A national patient and public colorectal research agenda: integration of consumer perspectives in bowel disease through early consultation.

AIM: There is a recognized need to include the views of patients and the public in prioritizing health research. This study aimed: (i) to explore patients' views on colorectal research; and (ii) to prioritize research topics with patients and the public. METHOD: In phase 1, 12 charitable organizations and patient groups with an interest in bowel disease were invited to attend a consultation exercise. Participants were briefed on 25 colorectal research topics prioritized by members of the Association of Coloproctology of Great Britain and Ireland. Focus groups were conducted and discussions were recorded with field notes. Analysis was conducted using principles of thematic analysis. In phase 2, a free public consultation was undertaken. Participants were recruited from newspaper advertisements, were briefed on the same research topics and were asked to rate the importance of each on a five-point Likert scale. Descriptive statistics were used to rank the topics. Univariable linear regression compared recorded demographic details with mean topic scores. RESULTS: Focus groups were attended by 12 patients who highlighted the importance of patient-centred information for trial recruitment and when selecting outcome measures. Some 360 people attended the public consultation, of whom 277 (77%) were recruited. Participants rated 'What is the best way to treat early cancer in the back passage?' highest, with 227 (85%) scoring it 4 or 5. There was no correlation between participant demographics and mean topic scores. CONCLUSION: The present study prioritized a colorectal research agenda with the input of patients and the public. Further research is required to translate this agenda into real improvements in patient care.

Multicentre study of short-course radiotherapy and transanal endoscopic microsurgery for early rectal cancer.

BACKGROUND: Organ-preserving treatment for early-stage rectal cancer may avoid the substantial perioperative morbidity and functional sequelae associated with total mesorectal excision (TME). The initial results of an organ-preserving approach using preoperative short-course radiotherapy (SCRT) and transanal endoscopic microsurgery (TEMS) are presented. METHODS: Patients with cT1-2N0 rectal cancers staged using high-quality MRI and endorectal ultrasonography received SCRT, with TEMS 8-10 weeks later, at four regional referral centres between 2007 and 2013. Patients were generally considered high risk for TME surgery (a small number refused TME). RESULTS: Following SCRT and TEMS, 60 (97 per cent) of 62 patients had an R0 resection. Histopathological staging identified 20 ypT0 tumours, 23 ypT1, 18 ypT2 and one ypT3. Preoperative uT category was significantly associated with a complete pathological response, which was achieved in 13 of 27 patients with uT0/uT1 disease and in five of 29 with uT2 (P = 0·010). Acute complications affected 19 patients, the majority following TEMS. No fistulas occurred and no stomas were formed. Surveillance detected four intraluminal local recurrences at a median follow-up of 13 months, all in patients with tumours staged as ypT2. Salvage TME achieved R0 resection in three patients and a stent was placed in one patient owing to co-morbidities. CONCLUSION: SCRT with TEMS was effective in the majority of patients considered high risk for (or who refused) TME surgery.

Combined endorectal ultrasonography and strain elastography for the staging of early rectal cancer.

AIM: Strain elastography is a novel approach to rectal tumour evaluation. The primary aim of this study was to correlate elastography to pT stages of rectal tumours and to assess the ability of the method to differentiate rectal adenomas (pT0) from early rectal cancer (pT1-2). Secondary aims were to compare elastography with endorectal ultrasonography (ERUS) and to propose a combined strain elastography and ERUS staging algorithm. METHOD: In all, 120 consecutive patients with a suspected rectal tumour were examined in this staging study. Patients receiving surgery without neoadjuvant radiotherapy were included (n = 59). All patients were examined with ERUS and elastography. Treatment decisions were made by multidisciplinary team (MDT) assessment, without considering the strain elastography examination. RESULTS: Histopathology identified 21 adenomas, 13 pT1, 9 pT2, 15 pT3 and one pT4. Mean elastography strain ratios were predictive of T stage (P = 0.01). Differentiation of adenomas from early rectal cancer (pT1-2) had sensitivity, specificity and accuracy of 0.82, 0.86 and 0.84 for elastography and 0.82, 0.62 and 0.72 for ERUS. A combined staging algorithm was developed to identify tumours eligible for local resection. Based on MDT evaluation 32% of tumours later identified as pT0 or pT1 were treated with total mesorectal excision, even though a local excision might have sufficed. Combined ERUS and elastography evaluation would have significantly reduced this number to 9% (P = 0.008). CONCLUSION: Elastography may improve the staging of adenomas and early rectal cancer compared with ERUS alone. Combined ERUS and elastography assessment is likely to further improve the selection of patients for local resection.

