Congenital hypertrophy of retinal pigment epithelium (CHRPE) in patients with familial adenomatous polyposis (FAP); a polyposis registry experience

BACKGROUND: Familial Adenomatous Polyposis (FAP) is an autosomal dominant condition giving rise to multiple adenomatous polyps in the colon which invariably become malignant by the fourth decade. Congenital hypertrophy of retinal pigment epithelium (CHRPE) is one of its extra intestinal manifestations early in childhood seen, present in 90% of FAP population and is easy to detect. FINDINGS: Patients diagnosed with FAP and at risk first degree family members were screened for CHRPE using a slit lamp and indirect ophthalmoscopy. The retina of 17 diagnosed FAP patients and 13 individuals at risk were examined. The site and size of CHRPE lesions were documented. Thirteen (76%) of 17 FAP patients (male-10, female – 7, median age - 30 years; range 15-55 years) had CHRPE lesions; seven (54%) had bilateral CHRPE lesions and six (46%) had unilateral lesions. A single lesion was detected in 6 (46%) while 7 (54%) patients had multiple lesions. Of 13 at risk individuals (7- male, female-6 ; median age 34; range 16-52 years), one was positive for CHRPE and 12 were free of retinal lesions. The sensitivity of the presence of a CHRPE lesion in association with colonic polyps in FAP was 76%, specificity 92%, positive predictive value 93%, and negative predictive value 75%. CONCLUSIONS: This study found a high sensitivity and specificity for a CHRPE lesion to be associated with colonic polyps of FAP and hence a useful screening method in a burdened health-care system. The method is minimally invasive and simple and would be of particular value in screening children at risk for FAP

Overall Survival of Elderly Patients Having Surgery for Colorectal Cancer Is Comparable to Younger Patients: Results from a South Asian Population

Introduction. There has been a continuous debate on whether elderly patients with colorectal cancer (CRC) fair worse. The aim of this study is to assess the thirty-day mortality (TDM) and overall survival (OS) of elderly patients undergoing surgery for CRC. Method. OS between two groups (≥70 versus <70 years) having surgery for CRC was analyzed. Demographics, tumour characteristics, and serological markers were considered as independent factors. Multivariable analysis was done using the Cox proportional hazard model. We also compared overall survival in the elderly versus those <60 and <50 years. Results. 477 patients, 160 elderly (55% male; median age 75, range 70–89) and 317 younger patients (49% male; median age 55, range 16 to 69), were studied. Overall survival in CRC patients ≥70 is comparable to <70 (P=0.45) and <60 years (P=0.08). Poor OS was observed in the ≥70 versus <50 years (P=0.03). TDM in the elderly was poor (P<0.05). Postoperative cardiac complication was the only determinant affecting survival in the elderly (P=0.01). Conclusion. OS in elderly CRC patients having surgery is not worse compared to <70 and <60 years although the TDM was higher. Postoperative cardiac complications significantly affected OS in those ≥70 compared to those <50 years. Chronological age alone should not negatively influence surgical decision-making in the elderly

