المؤلفون: Victoria K. Woodcock, Ji‐Li Chen, Karin Purshouse, Chrissie Butcher, Linda Collins, Caroline Haddon, Gillian Verrall, Leena Elhussein, Corran Roberts, Andrea Tarlton, Margarida Rei, Giorgio Napolitani, Mariolina Salio, Mark R. Middleton, Vincenzo Cerundolo, Jeremy Crew, Andrew S. Protheroe

المصدر: BJUI Compass, Vol 4, Iss 3, Pp 322-330 (2023)

مصطلحات موضوعية: bladder cancer, checkpoint inhibition, immunotherapy, intravesical, Phase 1, Diseases of the genitourinary system. Urology, RC870-923

الوصف: Abstract Objectives This study aimed to investigate the anti‐PD‐1 inhibitor pembrolizumab as a potential agent for use in non‐muscle‐invasive bladder cancer (NMIBC) by conducting a Phase 1 safety run‐in study to assess the safety and tolerability of intravesical pembrolizumab after transurethral resection of the bladder tumour (TURBT). Patients and methods Eligible patients had recurrent NMIBC for which adjuvant treatment post TURBT was a reasonable treatment option, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–1 and adequate end‐organ function. Pembrolizumab was administered by intravesical instillation once weekly for a total of six doses. Intra‐patient dose escalation was performed in three paired patient cohorts with doses starting at 50 mg and increasing through 100 mg to a maximum of 200 mg. Adverse events (AEs) were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v4.03 with dose limiting toxicity (DLT) defined as a clinically significant, drug‐related, Grade 4 haematological or Grade 3 or higher non‐haematological toxicity occurring within 7 days of administration of the first treatment at a given dose for that patient. Results Six patients were treated with no DLTs seen during dose escalation. Drug‐related AEs were of low grade and included dysuria and fatigue. All patients completed six doses of treatment as planned. Pharmacokinetic and pharmacodynamic assays did not detect any pembrolizumab in the serum following repeated intravesical administration, and no changes in peripheral immune cell populations were observed. Conclusions Administration of intravesical pembrolizumab was well tolerated and did not raise any safety concerns in patients with NMIBC following TURBT. There was no evidence of systemic absorption or systemic immune effects following intravesical administration. Further studies are required to assess whether intravesical administration has anti‐tumour activity.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2688-4526Test

الوصول الحر: https://doaj.org/article/d7395c1210aa4beeac995f4f6e98382cTest

المؤلفون: Nicholas F. Brown, Stasya M. Ng, Claire Brooks, Tim Coutts, Jane Holmes, Corran Roberts, Leena Elhussein, Peter Hoskin, Tim Maughan, Sarah Blagden, Paul Mulholland

المصدر: BMC Cancer, Vol 20, Iss 1, Pp 1-5 (2020)

مصطلحات موضوعية: Glioblastoma, Glioma, Ipilimumab, Temozolomide, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Median survival for patients with glioblastoma is less than a year. Standard treatment consists of surgical debulking if feasible followed by temozolomide chemo-radiotherapy. The immune checkpoint inhibitor ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has shown clinical efficacy in preclinical models of glioblastoma. The aim of this study is to explore the addition of ipilimumab to standard therapy in patients with glioblastoma. Methods/design Ipi-Glio is a phase II, open label, randomised study of ipilimumab with temozolomide (Arm A) versus temozolomide alone (Arm B) after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma. Planned accrual is 120 patients (Arm A: 80, Arm B: 40). Endpoints include overall survival, 18-month survival, 5-year survival, and adverse events. The trial is currently recruiting in seven centres in the United Kingdom. Trial registration ISRCTN84434175 . Registered 12 November 2018.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s12885-020-6624-yTest; https://doaj.org/toc/1471-2407Test