Endorectal ultrasonography, strain elastography and MRI differentiation of rectal adenomas and adenocarcinomas.

AIM: Strain elastography is a method for recording tissue hardness. Strain in different areas may be compared using strain ratio (SR). The aims of this study were to validate a previously proposed SR cut-off value of 1.25 for differentiating adenocarcinomas from adenomas and to compare the performance of endorectal ultrasonography (ERUS), strain elastography and MRI in the same patients. METHOD: A prospective evaluation of 120 consecutive patients with rectal neoplasia, using a predetermined elastography strain ratio cut-off value, was performed to differentiate adenomas from adenocarcinomas. ERUS and MRI were performed according to standard routine at Haukeland University Hospital, defining T0 as adenomas and T1-T4 as adenocarcinomas. Subsequent histopathology was used as the reference standard. RESULTS: Histopathological evaluation revealed 21 adenomas and 99 adenocarcinomas. Sensitivity, specificity and accuracy (with 95% CI) were as follows: ERUS: 0.96 (0.90-0.99), 0.62 (0.40-0.80) and 0.90 (0.83-0.94); elastography SR: 0.96 (0.90-0.99), 0.86 (0.66-0.96) and 0.94 (0.88-0.97); and MRI: 0.99 (0.94-1.00), 0.07 (0.00-0.31) and 0.87 (0.80-0.93). CONCLUSION: This study confirms that the elastography SR assessment accurately differentiates sessile adenomas from adenocarcinomas. SR assessment has a superior ability to differentiate adenomas and adenocarcinomas when compared with ERUS and MRI. MRI examination seems unable to recognize adenomas and should be interpreted with care when early-stage rectal neoplasia is suspected.

Biomarker-based treatment selection in early-stage rectal cancer to promote organ preservation.

BACKGROUND: Total mesorectal excision (TME) remains commonplace for T1-2 rectal cancer owing to fear of undertreating a small proportion of patients with node-positive disease. Molecular stratification may predict cancer progression. It could be used to select patients for organ-preserving surgery if specific biomarkers were validated. METHODS: Gene methylation was quantified using bisulphite pyrosequencing in 133 unirradiated rectal cancer TME specimens. KRAS mutation and microsatellite instability status were also defined. Molecular parameters were correlated with histopathological indices of disease progression. Predictive models for nodal metastasis, lymphovascular invasion (LVI) and distant metastasis were constructed using a multilevel reverse logistic regression model. RESULTS: Methylation of the retinoic acid receptor ß gene, RARB, and that of the checkpoint with forkhead and ring finger gene, CHFR, was associated with tumour stage (RARB: 51·9 per cent for T1-2 versus 33·9 per cent for T3-4, P < 0·001; CHFR: 5·5 per cent for T1-2 versus 12·6 per cent for T3-4, P = 0·005). Gene methylation associated with nodal metastasis included RARB (47·1 per cent for N- versus 31·7 per cent for N+; P = 0·008), chemokine ligand 12, CXCL12 (12·3 per cent for N- versus 8·9 per cent for N+; P = 0·021), and death-associated protein kinase 1, DAPK1 (19·3 per cent for N- versus 12·3 per cent for N+; P = 0·022). RARB methylation was also associated with LVI (45·1 per cent for LVI- versus 31·7 per cent for LVI+; P = 0·038). Predictive models for nodal metastasis and LVI achieved sensitivities of 91·1 and 85·0 per cent, and specificities of 55·3 and 45·3 per cent, respectively. CONCLUSION: This methylation biomarker panel provides a step towards accurate discrimination of indolent and aggressive rectal cancer subtypes. This could offer an improvement over the current standard of care, whereby fit patients are offered radical surgery.

Measures of performance and proficiency in robotic assisted surgery: a systematic review.

