Stroma AReactive Invasion Front Areas (SARIFA): a novel histopathologic biomarker in colorectal cancer patients and its association with the luminal tumour proportion.

BACKGROUND: Stroma AReactive Invasion Front Areas (SARIFA) is a novel prognostic histopathologic biomarker measured at the invasive front in haematoxylin & eosin (H&E) stained colon and gastric cancer resection specimens. The aim of the current study was to validate the prognostic relevance of SARIFA-status in colorectal cancer (CRC) patients and investigate its association with the luminal proportion of tumour (PoT). METHODS: We established the SARIFA-status in 164 CRC resection specimens. The relationship between SARIFA-status, clinicopathological characteristics, recurrence-free survival (RFS), cancer-specific survival (CSS), and PoT was investigated. RESULTS: SARIFA-status was positive in 22.6% of all CRCs. SARIFA-positivity was related to higher pT, pN, pTNM stage and high grade of differentiation. SARIFA-positivity was associated with shorter RFS independent of known prognostic factors analysing all CRCs (RFS: hazard ratio (HR) 2.6, p = 0.032, CSS: HR 2.4, p = 0.05) and shorter RFS and CSS analysing only rectal cancers. SARIFA-positivity, which was measured at the invasive front, was associated with PoT-low (p = 0.009), e.g., higher stroma content, and lower vessel density (p = 0.0059) measured at the luminal tumour surface. CONCLUSION: Here, we validated the relationship between SARIFA-status and prognosis in CRC patients and provided first evidence for a potential prognostic relevance in the subgroup of rectal cancer patients. Interestingly, CRCs with different SARIFA-status also showed histological differences measurable at the luminal tumour surface. Further studies to better understand the relationship between high luminal intratumoural stroma content and absence of a stroma reaction at the invasive front (SARIFA-positivity) are warranted and may inform future treatment decisions in CRC patients.

The gut microbiota in adults with cystic fibrosis compared to colorectal cancer.

BACKGROUND: Gut dysbiosis is implicated in colorectal cancer (CRC) pathogenesis. Cystic fibrosis (CF) is associated with both gut dysbiosis and increased CRC risk. We therefore compared the faecal microbiota from individuals with CF to CRC and screening samples. We also assessed changes in CRC-associated taxa before and after triple CF transmembrane conductance regulator (CFTR) modulator therapy. METHODS: Bacterial DNA amplification comprising V4 16S rRNA analysis was conducted on 84 baseline and 53 matched follow-up stool samples from adults with CF. These data were compared to an existing cohort of 430 CRC and 491 control gFOBT samples from the NHS Bowel Cancer Screening Programme. Data were also compared to 26 previously identified CRC-associated taxa from a published meta-analysis. RESULTS: Faecal CF samples had a lower alpha diversity and clustered distinctly from both CRC and control samples, with no clear clinical variables explaining the variation. Compared to controls, CF samples had an increased relative abundance in 6 of the 20 enriched CRC-associated taxa and depletion of 2 of the 6 taxa which have been reported as reduced in CRC. Commencing triple modulator therapy had subtle influence on the relative abundance of CRC-associated microbiota (n = 23 paired CF samples). CONCLUSIONS: CF stool samples were clearly dysbiotic, clustering distinctly from both CRC and control samples. Several bacterial shifts in CF samples resembled those observed in CRC. Studies assessing the impact of dietary or other interventions and the longer-term use of CFTR modulators on reducing this potentially pro-oncogenic milieu are needed.

Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.

BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guidelines has been acknowledged. METHODS: The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds. RESULTS: Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome-associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided. CONCLUSION: The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented.

Clinical and molecular characteristics and treatment outcomes of advanced right-colon, left-colon and rectal cancers: data from 1180 patients in a phase III trial of panitumumab with an extended biomarker panel.

