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Background: Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics., Patients and Methods: This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28., Findings: Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection., Interpretation: Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS., Trial Registration: EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, "Conditions and Principles which apply to all Clinical Trials" under the header "Principles based on Articles 2 to 5 of the EU GCP Directive" in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as 'ICH GCP'). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician., Competing Interests: The consultancy work declared for AL and ZN relates to advice unrelated to this clinical trial. This clinical trial was undertaken independently with academic leads (VS, SPB), via the Drugs, Devices, Diagnostics and Biomarkers Team (D3B) at Birmingham’s Cancer Research UK Clinical Trials Unit and sponsored by the University of Birmingham. The funder (Tikomed AB) provided support in the form of salary contribution for authors (VS, VH, DB, ACJ, SJ, CP, KB, DS, AL, ZN, and SPB) as part of the clinical trial funding, but did not have any additional role, either direct or indirect, in the clinical trial study design, data collection, data analysis, decision to publish, or preparation of the manuscript through the participation of the co-authors. This does not alter our adherence to PLOS-ONE policies on sharing data and materials., (Copyright: © 2024 Srinivasan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Response to neoadjuvant radiotherapy (RT) in rectal cancer has been associated with immune and stromal features that are captured by transcriptional signatures. However, how such associations perform across different chemoradiotherapy regimens and within individual consensus molecular subtypes (CMS) and how they affect survival remain unclear. In this study, gene expression and clinical data of pretreatment biopsies from nine cohorts of primary rectal tumors were combined (N = 826). Exploratory analyses were done with transcriptomic signatures for the endpoint of pathologic complete response (pCR), considering treatment regimen or CMS subtype. Relevant findings were tested for overall survival and recurrence-free survival. Immune and stromal signatures were strongly associated with pCR and lack of pCR, respectively, in RT and capecitabine (Cap)/5-fluorouracil (5FU)-treated patients (N = 387), in which the radiosensitivity signature (RSS) showed the strongest association. Upon addition of oxaliplatin (Ox; N = 123), stromal signatures switched direction and showed higher chances to achieve pCR than without Ox (p for interaction 0.02). Among Cap/5FU patients, most signatures performed similarly across CMS subtypes, except cytotoxic lymphocytes that were associated with pCR in CMS1 and CMS4 cases compared with other CMS subtypes (p for interaction 0.04). The only variables associated with survival were pCR and RSS. Although the frequency of pCR across different chemoradiation regimens is relatively similar, our data suggest that response rates may differ depending on the biological landscape of rectal cancer. Response to neoadjuvant RT in stroma-rich tumors may potentially be improved by the addition of Ox. RSS in preoperative biopsies provides predictive information for response specifically to neoadjuvant RT with 5FU., Significance: Rectal cancers with stromal features may respond better to RT and 5FU/Cap with the addition of Ox. Within patients not treated with Ox, high levels of cytotoxic lymphocytes associate with response only in immune and stromal tumors. Our analyses provide biological insights about the outcome by different radiotherapy regimens in rectal cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: A variety of definitions for a clinical near-complete response after neoadjuvant (chemo) radiotherapy for rectal cancer are currently used. This variety leads to inconsistency in clinical practice, long-term outcome, and trial enrollment., Objective: The aim of this study was to reach expert-based consensus on the definition of a clinical near-complete response after (chemo) radiotherapy., Design: A modified Delphi process, including a systematic review, 3 surveys, and 2 meetings, was performed with an international expert panel consisting of 7 surgeons and 4 radiologists. The surveys consisted of individual features, statements, and feature combinations (endoscopy, T2-weighted MRI, and diffusion-weighted MRI)., Setting: The modified Delphi process was performed in an online setting; all 3 surveys were completed online by the expert panel, and both meetings were hosted online., Main Outcome Measures: The main outcome was to reach consensus (80% or more agreement)., Results: The expert panel reached consensus on a 3-tier categorization of the near-complete response category based on the likelihood of the response to evolve into a clinical complete response after a longer waiting interval. The panelists agreed that a near-complete response is a temporary entity only to be used in the first 6 months after (chemo)radiotherapy. Furthermore, consensus was reached that the lymph node status should be considered when deciding on a near-complete response and that biopsies are not always needed when a near-complete response is found. No consensus was reached on whether primary staging characteristics have to be taken into account when deciding on a near-complete response., Limitations: This 3-tier subcategorization is expert-based; therefore, there is no supporting evidence for this subcategorization. Also, it is unclear whether this subcategorization can be generalized into clinical practice., Conclusions: Consensus was reached on the use of a 3-tier categorization of a near-complete response, which can be helpful in daily practice as guidance for treatment and to inform patients with a near-complete response on the likelihood of successful organ preservation. See Video Abstract., Un Consenso Internacional Basado En Expertos Acerca De La Definicin De Una Respuesta Clnica Casi Completa Despus De Quimioradioterapia Neoadyuvante Contra El Cncer De Recto: ANTECEDENTES:Actualmente, se utilizan una variedad de definiciones para una respuesta clínica casi completa después de quimioradioterapia neoadyuvante contra el cáncer de recto. Esta variedad resulta en inconsistencia en la práctica clínica, los resultados a largo plazo y la inscripción en ensayos.OBJETIVO:El objetivo de este estudio fue llegar a un consenso de expertos sobre la definición de una respuesta clínica casi completa después de quimioradioterapia.DISEÑO:Se realizó un proceso Delphi modificado que incluyó una revisión sistemática, 3 encuestas y 2 reuniones con un panel internacional de expertos compuesto por siete cirujanos y 4 radiólogos. Las encuestas consistieron en características individuales, declaraciones y combinaciones de características (endoscopía, T2W-MRI y DWI).AJUSTE:El proceso Delphi modificado se realizó en un entorno en línea; el panel de expertos completó las tres encuestas en línea y ambas reuniones se realizaron en línea.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue llegar a un consenso (≥80% de acuerdo).RESULTADOS:El panel de expertos llegó a un consenso sobre una categorización de tres niveles de la categoría de respuesta casi completa basada en la probabilidad de que la respuesta evolucione hacia una respuesta clínica completa después de un intervalo de espera más largo. Los panelistas coincidieron en que una respuesta casi completa es una entidad temporal que sólo debe utilizarse en los primeros 6 meses después de la quimioradioterapia. Además, se llegó a un consenso en que se debe considerar el estado de los nódulos linfáticos al decidir sobre una respuesta casi completa y que no siempre se necesitan biopsias cuando se encuentra una respuesta casi completa. No se llegó a un consenso sobre si se deben tener en cuenta las características primarias de estadificación al decidir una respuesta casi completa.LIMITACIONES:Esta subcategorización de 3 niveles está basada en expertos; por lo tanto, no hay evidencia que respalde esta subcategorización. Además, no está claro si esta subcategorización puede generalizarse a la práctica clínica.CONCLUSIONES:Se alcanzó consenso sobre el uso de una categorización de 3 niveles de una respuesta casi completa que puede ser útil en la práctica diaria como guía para el tratamiento y para informar a los pacientes con una respuesta casi completa sobre la probabilidad de una preservación exitosa del órgano. (Traducción - Dr. Aurian Garcia Gonzalez)., (Copyright © The ASCRS 2024.)