Robotic assisted surgery (RAS) has seen a global rise in adoption. Despite this, there is not a standardised training curricula nor a standardised measure of performance. We performed a systematic review across the surgical specialties in RAS and evaluated tools used to assess surgeons' technical performance. Using the PRISMA 2020 guidelines, Pubmed, Embase and the Cochrane Library were searched systematically for full texts published on or after January 2020-January 2022. Observational studies and RCTs were included; review articles and systematic reviews were excluded. The papers' quality and bias score were assessed using the Newcastle Ottawa Score for the observational studies and Cochrane Risk Tool for the RCTs. The initial search yielded 1189 papers of which 72 fit the eligibility criteria. 27 unique performance metrics were identified. Global assessments were the most common tool of assessment (n = 13); the most used was GEARS (Global Evaluative Assessment of Robotic Skills). 11 metrics (42%) were objective tools of performance. Automated performance metrics (APMs) were the most widely used objective metrics whilst the remaining (n = 15, 58%) were subjective. The results demonstrate variation in tools used to assess technical performance in RAS. A large proportion of the metrics are subjective measures which increases the risk of bias amongst users. A standardised objective metric which measures all domains of technical performance from global to cognitive is required. The metric should be applicable to all RAS procedures and easily implementable. Automated performance metrics (APMs) have demonstrated promise in their wide use of accurate measures.

STAR-TREC: An International Three-arm Multicentre, Partially Randomised Controlled Trial Incorporating an External Pilot.

AIM: Organ saving treatment for early-stage rectal cancer can reduce patient reported side effects compared to standard total mesorectal excision (TME) and preserve quality of life (QOL). An optimal strategy for achieving organ preservation and longer-term oncological outcomes are unknown, thus there is a need for high quality trials. METHOD: Can we Save the rectum by watchful waiting or TransAnal surgery following (chemo)Radiotherapy versus Total mesorectal excision for early REctal Cancer (STAR-TREC) is an international 3-arm multi-centre, partially randomised controlled trial incorporating an external pilot. In phase III, patients with cT1-3b N0 tumours, ≤40mm in diameter, who prefer organ preservation are randomised 1:1 between mesorectal long course chemoradiation versus mesorectal short course radiotherapy, with selective transanal microsurgery. Patients preferring radical surgery receive TME. STAR-TREC aims to recruit 380 patients to organ preservation and 120 to TME surgery. The primary outcome is the rate of organ preservation at 30 months. Secondary clinician reported outcomes include acute treatment-related toxicity, rate of non-operative management, non-regrowth pelvic tumour control at 36 months, non-regrowth disease free survival at 36 months, and overall survival at 60 months and patient reported toxicity, health related QOL at baseline, 12 and 24 months. Exploratory biomarker research uses circulating tumour DNA to predict response and relapse. DISCUSSION: STAR-TREC will prospectively evaluate contrasting therapeutic strategies and implement new measures including a smaller mesorectal target volume, 2-step response assessment and non-operative management for complete response. The trial will yield important information to guide routine management of patients with early-stage rectal cancer.

Methylation profiling of rectal cancer identifies novel markers of early-stage disease.

BACKGROUND: Radical surgery is the de facto treatment for early rectal cancer. Conservative surgery with transanal endoscopic microsurgery can achieve high rates of cure but the histopathological measures of outcome used to select local treatment lack precision. Biomarkers associated with disease progression, particularly mesorectal nodal metastasis, are urgently required. The aim was to compare patterns of gene-specific hypermethylation in radically excised rectal cancers with histopathological stage. METHODS: Locus-specific hypermethylation of 24 tumour suppressor genes was measured in 105 rectal specimens (51 radically excised adenocarcinomas, 35 tissues adjacent to tumour and 19 normal controls) using the methylation-specific multiplex ligation-dependent probe assay (MS-MLPA). Methylation values were correlated with histopathological indices of disease progression and validated using bisulphite pyrosequencing. RESULTS: Five sites (ESR1, CDH13, CHFR, APC and RARB) were significantly hypermethylated in cancer compared with adjacent tissue and normal controls (P < 0·050). Methylation at these sites was higher in Dukes' A than Dukes' 'D' cancers (P = 0·013). Methylation at two sites (GSTP1 and RARB) was individually associated with localized disease (N0 and M0 respectively; P = 0·006 and P = 0·008). Hypermethylation of at least two of APC, RARB, TIMP3, CASP8 and GSTP1 was associated with early (N0 M0) disease (N0, P = 0·002; M0, P = 0·044). Methylation levels detected by MS-MLPA and pyrosequencing were concordant. CONCLUSION: Locus-specific hypermethylation was more prevalent in early- than late-stage disease. Hypermethylation of two or more of a panel of five tumour suppressor genes was associated with localized disease.