BACKGROUND: Primary tumour location (PTL) is being adopted by clinicians to guide treatment decisions in metastatic colorectal cancer (mCRC). Here we test PTL as a predictive marker for panitumumab efficacy, and examine its relationship with an extended biomarker profile. We also examine rectal tumours as a separate location. PATIENTS AND METHODS: mCRC patients from the second-line PICCOLO trial of irinotecan versus irinotecan/panitumumab (IrPan). PTL was classified as right-PTL, left-PTL or rectal-PTL. PTL was assessed as a predictive biomarker for IrPan effect in RAS-wild-type (RAS-wt) patients (compared with irinotecan alone), then tested for independence alongside an extended biomarker profile (BRAF, epiregulin/amphiregulin (EREG/AREG) and HER3 mRNA expression). RESULTS: PTL data were available for 1180 patients (98.5%), of whom 558 were RAS-wt. High HER3 expression was independently predictive of panitumumab overall survival improvement, but PTL and EREG/AREG were not. IrPan progression-free survival (PFS) improvement compared with irinotecan was seen in left-PTL [hazard ratio (HR) = 0.61, P = 0.002) but not right-PTL (HR = 0.98, P = 0.90) (interaction P = 0.05; RAS/BRAF-wt interaction P = 0.10), or in rectal-PTL (HR = 0.82, P = 0.20) (interaction P = 0.14 compared with left-PTL; RAS/BRAF-wt interaction P = 0.04). Patients with right-PTL and high EREG/AREG or HER3 expression, had IrPan PFS improvement (high EREG/AREG HR = 0.20, P = 0.04; high HER3 HR = 0.33, P = 0.10) compared with irinotecan. Similar effect was seen for rectal-PTL patients (high EREG/AREG HR = 0.44, P = 0.03; high HER3 HR = 0.34, P = 0.05). CONCLUSIONS: RAS-wt patients with left-PTL are more likely to have panitumumab PFS advantage than those with right-PTL or rectal-PTL. However, an extended biomarker panel demonstrated significant heterogeneity in panitumumab PFS effect within a tumour location. AREG/EREG and HER3 mRNA expression identifies patients with right-PTL or rectal-PTL who achieve similar PFS effect with panitumumab as left-colon patients. Testing could provide a more reliable basis for clinical decision making. Further validation and development of these biomarkers is required to optimise routine patient care. CLINICAL TRIAL REGISTRATION: ISRCTN identifier: ISRCTN93248876.

Ex vivo specimen MRI and pathology confirm a rectosigmoid mesenteric waist at the junction of the mesorectum and mesocolon.

AIM: Continuity of the mesentery has recently been established and may provide an anatomical basis for optimal colorectal resectional surgery. Preliminary data from operative specimen measurements suggest there is a tapering in the mesentery of the distal sigmoid. A mesenteric waist in this area may be a risk factor for local recurrence of colorectal cancer. This study aimed to investigate the anatomical characteristics of the mesentery at the colorectal junction. METHOD: In this cross-sectional study, 20 patients were recruited. After planned colorectal resection, the surgical specimens were scanned in a MRI system and subsequently dissected and photographed as per national pathology guidelines. Mesenteric surface area and linear measurements were compared between MRI and pathology to establish the presence and location of a mesenteric waist. RESULTS: Specimen analysis confirmed that a narrowing in the mesenteric surface area was consistently apparent at the rectosigmoid junction. Above the anterior peritoneal reflection, the surface area and posterior distance of the mesentery of the upper rectum initially decreased before increasing as the mesentery of the sigmoid colon. These anatomical properties created the appearance of a mesenteric 'waist' at the rectosigmoid junction. Using the anterior reflection as a reference landmark, the rectosigmoid waist occurred at a mean height of 23.6 and 21.7 mm on MRI and pathology, respectively. CONCLUSION: A rectosigmoid waist occurs at the junction of the mesorectum and mesocolon, and is a mesenteric landmark for the rectum that is present on both radiology and pathology.

Radiologist and multidisciplinary team clinician opinions on the quality of MRI rectal cancer staging reports: how are we doing?

AIM: To evaluate the current opinion of magnetic resonance imaging (MRI) reports amongst specialist clinicians involved in colorectal cancer multidisciplinary teams (CRC MDTs). MATERIALS AND METHODS: Active participants at 16 UK CRC MDTs across a population of 5.7 million were invited to complete a questionnaire, this included 22 closed and three open questions. Closed questions used ordinal (Likert) scales to judge the subjective inclusion of tumour descriptors and impressions on the clarity and consistency of the MRI report. Open (free-text) questions allowed overall feedback and suggestions. RESULTS: A total of 69 participants completed the survey (21 radiologists and 48 other CRC MDT clinicians). Both groups highlighted that reports commonly omit the status of the circumferential resection margin (CRM; 83% versus 81% inclusion, other clinicians and radiologists, respectively, p>0.05), presence or absence of extra-mural venous invasion (EMVI; 67% versus 57% inclusion, p>0.05), and lymph node status (90% inclusion in both groups). Intra-radiologist agreement across MRI examinations is reported as 75% by other clinicians. Free-text comments included suggestions for template-style reports. CONCLUSION: Both groups recognise a proportion of MRI reports are suboptimal with key tumour descriptors omitted. There are also concerns around the presentation style of MRI reports and inter- and intra-radiologist report variability. The widespread implementation of standardised report templates may improve completeness and clarity of MRI reports for rectal cancer and thus clinical management and outcomes in rectal cancer.

