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AIM Clinical presentation with large bowel obstruction has been proposed as a predictor of poor long-term oncological outcomes after resection for colorectal cancer. This study examines the association between obstruction and recurrence and cancer-specific death after resection for colon cancer. METHOD Consecutive patients who underwent resection for colon cancer between 1995 and 2014 were drawn from a prospectively recorded hospital database with all surviving patients followed for at least 5 years. The outcomes of tumour recurrence and colon cancer-specific death were assessed by competing risks multivariable techniques with adjustment for potential clinical and pathological confounding variables. RESULTS Recurrence occurred in 271 of 1485 patients who had a potentially curative resection. In bivariate analysis, obstruction was significantly associated with recurrence [hazard ratio (HR) 2.23, CI 1.52-3.26, p

Objective To examine the independent prognostic value of ALN status in patients with stage III CRC. Summary of background data Early CRC staging classified nodal involvement by level of involved nodes in the operative specimen, including both locoregional and apical node status, in contrast to the American Joint Committee on Cancer/tumor nodes metastasis (TNM) system where tumors are classified by the number of nodes involved. Whether ALN status has independent prognostic value remains controversial. Methods Consecutive patients who underwent curative resection for Stage III CRC from 1995 to 2012 at Concord Hospital, Sydney, Australia were studied. ALN status was classified as: (i) ALN absent, (ii) ALN present but not histologically involved, (iii) ALN present and involved. Outcomes were the competing risks incidence of CRC recurrence and CRC-specific death. Associations between these outcomes and ALN status were compared with TNM N status results. Results In 706 patients, 69 (9.8%) had an involved ALN, 398 (56.4%) had an uninvolved ALN and 239 (33.9%) had no ALN identified. ALN status was not associated with tumor recurrence [adjusted hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.84-1.26] or CRC-specific death (HR 1.14, CI 0.91-1.43). However, associations persisted between TNM N-status and both recurrence (HR 1.58, CI 1.21-2.06) and CRC-specific death (HR 1.59, CI 1.19-2.12). Conclusions No further prognostic information was conferred by ALN status in patients with stage III CRC beyond that provided by TNM N status. ALN status is not considered to be a useful additional component in routine TNM staging of CRC.

Background Postoperative mortality after colorectal cancer surgery varies across hospitals and countries. The aim of this study was to test the Association of Coloproctologists of Great Britain and Ireland (ACPGBI) models as predictors of 30‐day mortality in an Australian cohort. Methods Data from patients who underwent surgery in six hospitals between 1996 and 2015 (CRC data set) were reviewed to test ACPGBI models, and patients from 79 hospitals in the Bi‐National Colorectal Cancer Audit between 2007 and 2016 (BCCA data set) were analysed to validate model performance. Recalibrated models based on ACPGBI risk models were developed, tested and validated on a data set of Australasian patients. Results Of 18 752 patients observed during the study, 6727 (CRC data set) and 3814 (BCCA data set) were analysed. The 30‐day mortality rate was 1·1 and 3·5 per cent in the CRC and BCCA data sets respectively. Both the original and revised ACPGBI models overestimated 30‐day mortality for the CRC data set (observed to expected (O/E) ratio 0·17 and 0·21 respectively). Their ability to correctly predict mortality risk was poor (P, The aim was to test the Association of Coloproctologists of Great Britain and Ireland (ACPGBI) original (2003) and revised (2010) models as predictors of 30‐day mortality in an Australian patient cohort, and then recalibrate these models using data from Australian patients. This study included 10 541 patients treated over a 20‐year interval in Australia and New Zealand. The ACPGBI models overestimated 30‐day mortality, and so both ACPGBI models should be used with caution in Australia. Mortality risk prediction after colorectal surgery

Aim Despite numerous reports over three decades, the association between perioperative blood transfusion and long-term outcomes after resection of colorectal cancer remains controversial. This cohort study used competing risks statistical methods to examine the association between transfusion and recurrence and colorectal cancer-specific death after potentially curative and noncurative resection. Method A hospital database provided prospectively recorded clinical, operative and follow-up information. All surviving patients were followed for at least 5 years. Data were analysed by multivariable competing risks regression. Results From 2575 patients in the period 1995-2010 inclusive, after exclusions, 2334 remained for analysis. Among 1941 who had a potentially curative resection and 393 who had a noncurative resection the transfusion rates were 24.9% and 33.6%, respectively. After potentially curative resection there was no significant bivariate association between transfusion and recurrence (HR 0.93, CI 0.74-1.16, P = 0.499) or between transfusion and colorectal cancer-specific death (HR 1.04, CI 0.82-1.33, P = 0.753). After noncurative resection there was no significant association between transfusion and cancer-specific death (HR 0.93, CI 0.73-1.19, P = 0.560). Multivariable models showed no material effect of potential confounder variables on these results. Conclusion The competing risks findings in this study showed no significant association between perioperative transfusion and recurrence or colorectal cancer-specific death.

For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status. A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration. From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73–0.90), DFS (OR, 0.73; 95% CI 0.66–0.81) and DSS (OR, 0.69; 95% CI 0.52–0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit. MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.

