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1. HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

Author

Milana A. Bergamino, Elena López-Knowles, Gabriele Morani, Holly Tovey, Lucy Kilburn, Eugene F. Schuster, Anastasia Alataki, Margaret Hills, Hui Xiao, Chris Holcombe, Anthony Skene, John F. Robertson, Ian E. Smith, Judith M. Bliss, Mitch Dowsett, Maggie C.U. Cheang, Abigail Evans, Adrian Ball, Akhil Johri, Ali Nejim, Alison Jones, Allan Corder, Amanda Thorne, Ambika Anand, Amitabha Chakrabarti, Anne Robinson, Anupam Modi, Ashraf Patel, Ashutosh Kothari, Brendan McFall, Caroline Mortimer, Caroline Lee, Charlie Chan, Charlotte Abson, Christopher Holcombe, Christopher Hinton, Ciaran Hollywood, Claire Murphy, Clare Crowley, Claudia Harding-Mackean, Clive Griffith, Conrad Lewanski, Daniel Rea, David Hwang, Derek Crawford, Dinesh Thekkinkattil, Douglas Ferguson, Douglas Adamson, Duncan Wheatley, Duraisamy Ravichandran, Ed Babu, Elaine Hyett, Fawzia Ashkanani, Fiona Hoar, Frances Kenny, Gary Dyke, Geoffrey Sparrow, null Gilbert, Giles Cunnick, Hafiz Algurafi, Helen Sweetland, Highes-Davies Prof, Hisham Hamed, Ian Smith, Ian Laidlaw, Ilyas Khattak, Jacqueline Newby, Jacqueline Rees-Lee, Jalal Kokan, Jane Barrett, Jay Dolatrai Naik, Jayant Vaidya, Jennifer Forrest, Jitendra Parmar, Jocelyn Adams, John Fox, Jonathan Roberts, Jonathan Dawson, Julie Doughty, Jull Donnelly, Kathleen Dunn, Kian Chin, Kieran Horgan, Kislaya Thakur, Ludger Barthelmes, Lynda Wyld, Madhumita Bhattacharyya, Maher Hadaki, Makam Kishore, Marcus Ornstein, Maria Bramley, Maria Bews-Hair, Marina Parton, Mark Sibbering, Mark Kissin, Mark Churn, Martin Hogg, Mary Quigley, Matthew Hatton, Matthew Winter, Matthew Adelekan, Michael Shere, Michael Carr, Michael Williams, Mohammed Absar, Muhammad Sharif, Muireann Kelleher, Nawaz Walji, Nicholas Williams, Nicholas Gallegos, Nigel Bundred, Olivia Hatcher, Perric Crellin, Peter Crane, Peter Donnelly, Peter Kneeshaw, Philip Walker, Prakash Sinha, Pudhupalayam Bhaskar, Racheal Soulsby, Radha Todd, Raghavan Vidya, Rakesh Mehra, Ramachandran Prasad, Ramsay Cutress, Ravi Sharma, Rebecca Roylance, Rebecca Goranova, Reem Ramzi Salman, Riccardo Bonom, Richard Johnson, Richard Sutton, Rick Linforth, Rob Coleman, Robert Grieve, Robert Leonard, Robert Reichert, Robert Kennedy, Roshan Agarwal, Rozenn Allerton, Russell Burcombe, Ruth Davis, Sankaran Narayanan, Sankaran Chandrasekharan, Sarah Vesty, Seema Seetharam, Serena Ledwidge, Shabana Iqbal, Shamaela Wahee, Shobha Silva, Simon Pain, Simon Holt, Simon Thomson, Simon Smith, Simon Ellenbogen, Siobhan Laws, Stephen Chan, Stephen Johnston, Steve Holt, Steven Thrush, Stuart McIntosh, Sumohan Chatterjee, Susan Cleator, Tamoor Usman, Tayo Johnson, Tibor Kovacs, Tracey Irvine, Urmila Barthkur, Vanessa Pope, Victoria Alexandra Brown, Vummiti Muralikrishna, Walid Samra, William Maxwell, and Zoe Winters

Subjects
Clinical Trials as Topic, Ki-67 Antigen, Receptors, Estrogen, Aromatase Inhibitors, Receptor, ErbB-2, Biomarkers, Tumor, Humans, Breast Neoplasms, Female, General Medicine, Neoplasm Recurrence, Local, Receptors, Progesterone, General Biochemistry, Genetics and Molecular Biology
Abstract

Background: oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. Methods: all available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki67 2wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. Findings: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki67 2wk (p2wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. Interpretation: our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse. Funding: Cancer Research UK (CRUK/07/015).

