chronic lymphocytic leukaemia.

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 (P0.001). Univariate and multivariate survival analysis (minimum follow-up 72 months or until death) revealed that20% pRb expression,30% pRb expression, and International Union Against Cancer stage2 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.