Background There is significant variation in attitude both towards the role of microsatellite instability (MSI) in predicting prognosis, and towards its role in guiding which Stage II colon cancer patients may benefit from adjuvant chemotherapy. Aim To examine the current status of specialist attitudes towards MSI in guiding prognosis and adjuvant therapy in stage II colon cancer. Methods The Pathology in Colon Cancer, Prognosis and Uptake of Adjuvant Therapy (PiCC UP) Australia and New Zealand questionnaire was distributed to colorectal surgeons, medical oncologists and pathologists after institutional board approval. A 5-scale Likert score was used to assess attitudes towards 23 pathological features for prognosis and 18 features for adjuvant therapy. Data were analysed using a rating scale and graded response model in item response theory (IRT) on STATA (Stata MP, version 15; StataCorp LP). Results 164 specialists (45 oncologists, 86 surgeons and 33 pathologists) participated. 80.5% regularly attended colorectal multidisciplinary team (MDT) meetings. 89.63% and 59.26% of specialists reported that MSI status was likely or definitely to influence prognosis in colon cancer and recommendations for adjuvant therapy in Stage II colon cancer respectively. IRT modelling was achieved in 17 pathological features for prognosis. MSI IRT score was 4.47 (95% CI: 4.05-4.68). IRT modelling was achieved in 10 pathological features for adjuvant therapy. MSI IRT score was 3.62 (2.89-4.15). MSI ranked 10 (of 17) in order of importance in determining prognosis and ranked three (of 10) in guiding adjuvant therapy. Conclusion MSI status is considered an important biomarker when selecting patients for adjuvant therapy in Stage II colon cancer. MSI is also considered useful in prognostication of colon cancer. MSI status was ranked similar to the tumour grade of differentiation and the presence of perineural invasion.

Conventionally, lymphatic spread is regarded as the principal mechanism by which haematogenous metastasis occurs in colorectal cancer. The aim of this cross sectional study was to determine the relative strengths of direct tumour spread, the presence of lymph node metastasis and histologically demonstrated venous invasion as drivers of haematogenous metastasis diagnosed at the time of resection of colorectal cancer. The data were drawn from a hospital database of consecutive bowel cancer resections between 1995 and 2017 inclusive. The presence of haematogenous metastasis was determined at the time of surgery by imaging or other investigations or operative findings. Where possible, histological confirmation was obtained. Specimen dissection and reporting followed a standardised procedure. Tumour staging was according to the 7th edition of the UICC/AJCC pTNM system. Analysis was by multivariable logistic regression. After exclusions 3133 patients remained, among whom 380 (12.1%) had one or more haematogenous metastases. In bivariate analyses, the frequency of haematogenous metastasis was directly associated with increasing T status (p

Microsatellite instability (MSI) in colorectal cancer (CRC) is a marker of immunogenicity and is associated with an increased abundance of tumour infiltrating lymphocytes (TILs). In this subgroup of colorectal cancer, it is unknown if these characteristics translate into a measurable difference in circulating tumour cell (CTC) release into peripheral circulation. This is the first study to compare MSI status with the prevalence of circulating CTCs in the peri-operative colorectal surgery setting. For this purpose, 20 patients who underwent CRC surgery with curative intent were enrolled in the study, and peripheral venous blood was collected at pre- (t1), intra- (t2), immediately post-operative (t3), and 14&ndash, 16 h post-operative (t4) time points. Of these, one patient was excluded due to insufficient blood sample. CTCs were isolated from 19 patients using the IsofluxTM system, and the data were analysed using the STATA statistical package. CTC number was presented as the mean values, and comparisons were made using the Student t-test. There was a trend toward increased CTC presence in the MSI-high (H) CRC group, but this was not statistically significant. In addition, a Poisson regression was performed adjusting for stage (I-IV). This demonstrated no significant difference between the two MSI groups for pre-operative time point t1. However, time points t2, t3, and t4 were associated with increased CTC presence for MSI-H CRCs. In conclusion, there was a trend toward increased CTC release pre-, intra-, and post-operatively in MSI-H CRCs, but this was only statistically significant intra-operatively. When adjusting for stage, MSI-H was associated with an increase in CTC numbers intra-operatively and post-operatively, but not pre-operatively.

Aim The recommended standard of care for patients after resection of Stage III colon cancer is adjuvant 5-fluorouracil based chemotherapy - FOLFOX (fluorouracil, leucovorin with oxaliplatin) - or CAPOX (capecitabine, oxaliplatin). This may be modified in older patients or depending on comorbidity. This has been challenged recently as the apparent benefit of adjuvant chemotherapy may arise from improvements in surgery or preoperative imaging or pathology staging. This study compares recurrence and colon-cancer-specific death between patients who received postoperative adjuvant chemotherapy and those who did not. Method Prospectively recorded data from 363 consecutive patients who had a resection for Stage III colonic adenocarcinoma between 1995 and 2010 inclusive were analysed. Surviving patients were followed for at least 5 years. The suitability of patients for chemotherapy was discussed routinely at multidisciplinary team meetings. The incidence of recurrence and colon-cancer-specific death was evaluated by competing risk methods. Results After adjustment for the competing risk of non-colorectal cancer death, there was no significant difference in recurrence between the 204 patients who received chemotherapy and the 159 who did not [hazard ratio (HR) 0.94, 95% CI 0.66-1.32, P = 0.700) and no significant difference in colon-cancer-specific death (HR 0.73, 95% CI 0.50-1.04, P = 0.084; HR 0.88, 95% CI 0.57-1.36, P = 0.577 after adjustment for relevant covariates). Conclusion These findings question the routine use of chemotherapy after complete mesocolic excision for Stage III colon cancer. Recurrence and cancer-specific death, assessed by competing risk methods, should be the standard outcomes for evaluating the effectiveness of adjuvant chemotherapy after potentially curative resection.