الوصول الحر: https://doaj.org/article/499d5079d98d4f31aaed547c17a9b1f4Test

المؤلفون: Gowri Gopalakrishna, Miranda Langendam, Rob Scholten, Patrick Bossuyt, Mariska Leeflang, Anna Noel-Storr, James Thomas, Iain Marshall, Byron Wallace, Penny Whiting, Clare Davenport, Gowri GopalaKrishna, Isabel de Salis, Sue Mallett, Robert Wolff, Richard Riley, Marie Westwood, Jos Kleinen, Gary Collins, Hans Reitsma, Karel Moons, Antonia Zapf, Annika Hoyer, Katharina Kramer, Oliver Kuss, J. Ensor, J. J. Deeks, E. C. Martin, R. D. Riley, Gerta Rücker, Susanne Steinhauser, Martin Schumacher, Joie Ensor, Kym Snell, Brian Willis, Thomas Debray, Jon Deeks, Lavinia Ferrante di Ruffano, Sian Taylor-Phillips, Chris Hyde, Stuart A. Taylor, Gauraang Batnagar, STREAMLINE COLON Investigators, STREAMLINE LUNG Investigators, METRIC Investigators, Lavinia Ferrante Di Ruffano, Farah Seedat, Aileen Clarke, Sarah Byron, Frances Nixon, Rebecca Albrow, Thomas Walker, Carla Deakin, Zhivko Zhelev, Harriet Hunt, Yaling Yang, Lucy Abel, James Buchanan, Thomas Fanshawe, Bethany Shinkins, Laure Wynants, Jan Verbakel, Sabine Van Huffel, Dirk Timmerman, Ben Van Calster, Aeliko Zwinderman, Jason Oke, Jack O’Sullivan, Rafael Perera, Brian Nicholson, Hannah L. Bromley, Tracy E. Roberts, Adele Francis, Denniis Petrie, G. Bruce Mann, Kinga Malottki, Holly Smith, Lucinda Billingham, Alice Sitch, Oke Gerke, Mie Holm-Vilstrup, Eivind Antonsen Segtnan, Ulrich Halekoh, Poul Flemming Høilund-Carlsen, Bernard G. Francq, Jac Dinnes, Julie Parkes, Walter Gregory, Jenny Hewison, Doug Altman, William Rosenberg, Peter Selby, Julien Asselineau, Paul Perez, Aïssatou Paye, Emilie Bessede, Cécile Proust-Lima, Christiana Naaktgeboren, Joris de Groot, Anne Rutjes, Johannes Reitsma, Emmanuel Ogundimu, Jonathan Cook, Yannick Le Manach, Yvonne Vergouwe, Romin Pajouheshnia, Rolf Groenwold, Karen Moons, Linda Peelen, Daan Nieboer, Bavo De Cock, Micael J. Pencina, Ewout W. Steyerberg, Jennifer Cooper, Nick Parsons, Chris Stinton, Steve Smith, Andy Dickens, Rachel Jordan, Alexandra Enocson, David Fitzmaurice, Peymane Adab, Charles Boachie, Gaj Vidmar, Karoline Freeman, Martin Connock, Rachel Court, Carl Moons, Jessica Harris, Andrew Mumford, Zoe Plummer, Kurtis Lee, Barnaby Reeves, Chris Rogers, Veerle Verheyden, Gianni D. Angelini, Gavin J. Murphy, Jeremy Huddy, Melody Ni, Katherine Good, Graham Cooke, George Hanna, Jie Ma, K. G. M. (Carl) Moons, Joris A. H. de Groot, Doug G. Altman, Johannes B. Reitsma, Gary S. Collins, Karel G. M. Moons, Douglas G. Altman, Adina Najwa Kamarudin, Ruwanthi Kolamunnage-Dona, Trevor Cox, Simone Borsci, Teresa Pérez, M.Carmen Pardo, Angel Candela-Toha, Alfonso Muriel, Javier Zamora, Sabina Sanghera, Syed Mohiuddin, Richard Martin, Jenny Donovan, Joanna Coast, Mikyung Kelly Seo, John Cairns, Elizabeth Mitchell, Alison Smith, Judy Wright, Peter Hall, Michael