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2. Phenotypes and genetic markers of cancer cachexia

Author

Johns, Neil and Fearon, Kenneth

Subjects
616.99, cancer, cachexia, genetics
Abstract

Cancer cachexia is a chronic wasting syndrome characterised by loss of weight, composed principally of muscle and fat. Patients with advanced cachexia demonstrate loss of appetite, early satiety, severe weight loss, weakness, anaemia and fluid retention. Affected individuals are also likely to report/experience decreased quality of life, decreased levels of physical performance, increased levels of fatigue, increased risks of treatment failure (be it chemotherapy, radiotherapy or surgery), increased risks of treatment side effects, and an increased mortality rate. Cachexia is therefore an extremely important, yet often underappreciated cause of cancer patient morbidity and mortality which requires urgent attention. Weight loss is significantly associated with cancer morbidity and mortality. It has been observed that half of all cancer patients experience weight loss and one-third lose more than 5% of their original body weight. Skeletal muscle loss appears to be the most significant event in cachexia and is associated with a poor outcome. However it is not known why some patients with the same tumour lose weight and muscle mass whilst others do not. The main aim of this thesis was to determine if the genetic makeup of individual patients might contribute to their propensity to lose weight or skeletal muscle. Previous studies had suggested an association between weight loss and SNPs on genes concerned with innate immunity and particularly the cell adhesion molecule Pselectin, however the strength of any gene association study depends on the precision with which it is possible to characterise the phenotype in question. A second aim of this thesis was to explore refining the clinical phenotyping of patients to discriminate those with evidence of muscle fibre atrophy versus those without. Phenotype The conventional phenotype for cachexia is weight loss (WL) but it is unknown the extent to which loss of body mass reflects loss of muscle or fat mass. Recent progress in cross sectional imaging analysis means that it is now possible to gain a direct measure of muscle mass from routine diagnostic CT scanning. However, in the absence of a longitudinal series of scans it is not possible to estimate whether low muscularity (LM) is longstanding or not. By combining a measure of active weight loss with low muscularity it was hoped that such a composite measure would reflect actual muscle loss/fibre atrophy. Compared with non-cachectic cancer patients, patients with LM or LM+ > 2%WL, mean muscle fibre diameter was reduced by about 25% (p = 0.02 and p = 0.001 respectively). No significant difference in muscle fibre diameter was observed if patients had WL alone. Regardless of classification, there was no difference in fibre number or proportion of fibre type across all myosin heavy chain isoforms. Mean muscle protein content was reduced and the ratio of RNA/DNA decreased in patients with either > 5%WL or LM+ > 2%WL. These findings support the use of composite measures (WL and LM) to try and identify those patients with evidence of active muscle fibre atrophy. This novel clinical phenotyping provides an accurate method to enable the conduct of candidate gene studies in the investigation of the genetics of cancer cachexia where the primary focus is on muscle wasting rather than overall weight loss. Genotype In an ideal world it would be possible to explore the entire genome and look for associations with the different phenotypes of cachexia. However, to do so would require considerable resource in terms of the cost of genome wide analysis and the cost of phenotyping large enough cohorts of patients (3000-10000). To address these issues I therefore adopted a candidate gene approach. A total of 154 genes associated with cancer cachexia were identified and explored for associated polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e. inflammation, loss of fat mass and/or lean mass and reduced survival). Such election of candidate genes and polymorphisms is a key element of multigene study design. The systematic review provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and to develop their potential as susceptibility biomarkers of cachexia. Phenotype – genotype associations A total of 1276 patients were recruited, phenotyped and genotyped. There were 545 new patients and 731 patients from a previous study. In our new cohort and in keeping with the previous literature, patients who carried the C allele of the rs6136 SNP in the SELP gene, were at a reduced risk of developing cachexia defined by WL. This association applied to all degrees of weight loss ( > 5%, > 10% or > 15%), and not just at the > 10% level as described previously in the literature. When examining newly identified SNPs in a stage 1 analysis for the weight loss phenotype that included 1276 cancer patients, twelve new candidate SNPs were significant. Six of these SNPs are associated with muscle metabolism in five genes (IGF1, CPN1, FOXO1, FOXO3, and ACVR2B), three are associated with adipose tissue metabolism in two genes (LEPR and TOMM40 (APOE on the reverse strand)), two with corticosteroid signalling in one gene (IFT172 (GCKR on the reverse strand)) and one with the immune response in one gene (TLR4). Two polymorphisms (rs1935949 and rs4946935) in the gene encoding for FOXO3 were consistently associated with WL of increasing severity ( > 5% and > 10%). On the basis that WL is a continuum in the cachectic process, the observation that both SELP and FOXO3 associate with the higher degrees of WL suggests that these genetic signatures may be of particular significance. The role of P-selectin in the genesis of cachexia remains to be determined. When examining all SNPs in a stage 1 analysis for the LM phenotype, 5 SNPs were associated significantly with the cachexia phenotype: (i) rs4291 in the angiotensin converting enzyme (ACE) gene in chromosome 17; this gene has been associated with muscle function and metabolism; (ii) rs10636 in chromosome 16 in the metallothionein 2a gene; this gene has been shown to be involved in zinc dyshomeostasis which may contribute to cancer cachexia; (iii) rs1190584 in chromosome 14 in the WDR20 gene; this gene encodes a WD repeat-containing protein that functions to preserve and regulate the activity of the USP12-UAF1 deubiquitinating enzyme complex; (iv) rs3856806 in the peroxisome proliferator-activated receptor gamma (PPARG) gene in chromosome 3 which has been demonstrated to be involved in fatty acid and glucose metabolism; and (v) rs3745012 in chromosome 18 in the lipin 2 (LPIN2) gene; this gene represents a candidate gene for human lipodystrophy, characterised by loss of body fat, fatty liver, hypertriglyceridemia, and insulin resistance. When examining all SNPs in a stage 1 analysis for the LM + > 2%WL phenotype 4 SNPs were associated significantly with the cachexia phenotype. rs12409877 in the leptin receptor (LEPR) located on chromosome 3, LEPR binds leptin and is involved in adipose tissue regulation. rs2268757 located in the activin receptor type-2B (ACVR2B) gene on chromosome 3, ACVR2B is a high affinity activin type 2 receptor which mediates signalling by a subset of TGF-β family ligands including myostatin, activin, GDF11 and others. SNPs in the tumour necrosis factor (TNF) (rs1799964) and ACE (rs4291) genes were also significantly associated with the phenotype. Whether genes demonstrating significant associations with the cachexia phenotypes had altered transcript expression in muscle from cancer patients with or without those phenotypes was also investigated.

