Immunohistochemistry testing for mismatch repair deficiency in Stage 2 colon cancer: A cohort study of two cancer centres.

BACKGROUND/OBJECTIVES: Adjuvant chemotherapy for Stage II colon cancer offers a small (2-3%) overall survival benefit and is not universally recommended. Mismatch repair deficiency (dMMR) confers an improved prognosis identifying patients unlikely to benefit from adjuvant chemotherapy. The aim of this study was to investigate the use of dMMR immunohistochemistry in two major cancer treatment centres. METHODS: Prospective data were collected on all patients with resected Stage II colon cancer between 2010 and 2015 across two large Australian hospitals. Data collected included patient demographics, tumour histology, dMMR immunohistochemistry, chemotherapy use, and outcomes. RESULTS: All 355 patients (56.1% female, median age 81) with resected Stage 2 Colon cancer entered on to the surgical database were included in this analysis. MMR testing was performed on 167 patient samples (47%), most occurred post-2013 (73.1% vs. 26.9% patients). dMMR rates were 34.1%. 25 (7.3%) received adjuvant chemotherapy, with no patient >80 years receiving treatment. Presence of ≥2 high-risk feature increased the likelihood of adjuvant chemotherapy. Only 3.6% dMMR patients received chemotherapy; both were young with high-risk features. 27/288 (7.6%) patients (with follow up) relapsed, with 7 disease-free post-resection of metastatic disease, 9 are alive with metastatic disease, and 11 deceased. CONCLUSIONS: Unlike clinical trial populations, Stage 2 colon cancer patients are often elderly, have high rates of dMMR tumours, are rarely offered chemotherapy, yet still have excellent outcomes. dMMR immunohistochemistry is being increasingly used to identify Stage 2 patients who do not require chemotherapy.

KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer.

PURPOSE: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse. EXPERIMENTAL DESIGN: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n = 65), lung (n = 50), and brain (n = 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n = 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial. RESULTS: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P = 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P < 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR = 2.1; 95% CI, 1.2 to 3.5, P = 0.007) but not liver relapse in patients from the VICTOR trial. CONCLUSIONS: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies.

Comparison of equipment management and cleaning protocols for rigid sigmoidoscopy.

BACKGROUND: To provide outcome data relating to cleaning of rigid sigmoidoscopy equipment comparing commonly used techniques, allowing a framework for general guidelines for use in clinical practice. METHODS: A total of 104 rigid sigmoidoscopies were performed in the rooms of two colorectal surgeons using standard techniques. A three-way randomization was performed adopting the following variables: enzymatic washing versus steam sterilization of the light head, disposable versus reusable bellows and use with versus without an air filter. Aerosol from each system was collected on agar plates, and review of colony count numbers was performed. RESULTS: Gross faecal contamination of the rigid sigmoidoscope light head did not occur during any of the procedures. One plate grew a single-gram negative colony; all other contaminated plates showed environmental flora only. Reusable bellows in combination with an air filter showed lower mean colony counts (environmental flora) from the pre-procedure cultures as well as from the bellows' cultures. CONCLUSION: Enteric flora in this study was rarely aerosolized, and the use of an air filter may decrease this likelihood even further. There is no advantage in using disposable insufflation bellows when compared with the reusable type, allowing considerable cost saving. Washing the light head between procedures with enzymatic solution is a safe cheap and effective method of decontamination.

Continuous wound infusion of local anesthetic for the control of pain after elective abdominal colorectal surgery.

PURPOSE: Local anesthetic wound infusion has been investigated in recent years as a potential alternative to standard analgesic regimens after major surgery. This study investigates the efficacy of a continuous wound infusion of ropivacaine in conjunction with best practice postoperative analgesia after midline laparotomy for abdominal colorectal surgery. METHODS: We performed a randomized, participant and outcome assessor-blinded, placebo-controlled trial on patients presenting for major abdominal colorectal surgery at our institution between December 2003 and February 2006. Patients were allocated to receive ropivacaine 0.54 percent or normal saline via a dual catheter Painbuster Soaker (I-Flow Corporation, OH, USA) continuous infusion device into their midline laparotomy wound for 72 hours postoperatively. RESULTS: A total of 310 patients were included in this study. The continuous wound infusion of ropivacaine after abdominal colorectal surgery conveys minimal benefit compared with saline wound infusion. No statistically significant difference could be shown for: pain at rest, morphine usage, length of stay, mobility, nausea, or return of bowel function. There was a small, statistically significant difference in mean pain on movement on Day 1 for the ropivacaine group (adjusted mean difference -0.6 (range, -1.08 to -0.13)). Although this trend continued on Days 2 and 3, the differences between groups were no longer statistically significant. CONCLUSIONS: Management of pain after major abdominal colorectal surgery is best achieved through adopting a multimodal approach to analgesia. Delivery of ropivacaine to midline laparotomy wounds via a Painbuster Soaker device is safe, but we have not demonstrated any significant clinical advantage over current best practice.