Published
2022

2. Breast Density Notification: Current UK National Practice

Author

Serena Ledwidge, Ahmed Al Naqqash, Robert Dickens, Louise Jones, Fatima Regrag, Tamara Suaris, Jennifer Hu, Hirah Rizki, Jajini Varghese, Shireen Gohari, Mark Wilkinson, Michael Faheem, and Laura Johnson

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Breast Neoplasms, State Medicine, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, medicine, Mammography, Breast screening, Humans, Breast density, Risk factor, Practice Patterns, Physicians', skin and connective tissue diseases, Disease Notification, Health policy, Early Detection of Cancer, Breast Density, medicine.diagnostic_test, business.industry, Cancer, medicine.disease, United Kingdom, surgical procedures, operative, 030104 developmental biology, Increased risk, Oncology, 030220 oncology & carcinogenesis, Family medicine, Female, business
Abstract

Increased breast density is a risk factor for breast cancer and can mask cancer on mammography. This survey attempts to understand clinician views regarding breast density notification in the United Kingdom. Two separate breast density surveys were distributed to radiologists and breast surgeons between May 2019 and May 2020. Invited participants were members of the British Society of Breast Radiology and the Association of Breast Surgeons. We received 232 completed questionnaires from 109 surgeons (71%) and 123 radiologists (41%). Fourteen percent of the surgeons reported discussing the increased risk of developing cancer with their patients, and 20% of the surgeons recommended further imaging compared with 50% of the radiologists. Fifty-two percent of surgeons and 28% of radiologists felt women should not be informed of their breast density scores considering the lack of National Health Service-funded supplementary imaging. Almost all respondents of this survey called for guidelines regarding the reporting and management of UK patients with increased breast density (90%). Density notification is becoming increasingly central to breast screening, and our results highlight an urgent need for a national consensus.

Published
2021

3. Therapeutic mammaplasty is a safe and effective alternative to mastectomy with or without immediate breast reconstruction

