Janindra Warusavitarne

Molecular pathways in colorectal cancer

Colorectal cancer (CRC) is the second most common newly diagnosed cancer and accounts for the second highest number of cancer related deaths in Australia, the third worldwide and of increasing importance in Asia. It arises through cumulative effects of inherited genetic predispositions and environmental factors. Genomic instability is an integral part in the transformation of normal colonic or rectal mucosa into carcinoma. Three molecular pathways have been identified: these are the chromosomal instability (CIN), the microsatellite instability (MSI), and the CpG Island Methylator Phenotype (CIMP) pathways. These pathways are not mutually exclusive, with some tumors exhibiting features of multiple pathways. Germline mutations are responsible for hereditary CRC syndromes (accounting for less than 5% of all CRC) while a stepwise accumulation of genetic and epigenetic alterations results in sporadic CRC. This review aims to discuss the genetic basis of hereditary CRC and the different pathways involved in the process of colorectal carcinogenesis.

Forty-Year Analysis of Colonoscopic Surveillance Program for Neoplasia in Ulcerative Colitis: An Updated Overview.

Objectives:This study provides an overview of the largest and longest-running colonoscopic surveillance program for colorectal cancer (CRC) in patients with long-standing ulcerative colitis (UC).Methods:Data were obtained from medical records, endoscopy, and histology reports. Primary end points were defined as death, colectomy, withdrawal from surveillance, or censor date (1 January 2013).Results:A total of 1,375 UC patients were followed up for 15,234 patient-years (median, 11 years per patient). CRC was detected in 72 patients (incidence rate (IR), 4.7 per 1,000 patient-years). Time-trend analysis revealed that although there was significant decrease in incidence of colectomy performed for dysplasia (linear regression, R=−0.43; P=0.007), IR of advanced CRC and interval CRC have steadily decreased over past four decades (Pearson’s correlation, −0.99; P=0.01 for both trends). The IR of early CRC has increased 2.5-fold in the current decade compared with past decade (χ2, P=0.045); however, its 10-year survival rate was high (79.6%). The IR of dysplasia has similarly increased (χ2, P=0.01), potentially attributable to the recent use of chromoendoscopy that was twice more effective at detecting dysplasia compared with white-light endoscopy (χ2, P<0.001). CRCs were frequently accompanied by synchronous CRC or spatially distinct dysplasia (37.5%). Finally, the risk of CRC was not significantly different between “indefinite” or low-grade dysplasia (log-rank, P=0.78).Conclusions:Colonoscopic surveillance may have a significant role in reducing the risk of advanced and interval CRC while allowing more patients to retain their colon for longer. Given the ongoing risk of early CRC, patients with any grade of dysplasia who are managed endoscopically should be monitored closely with advanced techniques.

Laparoscopically assisted vs. open elective colonic and rectal resection: a comparison of outcomes in English National Health Service Trusts between 1996 and 2006.

PURPOSE: This study was designed to compare outcomes after elective laparoscopic and conventional colorectal surgery over a ten-year period using data from the English National Health Service Hospital Episode Statistics database. METHODS: All elective colonic and rectal resections carried out in English Trusts between 1996 and 2006 were included. Univariate and multivariate analyses were used to compare 30 and 365-day mortality rates, 28-day readmission rates, and length of stay between laparoscopic and open surgery. RESULTS: Between the study dates 3,709 of 192,620 (1.9%) elective colonic and rectal resections were classified as laparoscopically assisted procedures. The 30-day and 365-day mortality rates were lower after laparoscopic resection than after open surgery (P < 0.05). After correction for age, gender, diagnosis, operation type, comorbidity, and social deprivation, laparoscopic surgery was a strong determinant of reduced 30-day (odds ratio, 0.57; 95% confidence interval, 0.44-0.74; P < 0.001) and one-year (odds ratio, 0.53; 95% confidence interval, 0.42-0.67; P < 0.001) mortality. Similarly, multivariate analysis confirmed that laparoscopic surgery was independently associated with reduced hospital stay (P < 0.001). Patients who received rectal procedures for malignancy, however, were more likely to be readmitted if laparoscopy rather than by a traditional method was used (11.9% vs. 9.1%, P = 0.003). CONCLUSION: In the present study, patients selected for laparoscopic colorectal surgery were associated with reduced postoperative mortality when compared with those undergoing the conventional technique. This finding merits further investigation.