BACKGROUND While most colorectal cancer (CRC) recurrences reportedly occur within 3 years following curative treatment, many studies are limited by short-term follow-up. This study examines the time to recurrence of CRC in a large Australian cohort with a long follow-up period and assesses whether time to recurrence has changed over time. METHODS A comprehensive prospective database of patients undergoing resection for CRC is maintained at Concord Hospital, Sydney. Demographic and time to recurrence data were extracted for patients who developed a recurrence following potentially curative resection for colon cancer from 1995 to 2010 and rectal cancer from 1971 to 2010. Non-deceased patients had a minimum of 5 years follow-up. RESULTS Between 1995 and 2010, 2575 patients with CRC underwent surgery. After exclusions, 386 had recurrence following potentially curative resection, ranging from 1 to 172.5 months (median 20.3) after treatment. Within 1 year, 27.5% recurred, 57.5% by 2 years, 74.6% by 3 years, 85.5% by 4 years and 89.6% by 5 years. There was no difference in time to recurrence between colon and rectal cancers (P = 0.674). Among patients having a potentially curative resection for rectal cancer between 1971 and 2010, 386 recurred. There was no difference in time to recurrence by decade (P = 0.863). CONCLUSION The majority of recurrences occurred within 3 years of curative treatment. Had surveillance been limited to 5 years, detection of more than 10% of recurrences would have been delayed. Time to recurrence for rectal cancer has not changed in over 40 years, despite treatment advances.

Aim The aim of this study was to investigate the detailed, in situ, morphology of Denonvilliers fascia (DVF) in cadavers using sheet plastination and confocal microscopy and to review and describe the optimal anterior plane for mobilisation of the distal rectum.. Method Six, male cadavers (age range, 46-87 years) were prepared as six sets of transverse (x2), coronal (x1) and sagittal (x3) plastinated sections which were examined under a confocal laser scanning microscope. Results In this study a consistent space between the anterior rectal wall and the posterior surface of the prostate and seminal vesicles above the level of the perineal body was termed the prerectal space. Within that prerectal space we identified fibres which take their origin from the external urethral sphincter (EUS), together with others from the longitudinal rectal muscle (LRM) and the connective tissue sheaths of neurovascular bundles. Neither the EUS- nor the LRM-originated fibres were continuous with the endopelvic fascia;they are interposed laterally and cranially by multiple neurovascular bundles. Further, our results suggest that the peritoneum does not descend deep within the prerectal space. Conclusion This study reveals the undisturbed, in situ, structural detail of membrane-like structures in the prerectal space and confirms that the optimal plane for anterolateral mobilization of the rectum is posterior to the multilayered DVF. This article is protected by copyright. All rights reserved.

Confusion remains as to what is meant by Denonvilliers' fascia. This review searched the literature on pelvic surgical anatomy to determine whether there is agreement with Denonvilliers' original description and its implication in defining the correct anterior plane of dissection when mobilizing the rectum. The original French description of the fascia was translated into English and then compared both with French and with English studies identified by searching PubMed, Medline and Scopus from 1836 to June 2015. Special emphasis was given to the years between 1980 and 2015 in order to capture the literature pertinent to, and following on from, the description of total mesorectal excision for rectal cancer. The final literature search revealed 16 studies from the original 2150 citations. Much of the debate was concerned with the origin and development of the fascia, arising from either the 'fusion' or the 'condensation' of local primitive tissue into a mature 'multilayered' structure. Controversy regarding the correct plane of rectal mobilization occurs as a result of different interpretations by surgeons, anatomists and radiologists and bears little resemblance to Denonvilliers' original description. This may reflect wide anatomical variability in the adult pelvis or a form of dissection artefact. Further study is required to investigate this. Logically, for both men and women, the plane of rectal mobilization should be behind Denonvilliers' fascia and between it and the fascia propria of the rectum.

BACKGROUND The aim of this study was to describe temporal trends in presentation, surgical management and immediate postoperative outcomes in patients recorded in a registry of colorectal cancer resections that was initiated at Concord Hospital, Sydney, Australia, in 1971. A companion paper describes tumour pathology and long-term recurrence and survival. METHODS This report is based on 5217 consecutive resections up to 2013, with no exclusions. Categories in variables examined were expressed as percentages over annual totals of relevant patients or annual mean values. The statistical significance of trends was examined by least squares regression. RESULTS The percentage of asymptomatic patients increased over time, whereas urgent presentations declined. Tumour size declined. The percentage of rectal cancers fell but the percentage of low rectal tumours rose. Initially, restorative rectal resections increased rapidly but later remained stable. There was no trend in medical complications, whereas surgical complications declined. Anastomotic leakage after restorative rectal resections declined but it was low and stable for colonic tumours. The rate of early reoperation remained stable, whereas 30-day mortality declined. Neoadjuvant radiotherapy for rectal cancer and adjuvant chemotherapy for stages B and C were introduced in 1992 and applied increasingly thereafter. CONCLUSION Our findings, based on a 43-year prospective study, indicate sustained trends towards the earlier diagnosis of colorectal cancer and favourable short-term outcomes following bowel resection.

