Statistical, Clinical, Methodological Evaluation of Local Recurrence Following Transanal Total Mesorectal Excision for Rectal Cancer: A Systematic Review.

BACKGROUND: A recent Norwegian moratorium challenged the status quo of transanal total mesorectal excision for rectal cancer by reporting increased early multifocal local recurrences. OBJECTIVE: The aim of this systematic review and meta-analysis was to evaluate the local recurrence rates following transanal total mesorectal excision as well as to assess statistical, clinical, and methodological bias in reports published to date. DATA SOURCES: The PubMed and MEDLINE (via Ovid) databases were systematically searched. STUDY SELECTION: Descriptive or comparative studies reporting rates of local recurrence at a median follow-up of 6 months (or more) after transanal total mesorectal excision were included. INTERVENTIONS: Patients underwent transanal total mesorectal excision. MAIN OUTCOME MEASURES: Local recurrence was any recurrence located in the pelvic surgery site. The untransformed proportion method of 1-arm meta-analysis was utilized. Untransformed percent proportion with 95% confidence interval was reported. Ad hoc meta-regression with the Omnibus test was utilized to assess risk factors for local recurrence. Among-study heterogeneity was evaluated: statistically by I2 and τ2, clinically by summary tables, and methodologically by a 33-item questionnaire. RESULTS: Twenty-nine studies totaling 2906 patients were included. The pooled rate of local recurrence was 3.4% (2.7%-4.0%) at an average of 20.1 months with low statistical heterogeneity (I2 = 0%). Meta-regression yielded no correlation between complete total mesorectal excision quality (p = 0.855), circumferential resection margin (p = 0.268), distal margin (p = 0.886), and local recurrence rates. Clinical heterogeneity was substantial. Methodological heterogeneity was linked to the excitement of novelty, loss aversion, reactivity to criticism, indication for transanal total mesorectal excision, nonprobability sampling, circular reasoning, misclassification, inadequate follow-up, reporting bias, conflict of interest, and self-licensing. LIMITATIONS: The studies included had an observational design and limited sample and follow-up. CONCLUSION: This systematic review found a pooled rate of local recurrence of 3.4% at 20 months. However, given the substantial clinical and methodological heterogeneity across the studies, the evidence for or against transanal total mesorectal excision is inconclusive at this time.

Perceptions of shared care among survivors of colorectal cancer from non-English-speaking and English-speaking backgrounds: a qualitative study.

BACKGROUND: Colorectal cancer (CRC) survivors experience difficulty navigating complex care pathways. Sharing care between GPs and specialist services has been proposed to improve health outcomes in cancer survivors following hospital discharge. Culturally and Linguistically Diverse (CALD) groups are known to have poorer outcomes following cancer treatment but little is known about their perceptions of shared care following surgery for CRC. This study aimed to explore how non-English-speaking and English-speaking patients perceive care to be coordinated amongst various health practitioners. METHODS: This was a qualitative study using data from face to face semi-structured interviews and one focus group in a culturally diverse area of Sydney with non-English-speaking and English-speaking CRC survivors. Participants were recruited in community settings and were interviewed in English, Spanish or Vietnamese. Interviews were recorded, transcribed, and analysed by researchers fluent in those languages. Data were coded and analysed thematically. RESULTS: Twenty-two CRC survivors participated in the study. Participants from non-English-speaking and English-speaking groups described similar barriers to care, but non-English-speaking participants described additional communication difficulties and perceived discrimination. Non-English-speaking participants relied on family members and bilingual GPs for assistance with communication and care coordination. Factors that influenced the care pathways used by participants and how care was shared between the specialist and GP included patient and practitioner preference, accessibility, complexity of care needs, and requirements for assistance with understanding information and navigating the health system, that were particularly difficult for non-English-speaking CRC survivors. CONCLUSIONS: Both non-English-speaking and English-speaking CRC survivors described a blend of specialist-led or GP-led care depending on the complexity of care required, informational needs, and how engaged and accessible they perceived the specialist or GP to be. Findings from this study highlight the role of the bilingual GP in assisting CALD participants to understand information and to navigate their care pathways following CRC surgery.

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.

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.

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.

Rectal cancer treatment and outcomes in elderly patients treated with curative intent.

