Prolonged interval to surgery following neoadjuvant chemoradiotherapy in locally advanced rectal cancer: A meta-analysis of randomized controlled trials.

BACKGROUND: Long-course neoadjuvant chemoradiotherapy (NCRT), followed by surgery after an interval of 6-8 weeks, represents standard of care for patients with locally advanced rectal cancer (LARC). Increasing this interval may improve rates of complete pathological response (pCR) and tumour downstaging. We performed a meta-analysis comparing standard (SI, within 8 weeks) versus longer (LI, after 8 weeks) interval from NCRT to surgery. METHODS: PubMed, Embase, and Cochrane databases were searched up to 31 August 2022. Randomized controlled trials (RCTs) comparing SI with LI after NCRT for LARC were included. The primary endpoint was pCR rate. Secondary endpoints included rates of R0 resection, circumferential resection margin positivity (+CRM), TME completeness, lymph node yield (LNY), operative duration, tumour downstaging (TD), sphincter preservation, mortality, postoperative complications, surgical site infection (SSI) and anastomotic leak (AL). Random effects models were used to calculate pooled effect size estimates. RESULTS: Four RCTs encompassing 867 patients were included. There were 539 males (62.1%). LI was associated with a higher pCR rate (OR 0.61, 95%CI â€‹= â€‹0.39-0.95, p â€‹= â€‹0.03), and more TD (OR 0.60, 95%CI â€‹= â€‹0.37-0.97, p â€‹= â€‹0.04) compared to SI. However, there was no difference in rates of R0 resection (p â€‹= â€‹0.87), +CRM (p â€‹= â€‹0.66), sphincter preservation (p â€‹= â€‹0.26), incomplete TME (p â€‹= â€‹0.49), LNY (p â€‹= â€‹0.55), SSI (p â€‹= â€‹0.33), AL (p â€‹= â€‹0.20), operative duration (p â€‹= â€‹0.07), mortality (p â€‹= â€‹0.89) or any surgical complication (p â€‹= â€‹0.91). CONCLUSIONS: A LI to surgery after NCRT for LARC increases pCR and TD rates. Local recurrence or survival were not assessed due to unavailable data. We recommend deferring TME until after an interval of 8 weeks following completion of NCRT.

Centralisation of rectal cancer care has improved patient survival in the republic of Ireland.

BACKGROUND: Centralisation of rectal cancer surgery to designated centres was a key objective of the Irish national cancer control program. A national audit of rectal cancer surgery indicated centralisation was associated with improved early surgical outcomes. This study aimed to determine the impact of implementation of the national cancer strategy on survival from rectal cancer. MATERIALS AND METHODS: Data were collected from the National Cancer Registry of Ireland to include all patients with Stage I-III rectal cancer undergoing rectal cancer surgery with curative intent between 2003 and 2012. Five-year overall survival and cancer-specific survival was compared between patients in the pre-centralisation (2003-2007) and post-centralisation period (2008-2012) and between patients receiving surgery in designated cancer centres and non-cancer centres. RESULTS: The proportion of rectal cancer surgery performed in a designated cancer centre increased from 42% during 2003-2007 to 58% during 2008-2012. Five-year overall survival increased from 66.1% in 2003-2007 to 73.5% in 2008-2012 (p < 0.001). Five-year cancer-specific survival increased from 75.3% in 2003-2007 to 81.9% in 2008-2012 (p < 0.001). Surgery in a cancer centre and surgery post-centralisation were significantly associated with overall and cancer specific survival using Cox proportional hazards regression. CONCLUSION: Survival following resection of rectal cancer was significantly improved following implementation of a national cancer strategy incorporating centralisation of rectal cancer surgery.

Mucinous and non-mucinous colorectal cancers show differential expression of chemotherapy metabolism and resistance genes.