Messenger, Nicola Calder, Nyantara Wickramasekera, Karen Vinall-Collier, Andrew Lewington, Johanna Damen, David Cairns, Michelle Hutchinson, Cathie Sturgeon, Liz Mitchel, Rebecca Kift, Sofia Christakoudi, Manohursingh Rungall, Paula Mobillo, Rosa Montero, Tjir-Li Tsui, Sui Phin Kon, Beatriz Tucker, Steven Sacks, Chris Farmer, Terry Strom, Paramit Chowdhury, Irene Rebollo-Mesa, Maria Hernandez-Fuentes, Johanna A. A. G. Damen, Thomas P. A. Debray, Pauline Heus, Lotty Hooft, Rob J. P. M. Scholten, Ewoud Schuit, Ioanna Tzoulaki, Camille M. Lassale, George C. M. Siontis, Virginia Chiocchia, Corran Roberts, Michael Maia Schlüssel, Stephen Gerry, James A. Black, Yvonne T. van der Schouw, Linda M. Peelen, Graeme Spence, David McCartney, Ann van den Bruel, Daniel Lasserson, Gail Hayward, Werner Vach, Antoinette de Jong, Coreline Burggraaff, Otto Hoekstra, Josée Zijlstra, Henrica de Vet, Sara Graziadio, Joy Allen, Louise Johnston, Rachel O’Leary, Michael Power, Louise Johnson, Ray Waters, John Simpson, Thomas R. Fanshawe, Peter Phillips, Andrew Plumb, Emma Helbren, Steve Halligan, Alastair Gale, Peggy Sekula, Willi Sauerbrei, Julia R. Forman, Susan J. Dutton, Yemisi Takwoingi, Elizabeth M. Hensor, Thomas E. Nichols, Emmanuelle Kempf, Raphael Porcher, Jennifer de Beyer, Douglas Altman, Sally Hopewell, John Dennis, Beverley Shields, Angus Jones, William Henley, Ewan Pearson, Andrew Hattersley, on behalf of the MASTERMIND consortium, Fueloep Scheibler, Anne Rummer, Sibylle Sturtz, Robert Großelfinger, Katie Banister, Craig Ramsay, Augusto Azuara-Blanco, Jennifer Burr, Manjula Kumarasamy, Rupert Bourne, Ijeoma Uchegbu, Jennifer Murphy, Alex Carter, Jen Murphy, Joachim Marti, Julie Eatock, Julie Robotham, Maria Dudareva, Mark Gilchrist, Alison Holmes, Phillip Monaghan, Sarah Lord, Andrew StJohn, Sverre Sandberg, Christa Cobbaert, Lieselotte Lennartz, Wilma Verhagen-Kamerbeek, Christoph Ebert, Andrea Horvath, for the Test Evaluation Working Group of the European Federation of Clinical Chemistry and Laboratory Medicine, Kevin Jenniskens, Jaime Peters, Bogdan Grigore, Obi Ukoumunne, Brooke Levis, Andrea Benedetti, Alexander W. Levis, John P. A. Ioannidis, Ian Shrier, Pim Cuijpers, Simon Gilbody, Lorie A. Kloda, Dean McMillan, Scott B Patten, Russell J. Steele, Roy C Ziegelstein, Charles H. Bombardier, Flavia de Lima Osório, Jesse R. Fann, Dwenda Gjerdingen, Femke Lamers, Manote Lotrakul, Sonia R Loureiro, Bernd Löwe, Juwita Shaaban, Lesley Stafford, Henk C. P. M. van Weert, Mary A. Whooley, Linda S. Williams, Karin A. Wittkampf, Albert S. Yeung, Brett D. Thombs, Chris Cooper, Tom Nieto, Claire Smith, Olga Tucker, Janine Dretzke, Andrew Beggs, Nirmala Rai, Sue Bayliss, Simon Stevens, Sue Mallet, Sudha Sundar, Emma Hall, Nuria Porta, David Lorente Estelles, Johann de Bono, on behalf of the CTC-STOP protocol development group