Published
2016

3. Current margin practice and effect on re-excision rates following the publication of the SSO-ASTRO consensus and ABS consensus guidelines: a national prospective study of 2858 women undergoing breast-conserving therapy in the UK and Ireland

Author

Tang, Sarah Shuk-Kay, Kaptanis, Sarantos, Haddow, James B., Mondani, Giuseppina, Elsberger, Beatrix, Tasoulis, Marios Konstantinos, Obondo, Christine, Johns, Neil, Ismail, Wisam, Syed, Asim, Kissias, Panayioti, Venn, Mary, Sundaramoorthy, Souganthy, Irwin, Gareth, Sami, Amtul S., Elfadl, Dalia, Baggaley, Alice, Remoundos, Dionysios Dennis, Langlands, Fiona, Charalampoudis, Petros, Barber, Zoe, Hamilton-Burke, Werbena L.S., Khan, Ayesha, Sirianni, Chiara, Merker, Louise Anne-Marie Grant, Saha, Sunita, Lane, Risha Arun, Chopra, Sharat, Dupré, Sophie, Manning, Aidan T., St John, Edward R., Musbahi, Aya, Dlamini, Nokwanda, McArdle, Caitlin L., Wright, Chloe, Murphy, James O., Aggarwal, Ravi, Dordea, Matei, Bosch, Karen, Egbeare, Donna, Osman, Hisham, Tayeh, Salim, Razi, Faraz, Iqbal, Javeria, Ledwidge, Serena F.C., Albert, Vanessa, and Masannat, Yazan

Published
2017
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4. Correction: Clinical Classification of Cancer Cachexia: Phenotypic Correlates in Human Skeletal Muscle.

Author

Johns, Neil, Hatakeyama, Shinji, Stephens, Nathan A., Degen, Martin, Degen, Simone, Frieauff, Wilfried, Lambert, Christian, Ross, James A., Roubenoff, Ronenn, Glass, David J., Jacobi, Carsten, and Fearon, Kenneth C. H.

Subjects
*WESTERN immunoblotting, *TUMOR classification, *SKELETAL muscle, *PUBLISHED articles, *CLUSTER sampling, *TUBULINS
Published
2024
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9. New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight loss

Author

Johns, Neil, Stretch, Cynthia, Tan, Benjamin H.L., Solheim, Tora S., Sørhaug, Sveinung, Stephens, Nathan A., Gioulbasanis, Ioannis, Skipworth, Richard J.E., Deans, D.A. Christopher, Vigano, Antonio, Ross, James A., Bathe, Oliver F., Tremblay, Michel L., Kaasa, Stein, Strasser, Florian, Gagnon, Bruno, Baracos, Vickie E., Damaraju, Sambasivarao, and Fearon, Kenneth C.H.