Standardised reports with a template format are superior to free text reports: the case for rectal cancer reporting in clinical practice.

PURPOSE: Rectal cancer staging with magnetic resonance imaging (MRI) allows accurate assessment and preoperative staging of rectal cancers. Therefore, complete MRI reports are vital to treatment planning. Significant variability may exist in their content and completeness. Template-style reporting can improve reporting standards, but its use is not widespread. Given the implications for treatment, we have evaluated current clinical practice amongst specialist gastrointestinal (GI) radiologists to measure the quality of rectal cancer staging MRI reports. MATERIALS AND METHODS: Sixteen United Kingdom (UK) colorectal cancer multi-disciplinary teams (CRC-MDTs) serving a population over 5 million were invited to submit up to 10 consecutive rectal cancer primary staging MRI reports from January 2016 for each radiologist participating in the CRC-MDT. Reports were compared to a reference standard based on recognised staging and prognostic factors influencing case management RESULTS: Four hundred ten primary staging reports were submitted from 41 of 42 (97.6%) eligible radiologists. Three hundred sixty reports met the inclusion criteria, of these, 81 (22.5%) used a template. Template report usage significantly increased recording of key data points versus non-template reports for extra-mural venous invasion (EMVI) status (98.8% v 51.6%, p < 0.01) and circumferential resection margin (CRM) status (96.3% v 65.9%, p < 0.01). Local tumour stage (97.5% v 93.5%, NS) and nodal status (98.8% v 96.1%, NS) were reported and with similar frequency. CONCLUSION: Rectal cancer primary staging reports do not meet published standards. Template-style reports have significant increases in the inclusion of key tumour descriptors. This study provides further support for their use to improve reporting standards and outcomes in rectal cancer. KEY POINTS: • MRI primary staging of rectal cancer requires detailed tumour descriptions as these alter the neoadjuvant and surgical treatments. • Currently, rectal cancer MRI reports in clinical practice do not provide sufficient detail on these tumour descriptors. • The use of template-style reports for primary staging of rectal cancer significantly improves report quality compared to free-text reports.

BACCHUS: A randomised non-comparative phase II study of neoadjuvant chemotherapy (NACT) in patients with locally advanced rectal cancer (LARC).

BACKGROUND: Chemoradiation (CRT) or short-course radiotherapy (SCRT) are standard treatments for locally advanced rectal cancer (LARC). We evaluated the efficacy/safety of two neoadjuvant chemotherapy (NACT) regimens as an alternative prior to total mesorectal excision (TME). METHODS/DESIGN: This multi-centre, phase II trial in patients with magnetic resonance imaging (MRI) defined high-risk LARC (>cT3b, cN2+ or extramural venous invasion) randomised patients (1:1) to FOLFOX + Bevacizumab (Arm 1) or FOLFOXIRI + bevacizumab (Arm 2) every 14 days for 6 cycles prior to surgery. Patients were withdrawn if positron emission tomography (PET) standardised uptake value (SUV) after 3 cycles failed to decrease by >30% or increased compared to baseline. Primary endpoint was pathological complete response rate (pCR). Secondary endpoints included adverse events (AE) and toxicity. Neoadjuvant rectal (NAR) scores based on "T" and "N" downstaging were calculated. FINDINGS: Twenty patients aged 18-75 years were randomised. The trial stopped early because of poor accrual. Seventeen patients completed all 6 cycles of NACT. One stopped due to myocardial infarction, 1 poor response on PET (both received CRT) and 1 committed suicide. 11 patients had G3 AE, 1 G4 AE (neutropenia), and 1 G5 (suicide). pCR (the primary endpoint) was 0/10 for Arm 1 and 2/10 for Arm 2 i.e. 2/20 (10%) overall. Median NAR score was 14·9 with 5 (28%), 7 (39%), and 6 (33%) having low, intermediate, or high scores. Surgical morbidity was acceptable (1/18 wound infection, no anastomotic leak/pelvic sepsis/fistulae). The 24-month progression-free survival rate was 75% (95% CI: 60%-85%). INTERPRETATION: The primary endpoint (pCR rate) was not met. However, FOLFOXIRI and bevacizumab achieved promising pCR rates, low NAR scores and was well-tolerated. This regimen is suitable for testing as the novel arm against current standards of SCRT and/or CRT in a future trial.