المصدر: Diagnostic and Prognostic Research, Vol 1, Iss 1, Pp 1-5 (2017)

مصطلحات موضوعية: Medicine (General), R5-920

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s41512-017-0011-4Test; https://doaj.org/toc/2397-7523Test

الوصول الحر: https://doaj.org/article/6e4d4aeef31d4a4ab5f1974912d6fe8cTest

المؤلفون: Ricky A. Sharma, Michael Partridge, William G. McKenna, Ruth Muschel, Phil Quirke, Julia A. Schnabel, Sharon B. Love, Susan Dutton, Gina Brown, Ewan M. Anderson, Somnath Mukherjee, Lai-Mun Wang, Claire Blesing, Lucy Boyle, Kwun-Ye Chu, Thomas P. MacGregor, Nicholas West, Monica Enescu, Jamie M. Franklin, Corran Roberts, Esme J. Hill

الوصف: Purpose: Nelfinavir, a PI3K pathway inhibitor, is a radiosensitizer that increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach.Experimental Design: Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1,250 mg b.i.d.) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pretreatment, after 7 days of nelfinavir and prior to the last fraction of RT. Biopsies taken pretreatment and 7 days after the last fraction of RT were analyzed for tumor cell density (TCD).Results: There were 3 drug-related grade 3 adverse events: diarrhea, rash, and lymphopenia. On DCE-MRI, there was a mean 42% increase in median Ktrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P = 0.01). Overall, 5 of 9 evaluable patients exhibited good tumor regression on MRI assessed by tumor regression grade (mrTRG).Conclusions: This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow. Clin Cancer Res; 22(8); 1922–31. ©2016 AACR.See related commentary by Meyn et al., p. 1834

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1d48be61bfbee8baea4bd21fb9afab1dTest
https://doi.org/10.1158/1078-0432.c.6524669Test

المؤلفون: Ricky A. Sharma, Michael Partridge, William G. McKenna, Ruth Muschel, Phil Quirke, Julia A. Schnabel, Sharon B. Love, Susan Dutton, Gina Brown, Ewan M. Anderson, Somnath Mukherjee, Lai-Mun Wang, Claire Blesing, Lucy Boyle, Kwun-Ye Chu, Thomas P. MacGregor, Nicholas West, Monica Enescu, Jamie M. Franklin, Corran Roberts, Esme J. Hill

الوصف: Supplementary Table 1: Laboratory values (Liver Function Tests) Supplementary Table 2: Overview of mean pCT parameters for tumour VOI on sequential scans Supplementary Table 3: Overview of median DCE-MRI parameters, Ktrans, Ve and Kep for tumour VOI on sequential scans. Mean across all patients of the median per patient values is shown. Supplementary Table 4: Correlations of baseline characteristics, mutation status & overall mrTRG score with TCD. Supplementary Table 5 Correlations of baseline characteristics, mutation status & overall mrTRG score with median Ktrans. Supplementary Table 6: Correlations of baseline characteristics, mutation status & overall mrTRG score with mean Blood Flow. Supplementary Figure 1: Axial and sagittal images from T2W MRI scans at baseline and 8 weeks after completion of therapy. Supplementary Figure 2: Perfusion parameter maps illustrating an increase in Blood Flow and reduction in MTT between Scans 2 and 3. Supplementary Figure 3: Examples of (a) positive immunohistochemistry staining in pre-treatment rectal tumour biopsies and (b) absent staining in negative control.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5d37adcd2427aeed26972cf2348585c1Test
https://doi.org/10.1158/1078-0432.22461002Test

المؤلفون: Paresh Vyas, Jamie D. Cavenagh, Michael Dennis, Shamyla Siddique, Richard J. Kelly, Srinivas P. Pillai, Mary Frances McMullin, Keith Wheatley, Louise Dudley, Sandeep Nagra, Manoj Raghavan, Angela Hamblin, Alison Kennedy, Natalia Garcia-Martin, Marlen Metzner, Corran Roberts, Emma Gbandi, Paul Ferguson, Lynn Swun Quek, Aimee E. Houlton, Charles F. Craddock

الوصف: Table S3. Variants detected by NGS targeted re-sequencing

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::30cac8136a16ee1bad22e1c2d07a962dTest
https://doi.org/10.1158/1078-0432.22468974.v1Test

المؤلفون: Paresh Vyas, Jamie D. Cavenagh, Michael Dennis, Shamyla Siddique, Richard J. Kelly, Srinivas P. Pillai, Mary Frances McMullin, Keith Wheatley, Louise Dudley, Sandeep Nagra, Manoj Raghavan, Angela Hamblin, Alison Kennedy, Natalia Garcia-Martin, Marlen Metzner, Corran Roberts, Emma Gbandi, Paul Ferguson, Lynn Swun Quek, Aimee E. Houlton, Charles F. Craddock