Author

S Potter, A Trickey, T Rattay, R L O'Connell, R Dave, E Baker, L Whisker, J Skillman, M D Gardiner, R D Macmillan, C Holcombe, Nicola L P Barnes, Jane Blazeby, Elizabeth Conroy, Rajiv V Dave, Matthew D Gardiner, Adrian Harnett, Chris Holcombe, Shelley Potter, Tim Rattay, Joanna Skillman, Paula Williamson, Rajgopal Achuthan, Shweta Aggarwal, Elizabeth Baker, Naren Basu, Lisa Brock, Patricia Fairbrother, Charlotte Ives, Abhilash Jain, Baek Kim, R Douglas Macmillan, John Murphy, Dennis Remoundos, Richard Sutton, Adam Trickey, Philip Turton, Kathryn Williams, Alain Curnier, Amir Tadros, Ivan Depasquale, Mairi Fuller, Roger Bourne, Steven Heys, Ishrak Hamo, Fatima Aloraifi, Laura Fopp, Radhika Bali, Sarah Bache, Sarah L Benyon, Michael S Irwin, Amit Agrawal, Charles M Malata, Claire Murphy, Adam Misky, Dennis Wayne Chicken, Nassreen Abdullah, Arnold D K Hill, Carolyn Cullinane, Gareth Irwin, Stuart A McIntosh, Sigi Refsum, Samantha Sloan, Peter Mallon, Chiara Sirianni, Ilyas Khattak, Geerthan Nagachandra, Pasupathy Kiruparan, Debasish Debanth, Simon Davey, Terry-Ann Curran, Matilda Svenning, Sasirekha Govindarajulu, Zenon Rayter, Rachel Ainsworth, Simon Cawthorn, Ajay Sahu, Sherif Wilson, Elena Prousskaia, Antonello Accurso, Nicola Rocco, Rosa Di Micco, Gennaro Limite, Raffaele Ceccarino, Raffaele Liccardo, Guido Coco, Metin Nizamoglu, Mary Morgan, Venkat Ramakrishnan, Giuseppe Catanuto, Alex Wilkins, Penelope McManus, Peter Kneeshaw, Kartikae Grover, Tapan Mahapatra, Brendan Wooler, Bilal Elahi, Naila Ihsan, Alexandra Bucknor, Dimitris Reissis, Judith Hunter, Simon Wood, Navid Jallali, Francis P Henry, Liaquat S Verjee, Jason Lee, Shazia M Khan, Iman Azmy, Julia Massey, Ciaran Hollywood, Michael Oluwajana, Sonia Bathla, Joanna Seward, Claudia Harding-MacKean, Risha Lane, Kothandaraman Murali, Bashishta Biswas, Pawel Trapszo, Seema Seetharam, Katy Kennedy, Louise Alder, Tomasz Graja, Khalid Amin, Jalal Kokan, Chandeena Roshanlall, Emma Gill, Dhananjay Kulkarni, J M Dixon, Oliver Young, Talha Saleem, M Biddle, Marie Kearns, Eva Weiler-Mithoff, Ben Chew, Andy Malyon, John Scott, David McGill, Iain Mackay, Salena Bains, Sara Barrows, Simon Pilgrim, Sheila Shokuhi, Kelly Lambert, Frances Kenny, Kalliope Valassiadou, Monika Kaushik, Jaroslaw Krupa, Dimitris Dragoumis, Pavlos Lampropoulos, Sarah Moss, Haitham Khalil, Anwar Haq, Balapathiran Balasubramanian, Petros Charalampoudis, Hisham Hamed, Ashutosh Kothari, Tibor Kovacs, Michael Douek, Iftikhar Mehmood, Biswajit Ray, Matthew Adelekan, Laura Humphreys, Salim Tayeh, Christina Choy, Laila Parvanta, Silvia Michieletto, Tania Saibene, James O'Brien, Sue Down, Sarah Downey, Jerome Pereira, A S Sami, Anzors Gvaramadze, Jibril A Jibril, Dinesh Thekkinkattil, S Udayasankar, Saira Khawaja, Yousef Shariaha, Simon Holt, Ruth James, Hirah Rizki, Katharine Kirkpatrick, Duraisamy Ravichandran, Deepak Shrestha, Ellora Barua, Deepika Akolekar, Ahmed Hamad, Eleftheria Kleidi, Susan Hignett, Vanessa Pope, Salma Naseem, Jennifer Isherwood, Rachel Soulsby, Amanda Taylor, Kian Chin, Dai Nguyen, Francesca Guest, Amanda Thorne, Valentina Lefemine, Chris Kirchhoff, Declan C Murphy, Michelle Lo, Ruth Harcourt, Simon J Pain, Maged I Hussien, Katalin Zechmeister, E M Sassoon, Andrea Figus, Richard M Haywood, Rozina Ali, Susanna Alexander, Konstantinos Geropantas, Daniel Epurescu, Rebecca Lewis, Oladapo Fafemi, Jasdeep Gahir, Tasha Gandamihardja, Jennett Kelsall, Nazli Muhibullah, Charlene Otieno, Fayyaz Mazari, Marta Dauria, Lisa Whisker, Douglas Macmillan, Eleanor Gutteridge, Tuabin Rasheed, Hazem Khout, Kristjan Asgeirsson, Stephen McCulley, Maria Donatella Mariniello, Manuela Roncella, Matteo Ghilli, Livio Colizzi, Elena Rossetti, Lo Russo Marzia, Loredana Fustaino, Alessandro Quattrini Li, Kate L Harvey, Rebecca Windle, Dionysios Dennis Remoundos, Pankaj Roy, Gael MacLean, Asha Adwani, Elena Popa, Steven Goh, Geeta Shetty, Sarah Clark, Lorenzo Bernaudo, Avi Agrawal, Lucy Mansfield, Sally Tebbal, Ashraf Patel, Veronica Grassi, Ojas Pujji, Kathryn Hamnett, Emily Granger, Michael Durbar, Panagiotis Pikoulas, Clare Garnsey, Philip Walker, Angela