Molecular subtyping improves prognostication of Stage 2 colorectal cancer.

BACKGROUND: Post-surgical staging is the mainstay of prognostic stratification for colorectal cancer (CRC). Here, we compare TNM staging to consensus molecular subtyping (CMS) and assess the value of subtyping in addition to stratification by TNM. METHODS: Three hundred and eight treatment-naïve colorectal tumours were accessed from our institutional tissue bank. CMS typing was carried out using tumour gene-expression data. Post-surgical TNM-staging and CMS were analysed with respect to clinicopathologic variables and patient outcome. RESULTS: CMS alone was not associated with survival, while TNM stage significantly explained mortality. Addition of CMS to TNM-stratified tumours showed a prognostic effect in stage 2 tumours; CMS3 tumours had a significantly lower overall survival (P = 0.006). Stage 2 patients with a good prognosis showed immune activation and up-regulation of tumour suppressor genes. CONCLUSIONS: Although stratification using CMS does not outperform TNM staging as a prognostic indicator, gene-expression based subtyping shows promise for improved prognostication in stage 2 CRC.

Long-term outcomes of the australasian randomized clinical trial comparing laparoscopic and conventional open surgical treatments for colon cancer: the Australasian Laparoscopic Colon Cancer Study trial.

OBJECTIVE: : We report a multicentered randomized controlled trial across Australia and New Zealand comparing laparoscopic-assisted colon resection (LCR) with open colon resection (OCR) for colon cancer. BACKGROUND: : Colon cancer is a significant worldwide health issue. This trial investigated whether the short-term benefits associated with LCR for colon cancer could be achieved safely, without survival disadvantages, in our region. METHODS: : A total of 601 patients with potentially curable colon cancer were randomized to receive LCR or OCR. Primary endpoints were 5-year overall survival, recurrence-free survival, and freedom from recurrence rates, compared using an intention-to-treat analysis. RESULTS: : On April 5, 2010, 587 eligible patients were followed for a median of 5.2 years (range, 1 week-11.4 years) with 5-year confirmed follow-up data for survival and recurrence on 567 (96.6%). Significant differences between the 2 trial groups were as follows: LCR patients were older at randomization, and their pathology specimens showed smaller distal resection margins; OCR patients had some worse pathology parameters, but there were no differences in disease stages. There were no significant differences between the LCR and OCR groups in 5-year follow-up of overall survival (77.7% vs 76.0%, P = 0.64), recurrence-free survival (72.7% vs 71.2%, P = 0.70), or freedom from recurrence (86.2% vs 85.6%, P = 0.85). CONCLUSIONS: : In spite of some differences in short-term surrogate oncological markers, LCR was not inferior to OCR in direct measures of survival and disease recurrence. These findings emphasize the importance of long-term data in formulating evidence-based practice guidelines.

Short-term outcomes of the Australasian randomized clinical study comparing laparoscopic and conventional open surgical treatments for colon cancer: the ALCCaS trial.

BACKGROUND: Laparoscopy has revolutionized many abdominal surgical procedures. Laparoscopic colectomy has become increasingly popular. The short- and long-term benefits and satisfactory surgical oncological treatment of colorectal cancer by laparoscopic-assisted resection remain topical. The long-term outcomes of all international randomized controlled trials are still awaited, and short-term outcomes are important in the interim. METHODS: Between January 1998 and April 2005, a multicenter, prospective, randomized clinical trial in patients with colon cancer was conducted. Six hundred and one eligible patients were recruited by 33 surgeons from 31 Australian and New Zealand centers. Patients were allocated to colectomy by either laparoscopic-assisted surgery (n = 294) or open surgery (n = 298). Patient demographics and secondary end-points, such as operative and postoperative complications, length of hospital stay, and histopathological data, will be presented in this article. Analysis was by intention-to-treat. Survival will be reported only as the study matures. RESULTS: Histopathological parameters were similar between the two groups, except in regard to distal resection margins. There was no statistically significant difference found in postoperative complications, reoperation rate, or perioperative mortality. Statistically significant differences in quicker return of gastrointestinal function and shorter hospital stay were identified in favor of laparoscopic-assisted resection. A statistically significant increased rate of infective complications was seen in cases converted from laparoscopic-assisted to open procedures but with no difference in reoperation or in-hospital mortality. CONCLUSIONS: Laparoscopic-assisted colonic resection gives significant improvements in return of gastrointestinal function and length of stay, with an increased operative time and no difference in the postoperative complication rate.