IntAct: intra-operative fluorescence angiography to prevent anastomotic leak in rectal cancer surgery: a randomized controlled trial.

AIM: Anastomotic leak (AL) is a major complication of rectal cancer surgery. Despite advances in surgical practice, the rates of AL have remained static, at around 10-15%. The aetiology of AL is multifactorial, but one of the most crucial risk factors, which is mostly under the control of the surgeon, is blood supply to the anastomosis. The MRC/NIHR IntAct study will determine whether assessment of anastomotic perfusion using a fluorescent dye (indocyanine green) and near-infrared laparoscopy can minimize the rate of AL leak compared with conventional white-light laparoscopy. Two mechanistic sub-studies will explore the role of the rectal microbiome in AL and the predictive value of CT angiography/perfusion studies. METHOD: IntAct is a prospective, unblinded, parallel-group, multicentre, European, randomized controlled trial comparing surgery with intra-operative fluorescence angiography (IFA) against standard care (surgery with no IFA). The primary end-point is rate of clinical AL at 90 days following surgery. Secondary end-points include all AL (clinical and radiological), change in planned anastomosis, complications and re-interventions, use of stoma, cost-effectiveness of the intervention and quality of life. Patients should have a diagnosis of adenocarcinoma of the rectum suitable for potentially curative surgery by anterior resection. Over 3 years, 880 patients from 25 European centres will be recruited and followed up for 90 days. DISCUSSION: IntAct will rigorously evaluate the use of IFA in rectal cancer surgery and explore the role of the microbiome in AL and the predictive value of preoperative CT angiography/perfusion scanning.

Clinicopathological, genomic and immunological factors in colorectal cancer prognosis.

BACKGROUND: Numerous factors affect the prognosis of colorectal cancer (CRC), many of which have long been identified, such as patient demographics and the multidisciplinary team. In more recent years, molecular and immunological biomarkers have been shown to have a significant influence on patient outcomes. Whilst some of these biomarkers still require ongoing validation, if proven to be worthwhile they may change our understanding and future management of CRC. The aim of this review was to identify the key prognosticators of CRC, including new molecular and immunological biomarkers, and outline how these might fit into the whole wider context for patients. METHODS: Relevant references were identified through keyword searches of PubMed and Embase Ovid SP databases. RESULTS: In recent years there have been numerous studies outlining molecular markers of prognosis in CRC. In particular, the Immunoscore® has been shown to hold strong prognostic value. Other molecular biomarkers are useful in guiding treatment decisions, such as mutation testing of genes in the epidermal growth factor receptor pathway. However, epidemiological studies continue to show that patient demographics are fundamental in predicting outcomes. CONCLUSION: Current strategies for managing CRC are strongly dependent on clinicopathological staging, although molecular testing is increasingly being implemented into routine clinical practice. As immunological biomarkers are further validated, their testing may also become routine. To obtain clinically useful information from new biomarkers, it is important to implement them into a model that includes all underlying fundamental factors, as this will enable the best possible outcomes and deliver true precision medicine.

The effect of a multidisciplinary regional educational programme on the quality of colon cancer resection.

AIM: Mesocolic plane surgery with central vascular ligation produces an oncologically superior specimen following colon cancer resection and appears to be related to optimal outcomes. We aimed to assess whether a regional educational programme in optimal mesocolic surgery led to an improvement in the quality of specimens. METHOD: Following an educational programme in the Capital and Zealand areas of Denmark, 686 cases of primary colon cancer resected across six hospitals were assessed by grading the plane of surgery and undertaking tissue morphometry. These were compared to 263 specimens resected prior to the educational programme. RESULTS: Across the region, the mesocolic plane rate improved from 58% to 77% (P < 0.001). One hospital had previously implemented optimal surgery as standard prior to the educational programme and continued to produce a high rate of mesocolic plane specimens (68%) with a greater distance between the tumour and the high tie (median for all fresh cases: 113 vs 82 mm) and lymph node yield (33 vs 18) compared to the other hospitals. Three of the other hospitals showed a significant improvement in the plane of surgical resection. CONCLUSION: A multidisciplinary regional educational programme in optimal mesocolic surgery improved the oncological quality of colon cancer specimens as assessed by mesocolic planes; however, there was no significant effect on the amount of tissue resected centrally. Surgeons who attempt central vascular ligation continue to produce more radical specimens suggesting that such educational programmes alone are not sufficient to increase the amount of tissue resected around the tumour.

