Low anterior resection syndrome phenotypes-Different symptom profiles for different patients.

AIM: Attention is increasingly being turned to functional outcomes as being central to colorectal cancer (CRC) survivorship. The current literature may underestimate the impact of evacuatory dysfunction on patient satisfaction with bowel function after anterior resection (AR) for CRC. The aim of this study was to investigate the impact of post-AR symptoms of storage and evacuatory dysfunction on patient satisfaction and health-related quality of life (HRQoL). METHOD: A cross-sectional study was performed at an Australian hospital of patients post-AR for CRC (2012-2021). The postoperative bowel function scores used were: low anterior resection syndrome (LARS), St Mark's incontinence, Cleveland Clinic constipation and Altomare obstructive defaecation syndrome scores. Eight 'storage' and 'evacuatory' dysfunction symptoms were derived. A seven-point Likert scale measured patient satisfaction. The SF36v2® measured HRQoL. Linear regression assessed the association between symptoms, patient satisfaction and HRQoL. RESULTS: Overall, 248 patients participated (mean age 70.8 years, 57.3% male), comprising 103 with rectal cancer and 145 with sigmoid cancer. Of the symptoms that had a negative impact on patient satisfaction, six reflected evacuatory dysfunction, namely excessive straining (p < 0.001), one or more unsuccessful bowel movement attempt(s)/24 h (p < 0.001), anal/vaginal digitation (p = 0.005), regular enema use (p = 0.004), toilet revisiting (p = 0.004) and >10 min toileting (p = 0.004), and four reflected storage dysfunction, namely leaking flatus (p = 0.002), faecal urgency (p = 0.005), use of antidiarrhoeal medication (p = 0.001) and incontinence-related lifestyle alterations (p < 0.001). A total of 130 patients (53.5%) had 'no LARS', 56 (23.1%) had 'minor LARS' and 57 (23.4%) had 'major LARS'. Fifty-seven (44.5%) patients classified as having 'no LARS' had evacuatory dysfunction. CONCLUSION: Postoperative storage and evacuatory dysfunction symptoms have an adverse impact on patient satisfaction and HRQoL post-AR. The importance of comprehensively documenting symptoms of evacuatory dysfunction is highlighted. Further research is required to develop a patient satisfaction-weighted LARS-specific HRQoL instrument.

Apical Node Involvement Does Not Influence Prognosis After Potentially Curative Resection for Stage III Colorectal Cancer: A Competing Risks Analysis.

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.

Recurrence and colon cancer-specific death in patients with large bowel obstruction requiring urgent operation: a competing risks analysis.

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 < 0.001] but this association became nonsignificant after adjustment for confounders (HR 1.53, CI 0.95-2.46, p = 0.080). Colon cancer-specific death occurred in 238 of 295 patients who had a noncurative resection. Obstruction was not significantly associated with cancer-specific death (HR 1.02, CI 0.72-1.45, p = 0.903). In patients who had a noncurative resection, the competing risks incidence of colon cancer-specific death was not significantly greater in obstructed than in unobstructed patients (HR 1.02, CI 0.72-1.45, p = 0.903). CONCLUSION: Whilst the immediate clinical challenge of an individual patient presenting with large bowel obstruction must be addressed by the surgeon, the patient's long-term oncological outcomes are unrelated to obstruction per se.

Denonvilliers' fascia in men: a sheet plastination and confocal microscopy study of the prerectal space and the presence of an optimal anterior plane when mobilizing the rectum for cancer.

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.

KRAS mutations and CDKN2A promoter methylation show an interactive adverse effect on survival and predict recurrence of rectal cancer.

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.

Mural and extramural venous invasion and prognosis in colorectal cancer.

BACKGROUND: Extramural venous invasion is a known independent predictor of poor prognosis after resection of colorectal adenocarcinoma, but the prognostic value of mural venous invasion alone and the association between venous invasion and prognosis within tumor stages has received little research attention. OBJECTIVE: This study aimed to determine whether associations between mural and extramural venous invasion and outcome differ among tumor stages after adjustment for other factors known to influence prognosis. DESIGN: This study is a retrospective analysis of prospectively collected data. SETTINGS: Data were drawn from a registry of 3040 consecutive patients undergoing resection between 1980 and 2005 under the care of specialist surgeons in a tertiary referral public hospital and an affiliated private hospital. A standardized protocol was used for the pathological assessment of specimens. MAIN OUTCOME MEASURES: The primary outcomes measured were overall survival, cancer-specific survival, and recurrence. RESULTS: There was no significant association between venous invasion and survival in stages A (n = 544) or B (n = 1078). In stage C (n = 899), overall survival time was significantly shorter in patients with mural invasion alone or extramural invasion (both p < 0.001) than in those without invasion, and this persisted after adjustment for other prognostic variables. Equivalent bivariate associations were found in stage D, but only the effect of extramural invasion persisted after adjustment. LIMITATIONS: Our findings arise from the experience of a single surgical group and may not be generalizable to other settings. Only hematoxylin and eosin staining was used. CONCLUSIONS: The association between venous invasion and prognosis was stage specific. Both mural venous invasion alone and extramural venous invasion independently predicted overall survival in patients with stage C tumors, but not in patients with stages A, B, or D tumors. Although mural invasion alone was rare, the separate reporting of both mural and extramural invasion in patients with stage C tumor is informative and desirable.