Methylation changes in colitis associated cancer and its correlation to SMAD7

Ulcerative colitis (UC) is an inflammatory condition affecting the mucosa of the large bowel and the occurrence is linked to the increase of developing colitis associated cancer (CAC). The identification of biomarkers to predict those who are at risk of progressing to CAC is needed to assist in early decision making for restorative surgery and improved outcome following surgery. However, previous attempts at the identification of consistent genetic biomarkers have not been successful, due to non-reproducibility of the results. This could attribute partly to variability in tissues used and partly to the complex pathophysiology. The regenerative stress in UC mucosa resulting in multiple structural mutations in genes may also be a cause for the variability. Therefore, the first aim of this study was the identification of differentially methylated genes to be used as potential biomarkers of malignant transformation at a precancerous stage. Whole genome bisulphite sequencing was carried out on laser captured epithelial cells on a pilot cohort of 8 samples of normal, inflamed, dysplastic and malignant colonic mucosa. Each sample was matched with adjacent non-neoplastic mucosa or buffy coat from the same patient as controls. Sixty-three hypomethylated and six hypermethylated gene promoters were identified as differentially methylated in the samples compared to the normal epithelium. These methylation changes were unique to the diseased tissue and were consistently found in each stage of the disease, suggesting they could be used as biomarkers for CAC. Out of these genes, 7 hypomethylated and 4 hypermethylated genes were identified as strongly related to CRC pathways. Similarly, the analysis of gene body methylation allowed the identification of further 10 hypomethylated and 2 hypermethylated genes related to CRC pathways. Moreover the identified genes could be annotated to cell adhesion related molecular function and disease processes, including UC and epithelial cancers. Amongst proteins and pathways of clinical importance, TGFβ, a molecule with anti-inflammatory properties, is inhibited in UC-affected mucosa. Recently, SMAD7, the principal intracellular inhibitor of the TGFβ pathway, has been proposed as a therapeutic target in UC. However, SMAD7 is shown to influence CRC development and progression in a less understood manner. Furthermore, studies in breast cancer indicate that SMAD7 influences methylation patterns of cancer-associated genes. Therefore investigating the potential effect of SMAD7 on CAC and differential methylation of related genes would provide insight into its role in CAC. The second and third aims of this study were therefore was to observe the behaviour pattern of SMAD7 at different stages of CAC and analyse the methylation pattern of identified SMAD7-associated genes. Immunohistochemistry and in situ hybridisation was performed on 53 and 33 samples from non-inflamed, inflamed, dysplastic and cancer tissues, respectively. SMAD7 was biphasically expressed in different stages of CAC: high expression during the inflammation and cancer stages was associated with a lower expression in the non-inflamed UC and dysplastic tissues. On the other hand, the downstream molecule pSMAD3 did not show a reduction in expression suggesting an escape of TGFβ from the inhibitory effect of SMAD7 in UC. The evaluation of the methylation patterns in cancer-associated genes supposedly influenced by SMAD7 (CDH1, CLDN4, DNMT1, CGN) did not demonstrate a consistent pattern of differential methylation. This data has strong clinical implications, as the biphasic expression of SMAD7 during precancerous stages suggests further evaluation is needed prior to using an antisense to inhibit SMAD7 in the clinic. In conclusion, this pilot study identified 27 potential genes with differential methylation, of which the expression of some has already been validated with RT-qPCR. The consistency of the methylation pattern of these genes across all stages of CAC and their annotation to cancer and cancer related biological processes make them strong potential candidates for an early biomarker in CAC. An extension of the analysis in a wider samples cohort and complete validation of each target will be necessary to validate their efficacy and lead to developing a clinically useful gene panel to predict CAC.Open Acces

Neoadjuvant Chemoradiation for Rectal Cancer Achieves Satisfactory Tumour Regression and Local Recurrence – Result of a Dedicated Multi-disciplinary Approach from a South Asian Centre

Abstract Background Pre-operative long-course chemoradiotherapy (CRT) for rectal cancer has resulted in improvement in rates of restorative rectal resection and local recurrence by inducing tumour downstaging and downsizing. Total mesorectal excision (TME) is a standardised surgical technique of low anterior resection aimed at the prevention of local tumour recurrence. The purpose of this study was to evaluate tumour response following CRT in a standardised group of patients with rectal cancer. Methods One hundred and thirty-one patients (79 male; 52 female, median age 57; interquartile range 47–62 years) of 153 with rectal cancer who underwent pre-operative long-course CRT were treated by standardised open low anterior resection at a median of 10 weeks post-CRT. Sixteen of 131 (12%) were 70 years or older. Median follow-up at the time of analysis was 15 months (interquartile range 6–45 months). Pathology reports were analysed based on AJCC-UICC classification using the TNM system. Data recorded were overall/subgrades of tumour regression; good, moderate or poor, lymph node harvest, local recurrence, disease-free and overall survival using standard statistical methods. Results 78% showed tumour regression post-CRT; 43% displayed good tumour regression/response while 22% had poor tumour regression/response. All patients had a pre-operative T-stage of either T3 or T4. Post-operation, good responders had a median T stage of T2 vs. T3 in poor responders (P = 0.0002). Overall, the median lymph node harvest was < 12. There was no difference in the number of nodes harvested in good vs. poor responders (Good/moderate-6 nodes vs. Poor- 8; P = 0.31). Good responders tended to have a lesser number of malignant nodes vs. poor responders (P = 0.31). Overall, local recurrence was 6.8% and the anal sphincter preservation rate was 89%. Predicted 5-year disease-free and overall survival were similar between good and poor responders. Conclusion Long-course CRT resulted in satisfactory tumour regression and enabled consideration for safe, sphincter-saving resection in rectal cancer. A dedicated multi-disciplinary team approach achieved a global benchmark for local recurrence in a resource-limited setting