Previous research has identified differences in mutation frequency in genes implicated in chemotherapy resistance between mucinous and non-mucinous colorectal cancers (CRC). We hypothesized that outcomes in mucinous and non-mucinous CRC may be influenced by expression of genes responsible for chemotherapy resistance. Gene expression data from primary tumor samples were extracted from The Cancer Genome Atlas PanCancer Atlas. The distribution of clinical, pathological, and gene expression variables was compared between 74 mucinous and 521 non-mucinous CRCs. Predictors of overall survival (OS) were assessed in a multivariate analysis. Kaplan-Meier curves were constructed to compare survival according to gene expression using the log rank test. The median expression of 5-FU-related genes TYMS, TYMP, and DYPD was significantly higher in mucinous CRC compared to non-mucinous CRC (p < 0.001, p = 0.003, p < 0.001, respectively). The median expression of oxaliplatin-related genes ATP7B and SRPK1 was significantly reduced in mucinous versus non-mucinous CRC (p = 0.004, p = 0.007, respectively). At multivariate analysis, age (odds ratio (OR) = 0.96, p < 0.001), node positive disease (OR = 0.49, p = 0.005), and metastatic disease (OR = 0.32, p < 0.001) remained significant negative predictors of OS, while high SRPK1 remained a significant positive predictor of OS (OR = 1.59, p = 0.037). Subgroup analysis of rectal cancers demonstrated high SRPK1 expression was associated with significantly longer OS compared to low SRPK1 expression (p = 0.011). This study highlights that the molecular differences in mucinous CRC and non-mucinous CRC extend to chemotherapy resistance gene expression. SRPK1 gene expression was associated with OS, with a prognostic role identified in rectal cancers.

Microsatellite instability and response to neoadjuvant chemoradiotherapy in rectal cancer: A systematic review and meta-analysis.

BACKGROUND: Response to neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer is variable. Identification of biomarkers to predict response is desirable in order to provide prognostic information and targeted therapy. Several studies have investigated microsatellite instability (MSI) as a predictor of response to CRT with contradictory results. This study aims to clarify the effect of MSI status on response to CRT in locally advanced rectal cancer through systematic review and meta-analysis. METHODS: A systematic search of PubMed, Embase and Cochrane databases was performed for all studies relating to MSI and response to CRT in rectal cancer using the search algorithm (Microsatellite Instability) AND (Chemoradiotherapy) AND (Rectal Cancer). From each included study the number of patients with MSI tumors and Microsatellite Stable (MSS) tumors and the numbers achieving pathological complete response (pCR) were recorded. Pooled outcome measures were determined using a random effects model and the odds ratio estimated with variance and 95% confidence interval. RESULTS: Nine published studies were identified reporting data on MSI and its effect on outcome after CRT for locally advanced rectal cancer. Five studies describing 5,877 patients included data on MSI and the number of patients achieving pCR. There was no significant association between MSI and pCR (MSI Vs MSS: 10.1% Vs 6.6%, OR 1.38, 95% CI: 0.7-2.72, p = 0.35). CONCLUSION: This meta-analysis concludes that there appears to be no significant difference in pCR rate following CRT in patients with MSI versus MSS rectal tumors.

The utility of preoperative radiological evaluation of early rectal neoplasia: a systematic review and meta-analysis.

AIM: The diagnostic role for preoperative imaging of clinically benign rectal adenomas is unclear. The objective of this systematic review and meta-analysis was to examine the diagnostic accuracy of preoperative imaging in distinguishing benign adenomas from rectal cancer. METHOD: A systematic search was performed for all studies published that correlated staging of clinically benign rectal adenomas with endorectal ultrasound (ERUS) or MRI and histology. Imaging was compared with postoperative histology and data on the numbers of true positives, false positives, true negatives and false negatives were extracted. Summary estimates of sensitivity and specificity with 95% CIs were calculated using a bivariate random effects model. The QUADAS2 tool was used to determine the methodological quality of included studies. RESULTS: Eleven studies describing 1511 patients were retrieved. A total of 1134 patients underwent local excision and 377 had a formal proctectomy. A benign rectal adenoma was diagnosed in 840 and 214 had a T1 rectal cancer. For confirming benign adenomas, the pooled sensitivity of ERUS was 0.81 (95% CI 0.69-0.89) and specificity was 0.85 (95% CI 0.68-0.93). For detecting occult T1 tumours, the pooled sensitivity of ERUS was 0.50 (95% CI 0.33-0.66) and specificity was 0.89 (95% CI 0.82-0.94). Quantitative analysis of MRI could not be performed due to insufficient studies. CONCLUSION: This study demonstrates the limited accuracy of preoperative ERUS in distinguishing benign adenomas from T1 rectal cancer. Preoperative imaging must be interpreted with caution to prevent over-staging and unnecessary proctectomy. We propose that clinically benign lesions may undergo local excision, with subsequent management based on final histology.