Robot-assisted surgery (RAS) continues to grow globally. Despite this, in the UK and Ireland, it is estimated that over 70% of surgical trainees across all specialities have no access to robot-assisted surgical training (RAST). This study aimed to provide educational stakeholders guidance on a pre-procedural core robotic surgery curriculum (PPCRC) from the perspective of the end user; the surgical trainee. The study was conducted in four Phases: P1: a steering group was formed to review current literature and summarise the evidence, P2: Pan-Specialty Trainee Panel Virtual Classroom Discussion, P3: Accelerated Delphi Process and P4: Formulation of Recommendations. Forty-three surgeons in training representing all surgical specialties and training levels contributed to the three round Delphi process. Additions to the second- and third-round surveys were formulated based on the answers and comments from previous rounds. Consensus opinion was defined as ≥ 80% agreement. There was 100% response from all three rounds. The resulting formulated guidance showed good internal consistency, with a Cronbach alpha of > 0.8. There was 97.7% agreement that a standardised PPCRC would be advantageous to training and that, independent of speciality, there should be a common approach (95.5% agreement). Consensus was reached in multiple areas: 1. Experience and Exposure, 2. Access and context, 3. Curriculum Components, 4 Target Groups and Delivery, 5. Objective Metrics, Benchmarking and Assessment. Using the Delphi methodology, we achieved multispecialty consensus among trainees to develop and reach content validation for the requirements and components of a PPCRC. This guidance will benefit from further validation following implementation., (© 2023. The Author(s).)