Published
2017
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10. Confirmed Bacillus anthracis infection among persons who inject drugs, Scotland, 2009-2010

Author

Booth, Malcolm, Donaldson, Lindsay, Cui, Xizhong, Sun, Junfeng, Cole, Stephen, Dailsey, Susan, Hart, Andrew, Johns, Neil, McConnell, Paul, McLennan, Tina, Parcell, Benjamin, Robb, Henry, Shippey, Benjamin, Sim, Malcolm, Wallis, Charles, and Eichacker, Peter Q.

Subjects
Mortality -- Maryland -- United Kingdom, Drugs -- Health aspects, Infection -- Health aspects, Antibacterial agents -- Health aspects, Skin -- Health aspects, Health
Abstract

Learning Objectives Upon completion of this activity, participants will be able to: 1. Distinguish patient factors associated with a higher risk for mortality from injection anthrax 2. Evaluate variables at [...]

Published
2014
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12. Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: a pilot study

Author

Ebhardt, H. Alexander, Degen, Simone, Tadini, Valentina, Schilb, Alain, Johns, Neil, Greig, Carolyn A., Fearon, Kenneth C.H., Aebersold, Ruedi, and Jacobi, Carsten

Subjects
Aged, 80 and over, Male, Aging, Sarcopenia, Cachexia, Proteome, Muscle Proteins, Cancer cachexia, Pilot Projects, Original Articles, Proteome quantification, SWATH‐MS, Signal transduction, TNF-alpha, Middle Aged, Muscular Atrophy, Journal Article, TNFα, Humans, Original Article, Female, Muscle, Skeletal, Cells, Cultured, Aged
Abstract

Background Cancer cachexia (cancer‐induced muscle wasting) is found in a subgroup of cancer patients leaving the patients with a poor prognosis for survival due to a lower tolerance of the chemotherapeutic drug. The cause of the muscle wasting in these patients is not fully understood, and no predictive biomarker exists to identify these patients early on. Skeletal muscle loss is an inevitable consequence of advancing age. As cancer frequently occurs in old age, identifying and differentiating the molecular mechanisms mediating muscle wasting in cancer cachexia vs. age‐related sarcopenia are a challenge. However, the ability to distinguish between them is critical for early intervention, and simple measures of body weight may not be sufficiently sensitive to detect cachexia early. Methods We used a range of omics approaches: (i) undepleted proteome was quantified using advanced high mass accuracy mass spectrometers in SWATH‐MS acquisition mode; (ii) phospho epitopes were quantified using protein arrays; and (iii) morphology was assessed using fluorescent microscopy. Results We quantified the soluble proteome of muscle biopsies from cancer cachexia patients and compared them with cohorts of cancer patients and healthy individuals with and without age‐related muscle loss (aka age‐related sarcopenia). Comparing the proteomes of these cohorts, we quantified changes in muscle contractile myosins and energy metabolism allowing for a clear identification of cachexia patients. In an in vitro time lapse experiment, we mimicked cancer cachexia and identified signal transduction pathways governing cell fusion to play a pivotal role in preventing muscle regeneration. Conclusions The work presented here lays the foundation for further understanding of muscle wasting diseases and holds the promise of overcoming ambiguous weight loss as a measure for defining cachexia to be replaced by a precise protein signature., Journal of Cachexia, Sarcopenia and Muscle, 8 (4), ISSN:2190-5991, ISSN:2190-6009

Published
2017
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13. The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Author