Meta-analysis of the molecular associations of mucinous colorectal cancer.

BACKGROUND: Mucinous differentiation occurs in 5-15 per cent of colorectal adenocarcinomas. This subtype of colorectal cancer responds poorly to chemoradiotherapy and has a worse prognosis. The genetic aetiology underpinning this cancer subtype lacks consensus. The aim of this study was to use meta-analytical techniques to clarify the molecular associations of mucinous colorectal cancer. METHODS: This study adhered to MOOSE guidelines. Databases were searched for studies comparing KRAS, BRAF, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), p53 and p27 status between patients with mucinous and non-mucinous colorectal adenocarcinoma. A random-effects model was used for analysis. RESULTS: Data from 46 studies describing 17 746 patients were included. Mucinous colorectal adenocarcinoma was associated positively with KRAS (odds ratio (OR) 1·46, 95 per cent c.i. 1·08 to 2·00, P = 0·014) and BRAF (OR 3·49, 2·50 to 4·87; P < 0·001) mutation, MSI (OR 3·98, 3·30 to 4·79; P < 0·001) and CIMP (OR 3·56, 2·85 to 4·43; P < 0·001), and negatively with altered p53 expression (OR 0·46, 0·31 to 0·67; P < 0·001). CONCLUSION: The genetic origins of mucinous colorectal adenocarcinoma are predominantly associated with BRAF, MSI and CIMP pathways. This pattern of molecular alterations may in part explain the resistance to standard chemotherapy regimens seen in mucinous adenocarcinoma.

Thirty-seven-year Population-based Study of Colorectal Cancer Rates in Renal Transplant Recipients in Ireland.

BACKGROUND: Renal transplantation is associated with an increased risk of neoplasia, including colorectal cancer (CRC). Advances in surgical techniques and immunosuppressive medications have resulted in increased survival rates of both patients and grafts, but the incidence of CRC in the Irish renal transplant population is currently unknown. The aim of this study is to review the incidence of CRC in the Irish renal transplant population and compare it to the general population. METHODS: A retrospective review of a prospectively maintained database of all renal transplant recipients in Ireland between January 1980 and July 2017 was performed. RESULTS: Thirty-three out of 4230 transplant recipients (men = 20, women = 13) developed CRC subsequent to transplantation and were eligible for inclusion in the series. The mean age at transplantation was 51.5 years, with patients developing CRC on average 10.9 years post-transplantation; 6.1% (n = 2/33) had stage IV disease at diagnosis. The majority of patients (87.8%) had a pathologic T stage of T3/T4 and 45.5% had involvement of locoregional lymph nodes (N1/N2); 42.4% also had a mucinous component at histopathologic assessment. The incidence of CRC was higher in the transplant population compared to the general population. CONCLUSION: This is the first population-based assessment of CRC development in the Irish renal transplant population. Our data suggest that Irish transplant recipients have an increased risk of being diagnosed with a more advanced tumor than the general population, with most being diagnosed almost a decade after transplantation. This highlights the need for increased awareness among patients and clinicians and the potential need for coordinated lifelong surveillance of this patient population to ensure early detection and treatment.

Trends in the treatment of rectal prolapse: a population analysis.

PURPOSE: Rectal prolapse is a common condition, with conflicting opinions on optimal surgical management. Existing literature is predominantly composed of case series, with a dearth of evidence demonstrating current, real-world practice. This study investigated recent national trends in management of rectal prolapse in the Republic of Ireland (ROI). METHODS: This population analysis used a national database to identify patients admitted in the ROI primarily for the management of rectal prolapse, as defined by the International Classification of Diseases, 10th Revision (ICD-10). Demographics, procedures, comorbidities, and outcomes were obtained for patients admitted from 2005 to 2015 inclusive. RESULTS: There were 2648 admissions with a primary diagnosis of rectal prolapse; 39.3% underwent surgical correction. The majority were treated with either a perineal resection (47.2%) or an abdominal rectopexy ± resection (45.1%). The population-adjusted rate of operative intervention increased over the study period, from 25 to 42 per million (p < 0.001), with no change in the mean age of patients over time (p = 0.229). The application of a laparoscopic approach increased over time (p = 0.001). Patients undergoing an abdominal rectopexy were younger than those undergoing a perineal procedure (64.1 ± 17.3 versus 75.2 ± 15.5 years, p < 0.001) despite having a similar Charlson Comorbidity Index (p = 0.097). The mortality rate for elective repair was 0.2%. CONCLUSIONS: Despite the popularization of ventral mesh rectopexy over the study period, perineal resection Delorme's procedure remains the most common procedure employed for the correction of rectal prolapse in the ROI, with specific approach determined by age.