Research quality and transparency, outcome measurement and evidence for safety and effectiveness in robot-assisted surgery: systematic review.

BACKGROUND: Robot-assisted surgery (RAS) has potential panspecialty surgical benefits. High-quality evidence for widespread implementation is lacking. This systematic review aimed to assess the RAS evidence base for the quality of randomized evidence on safety and effectiveness, specialty 'clustering', and outcomes for RAS research. METHODS: A systematic review was undertaken according to PRISMA guidelines. All pathologies and procedures utilizing RAS were included. Studies were limited to RCTs, the English language and publication within the last decade. The main outcomes selected for the review design were safety and efficacy, and study purpose. Secondary outcomes were study characteristics, funding and governance. RESULTS: Searches identified 7142 titles, from which 183 RCTs were identified for data extraction. The commonest specialty was urology (35·0 per cent). There were just 76 unique study populations, indicating significant overlap of publications; 103 principal studies were assessed further. Only 64·1 per cent of studies reported a primary outcome measure, with 29·1 per cent matching their registration/protocol. Safety was assessed in 68·9 per cent of trials; operative complications were the commonest measure. Forty-eight per cent of trials reported no significant difference in safety between RAS and comparator, and 11 per cent reported RAS to be superior. Efficacy or effectiveness was assessed in 80·6 per cent of trials; 43 per cent of trials showed no difference between RAS and comparator, and 24 per cent reported that RAS was superior. Funding was declared in 47·6 per cent of trials. CONCLUSION: The evidence base for RAS is of limited quality and variable transparency in reporting. No patterns of harm to patients were identified. RAS has potential to be beneficial, but requires continued high-quality evaluation.

A predictive model for local recurrence after transanal endoscopic microsurgery for rectal cancer.

BACKGROUND: The outcome of local excision of early rectal cancer using transanal endoscopic microsurgery (TEM) lacks consensus. Screening has substantially increased the early diagnosis of tumours. Patients need local treatments that are oncologically equivalent to radical surgery but safer and functionally superior. METHODS: A national database, collated prospectively from 21 regional centres, detailed TEM treatment in 487 subjects with rectal cancer. Data were used to construct a predictive model of local recurrence after TEM using semiparametric survival analyses. The model was internally validated using measures of calibration and discrimination. RESULTS: Postoperative morbidity and mortality were 14.9 and 1.4 per cent respectively. The Cox regression model predicted local recurrence with a concordance index of 0.76 using age, depth of tumour invasion, tumour diameter, presence of lymphovascular invasion, poor differentiation and conversion to radical surgery after histopathological examination of the TEM specimen. CONCLUSION: Patient selection for TEM is frequently governed by fitness for radical surgery rather than suitable tumour biology. TEM can produce long-term outcomes similar to those published for radical total mesorectal excision surgery if applied to a select group of biologically favourable tumours. Conversion to radical surgery based on adverse TEM histopathology appears safe for p T1 and p T2 lesions.

National prospective cohort study of the burden of acute small bowel obstruction.