BACKGROUND The aim of this study was to describe temporal trends in tumour pathology and long-term outcomes in 5217 patients recorded in a registry of colorectal cancer resections initiated at Concord Hospital, Sydney, Australia, in 1971. METHODS This report is based on consecutive resections up to December 2013, with no exclusions. Categories in variables examined were expressed as percentages over annual totals of relevant patients or annual mean values. The statistical significance of temporal trends was examined by least squares regression. RESULTS The percentages of patients with local spread beyond the muscularis propria, nodal metastasis, distant metastasis and tumour in a line of resection all declined significantly. In consequence, the percentage of stage D patients fell, whereas the percentage in stage A rose. Other tumour variables that increased significantly were polypoid morphology, contiguous adenoma and invasion of a free serosal surface. Tumours in which an adherent adjacent structure was partly or completely removed also increased. There were significant declines in high-grade malignancy, venous invasion and tumour size. The recurrence rate for rectal cancers declined significantly, whereas for rectal and colonic cancers combined, both the overall 5-year survival rate and the 5-year cancer-specific survival rate increased markedly. CONCLUSION These results show a reduction in adverse pathology findings and favourable trends in recurrence and survival after colorectal cancer resections in a high-incidence country over a period of 43 years.

Aim Complete mesocolic excision (CME) has been advocated as likely to improve the long-term oncological outcome of colon cancer resection, although there is a paucity of long-term results in the literature. The aim of this study was to supplement our previously published results on colon cancer resection based on a standardized technique of precise dissection along anatomical planes with high vascular ligation and to compare our long-term results with those of recent European studies of CME. Method Data were drawn from a prospective hospital registry of consecutive resections for colon cancer between 1996 and 2007, including follow-up to the end of 2012. The principal outcomes from potentially curative resections were 5-year Kaplan–Meier rates of local recurrence, systemic recurrence, overall survival and cancer-specific survival. Secondary outcomes for all resections were postoperative complications, number of lymph nodes retrieved and R0 status. Results For 779 potentially curative resections the local recurrence rate was 2.1% (95% CI 1.3–3.4), the systemic recurrence rate was 10.2% (95% CI 8.1–12.7), the 5-year overall survival rate was 76.2% (95% CI 73.0–79.0) and the cancer-specific survival rate was 89.8% (95% CI 87.3–91.9). For all 905 resections, rates of 14 surgical complications were low and not dissimilar to those in a comparable study. The median lymph node count was 15 (range 0–113). R0 status was confirmed in 883/905 patients (97.6%; 95% CI 96.4–98.5). Conclusion For colon cancer, meticulous dissection along anatomical planes together with high vascular ligation results in few complications, a high R0 rate, low recurrence and high survival.

The pTNM staging system for colorectal cancer (CRC) is not entirely effective in discriminating between potentially curative and non-curative resections because it does not account for local residual tumour in patients with stages I, II or III. This study aimed to evaluate the prognostic importance of histologically verified tumour in any line of resection of the bowel resection specimen (TLR) in relation to pTNM stages and to demonstrate how TLR may be integrated into pTNM staging. Information on patients in the period 1995 to 2010 with complete follow-up to the end of 2015 was extracted from a prospective database of CRC resections. The outcome variables were the competing risks incidence of CRC recurrence and CRC-specific death. After exclusions, 2220 patients remained. In 1930 patients with pTNM stages I-III tumour, recurrence was markedly higher in those with TLR than in those without (HR 6.0, 95% CI 4.2-8.5, p 0.001) and this persisted after adjustment for covariates associated with recurrence. CRC-specific death was markedly higher in the presence of TLR (HR 7.7, CI 5.3-11.2, p 0.001), which persisted after adjustment for relevant covariates. These results justify removing patients with TLR from pTNM stages I to III and placing them in stage IV, thereby allowing the categorisation of all patients with any known residual tumour into three prognostically distinct groups. This study demonstrates how TLR may be integrated into pTNM staging, thus improving the definition of the three stages which are considered potentially curable (I, II and III).

Purpose The REMARK guidelines give authors comprehensive and specific advice on the complete and transparent reporting of studies of prognostic tumor markers. The aim of this study was to use the REMARK guidelines to evaluate the quality of reporting in a sample of studies assessing tissue-based protein markers for survival after resection of colorectal cancer. Experimental design Eighty pertinent articles were scored according to their conformity to 26 items derived from the REMARK criteria. Results Overall, on a scale of adequacy of reporting that potentially ranged from 26 to 78, the median for these studies was 60 (interquartile range 54–64) and several criteria were adequately covered in a large proportion of studies. However, others were either not dealt with or inadequately covered, including description of the study design (35%), definition of survival endpoints (48%), adjuvant therapy (54%), follow-up procedures and time (59%), neoadjuvant therapy (63%), inclusion/exclusion criteria (73%), multivariable modeling methods and results (74%), and discussion of study limitations (85%). Conclusions and clinical relevance Inadequacies in presentation militate against comparability among protein marker studies and undermine the generalizability of their findings. The quality of reporting could be improved if journal editors were to require authors to ensure that their work satisfied the REMARK criteria.

Extensive surface profiles of colorectal cancer (CRC) cells and tumor infiltrating lymphocytes (TIL) have been obtained from 45 surgical resection samples. Live cells were captured on an antibody microarray and stained with fluorescently-labeled antibodies. Minimal panels of 11 CRC antigens (CD13, CD24, CD26, CD49d, CD138, CD166, CA-125, CA19-9, EGFR, Galectin-4 and HLA-DR) and 11 T-cell antigens (CD10, CD11b, CD11c, CD25, CD31, CD95, CD151, CD181, Galectin-4, CA19-9, TSP-1) provide signatures for relapse and survival. Hierarchical clustering of profiles from CRC cells and TIL identified groups of patients for survival, systemic relapse and death. The groups from CRC and TIL profiles for systemic relapse showed 79.2% concordance, enabling prediction of relapse after surgery. The results demonstrate communication between CRC cells and TIL.