O'Connell, Rachel L, Rattay, Tim, Dave, Rajiv V, Trickey, Adam, Skillman, Joanna, Barnes, Nicola LP, Gardiner, Matthew, Harnett, Adrian, Potter, Shelley, Holcombe, Chris, Blazeby, Jane, Conroy, Elizabeth, O'Brien, Ciara, Williamson, Paula, Curnier, Alain, Tadros, Amir, Depasquale, Ivan, Masannat, Yazan A, Smyth, Elizabeth, Fuller, Mairi, Bourne, Roger, Heys, Steven, Hamo, Ishrak, Aloraifi, Fatima, Fopp, Laura, Bali, Radhika, Bache, Sarah, Benyon, Sarah L, Irwin, Michael S, Agrawal, Amit, Malata, Charles M, Murphy, Claire, Misky, Adam, Chicken, Dennis Wayne, Abdullah, Nassreen, Hill, Arnold DK, Cullinane, Carolyn, Irwin, Gareth, McIntosh, Stuart A, Refsum, Sigi, Sloan, Samantha, Mallon, Peter, Sirianni, Chiara, Khattak, Ilyas, Nagachandra, Geerthan, Kiruparan, Pasupathy, Debanth, Debasish, Davey, Simon, Curran, Terry-Ann, Svenning, Matilda, Govindarajulu, Sasirekha, Rayter, Zenon, Ainsworth, Rachel, Cawthorn, Simon, Sahu, Ajay, Wilson, Sherif, Prousskaia, Elena, Accurso, Antonello, Rocco, Nicola, Di Micco, Rosa, Limite, Gennaro, Ceccarino, Raffaele, Liccardo, Raffaele, Coco, Guido, Nizamoglu, Metin, Morgan, Mary, Ramakrishnan, Venkat, Catanuto, Giuseppe, Wilkins, Alex, McManus, Penelope, Kneeshaw, Peter, Grover, Kartikae, Mahapatra, Tapan, Wooler, Brendan, Elahi, Bilal, Ihsan, Naila, Bucknor, Alexandra, Reissis, Dimitris, Hunter, Judith, Wood, Simon, Jallali, Navid, Henry, Francis P, Verjee, Liaquat S, Lee, Jason, Khan, Shazia M, Azmy, Iman, Massey, Julia, Hollywood, Ciaran, Oluwajana, Michael, Bathla, Sonia, Seward, Joanna, Harding-MacKean, Claudia, Lane, Risha, Murali, Kothandaraman, Biswas, Bashishta, Trapszo, Pawel, Seetharam, Seema, Kennedy, Katy, Alder, Louise, Graja, Tomasz, Amin, Khalid, Kokan, Jalal, Roshanlall, Chandeena, Gill, Emma, Kulkarni, Dhananjay, Dixon, JM, Young, Oliver, Saleem, Talha, Biddle, M, Kearns, Marie, Weiler-Mithoff, Eva, Chew, Ben, Malyon, Andy, Scott, John, McGill, David, Mackay, Iain, Bains, Salena, Barrows, Sara, Pilgrim, Simon, Shokuhi, Sheila, Lambert, Kelly, Kenny, Frances, Valassiadou, Kalliope, Kaushik, Monika, Krupa, Jaroslaw, Dragoumis, Dimitris, Ain, Quratul, Lampropoulos, Pavlos, Moss, Sarah, Khalil, Haitham, Haq, Anwar, Balasubramanian, Balapathiran, Charalampou-Dis, Petros, Hamed, Hisham, Kothari, Ashutosh, Kovacs, Tibor, Douek, Michael, Mehmood, Iftikhar, Ray, Biswajit, Adelekan, Matthew, Humphreys, Laura, Tayeh, Salim, Choy, Christina, Parvanta, Laila, Michieletto, Silvia, Saibene, Tania, O'Brien, James, Down, Sue, Downey, Sarah, Pereira, Jerome, Sami, AS, Gvaramadze, Anzors, Jibril, Jibril A, Thekkinkattil, Dinesh, Udayasankar, S, Khawaja, Saira, Shariaha, Yousef, Holt, Simon, James, Ruth, Rizki, Hirah, Kirkpatrick, Katharine, Ravichandran, Duraisamy, Shrestha, Deepak, Barua, Ellora, Akolekar, Deepika, Hamad, Ahmed, Kleidi, Eleftheria, Hignett, Susan, Pope, Vanessa, Naseem, Salma, Isherwood, Jennifer, Soulsby, Rachel, Taylor, Amanda, Chin, Kian, Nguyen, Dai, Guest, Francesca, Thorne, Amanda, Kirchhoff, Chris, Murphy, Declan C, Lo, Michelle, Harcourt, Ruth, Pain, Simon J, Hussien, Maged I, Zechmeister, Katalin, Sassoon, EM, Figus, Andrea, Haywood, Richard M, Ali, Rozina, Alexander, Susanna, Geropantas, Konstantinos, Epurescu, Daniel, Lewis, Rebecca, Fafemi, Oladapo, Gahir, Jasdeep, Gandamihardja, Tasha, Kelsall, Jennett, Muhibullah, Nazli, Otieno, Charlene, Mazari, Fayyaz, Dauria, Marta, Whisker, Lisa, Macmillan, Douglas, Gutteridge, Eleanor, Rasheed, Tuabin, Khout, Hazem, Asgeirsson, Kristjan, McCulley, Stephen, Mariniello, Maria Donatella, Roncella, Manuela, Ghilli, Matteo, Colizzi, Livio, Rossetti, Elena, Marzia, Lo Russo, Fustaino, Loredana, Li, Alessandro Quattrini, Harvey, Kate