Ethical issues with the disclosure of surgical trial short-term data.

BACKGROUND: This paper describes the distinctions between major surgical and pharmaceutical trials and questions the application of a common ethical paradigm to guide their conduct and reporting. METHODS: Surgical trials differ from other trials in cumulative therapeutic effects, operator dependence, the clinical setting, interdependence of short- and long-term outcomes, and equipoise. A principal tenant of randomized controlled trial management is the maintenance of interim data confidentiality. Its application to complete surgical short-term data is examined across a variety of common clinical trial circumstances that influence data integrity and the reliability of conclusions regarding the benefit-to-risk profile of experimental interventions. RESULTS: Complete perioperative results describe important treatment ends that cannot influence primary outcomes. These short-term results may inform patient consent, teaching and provide valuable procedural insights to surgeons outside trial precincts. CONCLUSION: Structured experimentation standards are necessary. But, the common paradigm applied across all clinical trials and the prohibition on short term data reporting may not serve the achievement of safe and effective advancements in surgery.

Australian and New Zealand study comparing laparoscopic and open surgeries for colon cancer in adults: organization and conduct.

This article describes the initiation and implementation of the multicentre Australia and New Zealand prospective randomized controlled clinical study comparing laparoscopic and conventional open surgical treatments of right-sided and left-sided potentially curable colon cancer (Australasian Laparoscopic Colon Cancer Study). Six hundred and one adult patients were admitted with a clinical diagnosis of a single adenocarcinoma based on a physical examination and colonoscopy, barium enema or computed tomography scan and randomly allocated to either laparoscopic or open surgery. The primary aim of the study is to compare 5-year mortality and tumour recurrence rates between the two groups. Secondary aims include comparisons of safety (intraoperative and early postoperative complications, wound site recurrence, postoperative recovery and 30-day mortality), quality of life, in-hospital costs and short-term mortality and tumour recurrence. The data for 592 patients have been collected. There are currently 3141 person years of follow up. In all 370 patients have been assessed at 5 years. This study shows that large cooperative Australia-New Zealand surgical trials can and should be carried out to address significant clinical issues. When possible, coherence with similar, concurrent international trial protocols ensures broader analyses and applicability of results. It is important to recognize that special attention to sustained funding, surgeon credentialing, clinical protocol standardization, data management, publication policy and the protection of study credibility is required from the outset. The Australasian Laparoscopic Colon Cancer Study will achieve its aims with 5-year assessments of all entered patients in March 2010.

Evidence that the notochord may be pivotal in the development of sacral and anorectal malformations.

BACKGROUND/PURPOSE: The notochord is known to organize normal development of central axial structures, such as the spinal cord, vertebral column, and anorectum, but its role in abnormal development of these organs has not been well documented. The current study has used Ethylenethiourea to induce anorectal malformations in fetal rats, allowing investigation of abnormalities of the notochord and their relationship to the axial structural abnormalities that occur. METHODS: Timed-mated pregnant rats were fed Ethylenethiourea by gavage on gestational day 10. Their embryos were harvested on gestational days 13 to 16 and sectioned in either the transverse or sagittal plane. Sections were stained with H and E and examined serially. RESULTS: Anorectal malformations were identified in 29 of 34 embryos and neural tube defects in 24, ranging from an accessory neural tube to lumbo-sacral rachischisis. There was no tail or only a rudimentary tail in the majority of embryos. Abnormalities of the notochord in the lumbo-sacral area included ventro-dorsal branching, ventral deviation, and ectopic notochordal tissue. Most abnormal notochord branches and ectopic notochordal tissue were abnormally close to or in contact with the wall of the cloaca or neural tube. CONCLUSIONS: Given the known role of the notochord in controlling normal development, this study would suggest that abnormal notochord development may be pivotal in producing neural tube defects and anorectal malformations, possibly by altering sonic hedgehog signalling.