Robotic-assisted colorectal surgery (RACS) is steadily increasing in popularity with an annual growth in the number of colorectal procedures undertaken robotically. Further upscaling of RACS requires structured and standardised robotic training to safeguard high-quality clinical outcomes. The aims of this systematic review were to assess the structure and assessment metrics of currently established RACS training programmes. A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines was performed. Searches were performed of the Ovid Medline, Embase and Web of Science databases between 2000 and 27th November 2021 to identify studies reporting on training curricula in RACS. Core components of training programmes and their relevant outcome assessment metrics were extracted. Thirteen studies were identified, with all training programmes designed for the da Vinci platform (Intuitive Surgical, Inc., Sunnyvale, CA, USA). Common elements of multimodal programmes included theoretical knowledge (76.9%), case observation (53.8%), simulation (100%) and proctored training (76.9%). Robotic skills acquisition was assessed primarily during the simulation phase (n = 4, 30.1%) and proctoring phase (n = 10, 76.9%). Performance metrics, consisting of time or assessment scores for VR simulation were only mandated in four (30.1%) studies. Objective assessment following proctored training was variably reported and employed a range of assessment metrics, including direct feedback (n = 3, 23.1%) or video feedback (n = 8, 61.5%). Five (38.4%) training programmes used the Global Assessment Score (GAS) forms. There is a broad consensus on the core multimodal components across current RACS training programmes; however, validated objective assessment is limited and needs to be appropriately standardised to ensure reproducible progression criteria and competency-based metrics are produced to robustly assess progression and competence., (© 2022. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Introduction: Patients with liver disease and portal hypertension frequently require surgery carrying high morbidity and mortality. Accurately estimating surgical risk remains challenging despite improved medical and surgical management., Areas Covered: This review aims to outline a comprehensive approach to preoperative assessment, appraise methods used to predict surgical risk, and provide an up-to-date overview of outcomes for patients with cirrhosis undergoing non-hepatic surgery., Expert Opinion: Robust preoperative, individually tailored, and precise risk assessment can reduce peri- and postoperative complications in patients with cirrhosis. Established prognostic scores aid stratification, providing an estimation of postoperative mortality, albeit with limitations. VOCAL-Penn Risk Score may provide greater precision than established liver severity scores. Amelioration of portal hypertension in advance of surgery may be considered, with prospective data demonstrating hepatic venous pressure gradient as a promising surrogate marker of postoperative outcomes. Morbidity and mortality vary between types of surgery with further studies required in patients with more advanced liver disease. Patient-specific considerations and practicing precision medicine may allow for improved postoperative outcomes.

Aim: Chemoradiotherapy (CRT) has great potential to downstage rectal cancer. Response assessment has been investigated in locally advanced rectal cancer but not in early stage rectal cancer. The aim is to characterize the diagnostic accuracy of endoscopy performed by surgical endoscopists compared to (diffusion-weighted, DWI) MRI only and a multimodal approach combining (DWI-)MRI and endoscopic information both analysed by an abdominal radiologist for response assessment in early rectal cancer after neoadjuvant CRT., Materials and Methods: Patients treated with neoadjuvant CRT for early distal rectal cancer (cT1-3 N0) followed by transanal endoscopic microsurgery were included. Three separate reassessment groups were analysed for response assessment using endoscopic evaluation alone versus (DWI-)MRI alone versus the combination of endoscopy with (DWI-)MRI with a focus on sensitivity and specificity and analysis using receiver operating characteristic curves., Results: Three cohorts (N = 36, N = 25 and N = 25, respectively) were analysed for response assessment. Of the endoscopy cohort, 16 of the 36 patients had a complete response. Area under the curve was 0.69 (0.66-0.74; pooled sensitivity 55.3%, pooled specificity 80.0%). Agreement for scoring separate endoscopic features was poor to moderate. Of the (DWI-)MRI cohort, 11 of the 25 patients had a complete response. Area under the curve for (DWI-)MRI alone was 0.55 (sensitivity 72.7%, specificity 42.9%). The areas under the receiver operating characteristic curve improved to 0.68 (sensitivity 90.9%, specificity 75.0%) when (DWI-)MRI was combined with endoscopic information, with 11 out of 25 patients with a complete response. The most accurate response assessment was made by combining endoscopy and (DWI-)MRI with a high negative predictive value (90.9%)., Conclusion: Good and complete responders after chemoradiation of early stage rectal cancer can be best assessed using a multimodality approach combining endoscopy and (DWI-)MRI., (© 2022 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