L, Windle, Rebecca, Remoundos, Dionysios Dennis, Roy, Pankaj, MacLean, Gael, Adwani, Asha, Popa, Elena, Goh, Steven, Shetty, Geeta, Clark, Sarah, Bernaudo, Lorenzo, Agrawal, Avi, Mansfield, Lucy, Tebbal, Sally, Patel, Ashraf, Grassi, Veronica, Pujji, Ojas, Hamnett, Kathryn, Basu, Naren, Granger, Emily, Durbar, Michael, Pikoulas, Panagiotis, Garnsey, Clare, Walker, Philip, Vollermere, Angela J, Michalakis, Ioannis, Jones, Robin, Youssef, Mina, Ives, Charlotte, Masood, Mohammad, Dunn, Julie, Olsen, Sisse, Ferguson, Douglas, Tillett, Rachel, Allan, Anna, Woollard, Alex, Canny, Rebecca, Woollard, Alexander, Mosahebi, Afshin, Hamilton, Stephen, Ghali, Shadi, Marsh, Daniel, Chana, Jagdeep, Sojitra, Nilesh, Younis, Ibby, Rainsbury, Dick, Chand, Natalie, Kalles, Vasileios, Stebbing, Anne, Harris, Kevin, Laws, Siobhan, Tansley, Anne, Mitchell, Geraldine, de Sousa, Emma, Henderson, Julia, Chandrashekar, Mysore, Pereira, Bernadette, Constantinou, Chloe, Elfadl, Dalia, Irakleidis, Foivos, Hernan, Izaro, Byrne, Miriam, To, Natalie, O'Connell, Rachel, Rusby, Jennifer, Barry, Peter, Krupa, Katerine, Allum, William, MacNeill, Fiona, Roche, Nicola, Gui, Gerald, Ramsey, Kelvin, Harris, Paul, James, Stuart, Power, Kieran, Sutton, Richard, McIntosh, Jamie, Laurence, Nicola, MacLennan, Louise, Milligan, Robert, Cain, Henry, Critchley, Adam, O'Donoghue, Joe, Kalra, Loraine, Collis, Nick, Weston-Petrides, Gina, Fiddes, Roanne, Brown, Victoria, Aertssen, Anna, Slade-Sharman, Diana, Khan, Mansoor, McGuiness, Caroline, Amorosi, Vittoria, Fabio, Santanelli di Pompeo, Exarchos, Georgios, Jiwa, Natasha, Hu, Jennifer, Ledwidge, Serena, Johnson, Laura, Peel, Anthony, Dhooma, Naseem, Farrell, Eric, Devane, Liam, Tevlin, Ruth, McDermott, Enda, Prichard, Ruth, Evoy, Denis, Rothwell, Jane, Geraghty, James, Morrison, Colin, Lawlor, Catriona, Langlands, Fiona, Taylor, Lauren, Turton, Philip, Achuthan, Raj, Horgan, Kieran, Mckenzie, Shireen, Hogan, Brian, Lansdown, Mark, Navin, Channegowda, Sherwin, Liz, Mortimer, Caroline, Garg, Neeraj, Adam, Rahma, Arif, Tahera, Kryjak, Zbigniew, Ali, Deedar, Sowdi, Ravi, Fage, Elena, Mylvaganam, Senthurun, Matey, Pilar, Vidya, Raghavan, Sircar, Tapan, Asaad, Oubida, Bhaskar, Pud, Dordea, Matei, Chrysafi, Ada, McCartan, Damian, Dave, Rajiv, Foster, Rachel, Wilson, Rebecca, Okwemba, Sylvia, Majeed, Yousef, Mathen, Vinod, Murphy, John, Barnes, Nicola, Gandhi, Ashu, Harvey, James, Kirwan, Cliona C, Johnson, Richard, Patel, Krupali, Ribas, Maria Dalmau, Vigneswaran, Natali, Challoner, Tom, Park, Alan, Rizkalla, Maged, Tomlins, Abigail, McEvoy, Kat, Jafferbhoy, Sadaf, Soumian, Soni, Narayanan, Sankaran, Kirby, Robert, Bajrusevic, Sladana, Maalo, Joseph, Charalambous, Michalis, Lai, Lee Min, Chong, Kelvin, Thomson, Simon, Monib, Sherif, Chagla, Leena, Audisio, Riccardo, Taghizadeh, Rieka, Iqbal, Azhar, James, Karen, Callaghan, Maria, Poonawala, Shabbir, Lund, Jonathan, Vinayagam, Raman, Thrush, Steven, Thomas, Rachel Bright, Mullan, Michelle, Taylor, Jevan, Yoshimura, Ryo, Mathew, Tom, Jones, Ben Mancey, Munot, Kailas, Nasr, Rana, Piper, Jenny, El-Sharief, Deena, Mustafa, Mohammed, Dumitru, Dorin, Christopoulos, Petros, O'Leary, Peter, Athanasiou, Irene, Johns, Neil, Mehta, Disha, Bibi, Saira, Syed, Farah, Koris, Jacob, Healy, Samuel, Shanks, Lindsay, Oliver, James, Bucata, Claudiu, Clarke, Natalie, Bignell, Kym, Akerlund, Malin, Brock, Lisa, Hallam, Kelly, Howes, Rachel, Armstrong, Alexander, Sethu, Claire, Zeidan, Bashar, Sjokvist, Olivia, Tasoulis, Marios, Sundaramoorthy, Souganthy, Harris, Chad, Wintrip, Dorothy, Lymperopoulos, N, Jain, Yogesh, Balata, Safa Ahmed, Grp, iBRA-2 Steering, and Collab, Breast Reconstruction Res