C-reactive protein as a predictor of anastomotic leak in the first week after anterior resection for rectal cancer.

AIM: Anastomotic leak (AL) after anterior resection results in increased morbidity, mortality and local recurrence. The aim of this study was to assess the ability of C-reactive protein (CRP) to predict AL in the first week after anterior resection for rectal cancer. METHOD: A retrospective review of a prospectively maintained database that included all patients undergoing anterior resection between January 2008 and December 2013 was performed. The ability of CRP to predict AL was assessed using area under the receiver-operating characteristics (AUC) curves. The severity of AL was defined using the International Study Group of Rectal Cancer (ISREC) grading system. RESULTS: Two-hundred and eleven patients were included in the study. Statistically significant differences in mean CRP values were found between those with and without an AL on postoperative days 5, 6 and 7. A CRP value of 132 mg/l on postoperative day 5 had an AUC of 0.75, corresponding to a sensitivity of 70%, a specificity of 76.6%, a positive predictive value of 16.3% and a negative predictive value of 97.5%. Multivariable analysis found that a CRP of > 132 mg/l on postoperative day 5 was the only statistically significant patient factor that was linked to an increased risk of AL (HR = 8.023, 95% CI: 1.936-33.238, P = 0.004). CONCLUSION: Early detection of AL may minimize postoperative complications. CRP is a useful negative predictive test for the development of AL following anterior resection.

Liberal perioperative fluid administration is an independent risk factor for morbidity and is associated with longer hospital stay after rectal cancer surgery.

INTRODUCTION Recent studies have advocated the use of perioperative fluid restriction in patients undergoing major abdominal surgery as part of an enhanced recovery protocol. Series reported to date include a heterogenous group of high- and low-risk procedures but few studies have focused on rectal cancer surgery alone. The aim of this study was to assess the effects of perioperative fluid volumes on outcomes in patients undergoing elective rectal cancer resection. METHODS A prospectively maintained database of patients with rectal cancer who underwent elective surgery over a 2-year period was reviewed. Total volume of fluid received intraoperatively was calculated, as well as blood products required in the perioperative period. The primary outcome was postoperative morbidity (Clavien-Dindo grade I-IV) and the secondary outcomes were length of stay and major morbidity (Clavien-Dindo grade III-IV). RESULTS Over a 2-year period (2012-2013), 120 patients underwent elective surgery with curative intent for rectal cancer. Median total intraoperative fluid volume received was 3680ml (range 1200-9670ml); 65/120 (54.1%) had any complications, with 20/120 (16.6%) classified as major (Clavien-Dindo grade III-IV). Intraoperative volume >3500ml was an independent risk factor for the development of postoperative all-cause morbidity (P=0.02) and was associated with major morbidity (P=0.09). Intraoperative fluid volumes also correlated with length of hospital stay (Pearson's correlation coefficient 0.33; P<0.01). CONCLUSIONS Intraoperative fluid infusion volumes in excess of 3500ml are associated with increased morbidity and length of stay in patients undergoing elective surgery for rectal cancer.

Endoscopic tattooing to aid tumour localisation in colon cancer: the need for standardisation.

BACKGROUND/AIMS: An increasing number of colon and rectal tumours are being resected using laparoscopic techniques. Identifying these tumours intraoperatively can be difficult. The use of tattooing can facilitate an easier resection; however, the lack of standardised guidelines can potentially lead to errors intraoperatively and potentially result in worse outcomes for patients. The aim of this study was to identify the most reliable method of preoperative tumour localisation from the available literature to date. METHODS: A literature review was undertaken to identify any articles related to endoscopic tattooing and tumour localisation during colorectal surgery. RESULTS: To date there is still mixed evidence regarding tattooing techniques and the choice of ink that should be used. There are numerous studies demonstrating safe tattooing techniques and highlighting the risks and benefits of different types of ink available. CONCLUSION: Based on the available studies we have recommended a standardised approach to endoscopic tattooing of colorectal tumours prior to laparoscopic resection.