Transanal Ileal Pouch-Anal Anastomosis for Ulcerative Colitis has Comparable Long-Term Functional Outcomes to Transabdominal Approach: A Multicentre Comparative Study

BACKGROUND: The transanal approach to ileal pouch-anal anastomosis [Ta-IPAA] provides better access to the lower pelvis with lower short-term morbidity in ulcerative colitis [UC]. The aim of this study was to assess the long-term functional outcomes after Ta-IPAA vs transabdominal IPAA [Abd-IPAA] in UC. METHODS: A multicentre cohort analysis was performed between March 2002 and September 2017. Patient characteristics, surgical details and postoperative outcomes were compared. CGQL [Cleveland global quality of life] score at 12 months with a functioning pouch was considered the primary end point. RESULTS: A total of 374 patients [100 Ta-IPAA vs 274 Abd-IPAA] were included. Ta-IPAA demonstrated a comparable overall quality of life [CGQL score] to Abd-IPAA [0.75 ± 0.11 vs 0.71 ± 0.14; respectively, p = 0.1]. Quality of life [7.71 ± 1.17 vs 7.30 ± 1.46; p = 0.04] and energy-level items [7.16 ± 1.52 vs 6.66 ± 1.68; p = 0.03] were significantly better after Ta-IPAA, while the quality of health item was comparable [7.68 ± 1.26 vs 7.64 ± 1.44; p = 0.96]. Analysis excluding anastomotic leaks did not change the overall CGQL scores. Stool frequencies [>10/24 h: 22% vs 21%; p = 1.0] and the rate of a single episode of major incontinence during the following 12-month period [27% vs 26%; p = 0.89] were similar. The differences in 30-day morbidity rates [33% vs 41%; p = 0.2] and anastomotic leak rates were not significant [6% vs 13%; p = 0.09]. CONCLUSIONS: This study provides evidence of comparable long-term functional outcome and quality of life after Ta-IPAA and Abd-IPAA for UC

Fistulizing Crohn's disease

Crohn's disease (CD), characterized by idiopathic transmural inflammation anywhere along the gastrointestinal (GI) tract, is increasing in incidence worldwide for unknown reasons. The transmural inflammation can result in inflammatory, stricturing, or penetrating (fistulizing) phenotypes, all of which are notoriously difficult to treat. When a patient has inflammatory disease, medical immunosuppressive therapy with corticosteorids, immunomodulators, or biologics may be helpful before a fibrostenotic disease process starts. Once there is fibrosis, bowel damage is difficult to reverse, and proximal fistulizing disease may develop. Fistulizing disease, one of the most notoriously difficult disease manifestations can also occur anywhere along the GI tract, affecting portions as proximal as the duodenum or as distal as the anus with perianal and rectovaginal fistulas (RVFs)

Predictive Factors and Risk Model for Positive Circumferential Resection Margin Rate after Transanal Total Mesorectal Excision in 2653 Patients with Rectal Cancer

The aim of this study was to determine the incidence of, and preoperative risk factors for, positive circumferential resection margin (CRM) after transanal total mesorectal excision (TaTME). Background: TaTME has the potential to further reduce the rate of positive CRM for patients with low rectal cancer, thereby improving oncological outcome. Methods: A prospective registry-based study including all cases recorded on the international TaTME registry between July 2014 and January 2018 was performed. Endpoints were the incidence of, and predictive factors for, positive CRM. Univariate and multivariate logistic regressions were performed, and factors for positive CRM were then assessed by formulating a predictive model. Results: In total, 2653 patients undergoing TaTME for rectal cancer were included. The incidence of positive CRM was 107 (4.0%). In multivariate logistic regression analysis, a positive CRM after TaTME was significantly associated with tumors located up to 1 cm from the anorectal junction, anterior tumors, cT4 tumors, extra-mural venous invasion (EMVI), and threatened or involved CRM on baseline MRI (odds ratios 2.09, 1.66, 1.93, 1.94, and 1.72, respectively). The predictive model showed adequate discrimination (area under the receiver-operating characteristic curve &gt;0.70), and predicted a 28% risk of positive CRM if all risk factors were present. Conclusion: Five preoperative tumor-related characteristics had an adverse effect on CRM involvement after TaTME. The predicted risk of positive CRM after TaTME for a specific patient can be calculated preoperatively with the proposed model and may help guide patient selection for optimal treatment and enhance a tailored treatment approach to further optimize oncological outcomes

Effects of pre-operative isolation on postoperative pulmonary complications after elective surgery: an international prospective cohort study an international prospective cohort study

We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care. We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care