Internal anal sphincter nerves - a macroanatomical and microscopic description of the extrinsic autonomic nerve supply of the internal anal sphincter.

AIM: The internal anal sphincter (IAS) contributes substantially to anorectal functions. While its autonomic nerve supply has been studied at the microscopic level, little information is available concerning the macroscopic topography of extrinsic nerve fibres. This study was designed to identify neural connections between the pelvic plexus and the IAS, provide a detailed topographical description, and give histological proof of autonomic nerve tissue. METHODS: Macroscopic dissection of pelvic autonomic nerves was performed under magnification in seven (five male, two female) hemipelvises obtained from body donors (67-92 years). Candidate structures were investigated by histological and immunohistochemical staining protocols to visualize nerve tissue. RESULTS: Nerve fibres could be traced from the anteroinferior edge of the pelvic plexus to the anorectal junction running along the neurovascular bundle anterolaterally to the rectum and posterolaterally to the prostate/vagina. Nerve fibres penetrated the longitudinal rectal muscle layer just above the fusion with the levator ani muscle (conjoint longitudinal muscle) and entered the intersphincteric space to reach the IAS. Histological and immunohistochemical findings confirmed the presence of nerve tissue. CONCLUSIONS: Autonomic nerve fibres supplying the IAS emerge from the pelvic plexus and are distinct to nerves entering the rectum via the lateral pedicles. Thus, they should be classified as IAS nerves. The identification and precise topographical location described provides a basis for nerve-sparing rectal resection procedures and helps to prevent postoperative functional anorectal disorders.

Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016

Tumor budding is a well-established independent prognostic factor in colorectal cancer but a standardized method for its assessment has been lacking. The primary aim of the International Tumor Budding Consensus Conference (ITBCC) was to reach agreement on an international, evidence-based standardized scoring system for tumor budding in colorectal cancer. The ITBCC included nine sessions with presentations, a pre-meeting survey and an e-book covering the key publications on tumor budding in colorectal cancer. The 'Grading of Recommendation Assessment, Development and Evaluation' method was used to determine the strength of recommendations and quality of evidence. The following 10 statements achieved consensus: tumor budding is defined as a single tumor cell or a cell cluster consisting of four tumor cells or less (22/22, 100%). Tumor budding is an independent predictor of lymph node metastases in pT1 colorectal cancer (23/23, 100%). Tumor budding is an independent predictor of survival in stage II colorectal cancer (23/23, 100%). Tumor budding should be taken into account along with other clinicopathological features in a multidisciplinary setting (23/23, 100%). Tumor budding is counted on H&E (19/22, 86%). Intratumoral budding exists in colorectal cancer and has been shown to be related to lymph node metastasis (22/22, 100%). Tumor budding is assessed in one hotspot (in a field measuring 0.785 mm2) at the invasive front (22/22, 100%). A three-tier system should be used along with the budding count in order to facilitate risk stratification in colorectal cancer (23/23, 100%). Tumor budding and tumor grade are not the same (23/23, 100%). Tumor budding should be included in guidelines/protocols for colorectal cancer reporting (23/23, 100%). Members of the ITBCC were able to reach strong consensus on a single international, evidence-based method for tumor budding assessment and reporting. It is proposed that this method be incorporated into colorectal cancer guidelines/protocols and staging systems.

Investigating the poor outcomes of BRAF-mutant advanced colorectal cancer: analysis from 2530 patients in randomised clinical trials.