J Vollermere, Ioannis Michalakis, Robin Jones, Mina Youssef, Mohammad Masood, Julie Dunn, Sisse Olsen, Douglas Ferguson, Rachel Tillett, Anna Allan, Alex Woollard, Rebecca Canny, Alexander Woollard, Afshin Mosahebi, Stephen Hamilton, Jagdeep Chana, Nilesh Sojitra, Ibby Younis, Dick Rainsbury, Natalie Chand, Vasileios Kalles, Anne Stebbing, Kevin Harris, Siobhan Laws, Anne Tansley, Geraldine Mitchell, Emma de Sousa, Julia Henderson, Mysore Chandrashekar, Bernadette Pereira, Chloe Constantinou, Dalia Elfadl, Foivos Irakleidis, Izaro Hernan, Miriam Byrne, Rachel O'Connell, Jennifer Rusby, Peter Barry, Katerine Krupa, William Allum, Fiona MacNeill, Nicola Roche, Gerald Gui, Kelvin Ramsey, Paul Harris, Stuart James, Jamie McIntosh, Nicola Laurence, Louise MacLennan, Robert Milligan, Henry Cain, Adam Critchley, Joe O'Donoghue, Loraine Kalra, Nick Collis, Gina Weston-Petrides, Roanne Fiddes, Victoria Brown, Anna Aertssen, Diana Slade-Sharman, Mansoor Khan, Caroline McGuiness, Vittoria Amorosi, Santanelli di Pompeo Fabio, Georgios Exarchos, Natasha Jiwa, Jennifer Hu, Serena Ledwidge, Laura Johnson, Anthony Peel, Naseem Dhooma, Eric Farrell, Liam Devane, Ruth Tevlin, Enda McDermott, Ruth Prichard, Denis Evoy, Jane Rothwell, James Geraghty, Colin Morrison, Catriona Lawlor, Fiona Langlands, Lauren Taylor, Raj Achuthan, Kieran Horgan, Shireen Mckenzie, Brian Hogan, Mark Lansdown, Channegowda Navin, Liz Sherwin, Caroline Mortimer, Neeraj Garg, Rahma Adam, Tahera Arif, Zbigniew Kryjak, Deedar Ali, Ravi Sowdi, Elena Fage, Senthurun Mylvaganam, Pilar Matey, Raghavan Vidya, Tapan Sircar, Oubida Asaad, Pud Bhaskar, Matei Dordea, Ada Chrysafi, Damian McCartan, Rajiv Dave, Rachel Foster, Rebecca Wilson, Sylvia Okwemba, Yousef Majeed, Ciara O'Brien, Vinod Mathen, Nicola Barnes, Ashu Gandhi, James Harvey, Cliona C Kirwan, Richard Johnson, Krupali Patel, Maria Dalmau Ribas, Natali Vigneswaran, Tom Challoner, Alan Park, Maged Rizkalla, Abigail Tomlins, Kat McEvoy, Sadaf Jafferbhoy, Soni Soumian, Sankaran Narayanan, Robert Kirby, Sladana Bajrusevic, Joseph Maalo, Michalis Charalambous, Lee Min Lai, Kelvin Chong, Simon Thomson, Sherif Monib, Leena Chagla, Riccardo Audisio, Rieka Taghizadeh, Azhar Iqbal, Karen James, Maria Callaghan, Shabbir Poonawala, Jonathan Lund, Raman Vinayagam, Steven Thrush, Rachel Bright Thomas, Michelle Mullan, Jevan Taylor, Ryo Yoshimura, Tom Mathew, Ben Mancey Jones, Kailas Munot, Rana Nasr, Jenny Piper, Deena El-Sharief, Mohammed Mustafa, Caitlin MacLeod, Elizabeth Smyth, Nina Saeed, Yazan Masannat, Amir Tan Mohd-Amin, Sam Sloan, Stuart McIntosh, Abdulla Ibrahim, Rathi Rathinaezhil, Eiman Khalifa, Penny McManus, Alexander Leeper, Jennifer McIlhenny, James Mansell, Keith Ogsto, Laszlo Romics, Shelia Shokuhi, Xiang Wei Jonathan Lee, Asmaa Al-Allak, Clare Fowler, Eleanore Massey, Fiona Court, Richard Hunt, Sarah Vestey, Mohsen Elgammal, Arish Noshirwani, Tehera Arif, Farah H Syed, Gazalla Safdar, Mohammed El-Abbar, Fiona Hogg, Pauline McGee, Vassilis Pitsinis, Jenny Smith, Sundus Makkiyah, Syed Mustafa, Dana Photiou, Ellie Gutteridge, Georgette Oni, Kelly Hallam, Kristjan Asgeirron, Marta D'Auria, Samim Al-zubaidi, James Bailey, Alexandra Tenovici, Dionysios-Dennis Remoundos, Nikos Chaidos, Oana Predescu, Jan Rezulski, Tholkifl Abdullah, Sujatha Udayasankar, Adam Talbot, Jagdeep Singh, Amy Smith, Angela Volleamere, Sarah Dean, Lashan Peiris, Olivia Sjokvist, Emma De Sousa, Aikaterini Micha, Amy Godden, Katherine Krupa, John Henton, Ruth Bennett, Stewart Nicholson, Guido Paolini, Luca Francesco Renzi, Santanelli Di Pompeo, Vitto Ria, Rebecca S Lewis, Sirwan Hadad, Anup Sharma, Delia Toomey, Dibyesh Banerjee, Sarah Shuk Kay Tang, Shireen McKenzie, Tanvir Ahmad, Kate Williams, Mohammed Absar, Nabila Nasir, Igor Jerzy Rychlik, Lynn Darragh, Ruth Johnston, Stephen Kirk, Jacqueline Rees-Lee, Michael Green, Abhishek Sharma, Jia Choong, Zaker Ullah, Ommen Koshy, Tamara Kiernan, Ajay Ashok Bhojwani, Rachel Bright-Thomas, Ged Byrne, Ibrahim Ibrahim, Lyndsey Highton, Owen Morris, Sumohan Chatterjee, Cliona Kirwan, Ben Mancey-Jones, Denna El Sharief, and Richard Frame