Background To our knowledge, immediate post-operative complication rates after resection of colorectal cancer (CRC) have not been compared between public and private hospitals in the Australian health care system. We compared the frequency of surgical and medical complications between a public tertiary referral hospital and a private hospital. Methods Data were drawn from a prospective registry of all patients having a resection for CRC between 2000 and 2010 performed by members of the Concord Hospital colorectal surgical unit, either at this hospital or at a single private hospital with which they were affiliated. Complication rates were compared after adjustment for preoperative and perioperative features by logistic regression. Results Among the 16 surgical complications, the only significant difference after adjustment for other features was a higher rate of septicaemia in the public hospital (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.1–4.6). Among the seven medical complications, the only significant differences were a higher risk of cardiac complications in patients with cardiac co-morbidity (OR 1.8, 95% CI 1.1–3.0) and of respiratory complications in patients without respiratory co-morbidity (OR 3.1, 95% CI 2.2–5.9) in the public hospital. Conclusion In this study, where the same group of surgeons performed all reported CRC resections in the two hospitals, no independent effect of the type of hospital was found on 15 of 16 surgical complications and 5 of 7 medical complications. Type of hospital had no impact on rates of specific complications apart from septicaemia and cardiorespiratory complications, which were higher in the public hospital.

Colonic and rectal cancers differ in their clinicopathologic features and treatment strategies. Molecular markers such as gene methylation, microsatellite instability and KRAS mutations, are becoming increasingly important in guiding treatment decisions in colorectal cancer. However, their association with clinicopathologic variables and utility in the management of rectal cancer is still poorly understood. We analyzed CDKN2A gene methylation, CpG island methylator phenotype (CIMP), microsatellite instability and KRAS/BRAF mutations in a cohort of 381 rectal cancers with extensive clinical follow-up data. BRAF mutations (2%), CIMP-high (4%) and microsatellite instability-high (2%) were rare, whereas KRAS mutations (39%), CDKN2A methylation (20%) and CIMP-low (25%) were more common. Only CDKN2A methylation and KRAS mutations showed an association with poor overall survival but these did not remain significant when analyzed with other clinicopathologic factors. In contrast, this prognostic effect was strengthened by the joint presence of CDKN2A methylation and KRAS mutations, which independently predicted recurrence of cancer and was associated with poor overall and cancer-specific survival. This study has identified a subgroup of more aggressive rectal cancers that may arise through the KRAS-p16 pathway. It has been previously shown that an interaction of p16 deficiency and oncogenic KRAS promotes carcinogenesis in the mouse and is characterized by loss of oncogene-induced senescence. These findings may provide avenues for the discovery of new treatments in rectal cancer.

OBJECTIVE: Prolonged ileus-the failure of postoperative ileus to resolve within a few days after major abdominal surgery-leads to significant medical consequences for the patient and costs to the hospital system. The aim of this retrospective analysis of prospectively collected data was to identify independent preoperative and intraoperative risk factors for prolonged ileus in a large consecutive series of patients who had undergone resection for colorectal cancer. METHODS: Patients were drawn from a hospital registry of 2400 consecutive resections over the period 1995-2009. Thirty-four potential predictors of prolonged ileus were analyzed by logistic regression. RESULTS: Prolonged ileus occurred in 14.0% of patients. Statistically significant independent predictors of prolonged ileus were male sex (OR: 1.7, P < 0.001), peripheral vascular disease (OR: 1.8, P < 0.001), respiratory comorbidity (OR: 1.6, P < 0.001), resection at urgent operation (OR: 2.2, P < 0.001), perioperative transfusion (OR: 1.6, P < 0.010), stoma constructed (OR: 1.4, P < 0.001), and operation lasting ≥3 hours (OR: 1.6, P < 0.001). CONCLUSIONS: These features can be used to alert medical and nursing staff to patients likely to experience prolonged ileus after bowel resection so that they can be monitored closely in the postoperative period and available treatments targeted toward them. These features may also be useful in the research context to facilitate the more efficient selection of high-risk patients as subjects in clinical trials of prevention or treatment.

Background Despite an extensive literature suggesting that high microsatellite instability (MSI-H) enhances survival and protects against recurrence after colorectal cancer resection, such effects remain controversial as many studies show only a weak bivariate association or no multivariable association with outcome. This study examined the relationship between MSI status and colorectal cancer outcomes with adjustment for death from other causes as a competing risk. Methods A hospital database of patients following colorectal cancer resection was interrogated for clinical, operative, pathology, adjuvant therapy and follow-up information. MSI-H status was determined by immunohistochemistry for mismatch repair protein deficiency. The cumulative incidence of recurrence and colorectal cancer-specific death was evaluated by competing risks methods. Results Among 1009 patients who had a resection between August 2002 and December 2008, and were followed to at least December 2013, there were 114 (11·3 per cent) with MSI-H (72·8 per cent aged at least 70 years; 63·2 per cent women). After potentially curative resection, with adjustment for non-colorectal cancer death as a competing risk and adjustment for 22 clinical, operative and pathological variables, there was no association between MSI-H and recurrence (hazard ratio (HR) 0·81, 95 per cent c.i. 0·42 to 1·57) or colorectal cancer-specific death (HR 0·73, 0·39 to 1·35) in this patient population. For palliative resections, there was no association between MSI-H and colorectal cancer-specific death (HR 0·65, 0·21 to 2·04). MSI-H was associated with non-colorectal cancer death after both curative (HR 1·55, 1·04 to 2·30) and palliative (HR 3·80, 1·32 to 11·00) resections. Conclusion Microsatellite instability status was not an independent prognostic variable in these patients.

