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1. Guardian crypt-base-goblet-cells protect the human colonic stem cell niche by triggering cholinergic calcium signal-dependent MUC2 secretion and luminal flushing

Author

Nicolas Pelaez-Llaneza, Victoria Jones, Christy Kam, Alvin Lee, Alyson Parris, Sean Tattan, Martin Loader, Jordan Champion, George Russam, Ben Miller, Nathalie Juge, Richard Wharton, Christopher Speakman, Sandeep Kapur, James Hernon, Adam Stearns, Irshad Shaik, Anatu Pal, Alexia Tsigka, Diogenis Batsoulis, and Mark Williams

Subjects
digestive system diseases
Abstract

Mucus secreting goblet cells play a vital role in the maintenance of tissue homeostasis. Here we report the discovery of an enigmatic mechanism for the generation of calcium signals that couple cholinergic input to secretion of hydrated mucus in the human colonic stem cell niche. Mechanistic insights for this study were derived from native human colonic crypts and crypt-like organoids expressing MUC2-mNEON. Importantly, we demonstrate that the human colonic stem cell niche is also a cholinergic niche, and that activation of muscarinic receptors initiates calcium signals at the apical pole of intestinal stem cells and neighbouring crypt-base-goblet-cells. The calcium signal ‘trigger zone’ is defined by a microdomain of juxtaposed calcium stores expressing TPC1 and InsP3R3 calcium channels. Co-activation of TPC1 and InsP3R3 is required for generation of cholinergic calcium signals and downstream secretion of hydrated mucus, which culminates in the flushing of the colonic stem cell niche.

Published
2022
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2. Radical surgery versus organ preservation via short-course radiotherapy followed by transanal endoscopic microsurgery for early-stage rectal cancer (TREC): a randomised, open-label feasibility study

Author

Simon P Bach, Alexandra Gilbert, Kristian Brock, Stephan Korsgen, Ian Geh, James Hill, Talvinder Gill, Paul Hainsworth, Matthew G Tutton, Jim Khan, Jonathan Robinson, Mark Steward, Christopher Cunningham, Bruce Levy, Alan Beveridge, Kelly Handley, Manjinder Kaur, Natalie Marchevsky, Laura Magill, Ann Russell, Philip Quirke, Nicholas P West, David Sebag-Montefiore, Gina Brown, Peter Antonio, Alex Vince, Nick Hilken, Chakanaka Sidile, Adrian Wilcockson, Richard Peto, Tom Crosby, Brendan Moran, Julie Olliff, Katti Ashok, Simone Slawik, Andrew Smethurst, Rajaram Sripadam, Veena Tagore, Monica Terlizzo, Bearn Philip, Robert Davies, Susan Dodd, Sharadah Essapen, Pasha Nisar, Alexandra Stewart, Jonathan Trickett, Bansal Ashish, Peter Billings, Palanichamy Chandran, Conor Corr, Edward Favill, Simon Gollins, Peter Marsh, Andrew Maw, Rakha Neupane, Ramesh Rajagopal, Rachel Cooper, John Griffith, Paul Hatfield, Andy Lowe, Julian Ostrowski, Rhian Simpson, Richard Adams, Robert Bleehen, Michael Davies, Meleri Morgan, Darren Boone, Nicola Lacey, Ian Seddon, Bruce Sizer, Helen Stunell, Shaobin Wu, Maher Hadaki, Dominic Blunt, Susan Cleator, Ara Darzi, Robert Goldin, Paul Ziprin, Mike Dobson, Mark Pitt, Shabbir Susnerwala, Deborah Williamson, Georgina Howarth, Stephen Lee, Paul Wright, Tim Hoare, Alan Horgan, Fiona McDonald, Stephanie Needham, John Scott, Timothy Simmons, Debashis Biswas, James Hernon, Gaurav Kapur, Sandeep Kapur, James Sington, Christopher Speakman, William Stebbings, Stuart Williams, Madhavi Adusumalli, Anil Agarwal, David Borowski, Dharmendra Garg, Mohammed Hegab, Catherine Hobday, Veena Rao, Jyotsna Shrimankar, Mohamed Tabaqchali, David Wilson, Oliver Jones, Neil Mortensen, Andrew Slater, Aron Szuts, Lai Wang, Bryan Warren, Andrew Weaver, Mukhtar Ahmad, Julian Alexander, Maxine Flubacher, David Tarver, Suhail Baluch, Richard Beable, David Cowlishaw, Antony Higginson, Prokopios Vogiatzis, Neil Cruickshank, Howard Joy, David Peake, Ulises Zanetto, Mark Saunders, Arthur Sun-Myint, Mark Teo, Arthur Allan, John Glaholm, Mark Goldstein, Rahul Hejmadi, Gerald Langman, Dion Morton, Cyril Nelson, Deborah Tattersall, Stephen Falk, Robert Longman, Huw Roach, Jamshed Shabbir, Golda Shelley-Fraser, Michael Thomas, Neil Cripps, Yasser Haba, Guy Harris, Max Hookway, Jay Simson, Angela Skull, Tijani Umar, and National Institute of Health Research