Pentax confocal endomicroscope: a novel imaging device for in vivo histology of the upper and lower gastrointestinal tract.

With advances in endoscopic imaging tools, it is becoming increasingly possible to find, assess and treat numerous gastrointestinal (GI) pathologies at the time of endoscopy. This article focuses on the newly developed Pentax confocal endomicroscope that enables in vivo microscopic imaging of the upper and lower GI tract in histological detail at the time of patient examination without the collection of biopsies. The optical imaging technique has the potential to revolutionize clinical workflows in endoscopy through high-resolution fluorescence imaging of cellular and subcellular detail from the surface and subepithelial layers of the GI mucosa. The device incorporates a full screen, high-resolution charge coupled device as well as a confocal microscope. Preliminary data from blinded clinical studies suggests that the use of this device can increase the diagnostic yield for disease detection in conditions such as ulcerative colitis and Barrett's esophagus, where diagnosis using white light endoscopy is problematic. The early detection and diagnosis of GI abnormalities through the collection of 'optical' biopsies or targeted mucosal excisional biopsies has the potential to improve patient outcomes and enable early therapeutic intervention.

A fluorescence confocal endomicroscope for in vivo microscopy of the upper- and the lower-GI tract.

BACKGROUND: This report describes the development and the clinical evaluation of a novel confocal endomicroscope for obtaining fluorescence images of cellular morphology of the mucosae of the upper- and the lower-GI tract in vivo. The work assessed the feasibility of performing in vivo microscopy at endoscopic examination and evaluated fluorescence imaging protocols. METHODS: Images were collected in real time by using two prototype endoscope configurations, featuring slightly different miniaturized fiber-optic confocal microscopes, fitted integrally into the tips of conventional endoscopes. Confocal scanning was performed at 488 nm illumination for excitation of exogenously applied fluorophores (topical acriflavine and intravenous fluorescein). The images were compared with conventional histology of biopsy specimens and the findings of white-light endoscopy. RESULTS: Confocal endomicroscopy enabled imaging of cellular and subcellular structures (i.e., nuclei) of the GI tract. The crypts of the colonic mucosa, the villi of the terminal ileum and duodenum, the gastric pits of the stomach, and the squamous epithelium of the distal esophagus could be clearly visualized. Acriflavine strongly contrasted the cell nuclei of the surface epithelium, including the absorptive epithelial cells and the mucous secreting goblet cells. Fluorescein stained the extracellular matrix of the surface epithelium and also the subepithelial layers of the lamina propria. Images at increasing depth beneath the epithelium showed the mucosal capillary network. The findings correlated with the histology of biopsy specimens. CONCLUSIONS: The development of a fluorescence confocal endomicroscope makes it practical to examine the upper- and the lower-GI mucosa in cellular detail during otherwise routine endoscopic examination. The results represent a major technical advance in the development of this new optical imaging modality for the in vivo examination of GI tissue.

Local recurrence following surgical treatment for carcinoma of the lower rectum.

BACKGROUND: The present paper examines the local recurrence rate following surgical treatment for carcinoma of the lower rectum with principally blunt dissection directed at tumour-specific mesorectal excision (including total mesorectal excision when appropriate). METHODS: During the period April 1987-December 1999, 123 consecutive resections for carcinoma of the middle and distal thirds of the rectum were performed. The patients had low anterior resection, ultra low anterior resection or abdomino-perineal resection. Ninety-six eligible patients underwent curative resection. The mean follow-up period was 66.8 months +/-44.3 (range 3-176 months). Data were available on all patients having been prospectively registered and retrospectively collated and computer coded. RESULTS: The overall rate of local recurrence was 5.2% (four recurrences following ultra low anterior resection and one following abdomino-perineal resection. No local recurrence occurred after low anterior resections.). Local recurrences occurred between 16 and 52 months from the time of resection, and the cumulative risk of developing local recurrence at 5 years for all patients was 7.6%. The overall 5-year cancer specific survival of the 96 patients was 80.8%, and the overall probability of being disease free at 5 years, including both local and distal recurrence, was 71.8%. CONCLUSION: The results of the present series confirm the safety of careful blunt techniques combined with sharp dissection for rectal mobilization along fascial planes resulting in extraction of an oncologic package with tumour-specific mesorectal excision (or total mesorectal excision when appropriate).