Background: Small bowel obstruction is a common surgical emergency, and is associated with high levels of morbidity and mortality across the world. The literature provides little information on the conservatively managed group. The aim of this study was to describe the burden of small bowel obstruction in the UK. Methods: This prospective cohort study was conducted in 131 acute hospitals in the UK between January and April 2017, delivered by trainee research collaboratives. Adult patients with a diagnosis of mechanical small bowel obstruction were included. The primary outcome was in-hospital mortality. Secondary outcomes included complications, unplanned intensive care admission and readmission within 30 days of discharge. Practice measures, including use of radiological investigations, water soluble contrast, operative and nutritional interventions, were collected. Results: Of 2341 patients identified, 693 (29·6 per cent) underwent immediate surgery (within 24 h of admission), 500 (21·4 per cent) had delayed surgery after initial conservative management, and 1148 (49·0 per cent) were managed non-operatively. The mortality rate was 6·6 per cent (6·4 per cent for non-operative management, 6·8 per cent for immediate surgery, 6·8 per cent for delayed surgery; P = 0·911). The major complication rate was 14·4 per cent overall, affecting 19·0 per cent in the immediate surgery, 23·6 per cent in the delayed surgery and 7·7 per cent in the non-operative management groups (P < 0·001). Cox regression found hernia or malignant aetiology and malnutrition to be associated with higher rates of death. Malignant aetiology, operative intervention, acute kidney injury and malnutrition were associated with increased risk of major complication. Conclusion: Small bowel obstruction represents a significant healthcare burden. Patient-level factors such as timing of surgery, acute kidney injury and nutritional status are factors that might be modified to improve outcomes.

Recommendations for Randomised Trials in Surgical Oncology.

Trials of surgical procedures in the treatment of malignant disease face a unique set of challenges. This review aimed to describe recommendations for the design, delivery and reporting of randomised trials in surgical oncology. A literature search was carried out without date limits to identify articles related to trial methodology research in surgery and surgical oncology. A narrative review was framed around two open National Institute of Health Research portfolio trials in colon and rectal cancer: the STAR-TREC trial (ISRCTN14240288) and the ROCCS trial (ISRCTN46330337). Twelve specific challenges were highlighted: standardisation of technique; pilot and feasibility studies; balancing treatments; the recruitment pathway; outcome measures; patient and public representation; trainee-led networks; randomisation; novel techniques and training; learning curves; blinding; follow-up. Evidence-based recommendations were made for the future design and conduct of surgical oncology trials. Better understanding of the challenges facing trials in the surgical treatment of cancer will accelerate high-quality evaluation and rapid adoption of innovation for the benefit of patient care.

The antioxidant n-acetylcysteine increases 5-fluorouracil activity against colorectal cancer xenografts in nude mice.

The antioxidant pyrrolidinedithiocarbamate improves the therapeutic efficacy of 5-fluorouracil (5-FU) against HCT-15 colorectal cancer cell line xenografts in nude mice without increasing toxicity to normal intestinal or hematopoietic tissues. In the current study we have shown that a similar clinically licensed antioxidant, N-acetylcysteine (200 mg/kg), can modulate the activity of 5-FU (120 mg/kg) against HCT-15 tumor xenografts in nude mice. We demonstrate that this effect is accompanied by a sustained elevation in p53-independent apoptosis without accompanying alterations in cell cycle kinetics. Extensive tumor necrosis is also a prominent feature of treatment; however, no significant impairment of neovascularization as assessed by intratumor microvessel density occurred. We believe that the clinical efficacy of N-acetylcysteine as an adjunct to 5-FU in advanced colorectal cancer should be investigated further.

The relevance of apoptosis for cellular homeostasis and tumorigenesis in the intestine.

Intestinal epithelium is a rapidly renewing tissue in which cell homeostasis is regulated by a balance among proliferation, growth arrest, differentiation and apoptosis (programmed cell death). Until recently, studies on oncogenesis have focused on the regulation of cell proliferation. The recognition that apoptosis must be understood to comprehend how appropriate cell numbers are maintained and how alterations in any part of the equation can contribute to malignancy has led to an explosion of research in this field. The first half of this review gives an overview of morphology and mechanisms of apoptosis, emphasizing key areas of genetic control such as the bcl-2 family and p53. The second half of the review focuses on the role of apoptosis in normal cellular homeostasis and tumorigenesis in the gastrointestinal epithelium. The importance of understanding the molecular biology of apoptotic pathways in cancer therapy and future directions are also addressed.

Regional localisation of p53-independent apoptosis determines toxicity to 5-fluorouracil and pyrrolidinedithiocarbamate in the murine gut.