The aim of this study was to describe temporal trends in presentation, surgical management and immediate postoperative outcomes in patients recorded in a registry of colorectal cancer resections that was initiated at Concord Hospital, Sydney, Australia, in 1971. A companion paper describes tumour pathology and long-term recurrence and survival.This report is based on 5217 consecutive resections up to 2013, with no exclusions. Categories in variables examined were expressed as percentages over annual totals of relevant patients or annual mean values. The statistical significance of trends was examined by least squares regression.The percentage of asymptomatic patients increased over time, whereas urgent presentations declined. Tumour size declined. The percentage of rectal cancers fell but the percentage of low rectal tumours rose. Initially, restorative rectal resections increased rapidly but later remained stable. There was no trend in medical complications, whereas surgical complications declined. Anastomotic leakage after restorative rectal resections declined but it was low and stable for colonic tumours. The rate of early reoperation remained stable, whereas 30-day mortality declined. Neoadjuvant radiotherapy for rectal cancer and adjuvant chemotherapy for stages B and C were introduced in 1992 and applied increasingly thereafter.Our findings, based on a 43-year prospective study, indicate sustained trends towards the earlier diagnosis of colorectal cancer and favourable short-term outcomes following bowel resection.

The aim of this study was to describe temporal trends in tumour pathology and long-term outcomes in 5217 patients recorded in a registry of colorectal cancer resections initiated at Concord Hospital, Sydney, Australia, in 1971.This report is based on consecutive resections up to December 2013, with no exclusions. Categories in variables examined were expressed as percentages over annual totals of relevant patients or annual mean values. The statistical significance of temporal trends was examined by least squares regression.The percentages of patients with local spread beyond the muscularis propria, nodal metastasis, distant metastasis and tumour in a line of resection all declined significantly. In consequence, the percentage of stage D patients fell, whereas the percentage in stage A rose. Other tumour variables that increased significantly were polypoid morphology, contiguous adenoma and invasion of a free serosal surface. Tumours in which an adherent adjacent structure was partly or completely removed also increased. There were significant declines in high-grade malignancy, venous invasion and tumour size. The recurrence rate for rectal cancers declined significantly, whereas for rectal and colonic cancers combined, both the overall 5-year survival rate and the 5-year cancer-specific survival rate increased markedly.These results show a reduction in adverse pathology findings and favourable trends in recurrence and survival after colorectal cancer resections in a high-incidence country over a period of 43 years.

Aim The study aimed to compare recent reports on standard and alternative methods of abdominoperineal excision for low rectal cancer regarding the rates of circumferential resection margin involvement and intra-operative bowel perforation. Method Data on rates of margin involvement and perforation were obtained from eight recently published reports and also from a prospective registry of resections at Concord Hospital. Rates of these outcomes and their 95% confidence intervals were evaluated. Results There was no evidence that extralevator abdominoperineal excision yielded significantly lower rates of resection margin involvement or intra-operative bowel perforation compared with standard abdominoperineal excision in six independent hospital- and population-based patient series. Abdominosacral resection of the rectum, on the other hand, did show significantly lower rates of these endpoints, albeit in selected patients. Conclusion The role of extralevator abdominoperineal excision and abdominosacral resection of the rectum should be investigated further in randomized controlled trials.

Aims: Controversy continues regarding the treatment of patients with resectable rectal cancer, particularly in regard to the effects of adjuvant therapies on long-term survival. The benefits of adjuvant chemotherapy alone in patients with stage III rectal cancer after curative resection remain unclear. The aim of this study was to compare the overall survival of patients who had received adjuvant chemotherapy after resection of a stage III rectal cancer (111 patients) with the survival of a historical control group who had surgery alone before chemotherapy was introduced (129 patients). Methods: Treatment and outcomes data were drawn from a prospective hospital registry of consecutive patients who had a resection for stage III rectal cancer. Results: The estimated Kaplan–Meier overall 5-year survival rate in patients who received chemotherapy (68.7%, 95% CI 58.3–77.1%, log-rank P

Tan K L, Jankova L, Chan C, Fung C L-S, Clarke C, Lin B P C, Robertson G, Molloy M, Chapuis P H, Bokey L, Dent O F & Clarke S J (2011) Histopathology 59, 1057–1070 Clinicopathological correlates and prognostic significance of glutathione S-transferase Pi expression in 468 patients after potentially curative resection of node-positive colonic cancer Aims: This study investigated the association between glutathione S-transferase Pi (GST Pi) expression, histopathology and overall survival in 468 patients after resection of stage C colonic adenocarcinoma. Methods and results: Data were drawn from a prospective hospital registry of consecutive bowel cancer resections with a minimum follow-up of 5 years. Nuclear and cytoplasmic GST Pi expression, assessed by both intensity of staining and percentage of stained cells at both the central part of the tumour and the invasive tumour front, were evaluated retrospectively by tissue microarray immunohistochemistry on archival specimens. The most effective measure of GST Pi expression was the percentage of immunostained nuclei in central tumour tissue, where >40% stained was associated significantly with high grade, invasion beyond the muscularis propria, involvement of a free serosal surface or apical node, and invasion into an adjacent organ or structure. After adjustment of other predictors, GST Pi expression remained independently prognostic for reduced overall survival (hazard ratio 1.4, P = 0.002). Conclusions: In patients with clinicopathological stage C colonic cancer, GST Pi expression is associated with features of tumour aggressiveness and with reduced overall survival. Further appropriately designed studies should aim to discover whether GST Pi can predict response to adjuvant chemotherapy.