Subjects
Adult, therapeutic mammaplasty, medicine.medical_specialty, Mammaplasty, medicine.medical_treatment, Kaplan-Meier Estimate, 030230 surgery, Young Adult, 03 medical and health sciences, Postoperative Complications, breast cancer, 0302 clinical medicine, Breast cancer, cohort study, medicine, Adjuvant therapy, Humans, breast reconstruction, Young adult, Mastectomy, collaborative, Aged, Proportional Hazards Models, Aged, 80 and over, Proportional hazards model, business.industry, Immediate breast reconstruction, oncological safety, conservative treatment, mastectomy, Middle Aged, medicine.disease, Surgery, Logistic Models, Treatment Outcome, 030220 oncology & carcinogenesis, Female, Breast reconstruction, business, Cohort study
Abstract

Therapeutic mammaplasty (TM) may be an alternative to mastectomy, but few well designed studies have evaluated the success of this approach or compared the short-term outcomes of TM with mastectomy with or without immediate breast reconstruction (IBR). Data from the national iBRA-2 and TeaM studies were combined to compare the safety and short-term outcomes of TM and mastectomy with or without IBR.The subgroup of patients in the TeaM study who underwent TM to avoid mastectomy were identified, and data on demographics, complications, oncology and adjuvant treatment were compared with those of patients undergoing mastectomy with or without IBR in the iBRA-2 study. The primary outcome was the percentage of successful breast-conserving procedures in the TM group. Secondary outcomes included postoperative complications and time to adjuvant therapy.A total of 2916 patients (TM 376; mastectomy 1532; mastectomy and IBR 1008) were included in the analysis. Patients undergoing TM were more likely to be obese and to have undergone bilateral surgery than those having IBR. However, patients undergoing mastectomy with or without IBR were more likely to experience complications than the TM group (TM: 79, 21·0 per cent; mastectomy: 570, 37·2 per cent; mastectomy and IBR: 359, 35·6 per cent; P 0·001). Breast conservation was possible in 87·0 per cent of patients who had TM, and TM did not delay adjuvant treatment.TM may allow high-risk patients who would not be candidates for IBR to avoid mastectomy safely. Further work is needed to explore the comparative patient-reported and cosmetic outcomes of the different approaches, and to establish long-term oncological safety.La mamoplastia terapéutica (therapeutic mammaplasty, TM) puede ser una alternativa a la mastectomía, pero hay pocos estudios bien diseñados que hayan evaluado el éxito de esta estrategia o hayan comparado los resultados a corto plazo de la TM con la mastectomía con o sin (+/-) reconstrucción mamaria inmediata (immediate breast reconstruction, IBR). Para comparar la seguridad y los resultados a corto plazo de la TM y la mastectomía +/- IBR se combinaron los datos de los estudios nacionales iBRA-2 y TeaM. MÉTODOS: En el estudio TeaM se identificó el subgrupo de pacientes al que se realizó una TM para evitar la mastectomía y se compararon los datos demográficos, las complicaciones, los resultados oncológicos y el tratamiento adyuvante con las pacientes sometidas a mastectomía +/- IBR del estudio iBRA-2. La variable principal fue el porcentaje de éxito de la cirugía conservadora de mama en el grupo TM. Las variables secundarias fueron las complicaciones postoperatorias y el intervalo de tiempo hasta el inicio del tratamiento adyuvante.Se incluyeron en el análisis 2.916 pacientes (TM n = 376; mastectomía n = 1.532; IBR n = 1.008). La TM era más frecuente en pacientes obesas o en las sometidas a cirugía bilateral en comparación con las pacientes con IBR. Sin embargo, las pacientes sometidas a una mastectomía +/- IBR tenían más probabilidades de desarrollar complicaciones que las del grupo TM (TM n = 79, 21,0%; mastectomía n = 570, 37,2%; mastectomía y IBR n = 359, 35,6%; P 0,001). La conservación de la mama fue posible en el 87% de las pacientes con TM y el procedimiento no retrasó el inicio del tratamiento adyuvante. CONCLUSIÓN: La TM puede permitir que pacientes de alto riesgo que no serían candidatas a IBR eviten la mastectomía de una forma segura. Se necesitan más trabajos para comparar los resultados percibidos por las pacientes y los estéticos de las diferentes estrategias terapéuticas y establecer la seguridad oncológica a largo plazo.