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., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Older patients with early-stage rectal cancer are under-represented in clinical trials and, therefore, little high-quality data are available to guide treatment in this patient population. The TREC trial was a randomised, open-label feasibility study conducted at 21 centres across the UK that compared organ preservation through short-course radiotherapy (SCRT; 25 Gy in five fractions) plus transanal endoscopic microsurgery (TEM) with standard total mesorectal excision in adults with stage T1-2 rectal adenocarcinoma (maximum diameter ≤30 mm) and no lymph node involvement or metastasis. TREC incorporated a non-randomised registry offering organ preservation to patients who were considered unsuitable for total mesorectal excision by the local colorectal cancer multidisciplinary team. Organ preservation was achieved in 56 (92%) of 61 non-randomised registry patients with local recurrence-free survival of 91% (95% CI 84-99) at 3 years. Here, we report acute and long-term patient-reported outcomes from this non-randomised registry group., Methods: Patients considered by the local colorectal cancer multidisciplinary team to be at high risk of complications from total mesorectal excision on the basis of frailty, comorbidities, and older age were included in a non-randomised registry to receive organ-preserving treatment. These patients were invited to complete questionnaires on patient-reported outcomes (the European Organisation for Research and Treatment of Cancer Quality of Life [EORTC-QLQ] questionnaire core module [QLQ-C30] and colorectal cancer module [QLQ-CR29], the Colorectal Functional Outcome [COREFO] questionnaire, and EuroQol-5 Dimensions-3 Level [EQ-5D-3L]) at baseline and at months 3, 6, 12, 24, and 36 postoperatively. To aid interpretation, data from patients in the non-randomised registry were compared with data from those patients in the TREC trial who had been randomly assigned to organ-preserving therapy, and an additional reference cohort of aged-matched controls from the UK general population. This study is registered with the ISRCTN registry, ISRCTN14422743, and is closed., Findings: Between July 21, 2011, and July 15, 2015, 88 patients were enrolled onto the TREC study to undergo organ preservation, of whom 27 (31%) were randomly allocated to organ-preserving therapy and 61 (69%) were added to the non-randomised registry for organ-preserving therapy. Non-randomised patients were older than randomised patients (median age 74 years [IQR 67-80] vs 65 years [61-71]). Organ-preserving treatment was well tolerated among patients in the non-randomised registry, with mild worsening of fatigue; quality of life; physical, social, and role functioning; and bowel function 3 months postoperatively compared with baseline values. By 6-12 months, most scores had returned to baseline values, and were indistinguishable from data from the reference cohort. Only mild symptoms of faecal incontinence and urgency, equivalent to less than one episode per week, persisted at 36 months among patients in both groups., Interpretation: The SCRT and TEM organ-preservation approach was well tolerated in older and frailer patients, showed good rates of organ preservation, and was associated with low rates of acute and long-term toxicity, with minimal effects on quality of life and functional status. Our findings support the adoption of this approach for patients considered to be at high risk from radical surgery., Funding: Cancer Research UK., Competing Interests: Declaration of interests AG is funded by a Cancer Research UK clinical trial fellowship (CRUK/28301). PQ and NPW were funded by a programme grant from Yorkshire Cancer Research. PQ is a National Institute for Health and Care Research senior investigator. NPW reports personal fees from Eisai. KB reports stock ownership in GlaxoSmithKline and UCB. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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. 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 three-arm multicentre, partially randomized controlled trial incorporating an external pilot. In phase III, patients with cT1-3b N0 tumours, ≤40 mm in diameter, who prefer organ preservation are randomized 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 quality of life 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, two-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., (© 2022 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Multimodal treatment strategies for patients with rectal cancer are increasingly including the possibility of organ preservation, through nonoperative management or local excision. Organ preservation strategies can enable patients with a complete response or near-complete clinical responses after radiotherapy with or without concomitant chemotherapy to safely avoid the morbidities associated with radical surgery, and thus to maintain anorectal function and quality of life. However, standardization of the key outcome measures of organ preservation strategies is currently lacking; this includes a lack of consensus of the optimal definitions and selection of primary end points according to the trial phase and design; the optimal time points for response assessment; response-based decision-making; follow-up schedules; use of specific anorectal function tests; and quality of life and patient-reported outcomes. Thus, a consensus statement on outcome measures is necessary to ensure consistency and facilitate more accurate comparisons of data from ongoing and future trials. Here, we have convened an international group of experts with extensive experience in the management of patients with rectal cancer, including organ preservation approaches, and used a Delphi process to establish the first international consensus recommendations for key outcome measures of organ preservation, in an attempt to standardize the reporting of data from both trials and routine practice in this emerging area., (© 2021. Springer Nature Limited.)