The elderly population comprises a significant proportion of patients diagnosed with rectal cancer. However, there is a lack of evidence to guide treatment decisions in this group. Thus, this multicentre study compares the histopathology, treatment patterns and outcomes between the elderly and young populations with non-metastatic rectal cancer. The present study reported on the clinicopathological variables, treatment modalities and survival outcomes in 736 patients diagnosed with non-metastatic rectal cancer between 2006 and 2015. Patients were divided into the following two groups, <70 and ≥70 years of age, which were compared using Chi-square and survival outcome analysis using Kaplan-Meier. Elderly patients made up nearly half of the cohort and were less likely to undergo trimodality therapy or be discussed in a multidisciplinary meeting. Surgery in the elderly patients was associated with increased mortality. Elderly patients had worse cancer-specific survival (75 vs. 85%), which was particularly evident in stage III disease (hazard ratio, 2.1). Elderly patients in this subgroup treated with trimodality therapy had similar survival outcomes to younger patients. Elderly patients with locally advanced rectal cancer comprise a large proportion of the patient cohort. Consideration should be given for trimodality therapy in this group, taking into account biological age, especially in the context of increasing life expectancy and improvement in the management of age-related comorbidities.

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.

Association Between Microsatellite Instability Status and Peri-Operative Release of Circulating Tumour Cells in Colorectal Cancer.

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 14-16 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.

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).

A self administered reliable questionnaire to assess lower bowel symptoms.

BACKGROUND: Bowel symptoms are considered indicators of the presence of colorectal cancer and other bowel diseases. Self administered questionnaires that elicit information about lower bowel symptoms have not been assessed for reliability, although this has been done for upper bowel symptoms. Our aim was to develop a self administered questionnaire for eliciting the presence, nature and severity of lower bowel symptoms potentially related to colorectal cancer, and assess its reliability. METHODS: Immediately before consulting a gastroenterologist or colorectal surgeon, 263 patients likely to have a colonoscopy completed the questionnaire. Reliability was assessed in two ways: by assessing agreement between patient responses and (a) responses given by the doctor at the consultation; and (b) responses given by patients two weeks later. RESULTS: There was more than 75% agreement for 78% of the questions for the patient-doctor comparison and for 92% of the questions for the patient-patient comparison. Agreement for the length of time a symptom was present, its severity, duration, frequency of occurrence and whether or not medical consultation had been sought, all had agreement of greater than 70%. Over all questions, the chance corrected agreement for the patient-doctor comparison had a median kappa of 65% (which represents substantial agreement), interquartile range 57-72%. The patient-patient comparison also showed substantial agreement with a median kappa of 75%, interquartile range 68-81%. CONCLUSION: This self administered questionnaire about lower bowel symptoms is a useful way of eliciting details of bowel symptoms. It is a reliable instrument that is acceptable to patients and easily completed. Its use could guide the clinical consultation, allowing a more efficient, comprehensive and useful interaction, ensuring that all symptoms are assessed. It will also be a useful tool in research studies on bowel symptoms and their predictive value for colorectal cancer and other diseases. Studies assessing whether bowel symptoms predict the presence of colorectal cancer should provide estimates of the reliability of the symptom elicitation.

Nature and Architecture of the Puboprostatic Ligament: A Macro- and Microscopic Cadaveric Study Using Epoxy Sheet Plastination.

OBJECTIVE: To investigate the nature and the architecture of the puboprostatic ligament (PPL) and its relationship with surroundings. MATERIALS AND METHODS: Six adult male cadaveric pelvises (age range, 46-87 years) were prepared as serial transverse (2 sets), coronal (1 set), or sagittal (3 sets) plastinated sections, and were examined under a stereoscope and a confocal microscope. The thickness of the section was 2.5 mm, the interval between 2 adjacent sections was about 0.9 mm, and a total of about 70 serial sections per set were collected. RESULTS: First, the musculotendinous sheet of the pubococcygeus contributed to the visceral endopelvic fascia, decussated in front of the detrusor apron, and fixed to the pubis. Second, anteriorly to the prostate, the detrusor apron split up into anterior, middle, and posterior layers, which contributed to the PPL, the fascial sheaths of the dorsal vascular complex, and the anterior fibromuscular stroma of the prostate, respectively. Third, the PPL originated from both the detrusor apron and the decussated and undecussated fibers of the pubococcygeus, and inserted onto the pubis. CONCLUSION: This study revealed the nature and the architecture of the PPL and its relationship with surroundings. These findings provide new insights in the "suspensory system" involving the urinary continence and may incite for future surgical techniques that aim to preserve the decussated pubococcygeus and the intactness of a pubococcygeus-detrusor apron complex during radical retropubic prostatectomy.