Subjects
Adult, Cancer Research, medicine.medical_specialty, Time Factors, medicine.medical_treatment, Mammaplasty, trainee collaboratives, Breast Neoplasms, Article, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Breast cancer, breast cancer, Adjuvant therapy, cohort study, Medicine, Humans, Prospective Studies, Prospective cohort study, Mastectomy, Aged, Cancer, Aged, 80 and over, Manchester Cancer Research Centre, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, adjuvant therapy, immediate breast reconstruction, Middle Aged, medicine.disease, Surgery, Radiation therapy, Oncology, Centre for Surgical Research, Chemotherapy, Adjuvant, Outcomes research, 030220 oncology & carcinogenesis, Surgical oncology, Female, Breast reconstruction, business, Complication, Cohort study
Abstract

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy.Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored.Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays.Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients.

Published
2019
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15. P035. Comparison of post-operative patient satisfaction and health-related quality of life following latissimus dorsi (LD) flap breast reconstruction, deep inferior epigastric perforator (DIEP) flap breast reconstruction and bilateral therapeutic mammoplasty using BREAST-Q questionnaire

Author

Wolska, Joanna, primary, Ammari, Tareq, additional, Johns, Neil, additional, Schaverien, Mark, additional, Raine, Cameron, additional, Dixon, Michael, additional, Butterworth, Mark, additional, Bahia, Hilal, additional, Hamilton, Stuart, additional, Addison, Patrick, additional, Cahoon, Neil, additional, Anderson, William, additional, and Majdak-Paredes, Ewa, additional

Published
2019
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18. New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight loss

Author

Johns, Neil, Stretch, Cynthia, Tan, Benjamin H.L., Solheim, Tora S., Sørhaug, Sveinung, Stephens, Nathan A., Gioulbasanis, Ioannis, Skipworth, Richard J.E., Deans, D.A. Christopher, Vigano, Antonio, Ross, James A., Bathe, Oliver F., Tremblay, Michel L., Kaasa, Stein, Strasser, Florian, Gagnon, Bruno, Baracos, Vickie E., Damaraju, Sambasivarao, and Fearon, Kenneth C.H.

Subjects
Adult, Male, Cachexia, Genotype, Polymorphism, Single Nucleotide, Young Adult, Neoplasms, Weight Loss, Genetics, Humans, Muscle, Skeletal, Letters to the Editor, Letter to the Editor, Cancer, Aged, Retrospective Studies, Aged, 80 and over, Nucleotides, Original Articles, Middle Aged, Muscular Atrophy, Phenotype, Original Article, Female, Polymorphisms, Tomography, X-Ray Computed, Transcriptome
Abstract

BACKGROUND: Cachexia affects the majority with advanced cancer. Based on current demographic and clinical factors, it is not possible to predict who will develop cachexia or not. Such variation may, in part, be due to genotype. It has recently been proposed to extend the diagnostic criteria for cachexia to include a direct measure of low skeletal muscle index (LSMI) in addition to weight loss (WL). We aimed to explore our panel of candidate single nucleotide polymorphism (SNPs) for association with WL +/- computerized tomography-defined LSMI. We also explored whether the transcription in muscle of identified genes was altered according to such cachexia phenotype METHODS: A retrospective cohort study design was used. Analysis explored associations of candidate SNPs with WL (n = 1276) and WL + LSMI (n = 943). Human muscle transcriptome (n = 134) was analysed using an Agilent platform.RESULTS: Single nucleotide polymorphisms in the following genes showed association with WL alone: GCKR, LEPR, SELP, ACVR2B, TLR4, FOXO3, IGF1, CPN1, APOE, FOXO1, and GHRL. SNPs in LEPR, ACVR2B, TNF, and ACE were associated with concurrent WL + LSMI. There was concordance between muscle-specific expression for ACVR2B, FOXO1 and 3, LEPR, GCKR, and TLR4 genes and LSMI and/or WL (P CONCLUSIONS: The rs1799964 in the TNF gene and rs4291 in the ACE gene are new associations when the definition of cachexia is based on a combination of WL and LSMI. These findings focus attention on pro-inflammatory cytokines and the renin-angiotensin system as biomarkers/mediators of muscle wasting in cachexia.