Subjects
Transanal Endoscopic Microsurgery, medicine.medical_specialty, medicine.medical_treatment, Population, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, medicine, Humans, Organ Sparing Treatments, Radical surgery, Stage (cooking), education, TREC collaborators, education.field_of_study, Hepatology, business.industry, Rectal Neoplasms, Gastroenterology, Articles, Organ Preservation, Microsurgery, Total mesorectal excision, Neoadjuvant Therapy, Surgery, Radiation therapy, 030220 oncology & carcinogenesis, Feasibility Studies, 030211 gastroenterology & hepatology, business
Abstract

Summary 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, χ2 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, χ2 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.

Published
2021

3. Prophylactic biological mesh reinforcement versus standard closure of stoma site (ROCSS): a multicentre, randomised controlled trial

Author

Aneel Bhangu, Dmitri Nepogodiev, Natalie Ives, Laura Magill, James Glasbey, Colm Forde, Thue Bisgaard, Kelly Handley, Samir Mehta, Dion Morton, Thomas Pinkney, James Brown, Kaori Futaba, Sarah Khan, Arvind Pallan, Abhilasha Patel, Steve Ashdown-Phillips, Tracy Roberts, Susan Jowett, Lorraine Munetsi, Andrew Torrance, Nicholas Hilken, Matt Hill, Mark Hunter, Susan Leek, Helen Lilly, Amruta Sawant, Alexandra Vince, Michael Walters, Willem Bemelman, Marjolein Blussé, Wernard Borstlap, Olivier RC Busch, Christianne Buskens, Charlotte Klaver, Hendrik Marsman, Oddeke van Ruler, Pieter Tanis, Emma Westerduin, Dennis Wicherts, Parthasarathi Das, Sharadah Essapen, Victoria Frost, Ana Glennon, Catherine Gray, Anwar Hussain, Lisa McNichol, Pasha Nisar, Humphrey Scott, Jonathan Trickett, Prateesh Trivedi, Daniel White, Talakalukoppa Amarnath, Rohan Ardley, Robin Gupta, Emily Hall, Kathryn Hodgkins, Harjeet Narula, Terri-Ann Sewell, John M Simms, Julie Toms, Tim White, Angela Atkinson, Dan Beral, Nicola Lancaster, Felicity Mackenzie, Tim Wilson, David Cruttenden-Wood, Jackie Gibbins, Mark Halls, Dennise Hill, Karen Hogben, Stephanie Jones, Michael J Lamparelli, Mark Lewis, Sarah Moreton, Paul Ng, Arabis Oglesby, James Orbell, Benjamin Stubbs, Krishnan Subramanian, Anjay Talwar, Simon Wilsher, Mohammed Al-Rashedy, Catherine Fensom, Muhammed Gok, Lisa Hardstaff, Kamran Malik, Mohammed Sadat, Barbara Townley, Lesley Wilkinson, Tracey Cosier, Sudhakar Mangam, Mohamed Rabie, Graham Broadley, John Canny, Simon Fallis, Nikki Green, Ahmed Hawash, Sharad Karandikar, Mehboob Mirza, Edward Rawstorne, Julie Reddan, Jonathan Richardson, Chris Thompson, Kathryn Waite, Haney Youssef, Lindsey De Nes, Steffen Rosenstock, Pernille Strandfelt, Mikkel Westen, Kamal Aryal, Kirosh Shankar Kshatriya, Roshan Lal, Vamsi Velchuru, Elva Wilhelmsen, Ayesha Akbar, Anthony Antoniou, Sue Clark, Pooja Datt, Jason Goh, Ian Jenkins, Robin Kennedy, Yasuko Maeda, Piero Nastro, Harriet Owen, Robin KS Phillips, Janindra Warusavitarne, Joanne Bradley-Potts, Peter Charleston, Hamish Clouston, Sarah Duff, Taher Fatayer, Anna Gipson, Nick Heywood, Muneer Junejo, James Kennedy, Helen Lalor, Chris Manning, Richard McCormick, Kathryn Parmar, Stephen Preston, Aswatha Ramesh, Abhiram Sharma, Karen Telford, Abidemi Adeosun, Toby Hammond, Susan Smolen, Joanne Topliffe, James G Docherty, Michael Lim, Kathleen Macleod, Eimar Monaghan, Lesley Patience, Ian Thomas, Kenneth G Walker, Michael Walker, Angus JM Watson, Amanda Burgess, Yasser Ghanem, Georgina Glister, Sandeep Kapur, Abhilash Paily, Atanu Pal, Rathinam Ravikumar, Melissa Rosbergen, Kevin Sargen, Christopher Speakman, Anil K Agarwal, Amlan Banerjee, David Borowski, Dharmendra Garg, Talvinder Gill, Tracey