Pyrrolidinedithiocarbamate (PDTC) enhanced the activity of 5-fluorouracil (5-FU) in a colorectal cancer xenograft model. Pyrrolidinedithiocarbamate also reduced gastrointestinal toxicity associated with 5-FU therapy in large but not small bowel. We sought to clarify the basis of this differential enteric toxicity. Apoptosis and mitosis were assessed on a cell positional basis in small and large intestinal crypts of p53 wild-type (+/+) and p53 null (-/-) mice 6, 12, 24, 36, 48 and 72 h after the administration of high (200 mg kg(-1)) or low (40 mg kg(-1)) dose 5-FU+/-250 mg kg(-1) PDTC. Regimens were chosen to model a single human dose and a weekly schedule. The effects of another antioxidant N-acetylcysteine (NAC) were also investigated. Large intestinal crypts affect apoptosis purely by p53-dependent mechanisms, whereas small intestinal crypts are able to initiate both p53-dependent and -independent pathways following treatment with 5-FU. Pyrrolidinedithiocarbamate and NAC antagonised p53-dependent but potentiated p53-independent apoptotic activity. Consequently, the proportion of surviving clonogens increased in the large but not in the small intestine. Regional availability of p53-dependent and -independent apoptotic pathways in small and large intestine together with separate modulation of these pathways by antioxidants explains the different regional enterotoxicity following 5-FU therapy.

Stem cells: the intestinal stem cell as a paradigm.

Stem cell research provides a foundation for therapeutic advancement in oncology, clinical genetics and a diverse array of degenerative disorders. For example, the elucidation of pathways governing proliferative regulation and differentiation within cellular systems will result in medical strategies aimed at the root cause of cancer. At present the characterization of reliable stem cell markers is the immediate aim in this particular field. Over the past 30 years investigators have determined many of the physical and functional properties of stem cells through careful and imaginative experimentation. Intestinal stem cells reside at the crypt base and give rise to all cell types found within the crypt. They readily undergo altruistic apoptosis in response to toxic stimuli although their progeny are hardier and will regain stem cell function to repopulate the tissue compartment, giving rise to the concept of a proliferative hierarchy. Contention exists when deciding whether the full complement of cells within a crypt is derived from either a single or multiple stems. Evidence has also arisen to challenge the long held view that colorectal tumours arise from a single mutated stem cell, as early adenomas from a human XO/XY mosaic contained distinct clones. Mechanisms governing the stem cell cycle and subsequent proliferative activity largely remain obscure. The adenomatous polyposis coli gene product has, however, been shown to promote the degradation of beta-catenin, an enhancer of cell proliferation, thereby downregulating this activity in healthy individuals.

Pyrrolidinedithiocarbamate increases the therapeutic index of 5-fluorouracil in a mouse model.

BACKGROUND & AIMS: The thiol-containing antioxidant pyrrolidinedithiocarbamate (PDTC) enhances the cytotoxic efficacy of 5-fluorouracil (5-FU) against human colorectal cancer cell lines in vitro and in vivo. This process appears to be mediated by a sustained increase in p21 expression, independent of p53 function, resulting in growth arrest and apoptosis. We determined whether PDTC augmented 5-FU intestinal toxicity in non-tumor-bearing mice. METHODS: Apoptotic and mitotic indices were measured in the small and large intestine on a cell positional basis at intervals throughout the 72-hour period after administration of 5-FU (40 mg/kg) and PDTC (250 mg/kg). The proportion of crypts regenerating after 5-FU (600-1200 mg/kg) and PDTC (500 mg/kg) was also measured. RESULTS: 5-FU therapy induces substantial apoptotic cell death with simultaneous inhibition of mitotic activity within the small and large intestinal epithelium. PDTC reduces 5-FU-induced apoptotic events in the colon by 49%, predominantly among clonogenic stem and transit cells while promoting the early recovery of mitotic activity. As a consequence, PDTC increased the proportion of regenerating colonic crypts after 5-FU therapy. PDTC did not, however, significantly modulate 5-FU toxicity in the small intestine. CONCLUSIONS: PDTC does not augment the intestinal toxicity of 5-FU and actually protects the colonic mucosa. These results support further investigation of PDTC and related compounds as treatments for colorectal cancer.