Published
2016
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19. Alterations in the in vitro and in vivo regulation of muscle regeneration in healthy ageing and the influence of sarcopenia

Author

Brzeszczyńska, Joanna, primary, Meyer, Angelika, additional, McGregor, Robin, additional, Schilb, Alain, additional, Degen, Simone, additional, Tadini, Valentina, additional, Johns, Neil, additional, Langen, Ramon, additional, Schols, Annemie, additional, Glass, David J., additional, Roubenoff, Ronenn, additional, Ross, James A., additional, Fearon, Kenneth C.H., additional, Greig, Carolyn A., additional, and Jacobi, Carsten, additional

Published
2017
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21. Risk factors, complications and survival after upper abdominal surgery: a prospective cohort study

Author

Aahlin, Eirik Kjus, Tranø, Geir, Johns, Neil, Horn, Arild, Søreide, Jon Arne, Fearon, Kenneth Christopher H., Revhaug, Arthur, and Lassen, Kristoffer

Subjects
Adult, Male, Sarcopenia, Gastrointestinal, Cachexia, Medisinske fag: 700::Klinisk medisinske fag: 750::Kar- og thoraxkirurgi: 782 [VDP], Postoperative Complications, Risk Factors, Abdomen, Outcome Assessment, Health Care, Weight Loss, Humans, Prospective Studies, Midical sciences: 700::Clinical medical sciences: 750::Vascular and thoracic surgery: 782 [VDP], Serum Albumin, Cancer, Aged, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Kar- og thoraxkirurgi: 782, Hepatopancreatobiliary, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Vascular and thoracic surgery: 782, Middle Aged, Survival Rate, Preoperative Period, Body Composition, Surgery, Female, Biomarkers, Research Article
Abstract

BACKGROUND: Preoperative weight loss and abnormal serum-albumin have traditionally been associated with reduced survival. More recently, a correlation between postoperative complications and reduced long-term survival has been reported and the significance of the relative proportion of skeletal muscle, visceral and subcutaneous adipose tissue has been examined with conflicting results. We investigated how preoperative body composition and major non-fatal complications related to overall survival and compared this to established predictors in a large cohort undergoing upper abdominal surgery.METHODS: From 2001 to 2006, 447 patients were included in a Norwegian multicenter randomized controlled trial in major upper abdominal surgery. Patients were now, six years later, analyzed as a single prospective cohort and overall survival was retrieved from the National Population Registry. Body composition indices were calculated from CT images taken within three months preoperatively.RESULTS: Preoperative serum-albumin 5 % (HR = 1.38, p = 0.023) were independently associated with reduced survival. There was no association between any of the preoperative body composition indices and reduced survival. Major postoperative complications were independently associated with reduced survival but only as long as patients who died within 90 days were included in the analysis.CONCLUSIONS: Our study has confirmed the robust significance of the traditional indicators, preoperative serum-albumin and weight loss. The body composition indices did not prove beneficial as global indicators of poor prognosis in upper abdominal surgery. We found no association between non-fatal postoperative complications and long-term survival.

Published
2015
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23. Ken Fearon

Author

Skipworth, Richard J.E., primary, Stephens, Nathan A., additional, Johns, Neil, additional, Guttridge, Denis C., additional, Tisdale, Michael J., additional, Baracos, Vickie E., additional, and Glass, David J., additional

Published
2016
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24. New genetic signatures associated with cancer cachexia as defined by low skeletal muscle index and weight loss

Author

Johns, Neil, primary, Stretch, Cynthia, additional, Tan, Benjamin H.L., additional, Solheim, Tora S., additional, Sørhaug, Sveinung, additional, Stephens, Nathan A., additional, Gioulbasanis, Ioannis, additional, Skipworth, Richard J.E., additional, Deans, D.A. Christopher, additional, Vigano, Antonio, additional, Ross, James A., additional, Bathe, Oliver F., additional, Tremblay, Michel L., additional, Kaasa, Stein, additional, Strasser, Florian, additional, Gagnon, Bruno, additional, Baracos, Vickie E., additional, Damaraju, Sambasivarao, additional, and Fearon, Kenneth C.H., additional

Published
2016
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25. Loss of oxidative defense and potential blockade of satellite cell maturation in the skeletal muscle of patients with cancer but not in the healthy elderly

Author

Brzeszczyńska, Joanna, primary, Johns, Neil, additional, Schilb, Alain, additional, Degen, Simone, additional, Degen, Martin, additional, Langen, Ramon, additional, Schols, Annemie, additional, Glass, David J, additional, Roubenoff, Ronenn, additional, Greig, Carolyn A., additional, Jacobi, Carsten, additional, Fearon, Kenneth CH., additional, and Ross, James A., additional

Published
2016
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27. Alterations in the <italic>in vitro</italic> and <italic>in vivo</italic> regulation of muscle regeneration in healthy ageing and the influence of sarcopenia.