Johnston, Susan Kelsey, Phanibhushana Chakravarthy Munipalle, Mohamed Tabaqchali, Deborah Wilson, Austin Acheson, Heather Cripps, Ahmed El-Sharkawy, Oliver Ng, Parveen Sharma, Kym Ward, Dawne Chandler, Edward Courtney, John Bunni, Katrina Butcher, Stephen Dalton, Ian Flindall, Joyce Katebe, Pratik Roy, Jeremy Tate, Tracy Vincent, Michael ER Williamson, James Wood, Mark Bignell, Graham Branagan, Jack Broardhurst, Helen Chave, Hilary Dean, Nigel D'Souza, Gemma Foster, Simon Sleight, Rupesh Sutaria, Ishmail Ahmed, Misra Rai Budhoo, Julie Colley, Neil Cruickshank, Kathryn Gill, Anne Hayes, Howard Joy, Carrington Kamabjha, James Plowright, Simon Radley, Mr Rea, Vijay Thumbe, Philip Varghese, Richard Wilkin, Elzbieta Zulueta, Lynne Allsop, Bence Atkari, Krishnamurthy Badrinath, Prita Daliya, Mukul Dube, Cheryl Heeley, Richard Hind, Dominic Nash, Andrea Palfreman, Oliver Peacock, Nicholas Watson, Michelle Blodwell, Ali Javaid, Ashiq Mohamad, Karim Muhammad, Nafees Qureshi, Stephanie Ridgway, Kamran Siddiqui, Mamoon Solkar, Joanne Vere, Alexander Wordie, Jessica Chang, Sanaa Elgaddal, Marie Green, Marianne Hollyman, Nazzia Mirza, Jayne Rankin, Graham Williams, Wadah Ali, Anne Hardwick, Zakir Mohamed, Ahmad Navid, Kimberley Netherton, Mugurel Obreja, Milind Rao, Joanna Stringer, Athula Tennakoon, Timothy Bullen, Mansoor Butt, Robin Dawson, Sarah Dawson, Martin Farmer, Veerabhadram Garimella, Zoe Gates, Lisa Wilkings, Neil Yeomans, Olufunso Adedeji, Rashid Alalawi, Aamed Al Araimi, Shazad Ashraf, Simon Bach, Andrew Beggs, Carmen Cagigas, Mit Dattani, Nikolletta Dimitriou, Manijeh Ghods-Ghorbani, David Gourevitch, Geoffrey Haydon, Tariq Ismail, Christopher Keh, Dion G Morton, Mandip Narewal, Trifonas Papettas, Tom Pinkney, Aaron Poh, Edward Ranstorne, Timothy J Royle, Tahir Shah, Jagdeep Singh, Chris Smart, Nigel Suggett, Muhammad Tayyab, Deepak Vijayan, Ravinder Vohra, Naseem Wairaich, Denise Yeung, Richard Bamford, Joanne Chambers, David Cotton, Rebecca Houlihan, James Kynaston, Rob Longman, Amelia Lowe, David Messenger, Anwar Owais, Catherine Phillpott, Jamshed Shabbir, Phil Baragwanath, Charlotte El-Sayed, Anne Gaunt, Chetan Khatri, Peter McCullough, Stephen Ward, Ross Obukofe, Robert Stroud, David Mason, Nigel Williams, Ling S Wong, Sanjay Chaudhri, Jill Cooke, Melissa Cunha, Howard Fairey, Michael Norwood, Baljit Singh, Sarah Thomasset, Sian Abbott, Sarah Addison, James Archer, Robert Church, Erika Holford, Fionnaula Lenehan, Steve Odogwu, Lisa Richardson, Jane Sidebotham, Elaine Swan, Alison Tilley, Lynda Wagstaff, Isobel Amey, Yolanda Baird, Neil Cripps, Susanna Greenslade, Guy Harris, Bruce Levy, Paul Mckenzie, Alison Misselbrook, Sally Moore, Angela Skull, Deborah Nicol, Bala Reddy, Jessica Thrush, Miriam Iglesias Vecchio, Yvonne Dunn, Claire Williams, Sanjay Furtado, Michael Gill, Lydia Gilmore, Paul Goldsmith, Cezary Kocialkowski, Sadasivam Loganathan, Rabindra Nath, Marius Paraoan, Tracey Taylor, Andrew Allison, Joanna Allison, Nathan Curtis, Richard Dalton, Conrad D'Costa, Godwin Dennison, Jake Foster, Nader Francis, James Gibbons, Mohammed Hamdan, Alison Lewis, Jonathan Ockrim, Rishabha Sharma, Katie Spurdle, Saseendran Varadharajan, Assad Aghahoseini, David J Alexander, Dibyendu Bandyopadhyay, Ian Bradford, Praminthra Chitsabesan, Zoe Coleman, Andrew Gibson, Kostas Lasithiotakis, Dimitrios Panagiotou, Konstantinos Polyzois, Stevan Stojkovic, Nicholas Woodcock, Monica Wright, Rachel Hargest, Richard Jackson, Arumugam Rajesh, Olagunju Ogunbiyi, Andrew Slater, Ly-Mee Yu, Surgery, AGEM - Digestive immunity, AGEM - Re-generation and cancer of the digestive system, AGEM - Endocrinology, metabolism and nutrition, and Graduate School