Complete mesocolic excision for colon cancer: current status and controversies.

According to Hohenberger's original description, complete mesocolic excision for colon cancer involves precise dissection of the avascular embryonic plane between the parietal retroperitoneum and visceral peritoneum of the mesocolon. This ensures mesocolic integrity, access to high ligation of the supplying vessels at their origin and an associated extended lymphadenectomy. Results from centres which have adopted this approach routinely have demonstrated that oncological outcomes can be improved by the rigorous implementation of established principles of cancer surgery. Meticulous anatomical dissection along embryonic planes is a well-established principle of precision cancer surgery used routinely by the specialist colorectal surgeon. Therefore, the real question concerns the need for true central vascular ligation and associated extended (D3) lymphadenectomy or otherwise, particularly along the superior mesenteric vessels when performing a right colectomy. Whether this approach results in improved overall or disease-free survival remains unclear and its role remains controversial particularly given the potential for significant morbidity associated with a more extensive central vascular dissection. Current literature is limited by considerable bias, as well as inconsistent and variable terminology, and the results of established randomized trials are awaited. As a result of the current state of equipoise, various national guidelines have disparate recommendations as to when complete mesocolic excision should be performed if at all. This article aims to review the rationale for and technical aspects of complete mesocolic excision, summarize available short and long term outcome data and address current controversies.

Risk factors for prolonged ileus after resection of colorectal cancer: an observational study of 2400 consecutive patients.

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.

Right hemicolectomy anastomotic leak study: a review of right hemicolectomy in the binational clinical outcomes registry (BCOR).

BACKGROUNDS: Surgery remains mainstay management for colon cancer. Post-operative anastomotic leak (AL) carries significant morbidity and mortality. Rates of, and risk factors associated with AL following right hemicolectomy remain poorly documented across Australia and New Zealand. This study examines the Bowel Cancer Outcomes Registry (BCOR) to address this. METHODS: A retrospective cohort study was undertaken of consecutive BCOR-registered right hemicolectomy patients undergoing resection for colon cancer (2007-2021). The primary outcome measure was AL incidence. Clinicopathological data were extracted from the BCOR. Factors associated with AL and primary anastomosis were identified using logistic regression. AL-rate trends were assessed by linear regression. RESULTS: Of 13 512 patients who had a right hemicolectomy (45.2% male, mean age 72.5 years, SD 12.1), 258 (2.0%) had an AL. On multivariate analysis, male sex (OR 1.33; 95% CI 1.03-1.71) and emergency surgery (OR 1.41; 95% CI 1.04-1.92) were associated with AL. Private health insurance status (OR 0.66; 95% CI 0.50-0.88) and minimally-invasive surgery (OR 0.61; 95% CI 0.47-0.79) were protective for AL. Anastomotic technique (handsewn versus stapled) was not associated with AL (P = 0.84). Patients with higher ASA status (OR 0.47; 95% CI 0.39-0.58), advanced tumour stage (OR 0.56; 95% CI 0.50-0.63), and emergency surgery (OR 0.16; 95% CI 0.13-0.20) were less likely to have a primary anastomosis. AL-rate and year of surgery showed no association (P = 0.521). CONCLUSION: The AL rate in Australia and New Zealand following right hemicolectomy is consistent with the published literature and was stable throughout the study period. Sex, emergency surgery, insurance status, and minimally invasive surgery are associated with AL incidence.

Splenic flexure cancer survival: a 25-year experience and implications for complete mesocolic excision (CME) and central vascular ligation (CVL).