Low levels of Caspase-3 predict favourable response to 5FU-based chemotherapy in advanced colorectal cancer: Caspase-3 inhibition as a therapeutic approach.

Colorectal cancer (CRC) is one of the most common cancers in the Western world. 5-Fluorouracil (5FU)-based chemotherapy (CT) remains the mainstay treatment of CRC in the advanced setting, and activates executioner caspases in target cells. Executioner caspases are key proteins involved in cell disassembly during apoptosis. Activation of executioner caspases also has a role in tissue regeneration and repopulation by stimulating signal transduction and cell proliferation in neighbouring, non-apoptotic cells as reported recently. Tissue microarrays (TMAs) consisting of tumour tissue from 93 stage II and III colon cancer patients were analysed by immunohistochemistry. Surprisingly, patients with low levels of active Caspase-3 had an increased disease-free survival time. This was particularly pronounced in patients who received 5FU-based adjuvant CT. In line with this observation, lower serum levels of active Caspase-3 were found in patients with metastasised CRC who revealed stable disease or tumour regression compared with those with disease progression. The role of Caspase-3 in treatment responses was explored further in primary human tumour explant cultures from fresh patient tumour tissue. Exposure of explant cultures to 5FU-based CT increased the percentage of cells positive for active Caspase-3 and Terminal Deoxynucleotidyl Transferase dUTP Nick end Labelling (TUNEL), but also the expression of regeneration and proliferation markers ß-Catenin and Ki-67, as well as cyclooxygenase-2 (COX-2). Of note, selective inhibition of Caspase-3 with Ac-DNLD-CHO, a selective, reversible inhibitor of Caspase-3, significantly reduced the expression of proliferation markers as well as COX-2. Inhibition of COX-2 with aspirin or celecoxib did not affect Caspase-3 levels but also reduced Ki-67 and ß-Catenin levels, suggesting that Caspase-3 acted via COX-2 to stimulate cell proliferation and tissue regeneration. This indicates that low levels of active Caspase-3 may represent a new predictor of CT responsiveness, and inhibition of Caspase-3, or antagonising downstream effectors of Caspase-3 paracrine signalling, such as COX-2 may improve patient outcomes following CT in advanced CRC.

High levels of X-linked Inhibitor-of-Apoptosis Protein (XIAP) are indicative of radio chemotherapy resistance in rectal cancer.

BACKGROUND: The mainstay of treatment in rectal cancer is neoadjuvant radio chemotherapy prior to surgery, in an attempt to downstage the tumour, allowing for more complete removal during surgery. In 40 % of cases however, this neoadjuvant radio chemotherapy fails to achieve tumour regression, partly due insufficient apoptosis signaling. X-linked Inhibitor of Apoptosis Protein (XIAP) is an anti-apoptotic protein that has been reported to contribute to disease progression and chemotherapy resistance. METHODS: We obtained rectal biopsy normal and matched tumour tissue from 29 rectal cancer patients with varying degrees of tumour regression, and using Western blot, examined anti-apoptotic XIAP and pro-apoptotic Smac protein levels in these tissues, with the aim to examine whether disturbed XIAP/Smac levels may be an indicator of neoadjuvant radio chemotherapy resistance. Expression of inhibitor of apoptosis proteins cIAP-1 and cIAP-2 was also examined. RESULTS: We found that levels of XIAP increased in accordance with the degree of radio chemotherapy resistance of the tissue. Levels of this protein were also significantly higher in tumour tissue, compared to matched normal tissue in highly resistant tissue. In contrast, Smac protein levels did not increase with radio chemotherapy resistance, and the protein was similarly expressed in normal and tumour tissue, indicating a shift in the balance of these proteins. Post treatment surgical resection tissue was available for 8 patients. When we compared matched tissue pre- and post- radio chemotherapy we found that XIAP levels increased significantly during treatment in both normal and tumour tissue, while Smac levels did not change. cIAP-1 and cIAP-2 levels were not differentially expressed in varying degrees of radio chemotherapy resistance, and neoadjuvant therapy did not alter expression of these proteins. CONCLUSION: These data indicate that disturbance of the XIAP/Smac balance may be a driver of radio chemotherapy resistance, and hence high levels of XIAP may be a useful indicator of neoadjuvant radio chemotherapy resistance in rectal cancer. Moreover, as XIAP levels increase with radio chemotherapy it is possible that a subset of more resistant tumour cells survive this treatment and may be resistant to further adjuvant treatment. Patients with resistant tumours highly expressing XIAP may benefit from alternative treatment strategies, such as Smac mimetics post neoadjuvant radio chemotherapy.