Background: To improve strategies for the treatment of BRAF-mutant advanced colorectal cancer (aCRC) patients, we examined individual data from patients treated with chemotherapy alone in three randomised trials to identify points on the treatment pathway where outcomes differ from BRAF wild-types. Patients and methods: 2530 aCRC patients were assessed from three randomised trials. End-points were progression-free survival, response rate, disease control rate, post-progression survival (P-PS) and overall survival. Treatments included first-line oxaliplatin/fluorouracil (OxFU) and second-line irinotecan. Clinicians were unaware of BRAF-status. Results: 231 patients (9.1%) had BRAF-mutant tumours. BRAF-mutation conferred significantly worse survival independent of associated clinicopathological factors known to be prognostic. Compared with wild-type, BRAF-mutant patients treated with first-line OxFU had similar DCR (59.2% versus 72%; adjusted OR = 0.76, P = 0.24) and PFS (5.7 versus 6.3 months; adjusted HR = 1.14, P = 0.26). Following progression on first-line chemotherapy, BRAF-mutant patients had a markedly shorter P-PS (4.2 versus 9.2 months, adjusted HR = 1.69, P < 0.001). Fewer BRAF-mutant patients received second-line treatment (33% versus 51%, P < 0.001), but BRAF-mutation was not associated with inferior second-line outcomes (RR adjusted OR = 0.56, P = 0.45; PFS adjusted HR = 1.01, P = 0.93). Significant clinical heterogeneity within the BRAF-mutant population was observed: a proportion (24.3%) had good first-line PFS and P-PS (both >6 months; OS = 24.0 months); however, 36.5% progressed rapidly through first-line chemotherapy and thereafter, with OS = 4.7 months. Conclusions: BRAF-mutant aCRC confers a markedly worse prognosis independent of associated clinicopathological features. Chemotherapy provides meaningful improvements in outcome throughout treatment lines. Post-progression survival is markedly worse and vigilance is required to ensure appropriate delivery of treatment after first-line progression.

Wide Variation in the Use of Radiotherapy in the Management of Surgically Treated Rectal Cancer Across the English National Health Service.

AIMS: Radiotherapy is an important treatment modality in the multidisciplinary management of rectal cancer. It is delivered both in the neoadjuvant setting and postoperatively, but, although it reduces local recurrence, it does not influence overall survival and increases the risk of long-term complications. This has led to a variety of international practice patterns. These variations can have a significant effect on commissioning, but also future clinical research. This study explores its use within the large English National Health Service (NHS). MATERIALS AND METHODS: Information on all individuals diagnosed with a surgically treated rectal cancer between April 2009 and December 2010 were extracted from the Radiotherapy Dataset linked to the National Cancer Data Repository. Individuals were grouped into those receiving no radiotherapy, short-course radiotherapy with immediate surgery (SCRT-I), short-course radiotherapy with delayed surgery (SCRT-D), long-course chemoradiotherapy (LCCRT), other radiotherapy (ORT) and postoperative radiotherapy (PORT). Patterns of use were then investigated. RESULTS: The study consisted of 9201 individuals; 4585 (49.3%) received some form of radiotherapy. SCRT-I was used in 12.1%, SCRT-D in 1.2%, LCCRT in 29.5%, ORT in 4.7% and PORT in 2.3%. Radiotherapy was used more commonly in men and in those receiving an abdominoperineal excision and less commonly in the elderly and those with comorbidity. Significant and substantial variations were also seen in its use across all the multidisciplinary teams managing this disease. CONCLUSION: Despite the same evidence base, wide variation exists in both the use of and type of radiotherapy delivered in the management of rectal cancer across the English NHS. Prospective population-based collection of local recurrence and patient-reported early and late toxicity information is required to further improve patient selection for preoperative radiotherapy.

The anatomy of the perineal body in relation to abdominoperineal excision for low rectal cancer.

AIM: Dissection of the perineal body (PB) during abdominoperineal excision (APE) for low rectal cancer is often difficult due to the lack of a natural plane of dissection. Understanding the PB and its relation to the anorectum is essential to permit safe dissection during the perineal phase of the operation and avoid damage to the anorectum and urogenital organs. This study describes the anatomy and histology of the PB relevant to APE. METHOD: Six human adult cadaver pelvic exenteration specimens (three male, three female) from the Leeds GIFT Research Tissue Programme were studied. Paraffin-embedded mega-blocks were produced and serially sectioned at 50- and 250-µm intervals. Sections were stained by immunohistochemistry to show collagen, elastin and smooth muscle. RESULTS: The PB was cylindrically shaped in the male specimens and wedge-shaped in the female ones. Although centrally located between the anal and urogenital triangles, it was nearly completely formed by muscle fibres derived from the rectal muscularis propria. Thick bundles of smooth muscle, mostly arising from the longitudinal muscle, inserted into the PB and levator ani muscle (LAM). The recto-urethralis muscle originated from the PB and separated the anterolateral PB from the urogenital organs. CONCLUSION: Smooth muscle fibres derived from the rectal muscularis propria extend into the PB and LAM and appear to fix the anorectum. Dissection of the PB during APE is safe only when the smooth muscle fibres that extend into the PB are divided.