Author

Brzeszczyńska, Joanna, Meyer, Angelika, McGregor, Robin, Schilb, Alain, Degen, Simone, Tadini, Valentina, Johns, Neil, Langen, Ramon, Schols, Annemie, Glass, David J., Roubenoff, Ronenn, Ross, James A., Fearon, Kenneth C. H., Greig, Carolyn A., and Jacobi, Carsten

Subjects
MUSCLE regeneration, SARCOPENIA, SATELLITE cells, MYOGENESIS, BIOMARKERS
Abstract

Abstract: Background: Sarcopenia is defined as the age‐related loss of skeletal muscle mass and function. While all humans lose muscle with age, 2–5% of elderly adults develop functional consequences (disabilities). The aim of this study was to investigate muscle myogenesis in healthy elderly adults, with or without sarcopenia, compared with middle‐aged controls using both in vivo and in vitro approaches to explore potential biomarker or causative molecular pathways associated with sarcopenic versus non‐sarcopenic skeletal muscle phenotypes during ageing. Methods: Biomarkers of multiple molecular pathways associated with muscle regeneration were analysed using quantitative polymerase chain reaction in quadriceps muscle samples obtained from healthy elderly sarcopenic (HSE, n = 7) or non‐sarcopenic (HENS, n = 21) and healthy middle‐aged control (HMC, n = 22) groups. An in vitro system of myogenesis (using myoblasts from human donors aged 17–83 years) was used to mimic the environmental challenges of muscle regeneration over time. Results: The muscle biopsies showed evidence of satellite cell activation in HENS (Pax3, P < 0.01, Pax7, P < 0.0001) compared with HMC. Early myogenesis markers Myogenic Differentiation 1 (MyoD1) and Myogenic factor 5 (Myf5) (P < 0.0001) and the late myogenesis marker myogenin (MyoG) (P < 0.01) were increased in HENS. In addition, there was a 30‐fold upregulation of TNF‐α in HENS compared with HMC (P < 0.0001). The in vitro system demonstrated age‐related upregulation of pro‐inflammatory cytokines (2‐fold upregulation of interleukin (IL)‐6, IL‐8 mRNA, increased secretion of tumor necrosis factor‐α (TNF‐α) and IL‐6, all P < 0.05) associated with impaired kinetics of myotube differentiation. The HSE biopsy samples showed satellite cell activation (Pax7, P < 0.05) compared with HMC. However, no significant upregulation of the early myogenesis (MyoD and Myf5) markers was evident; only the late myogenesis marker myogenin was upregulated (P < 0.05). Higher activation of the oxidative stress pathway was found in HENS compared with the HSE group. In contrast, there was 10‐fold higher upregulation of HSPA1A a stress‐induced chaperone acting upon misfolded proteins in HSE compared with the HENS group. Conclusions: Both pathological and adaptive processes are active in skeletal muscle during healthy ageing. Muscle regeneration pathways are activated during healthy ageing, but there is evidence of dysregulation in sarcopenia. In addition, increased cellular stress, with an impaired oxidative‐stress and mis‐folded protein response (HSPA1A), may be associated with the development of sarcopenia. The in vitro system of young and old myoblasts replicated some of the differences between young and old muscle. [ABSTRACT FROM AUTHOR]

Published
2018
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31. ConfirmedBacillus anthracisInfection among Persons Who Inject Drugs, Scotland, 2009–2010

Author

Booth, Malcolm, primary, Donaldson, Lindsay, additional, Cui, Xizhong, additional, Sun, Junfeng, additional, Cole, Stephen, additional, Dailsey, Susan, additional, Hart, Andrew, additional, Johns, Neil, additional, McConnell, Paul, additional, McLennan, Tina, additional, Parcell, Benjamin, additional, Robb, Henry, additional, Shippey, Benjamin, additional, Sim, Malcolm, additional, Wallis, Charles, additional, and Eichacker, Peter Q., additional

Published
2014
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33. Clinical Classification of Cancer Cachexia: Phenotypic Correlates in Human Skeletal Muscle

Author

Johns, Neil, primary, Hatakeyama, Shinji, additional, Stephens, Nathan A., additional, Degen, Martin, additional, Degen, Simone, additional, Frieauff, Wilfried, additional, Lambert, Christian, additional, Ross, James A., additional, Roubenoff, Ronenn, additional, Glass, David J., additional, Jacobi, Carsten, additional, and Fearon, Kenneth C. H., additional

Published
2014
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37. The colon‐selective spasmolytic otilonium bromide inhibits muscarinic M3 receptor‐coupled calcium signals in isolated human colonic crypts

Author

Lindqvist, Susanne, primary, Hernon, James, additional, Sharp, Paul, additional, Johns, Neil, additional, Addison, Sarah, additional, Watson, Mark, additional, Tighe, Richard, additional, Greer, Shaun, additional, Mackay, Jean, additional, Rhodes, Michael, additional, Lewis, Michael, additional, Stebbings, William, additional, Speakman, Chris, additional, Evangelista, Stefano, additional, Johnson, Ian, additional, and Williams, Mark, additional

Published
2002
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