In 1991 this journal published the report of an international working party to the World Congress of Gastroenterology regarding the clinicopathological staging of colorectal cancer. Since that time staging has continued to evolve as further prognostic factors in colorectal cancer have been elucidated in studies of increasingly large databases in several countries. This review summarizes several of the key issues that have arisen during this evolutionary process and raises matters which still remain controversial in staging at the present time.

Aim Several recent studies have attempted to evaluate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting the likelihood of tumour involvement of the postoperative circumferential resection margin (CRM) in rectal cancer with the intention of selecting patients who might benefit from neoadjuvant therapy and as a guide to surgery. The aim of this study was to assess whether such studies can provide a valid answer as to whether preoperative MRI can accurately predict CRM involvement by tumour. Method The study design and methodology of studies on this topic were critically examined. Results Features identified as affecting the efficacy of these studies were: representativeness of patients, definition of the margin assessed by MRI and by histology, lack of blinding of surgeons and pathologists to MRI results, effect of neoadjuvant treatment, and number of patients studied. Conclusion Because of methodological inadequacies in studies completed to date, there is insufficient evidence of the ability of a positive MRI result to predict an involved CRM. Although MRI may be able to identify a tumour that has extended to the mesorectal fascia and/or intersphincteric plane, logically, it cannot indicate where the surgical boundary of the resection will ultimately lie, and therefore cannot validly predict an involved CRM and should not be relied upon for this purpose.

Purpose The aim of this study was to investigate the relationship between tumor budding and other pathology features and overall survival after resection of clinicopathological stage III colon cancer. Methods The number of buds and other histopathological features were assessed in 477 patients who were operated on between 1971 and 2001, with follow-up to December 2006. Overall survival was analyzed using the Kaplan-Meier method and Cox regression. Results The number of buds was dichotomized as low (0 to 8) vs high (>or=9). High budding was more common in men, in high-grade tumors, in the presence of venous invasion, and where the tumor had involved a free serosal surface, but budding was not associated with 8 other clinical and pathological features. The 5-year survival rate for patients with 0 to 8 buds was 51.0% (95% confidence interval, 44.9-55.1), whereas that for patients with 9 or more buds was 33.9% (95% confidence interval, 25.2-42.8). This association, however, disappeared after adjustment for other variables independently associated with survival (hazard ratio, 1.2; 95% confidence interval, 0.94-1.54; P = .139). Conclusion In stage III colon cancer, tumor budding did not provide additional independent prognostic information beyond that given by routine pathology reporting.

Fung C L-S, Chan C, Jankova L, Dent O F, Robertson G, Molloy M, Bokey L, Chapuis P H, Lin B P C & Clarke S J (2010) Histopathology56, 319–330 Clinicopathological correlates and prognostic significance of maspin expression in 450 patients after potentially curative resection of node-positive colonic cancer Aims: The tumour suppressor maspin has been investigated for its association with conventional histopathological features in colorectal cancer and for its potential as an independent predictor of survival and response to adjuvant chemotherapy. The aim of this study was to examine associations between maspin expression, other histopathology and survival in a large consecutive series of patients after potentially curative resection of node-positive colonic adenocarcinoma. Methods and results: Nuclear and cytoplasmic maspin expression in both superficial and deep parts of the tumour were assessed retrospectively by tissue microarray and immunohistochemistry in specimens from 450 patients whose other histopathology had been recorded in a prospective hospital registry of large bowel cancer resections from 1971 to 2001 with a minimum follow-up of 5 years. Among 13 clinicopathological features examined, the only associations that persisted across all four maspin assessments were stronger expression in right- than in left-sided tumours (P = 0.001–0.011) and stronger expression in high-grade tumours (P

Objective The aim of this study was to determine the demand for hospital resources generated by anastomotic leakage, including surgical, medical, imaging, pathology, and other allied health consultations or services and length of postoperative hospital stay. Method Data were obtained from a comprehensive, prospective hospital registry of all resections for colorectal cancer from January 1995 to December 2004 and from retrospective review of patients’ notes. Results Forty-one patients with a leak spent 92 days in intensive care, required 129 days of total parenteral nutrition, 69 days of enteric feeding and 41 days on ventilation and had a median postoperative hospital stay of 28 days (range 11–104). These patients required 24 re-operations and 2273 separate medical consultations or allied services. Conclusion Anastomotic leakage generates a very considerable demand for hospital resources and diverts these resources from the hospital population at large.

The aim of this study was to determine whether the previously noted poorer survival of men after resection of colorectal cancer varied among clinicopathological tumor stages.The question of whether sex is independently associated with prognosis after resection of colorectal cancer has been examined in numerous studies over the past 2 decades, but with conflicting results.Data on 3,301 patients were drawn from a comprehensive, prospective hospital registry of all resections for colorectal cancer performed between January 1971 and December 2005. Statistical analysis employed Kaplan Meier estimation and relative survival analysis to adjust for differential male/female life expectancy in the general population.The relative survival of males was significantly less than that of females (P = 0.004) only in stage B. This was not accounted for by other negative pathology features and cause of death did not differ significantly between males and females. However, men with stage B tumor were more likely than women to experience postoperative morbidity, particularly a respiratory complication or a surgical complication requiring urgent reoperation. The sex difference in relative survival persisted among patients who had either a respiratory complication or an urgent reoperation (P = 0.003) but disappeared among those who had neither (P = 0.193).The poorer survival of men with stage B tumor was attributable to their greater postoperative morbidity which led to the earlier death of some due to causes unrelated to their colorectal cancer.