Confocal laser endoscopy for diagnosing intraepithelial neoplasias and colorectal cancer in vivo.

BACKGROUND & AIMS: A confocal laser endoscopy system has recently been developed that may allow subsurface imaging of living cells in colonic tissue in vivo. The aim of the present study was to assess its potential for prediction of histology during screening colonoscopy for colorectal cancer. METHODS: Twenty-seven patients underwent colonoscopy with the confocal endoscope using acriflavine hydrochloride or fluorescein sodium with blue laser illumination. Furthermore, 42 patients underwent colonoscopy with this system using fluorescein sodium. Standardized locations and circumscript lesions were examined by confocal imaging before taking biopsy specimens. Confocal images were graded according to cellular and vascular changes and correlated with conventional histology in a prospective and blinded fashion. RESULTS: Acriflavine hydrochloride and fluorescein sodium both yielded high-quality images. Whereas acriflavine hydrochloride strongly labeled the superficial epithelial cells, fluorescein sodium offered deeper imaging into the lamina propria. Fluorescein sodium was thus used for the prospective component of the study in which 13,020 confocal images from 390 different locations were compared with histologic data from 1038 biopsy specimens. Subsurface analysis during confocal laser endoscopy allowed detailed analysis of cellular structures. The presence of neoplastic changes could be predicted with high accuracy (sensitivity, 97.4%; specificity, 99.4%; accuracy, 99.2%). CONCLUSIONS: Confocal laser endoscopy is a novel diagnostic tool to analyze living cells during colonoscopy, thereby enabling virtual histology of neoplastic changes with high accuracy. These newly discovered diagnostic possibilities may be of crucial importance in clinical practice and lead to an optimized rapid diagnosis of neoplastic changes during ongoing colonoscopy.

Men with colorectal cancer are predisposed to prostate cancer.

BACKGROUND: The objective of the present study was to investigate the relationship between colorectal and prostate cancer. METHODS: All Victorian men who developed metachronous colorectal and prostate cancer with the first primary diagnosed between 1982 and 1993 were identified retrospectively from the Victorian Cancer Registry and were followed up to the end of 1995. Analyses were stratified by age group and years of follow up. The cause of death in those men who had prostate cancer following colorectal cancer was determined. The stage of colorectal cancer was compared between men with and without second primary prostate cancer and the grade of prostate cancer was compared with men who did not have a prior colorectal cancer. RESULTS: Men who develop colorectal cancer are at increased risk of prostate cancer, with the greatest risk in men under the age of 65 (Relative risk approximately 2). Men with first primary colorectal cancer are more likely to develop prostate cancer than colorectal second primaries, and men who develop second primary prostate cancer are more likely to die of prostate cancer than colorectal cancer. CONCLUSIONS: Younger men diagnosed with colorectal cancer are at increased risk of prostate cancer. However, there is no direct evidence that screening for prostate cancer leads to a reduction in mortality. This should be considered when discussing long-term follow up.

Transanal endoscopic microsurgery: the first 50 cases.

BACKGROUND: Transanal endoscopic microsurgery is a form of minimally invasive rectal surgery first used at Cabrini Hospital in April 1997. This paper presents a prospective analysis of the first 50 cases with a median follow up of 33 months (range 20-48 months). METHODS: Prospective data was obtained from all cases between April 1997 and June 2000. RESULTS: Forty-nine patients (30 men and 19 women) underwent 50 procedures. Thirty-six had benign lesions and 14 malignant. The mean distance of the lower edge of the lesion from the anal verge was 8.7 cm. Three cases were converted to traditional transanal or transabdominal operations. Full-thickness excision was performed on 26 patients and the rectal wound was closed in 13 cases. The mean duration of transanal endoscopic microsurgery was 67 min (range 20-175), with a mean blood loss of 24 mL (0-300). The mean diameter and area of the fixed specimen was 3.7 cm (1.5-9.8) and 11.4 cm2 (0.8-18.9), respectively. Complications included postoperative fever (3), urinary retention (1) and per rectum bleeding (1). There was one death. The mean length of stay was 4 days. Histology confirmed complete excision in 39 (78%) cases and there have been two instances of local recurrence of adenoma (5%). CONCLUSIONS: Transanal endoscopic microsurgery is an effective, safe and cost-beneficial procedure for local excision of selected lesions in the middle and upper thirds of the rectum.