Published
2020
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5. Antibodies to Acetylcholine Receptor in Parous Women with Myasthenia: Evidence for Immunization by Fetal Antigen

Author

Angela Vincent, Nick Willcox, G. P. Sims, David Beeson, Serena Ledwidge, David I. Stott, and Ian Matthews

Subjects
Adult, Fetal Proteins, medicine.medical_specialty, animal structures, Molecular Sequence Data, Immunoglobulin Variable Region, Cholinergic Antagonists, Neuromuscular junction, Epitope, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Antigen, Pregnancy, Internal medicine, Myasthenia Gravis, medicine, Humans, Receptors, Cholinergic, Amino Acid Sequence, Molecular Biology, Autoantibodies, 030304 developmental biology, Acetylcholine receptor, 0303 health sciences, Fetus, Base Sequence, biology, Computational Biology, Cell Biology, medicine.disease, Myasthenia gravis, 3. Good health, Pregnancy Complications, Parity, medicine.anatomical_structure, Endocrinology, QR180, Immunology, biology.protein, Female, Immunoglobulin Light Chains, Antibody, Clone (B-cell biology), 030217 neurology & neurosurgery
Abstract

The weakness in myasthenia gravis (MG) is mediated by autoantibodies against adult muscle acetylcholine receptors (AChR) at the neuromuscular junction; most of these antibodies also bind to fetal AChR, which is present in the thymus. In rare cases, babies of mothers with MG, or even of asymptomatic mothers, develop a severe developmental condition, arthrogryposis multiplex congenita, caused by antibodies that inhibit the ion channel function of the fetal AChR while not affecting the adult AChR. Here we show that these fetal AChR inhibitory antibodies are significantly more common in females sampled after pregnancy than in those who present before pregnancy, suggesting that they may be induced by the fetus. Moreover, we were able to clone high-affinity combinatorial Fab antibodies from thymic cells of two mothers with MG who had babies with arthrogryposis multiplex congenita. These Fabs were highly specific for fetal AChR and did not bind the main immunogenic region that is common to fetal and adult AChR. The Fabs show strong biases to VH3 heavy chains and to a single Vkappa1 light chain in one mother. Nevertheless, they each show extensive intraclonal diversification from a highly mutated consensus sequence, consistent with antigen-driven selection in successive steps. Collectively, our results suggest that, in some cases of MG, initial immunization against fetal AChR is followed by diversification and expansion of B cells in the thymus; maternal autoimmunity will result if the immune response spreads to the main immunogenic region and other epitopes common to fetal and adult AChR.