Background: Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision., Methods: TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8-10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743., Findings: Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ 2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ 2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months' follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients., Interpretation: Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules., Funding: Cancer Research UK., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2020 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of British Journal of Surgery Society.)

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.

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., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

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., (© 2016 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

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., (© 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.)

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., (© 2014 The Authors. Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

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., (Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.)

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 β 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., (© 2014 The Authors. BJS published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Transanal endoscopic microsurgery (TEMS) is a well established method of accurate resection of specimens from the rectum under binocular vision. This review examines its role in the treatment of benign conditions of the rectum and the evidence to support its use and compliment existing endoscopic treatments. The evolution of TEMS in early rectal cancer and the concepts and outcomes of how it has been utilised to treat patients so far are presented. The bespoke nature of early rectal cancer treatment is changing the standard algorithms of rectal cancer care. The future of TEMS in the organ preserving treatment of early rectal cancer is discussed and how as clinicians we are able to select the correct patients for neoadjuvant or radical treatments accurately. The role of radiotherapy and outcomes from combination treatment using TEMS are presented with suggestions for areas of future research., (Copyright © 2014. Published by Elsevier Ltd.)

Background: Formalin fixation, duration of tissue storage and tissue enrichment techniques can affect DNA methylation yield but these effects have not been quantitatively measured. The aim is to investigate the relative impact of these conditions on DNA methylation in rectal cancer., Methods: 10 rectal cancers with matched undissected fresh frozen tissues, laser capture microdissected (LCM) formalin-fixed paraffin-embedded (FFPE) tissues, manual macrodissected FFPE tissues, adjacent normal mucosa and stromal tissues were analysed for APC and LINE-1 methylation using bisulphite pyrosequencing., Results: FFPE cancer tissues, which had been stored for at least 4 years showed similar APC and LINE-1 methylation changes to matched fresh frozen cancer tissues. Laser capture microdissection did not increase the degree of methylation detected compared to manual macrodissection. Analysis of stromal tissues showed that they had undergone significant methylation changes compared to adjacent macroscopically normal mucosa, but not to the same extent as cancer tissues., Conclusion: Reliable DNA methylation results can be obtained from FFPE rectal cancer tissues, which have been in long-term storage. Because only minor differences in methylation between macrodissected and LCM cancer tissues were found, our results do not support the routine use of LCM to enrich for cancer cells for DNA methylation studies., (© 2013.)

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., (Copyright © 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Although proctocolectomy and ileal pouch surgery is a routine part of modern-day management for complicated ulcerative colitis, these patients are often debilitated and require close and attentive management in the early postoperative period. Here we present a rare but clinically important postoperative complication.

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.

Ulcerative colitis (UC) is a relapsing and remitting disease characterised by chronic mucosal and submucosal inflammation of the colon and rectum. Treatment may vary depending upon the extent and severity of inflammation. Broadly speaking medical treatments aim to induce and then maintain remission. Surgery is indicated for inflammatory disease that is refractory to medical treatment or in cases of neoplastic transformation. Approximately 25% of patients with UC ultimately require colectomy. Ileal pouch-anal anastomosis (IPAA) has become the standard of care for patients with ulcerative colitis who ultimately require colectomy. This review will examine indications for IPAA, patient selection, technical aspects of surgery, management of complications and long term outcome following this procedure.

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.

Ileal pouch-anal anastomosis (IPAA) has become the standard of care for the 25% of patients with ulcerative colitis who ultimately require colectomy. IPAA is favored by patients because it avoids the necessity for a long-term stoma. This review examines how 3 decades of experience with IPAA has molded current practice, highlighting 5- and 10-year follow-up of large series to determine durability and functional performance, in addition to causes of failure and the management of complications.

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.

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.

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.

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.