Transanal Total Mesorectal Excision: International Registry Results of the First 720 Cases

Objective: This study aims to report short-term clinical and oncological outcomes from the international transanal Total Mesorectal Excision (taTME) registry for benign and malignant rectal pathology. Background: TaTME is the latest minimally invasive transanal technique pioneered to facilitate difficult pelvic dissections. Outcomes have been published from small cohorts, but larger series can further assess the safety and efficacy of taTME in the wider surgical population. Methods: Data were analyzed from 66 registered units in 23 countries. The primary endpoint was “good-quality TME surgery.” Secondary endpoints were short-term adverse events. Univariate and multivariate regression analyses were used to identify independent predictors of poor specimen outcome. Results: A total of 720 consecutively registered cases were analyzed comprising 634 patients with rectal cancer and 86 with benign pathology. Approximately, 67% were males with mean BMI 26.5 kg/m2. Abdominal or perineal conversion was 6.3% and 2.8%, respectively. Intact TME specimens were achieved in 85%, with minor defects in 11% and major defects in 4%. R1 resection rate was 2.7%. Postoperative mortality and morbidity were 0.5% and 32.6% respectively. Risk factors for poor specimen outcome (suboptimal TME specimen, perforation, and/or R1 resection) on multivariate analysis were positive CRM on staging MRI, low rectal tumor <2 cm from anorectal junction, and laparoscopic transabdominal posterior dissection to <4 cm from anal verge. Conclusions: TaTME appears to be an oncologically safe and effective technique for distal mesorectal dissection with acceptable short-term patient outcomes and good specimen quality. Ongoing structured training and the upcoming randomized controlled trials are needed to assess the technique further.

Nonelective Excisional Colorectal Surgery in English National Health Service Trusts: A Study of Outcomes from Hospital Episode Statistics Data between 1996 and 2007

BACKGROUND Nonelective colorectal surgery is associated with substantial patient morbidity and mortality. This study sought to describe the practice of emergency colorectal surgery in the United Kingdom during an 11-year period using the Hospital Episode Statistics (HES) database. STUDY DESIGN All nonelective admissions in patients undergoing 1 of 8 colorectal resectional procedures between 1996 and 2007 were included. Time trends, univariate, and multivariate mortality and length of stay outcomes were analyzed. RESULTS A total of 102,236 major urgent/emergency procedures were performed in English National Health Service Trusts between April 1996 and March 2007. Thirty-day in-hospital postoperative mortality rates in patients with colorectal cancer and diverticular disease were 13.3% and 15.4%, respectively. The corresponding 1-year postoperative mortality was 34.7% and 22.6%. On multivariate analysis, benign diagnosis, advanced age, high comorbidity score, social deprivation, and specific procedure types were independent predictors of early and 1-year postoperative mortality (p < 0.001). Independent risk factors for extended hospital stay were advanced age, social deprivation, distal (compared with proximal) bowel resection, and a diagnosis of ulcerative colitis (p < 0.001). CONCLUSIONS HES data suggest that in everyday practice, postoperative mortality among patients undergoing nonelective admission followed by colorectal resection is high. Additional investigation is required to assess the reliability of HES data for monitoring institutional variation in this context.

Expression of S100A2 Calcium-Binding Protein Predicts Response to Pancreatectomy for Pancreatic Cancer

BACKGROUND & AIMS Current methods of preoperative staging and predicting outcome following pancreatectomy for pancreatic cancer (PC) are inadequate. We evaluated the utility of multiple biomarkers from distinct biologic pathways as potential predictive markers of response to pancreatectomy and patient survival. METHODS We assessed the relationship of candidate biomarkers known, or suspected, to be aberrantly expressed in PC, with disease-specific survival and response to therapy in a cohort of 601 patients. RESULTS Of the 17 candidate biomarkers examined, only elevated expression of S100A2 was an independent predictor of survival in both the training (n = 162) and validation sets (n = 439; hazard ratio [HR], 2.19; 95% confidence interval [CI]: 1.48-3.25; P < .0001) when assessed in a multivariate model with clinical variables. Patients with high S100A2 expressing tumors had no survival benefit with pancreatectomy compared with those with locally advanced disease, whereas those without high S100A2 expression had a survival advantage of 10.6 months (19.4 vs 8.8 months, respectively) and a HR of 3.23 (95% CI: 2.39-4.33; P < .0001). Of significance, patients with S100A2-negative tumors had a significant survival benefit from pancreatectomy even in the presence of involved surgical margins (median, 15.7 months; P = .0007) or lymph node metastases (median, 17.4 months; P = .0002). CONCLUSIONS S100A2 expression is a good predictor of response to pancreatectomy for PC and suggests that high S100A2 expression may be a marker of a metastatic phenotype. Prospective measurement of S100A2 expression in diagnostic biopsy samples has potential clinical utility as a predictive marker of response to pancreatectomy and other therapies that target locoregional disease.