Comparative outcomes of total parenteral nutrition use in patients aged greater or less than 80 years of age.

OBJECTIVES: Total-parenteral-nutrition (TPN) can act as a bridge to enteral nutrition. The current study aims to explore the outcomes of TPN use in older adults which are at present poorly defined. DESIGN, SETTING AND PARTICIPANTS: Data on 172 patients who received TPN between January-December 2011 were prospectively recorded and examined. RESULTS: Mean age was 62.7 ± 16.8 years (12.8% ≥ 80 years). Those ≥ 80 years were less often male (31.8% Vs 57.3%, P=0.038) and had no history of hepatic dysfunction (0.0% Vs 16.7%, P=0.025). In those ≥ 80 years the indication was more often suspected ileus (40.9% Vs 13.3%, P=0.004). Patients ≥ 80 years developed hypertriglyceridaemia less frequently (7.7% Vs 36.2%, P=0.031). There was no difference in the duration of TPN administration, the rate of TPN line sepsis, serum electrolyte derangement or glycaemic control. Change in serum albumin over the course of treatment did not differ (≥ 80 Vs <80 years, -0.28 ± 0.62 mg/dL Vs -2.00 ± 1.57 mg/dL, P=0.323). CONCLUSIONS: These data suggest TPN use is safe in patients aged ≥ 80 years and advanced age alone should not preclude TPN use.

BCL2 protein signalling determines acute responses to neoadjuvant chemoradiotherapy in rectal cancer.

UNLABELLED: In locally advanced rectal cancer, neoadjuvant chemoradiotherapy is performed prior to surgery to downstage the tumour. Thirty to 40 % of patients do not respond. Defects in apoptotic machinery lead to therapy resistance; however, to date, no study quantitatively assessed whether B cell lymphoma 2 (BCL2)-dependent regulation of mitochondrial apoptosis, effector caspase activation downstream of mitochondria or a combination of both predicts patient responses. In a cohort of 20 rectal cancer patients, we performed protein profiling of tumour tissue and employed validated ordinary differential equation-based systems models of apoptosis signalling to calculate the ability of cancer cells to undergo apoptosis. Model outputs were compared to clinical responses. Systems modelling of BCL2-signalling predicted patients in the poor response group (p = 0.0049). Systems modelling also demonstrated that rectal cancers depended on BCL2 rather than B cell lymphoma-extra large (BCL(X)L) or myeloid cell leukemia 1 (MCL1) for survival, suggesting that poor responders may benefit from therapy with selective BCL2 antagonists. Dynamic modelling of effector caspase activation could not stratify patients with poor response and did not further improve predictive power. We deliver a powerful patient stratification tool identifying patients who will likely not benefit from neoadjuvant chemoradiotherapy and should be prioritised for surgical resection or treatment with BCL2 antagonists. KEY MESSAGES: Modelling BCL2-family proteins identifies patients unresponsive to therapy. Caspase activation downstream of mitochondria cannot identify these patients. Rectal tumours of poor responders are BCL2- but not BCL-XL-dependent. DR_MOMP allows clinicians to identify patients who would not benefit from therapy. DR_MOMP is also a useful patient stratification tool for BCL2 antagonists.

Global DNA methylation is altered by neoadjuvant chemoradiotherapy in rectal cancer and may predict response to treatment - A pilot study.