Background: The aim of this study was to determine the extent to which pathology reporting of colorectal cancers notified to the New South Wales Central Cancer Registry during 2000 conformed to guidelines promulgated by the National Health and Medical Research Council. Methods: De-identified reports for 2233 resected specimens of primary invasive colorectal carcinoma were coded according to a standardized system to compile information on 28 clinical and pathology features. An overall score for each report was calculated by computing the number out of 13 essential features specified in the guidelines for which data had been recorded explicitly and unambiguously in the report. Results: The overall score ranged from 3 to 13 features with a mean of 9. No more than 7 features were reported explicitly in just less than one quarter of the reports and no more than 10 in three quarters. There were only 110 reports (4.9%) that included all features. Information on direct spread and nodal metastasis was well reported; resection margins less so. Many reports lacked information on metastases beyond the operative field, the involvement of deep or circumferential resection margins and tumour stage. Conclusion: In some respects pathology reports of resected colorectal cancer specimens displayed a high level of completeness. Some important features, however, were poorly described. Reporting could be improved if surgeons were to use a standardized form to convey clinical information to the pathologist and if pathologists were to report in a structured or synoptic format, explicitly recording the presence or absence of each feature in a standard list.

Objective To determine whether the presence of tumour at a free serosal surface was independently associated with pelvic recurrence or survival in patients who had a resection for clinicopathological stage B or stage C rectal cancer and who had not received adjuvant therapy. Method Data were drawn from a comprehensive, prospective hospital registry of all resections for rectal cancer from January 1971 to December 1998 with follow up to December 2003. Statistical analysis employed the χ2 test or Fisher's exact probability, Kaplan–Meier estimation and proportional hazards regression, with a significance level of ≤0.05 and 95% confidence intervals (CI). Results In 665 patients with stages B or C tumour, 35 (5.3%; CI 3.7–7.2%) had tumour at a free serosal surface. These comprised 6/332 (1.8%; CI 0.8–3.7%) patients with stage B tumour and 29/333 (8.7%; CI 6.1–12.2%) with stage C tumour. After adjustment for other relevant variables, involvement of a free serosal surface was significantly associated with pelvic recurrence [hazard ratio (HR) 2.7; CI 1.3–5.5] and diminished survival (HR 1.6; CI 1.1–2.4) but not with systemic (only) recurrence. Conclusion This study has confirmed that direct tumour spread to a free serosal surface independently predicts pelvic recurrence and diminished survival after resection of clinicopathological stage B and C rectal cancer. This feature should always be sought by the pathologist and reported when present, and noted by the surgeon and oncologist. Serosal involvement should be evaluated further for its utility in selecting patients for adjuvant therapy.

Objective: To investigate predictors of evidence-based surgical care in a populationbased sample of patients with newly diagnosed colorectal cancer. Design, patients and setting: Prospective audit of all new patients with colorectal cancer reported to the New South Wales Central Cancer Registry between 1 February 2000 and 31 January 2001. Main outcome measures: Concordance with seven guidelines from the 1999 Australian evidence-based guidelines for colorectal cancer; predictors of guideline concordance; the mean proportion of relevant guidelines followed for individual patients. Results: Questionnaires were received for 3095 patients (91.6%). Between 0 and 100% of relevant guidelines were followed for individual patients (median, 67%). Concordance with individual guidelines varied considerably. Patient age independently predicted nonconcordance with guidelines for adjuvant therapy and preoperative radiotherapy. Adjuvant chemotherapy was more likely if a patient with node-positive colon cancer was treated in a metropolitan hospital or by a general surgeon. Surgeons with a high caseload or specialty in colorectal cancer were more likely to perform colonic pouch reconstruction, prescribe thromboembolism or antibiotic prophylaxis, and were less likely to refer patients with high-risk rectal cancer for adjuvant radiotherapy. Bowel preparation was less likely among older patients and in high-caseload hospitals. Conclusion: Effective strategies to fully implement national colorectal cancer guidelines are needed. In particular, increasing the use of appropriate adjuvant therapy should be a

Objective Circumferential resection margin involvement (CRMI) after resection of rectal cancer is regarded as a risk factor for local recurrence. We have been able to identify only nine peer-reviewed English-language publications which focus primarily on this association, and they report widely differing rates of local recurrence. The aims of this study were to review possible reasons for this variability and to assess the evidence for the micrometrically measured threshold defining CRMI. Method Methodological and statistical evaluation of relevant literature. Results Several factors which could account for this variability are discussed including the nature of the patient series, surgical technique, curative vs palliative resections, pathology technique, the definition of CRMI, adjuvant therapy, tumour stage, definition and ascertainment of local recurrence, length of follow-up and method of analysis. The objective evidence for the conventional definition of CRMI as tumour 1 mm or less from a circumferential margin is considered along with the evidence supporting a recent proposal that the margin be extended to 2 mm or less. The evidence is numerically weak in both cases and we believe that neither definition should be set in concrete at this stage. Conclusion Pending further research, we recommend that routine pathology reports should record frank tumour transection, if present, or otherwise report the histological width of the margin between the tumour and the nearest circumferential line of resection in millimetres. The definition of CRMI should be simply histological evidence of tumour in a line of resection, that is, a margin of 0 mm. The definition of CRMI as a margin of 1 mm should not be adopted as a basis for assessing the quality of surgery.