Bevacizumab and Combination Chemotherapy in rectal cancer Until Surgery (BACCHUS): a phase II, multicentre, open-label, randomised study of neoadjuvant chemotherapy alone in patients with high-risk cancer of the rectum.

BACKGROUND: In locally advanced rectal cancer (LARC) preoperative chemoradiation (CRT) is the standard of care, but the risk of local recurrence is low with good quality total mesorectal excision (TME), although many still develop metastatic disease. Current challenges in treating rectal cancer include the development of effective organ-preserving approaches and the prevention of subsequent metastatic disease. Neoadjuvant systemic chemotherapy (NACT) alone may reduce local and systemic recurrences, and may be more effective than postoperative treatments which often have poor compliance. Investigation of intensified NACT is warranted to improve outcomes for patients with LARC. The objective is to evaluate feasibility and efficacy of a four-drug regimen containing bevacizumab prior to surgical resection. METHODS/DESIGN: This is a multi-centre, randomized phase II trial. Eligible patients must have histologically confirmed LARC with distal part of the tumour 4-12 cm from anal verge, no metastases, and poor prognostic features on pelvic MRI. Sixty patients will be randomly assigned in a 1:1 ratio to receive folinic acid + flurourcil + oxaliplatin (FOLFOX) + bevacizumab (BVZ) or FOLFOX + irinotecan (FOLFOXIRI) + BVZ, given in 2 weekly cycles for up to 6 cycles prior to TME. Patients stop treatment if they fail to respond after 3 cycles (defined as ≥ 30 % decrease in Standardised Uptake Value (SUV) compared to baseline PET/CT). The primary endpoint is pathological complete response rate. Secondary endpoints include objective response rate, MRI tumour regression grade, involved circumferential resection margin rate, T and N stage downstaging, progression-free survival, disease-free survival, overall survival, local control, 1-year colostomy rate, acute toxicity, compliance to chemotherapy. DISCUSSION: In LARC, a neoadjuvant chemotherapy regimen - if feasible, effective and tolerable would be suitable for testing as the novel arm against the current standards of short course preoperative radiotherapy (SCPRT) and/or fluorouracil (5FU)-based CRT in a future randomised phase III trial. TRIAL REGISTRATION: Clinical trial identifier BACCHUS: NCT01650428.

Understanding the surgical pitfalls in total mesorectal excision: Investigating the histology of the perirectal fascia and the pelvic autonomic nerves.

AIM: Excellent understanding of fasciae and nerves surrounding the rectum is necessary for total mesorectal excision (TME). However, fasciae anterolateral to the rectum and surrounding the low rectum are still poorly understood. We studied the perirectal fascia enfolding the extraperitoneally located part of the rectum in en-bloc cadaveric specimens and the University Medical Center Utrecht (UMCU) pelvic dataset, and describe implications for TME. METHODS: Four donated human adult cadaveric specimens (two males, two females) were obtained through the Leeds GIFT Research Tissue Programme. Paraffin-embedded blocks were produced and serially sectioned at 50 and 250 µm intervals. Whole mount sections were stained with haematoxylin & eosin, Masson's trichrome and Millers' elastin. Additionally, the UMCU pelvic dataset including digitalised cryosections of a female pelvis in three axes was studied. RESULTS: The mid and lower rectum were surrounded by a multi-layered perirectal fascia, of which the mesorectal fascia (MRF) and parietal fascia bordered the 'holy plane'. There was no extra constant fascia forming a potential surgical plane. Nerves ran laterally to the MRF. More caudally, the mesorectal fat strongly reduced and the MRF approached the rectal muscularis propria. The MRF had a variable appearance in terms of thickness and completeness, most prominently at the anterolateral lower rectum. CONCLUSION: Dissection onto the MRF allows nerve preservation in TME. Rectal surgeons are challenged in doing so as the MRF varies in thickness and shows gaps, most prominently at the anterolateral lower rectum. At this site, the risk of entering the mesorectum is great and may result in an incomplete specimen.