AIM: In rectal cancer, not all tumours display a response to neoadjuvant treatment. An accurate predictor of response does not exist to guide patient-specific treatment. DNA methylation is a distinctive molecular pathway in colorectal carcinogenesis. Whether DNA methylation is altered by neoadjuvant treatment and a potential response predictor is unknown. We aimed to determine whether DNA methylation is altered by neoadjuvant chemoradiotherapy (CRT) and to determine its role in predicting response to treatment. PATIENTS AND METHODS: Fifty-three (n = 53) patients with locally advanced rectal cancers treated with neoadjuvant CRT followed by surgery were identified from the pathology databases of 2 tertiary referral centres over a 4-year period. Immunohistochemical staining of treatment specimens was carried out using the 5-Methylcytidine (Eurogentec, Seraing, Belgium) antibody. Quantitative analysis of staining was performed using an automated image analysis platform. The modified tumour regression grading system was used to assess tumour response to neoadjuvant therapy. RESULTS: Seven (13%) patients showed complete pathological response while 46 (87%) patients were partial responders to neoadjuvant treatment. In 38 (72%) patients, significant reduction in methylation was observed in post-treatment resection specimens compared to pre-treatment specimens (171.5 vs 152.7, p = 0.01); in 15 (28%) patients, methylation was increased. Pre-treatment methylation correlated significantly with tumour regression (p < 0.001), T-stage (p = 0.005), and was able to predict complete and partial pathological responders (p = 0.01). CONCLUSION: Neoadjuvant CRT appears to alter the rectal cancer epigenome. The significant correlation between pre-treatment DNA methylation with tumour response suggests a potential role for methylation as a biomarker of response.

Vertical rectus abdominis myocutaneous flap and quality of life following abdominoperineal excision for rectal cancer: a multi-institutional study.

BACKGROUND: To obtain a clear surgical margin, abdominoperineal excision (APE) for rectal cancer frequently leaves a large perineal defect surrounded by irradiated tissue. A vertical rectus abdominis myocutaneous (VRAM) flap may facilitate healing of this wound. The current study aims to determine the effect of VRAM flap perineal reconstruction following APE on patient quality of life (QOL). METHODS: This is a retrospective cohort study from a prospectively collected database. Data on QOL were assessed via telephone questionnaire using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30, EORTC QLQ-C29 and the Cleveland Clinic QOL questionnaires. RESULTS: Twenty-seven patients underwent primary perineal closure, and 12 patients underwent a VRAM flap perineal reconstruction. The mean duration of follow-up was 16.8 months. Overall, there was no significant difference in the Cleveland Clinic QOL score between groups (VRAM vs. no VRAM: 0.7 ± 0.2 vs. 0.7 ± 0.2, p 0.735). Patients in the VRAM group had lower levels of fatigue (5.5 ± 9.9 vs. 23.6 ± 19.2, p 0.004). Patients in the VRAM group had reduced sore skin scores around the stoma site (11.0 ± 16.2 vs. 31.8 ± 31.1, p 0.036). VRAM flap was associated with an increased incidence of abdominal wall hernia (VRAM vs. no VRAM: 25 % vs. 0 %, p 0.024). CONCLUSIONS: This study is limited by its non-randomized retrospective design and relatively small sample size. A significant difference in patient QOL was not demonstrated between VRAM flap and primary perineal closure after APE for rectal cancer. Further studies in this area are warranted.

The prognostic value of tumour regression grade following neoadjuvant chemoradiation therapy for rectal cancer.

AIM: To date, there is no uniform consensus on whether tumour regression grade (TRG) is predictive of outcome in rectal cancer. Furthermore, the lack of standardization of TRG grading is a major source of variability in published studies. The aim of this study was to evaluate the prognostic impact of TRG in a cohort of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation therapy (CRT). In addition to the Mandard TRG, we utilized four TRG systems modified from the Mandard TRG system and applied them to the cohort to assess which TRG system is most informative. METHOD: One-hundred and fifty-three patients with a T3/T4 and/or a node-positive rectal cancer underwent neoadjuvant 5-fluorouracil-based CRT followed by surgical resection. RESULTS: Thirty-six (23.5%) patients achieving complete pathological response (ypCR) had a 5-year disease-free survival (DFS) rate of 100% compared with a DFS rate of 74% for 117 (76.5%) patients without ypCR (P = 0.003). The Royal College of Pathologists (RCPath) TRG best condenses the Mandard five-point TRG by stratifying patients into three groups with distinct 5-year DFS rates of 100%, 86% and 67%, respectively (P = 0.001). In multivariate analysis, pathological nodal status and circumferential resection margin (CRM) status, but not TRG, remained significant predictors of DFS (P = 0.002, P = 0.035 and P = 0.310, respectively). CONCLUSION: Our findings support the notion that ypCR status, nodal status after neoadjuvant CRT and CRM status, but not TRG, are predictors of long-term survival in patients with locally advanced rectal cancer.