Published
2002
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6. Surgery in tropical diseases

Author

Serena Ledwidge and Simon Fisher

Subjects
medicine.medical_specialty, business.industry, Medicine, business, Surgery
Abstract

Whether you exercise a desire to experience surgery abroad during your student elective or whether you want to take the opportunity to enhance your career aspirations in far-flung regions, knowledge of common surgi­cal presentations of tropical disease is a prerequisite. Moreover, with the ability conferred by modern jet travel to translocate to almost any area of the globe within 48h, you may well encounter these conditions in your local general hospital clinic or emergency department, in visitors to the country or in travellers returning home from foreign excursions. This chapter tests you on your knowledge of presentations, investi­gations, and management of diseases such as malaria, schistosomiasis, amoebiasis, and filariasis, conditions native to a variety of geographical locations. Some diseases such as hydatid still remain endemic in regions closer to the UK. A sound understanding of parasitic life cycles, modes of exposure to, and manifestations of infection, and principles of treatment, will help you to diagnose and manage these conditions whether they are encountered unexpectedly, or prevalent in your geographical location.

Published
2014
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7. Trauma surgery

Author

Sebastian Dawson-Bowling and Serena Ledwidge

Abstract

Appreciation of the ‘golden hour’ for resuscitation, and adoption of prin­ciples of the advanced trauma life support (ATLS) system are key factors in improving outcome for the patient with major injuries. Adherence to the strict protocols of the ABCDEs of the primary survey enables the trauma team to identify and deal with life-threatening conditions, prior to definitive treatment of problems with lesser immediacy. The clinician who understands the mechanism of injury will main­tain heightened levels of suspicion for clinical signs which point to well-recognized conditions resulting in early mortality and morbidity, for instance, tension pneumothorax, cardiac tamponade, and rising intrac­ranial pressure. This chapter will probe your grasp of the principles of trauma manage­ment. You will also be tested on common patterns of thoracic, abdomi­nal, vascular, and cranial injuries. Whilst clinical presentations of civilian trauma have remained consist­ent in recent years, the impact of military trauma in worldwide theatres of conflict has stimulated numerous advances in the management of trauma. The current impetus for reorganization of trauma services in the UK is tacit acknowledgement of the improvement in outcomes that can be achieved by adherence to recognized protocols in this challenging and demanding field of surgery.

Published
2014
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8. Surgical pathology

Author

Serena Ledwidge

Abstract

Understanding of the fundamental processes of pathology is essential both to the understanding of how many surgical conditions arise and develop and to the vital role of appreciating the principles of how best to treat conditions. For example, the nature and behaviour of infecting organisms determines whether radical debridement of tissue or simple surgical drainage is required; the stage and grade of tumours influence not only the choice of surgical procedure but the use of adjuvant thera­pies. These ‘surgical’ pathologies are often seen as rather ‘old-fashioned’ compared to the emphasis on cell and molecular biology so often found in books describing medical specialities but they form the bulk of the processes of disease suffered worldwide and remain fundamental to the skilled practice of surgery today.

Published
2014
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9. 15. VTE prophylaxis in breast surgery – What are we doing?

Author

Jasdeep Gahir, Sophie Helme, Syeda Nadia Shah Gilani, Andrew D Baildam, Jake Sloane, Serena Ledwidge, and Jennifer Hu

Subjects
medicine.medical_specialty, Oncology, business.industry, Breast surgery, medicine.medical_treatment, General surgery, Medicine, Surgery, General Medicine, Vte prophylaxis, business
Published
2014
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10. An Audit of the predictive value of preoperative axillary ultrasound scan in patients with early breast cancer – A UK centre experience

Author

Caroline Cozon, Andrew D Baildam, Qaisra Gilani, Tamara Suaris, Jennifer Hu, Charlotte Gould, Jasdeep Gahir, and Serena Ledwidge

Subjects
Axillary ultrasound, medicine.medical_specialty, Oncology, business.industry, Medicine, Surgery, In patient, General Medicine, Radiology, Audit, business, Predictive value, Early breast cancer
Published
2014
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