BACKGROUND: The management of splenic flexure cancers (SFCs) in the era of complete mesocolic excision (CME) and central vascular ligation (CVL) is challenging because of its variable lymphatic drainage. This study aimed to compare survival outcomes for SFCs and non-SFCs, and better understand the clinicopathological characteristics which may define a distinct SFC phenotype. METHODS: An observational cohort study at Concord Hospital, Sydney was conducted with patients who underwent resection for colon adenocarcinoma (1995-2019). Clinicopathological data were extracted from a prospective database. Overall survival (OS) and disease-free survival (DFS) estimates and their associations to clinicopathological variables were investigated with Kaplan-Meier and Cox regression analyses. RESULTS: Of 2149 patients with colon cancer, 129 (6%) had an SFC. The overall 5-year OS and DFS rates were 63.6% (95% CI 62.5-64.7) and 59.4% (95% CI 58.3-60.5), respectively. SFCs were not associated with OS (P = 0.6) or DFS (P = 0.5). SFCs were more likely to present urgently (P < 0.001) with obstruction (P < 0.001) or perforation (P = 0.03), and more likely to require an open operation (P < 0.001). These characteristics were associated with poorer survival outcomes. No differences were noted between SFCs and non-SFCs with respect to tumour stage (P = 0.3). CONCLUSION: SFCs have a distinct phenotype, the individual characteristics of which are associated with poorer survival. However, the survivals of SFCs and non-SFCs are similar, possibly because the most important determinant of outcome, tumour stage, is no different between the groups. This may have implications for the surgical approach to SFCs with respect to standardization of CME and CVL surgery for these cancers.

Glutathione S-transferase Pi expression predicts response to adjuvant chemotherapy for stage C colon cancer: a matched historical control study.

BACKGROUND: This study examined the association between overall survival and Glutathione S-transferase Pi (GST Pi) expression and genetic polymorphism in stage C colon cancer patients after resection alone versus resection plus 5-fluourouracil-based adjuvant chemotherapy. METHODS: Patients were drawn from a hospital registry of colorectal cancer resections. Those receiving chemotherapy after it was introduced in 1992 were compared with an age and sex matched control group from the preceding period. GST Pi expression was assessed by immunohistochemistry. Overall survival was analysed by the Kaplan-Meier method and Cox regression. RESULTS: From an initial 104 patients treated with chemotherapy and 104 matched controls, 26 were excluded because of non-informative immunohistochemistry, leaving 95 in the treated group and 87 controls. Survival did not differ significantly among patients with low GST Pi who did or did not receive chemotherapy and those with high GST Pi who received chemotherapy (lowest pair-wise p = 0.11) whereas patients with high GST Pi who did not receive chemotherapy experienced markedly poorer survival than any of the other three groups (all pair-wise p <0.01). This result was unaffected by GST Pi genotype. CONCLUSION: Stage C colon cancer patients with low GST Pi did not benefit from 5-fluourouracil-based adjuvant chemotherapy whereas those with high GST Pi did.

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.

Clinicopathological staging of colorectal cancer: Evolution and consensus-an Australian perspective.

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.

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<0.001-0.007). There was no significant association between intensity of maspin expression and overall survival. CONCLUSIONS: In this large and thoroughly documented series of patients with clinicopathological stage C colonic tumour, maspin expression was correlated with few other conventional histopathology variables and was not a significant prognostic factor.

Tumor budding and survival after potentially curative resection of node-positive colon cancer.

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.

HLA-DR expression is associated with better prognosis in sporadic Australian clinicopathological Stage C colorectal cancers.

Predicting patient outcome for colorectal carcinoma (CRC) with lymph node but not distant metastases remains challenging. Various prognostic markers have been identified including microsatellite instability (MSI) and possibly expression of the MHC Class II protein, HLA-DR. About 15% of sporadic CRC exhibits MSI associated with methylation of the DNA mismatch repair gene hMLH1 promoter. In addition, a significant proportion of unselected CRC demonstrates expression of HLA-DR. We sought to examine the relationship between HLA-DR expression, MSI status and prognosis in sporadic Australian Clinicopathological (ACP) Stage C CRC. Two hundred seventy consecutive patients with sporadic ACP Stage C CRC were treated at Concord Repatriation General Hospital between 1986 and 1992. None of these patients received adjuvant chemotherapy and all were followed for a minimum of 5 years or until death. DNA was extracted from paraffin sections and MSI status determined by PCR. HLA-DR expression was determined immunohistochemically using an antibody against the HLA-DR alpha chain. MSI status could be assigned in 235 cases: 176 CRCs (74.9%) were microsatellite stable, whereas 23 (9.8%) had high levels of MSI (MSI-H) and 36 (15.3%) had low levels of MSI (MSI-L). HLA-DR expression by CRC cells was seen in 148 (60.1%) cases and correlated with the presence of tumor-infiltrating lymphocytes (p = 0.0005) and peritumoral lymphocytes (p = 0.003), but not other clinicopathological features or MSI status. HLA-DR-positive CRCs were strongly associated with better patient outcome (p < 0.0001).

The importance of tumor stage and relative survival analysis for the association between sex and survival after resection of colorectal cancer.

OBJECTIVE: 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. SUMMARY BACKGROUND DATA: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.