Systematic review: the combined surgical and medical treatment of fistulising perianal Crohn's disease

The management of perianal Crohns fistulas represents a significant challenge. A combination of medical and surgical therapy, guided by radiology, is often required.

The role of chemotherapy in microsatellite unstable (MSI-H) colorectal cancer

IntroductionHigh-frequency microsatellite instability (MSI-H) is an alternate pathway of colorectal carcinogenesis, which accounts for 15% of all sporadic colorectal cancers. These tumours arise from mutations in the DNA mismatch repair system and thus have different responses to chemotherapeutic agents compared to microsatellite stable (MSS) cancers.ObjectiveThis review aims to summarise the available literature on the responses to chemotherapy in MSI-H colorectal cancer (CRC).Results and discussion5 Fluorouracil (5FU) is commonly used as a chemotherapeutic agent in colon cancer and in vitro evidence shows reduced response to 5FU in MSI-H CRC. The clinical evidence is conflicting but favours a reduced response to 5FU in MSI-H CRC. Several newer agents such as COX-2 inhibitors and irinotecan are also reviewed.ConclusionAvailable evidence suggests that MSI-H CRC have different behaviour patterns and response to chemotherapy compared with MSS CRC.

Low-Grade Dysplasia in Ulcerative Colitis: Risk Factors for Developing High-Grade Dysplasia or Colorectal Cancer

OBJECTIVES:The aim of this study was to identify risk factors associated with development of high-grade dysplasia (HGD) or colorectal cancer (CRC) in ulcerative colitis (UC) patients diagnosed with low-grade dysplasia (LGD).METHODS:Patients with histologically confirmed extensive UC, who were diagnosed with LGD between 1993 and 2012 at St Mark’s Hospital, were identified and followed up to 1 July 2013. Demographic, endoscopic, and histological data were collected and correlated with the development of HGD or CRC.RESULTS:A total of 172 patients were followed for a median of 48 months from the date of initial LGD diagnosis (interquartile range (IQR), 15–87 months). Overall, 33 patients developed HGD or CRC (19.1% of study population; 20 CRCs) during study period. Multivariate Cox proportional hazard analysis revealed that macroscopically non-polypoid (hazard ratio (HR), 8.6; 95% confidence interval (CI), 3.0–24.8; P<0.001) or invisible (HR, 4.1; 95% CI, 1.3–13.4; P=0.02) dysplasia, dysplastic lesions ≥1 cm in size (HR, 3.8; 95% CI, 1.5–13.4; P=0.01), and a previous history of “indefinite for dysplasia” (HR, 2.8; 95% CI, 1.2–6.5; P=0.01) were significant contributory factors for HGD or CRC development. Multifocal dysplasia (HR, 3.9; 95% CI, 1.9–7.8; P<0.001), metachronous dysplasia (HR, 3.5; 95% CI, 1.6–7.5; P=0.001), or a colonic stricture (HR, 7.4; 95% CI, 2.5–22.1; P<0.001) showed only univariate correlation to development of HGD or CRC.CONCLUSIONS:Lesions that are non-polypoid or endoscopically invisible, large (≥1 cm), or preceded by indefinite dysplasia are independent risk factors for developing HGD or CRC in UC patients diagnosed with LGD.

A meta-analysis of outcomes following use of somatostatin and its analogues for the management of enterocutaneous fistulas.

Objective:Several randomized control trials (RCTs) have compared somatostatin and its analogues versus a control group in patients with enterocutaneous fistulas (ECF). This study meta-analyzes the literature and establishes whether it shows a beneficial effect on ECF closure. Methods:We searched MEDLINE, EMBASE, CINAHL, Cochrane, and PubMed databases according to PRISMA guidelines. Seventy-nine articles were screened. Nine RCTs met the inclusion criteria. Statistical analyses were performed using Review Manager 5.1. Results:Somatostatin analogues versus controlNumber of fistula closed: A significant number of ECF closed in the somatostatin analogue group compared to control group, P = 0.002.Time to closure: ECF closed significantly faster with somatostatin analogues compared to controls, P < 0.0001.Mortality: No significant difference between somatostatin analogues and controls, P = 0.68.Somatostatin versus controlNumber of fistula closed: A significant number of ECF closed with somatostatin as compared to control, P = 0.04.Time to closure: ECF closed significantly faster with somatostatin than controls, P < 0.00001.Mortality: No significant difference between somatostatin and controls, P = 0.63 Conclusions:Somatostatin and octreotide increase the likelihood of fistula closure. Both are beneficial in reducing the time to fistula closure. Neither has an effect on mortality. The risk ratio (RR) for somatostatin was higher than the RR for analogues. This may suggest that somatostatin could be better than analogues in relation to the number of fistulas closed and time to closure. Further studies are required to corroborate these apparent findings.