Subjects
Adult, Male, medicine.medical_specialty, Hernia, Incisional hernia, Colon, medicine.medical_treatment, 030204 cardiovascular system & hematology, Article, law.invention, Abdominal wall, 03 medical and health sciences, Ileostomy, 0302 clinical medicine, Ileus, Postoperative Complications, Randomized controlled trial, Double-Blind Method, law, General & Internal Medicine, medicine, Incisional Hernia, Humans, 030212 general & internal medicine, Prospective Studies, 11 Medical and Health Sciences, Aged, Intention-to-treat analysis, business.industry, Incidence (epidemiology), Surgical Stomas, Abdominal Wound Closure Techniques, General Medicine, Prostheses and Implants, Middle Aged, Surgical Mesh, medicine.disease, 3. Good health, Surgery, medicine.anatomical_structure, Relative risk, Female, Collagen, business, Reinforcement of Closure of Stoma Site (ROCSS) Collaborative and West Midlands Research Collaborative
Abstract

Summary Background Closure of an abdominal stoma, a common elective operation, is associated with frequent complications; one of the commonest and impactful is incisional hernia formation. We aimed to investigate whether biological mesh (collagen tissue matrix) can safely reduce the incidence of incisional hernias at the stoma closure site. Methods In this randomised controlled trial (ROCSS) done in 37 hospitals across three European countries (35 UK, one Denmark, one Netherlands), patients aged 18 years or older undergoing elective ileostomy or colostomy closure were randomly assigned using a computer-based algorithm in a 1:1 ratio to either biological mesh reinforcement or closure with sutures alone (control). Training in the novel technique was standardised across hospitals. Patients and outcome assessors were masked to treatment allocation. The primary outcome measure was occurrence of clinically detectable hernia 2 years after randomisation (intention to treat). A sample size of 790 patients was required to identify a 40% reduction (25% to 15%), with 90% power (15% drop-out rate). This study is registered with ClinicalTrials.gov, NCT02238964. Findings Between Nov 28, 2012, and Nov 11, 2015, of 1286 screened patients, 790 were randomly assigned. 394 (50%) patients were randomly assigned to mesh closure and 396 (50%) to standard closure. In the mesh group, 373 (95%) of 394 patients successfully received mesh and in the control group, three patients received mesh. The clinically detectable hernia rate, the primary outcome, at 2 years was 12% (39 of 323) in the mesh group and 20% (64 of 327) in the control group (adjusted relative risk [RR] 0·62, 95% CI 0·43–0·90; p=0·012). In 455 patients for whom 1 year postoperative CT scans were available, there was a lower radiologically defined hernia rate in mesh versus control groups (20 [9%] of 229 vs 47 [21%] of 226, adjusted RR 0·42, 95% CI 0·26–0·69; p

Published
2019

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