الوصف: Table S1. Details for NGS amplicons

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2349da5f2731fe9b5293126d52cd1ddbTest
https://doi.org/10.1158/1078-0432.22468977.v1Test

المؤلفون: Paresh Vyas, Jamie D. Cavenagh, Michael Dennis, Shamyla Siddique, Richard J. Kelly, Srinivas P. Pillai, Mary Frances McMullin, Keith Wheatley, Louise Dudley, Sandeep Nagra, Manoj Raghavan, Angela Hamblin, Alison Kennedy, Natalia Garcia-Martin, Marlen Metzner, Corran Roberts, Emma Gbandi, Paul Ferguson, Lynn Swun Quek, Aimee E. Houlton, Charles F. Craddock

الوصف: Table S2. Details of Exons covered Table S4. Details of antibodies/ streptavidin used Table S5. Summary of longitudinal progenitor LSC quantitation by FACS Table S6. Overview of toxicities Figure S1. Progenitor LSC FACS gating strategy Figure S2. Kaplan-Meier plot for duration of response Figure S3. Forest plot of sub group analysis in overall response rate and overall survival.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b4008f6bb20cdb6eb9a1403c23f11f16Test
https://doi.org/10.1158/1078-0432.22468971.v1Test

المؤلفون: Paresh Vyas, Jamie D. Cavenagh, Michael Dennis, Shamyla Siddique, Richard J. Kelly, Srinivas P. Pillai, Mary Frances McMullin, Keith Wheatley, Louise Dudley, Sandeep Nagra, Manoj Raghavan, Angela Hamblin, Alison Kennedy, Natalia Garcia-Martin, Marlen Metzner, Corran Roberts, Emma Gbandi, Paul Ferguson, Lynn Swun Quek, Aimee E. Houlton, Charles F. Craddock

الوصف: Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML), but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA, but this has not been prospectively studied in patients with AML.Experimental Design: We compared outcomes in 259 adults with AML (n = 217) and MDS (n = 42) randomized to receive either AZA monotherapy (75 mg/m2 × 7 days every 28 days) or AZA combined with VOR 300 mg twice a day on days 3 to 9 orally. Next-generation sequencing was performed in 250 patients on 41 genes commonly mutated in AML. Serial immunophenotyping of progenitor cells was performed in 47 patients.Results: Co-administration of VOR did not increase the overall response rate (P = 0.84) or overall survival (OS; P = 0.32). Specifically, no benefit was identified in either de novo or relapsed AML. Mutations in the genes CDKN2A (P = 0.0001), IDH1 (P = 0.004), and TP53 (P = 0.003) were associated with reduced OS. Lymphoid multipotential progenitor populations were greatly expanded at diagnosis and although reduced in size in responding patients remained detectable throughout treatment.Conclusions: This study demonstrates no benefit of concurrent administration of VOR with AZA but identifies a mutational signature predictive of outcome after AZA-based therapy. The correlation between heterozygous loss of function CDKN2A mutations and decreased OS implicates induction of cell-cycle arrest as a mechanism by which AZA exerts its clinical activity. Clin Cancer Res; 23(21); 6430–40. ©2017 AACR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3c0327fb5df6da2c1e7558e937576087Test
https://doi.org/10.1158/1078-0432.c.6527109Test

المؤلفون: Raja Reddy, Kevin G. Blyth, Matthew Knight, Robert J. Hallifax, Stefan J. Marciniak, Corran Roberts, John Harvey, Edward McKeown, Azim Ijaz, James A Cameron, Magda Laskawiec-Szkonter, Marie-Clare Harris, Christy Peter, Andrew R. Leitch, John P. Corcoran, Nick A Maskell, N. Maddekar, Amrithraj Bhatta, Robert C. Miller, Najib M. Rahman, Alex West, Parthipan Sivakumar, Stephen Gerry, Andrew E. Stanton, Ian Fairburn, Steven Walker

المصدر: Clinical problems.

مصطلحات موضوعية: business.industry, Anesthesia, Ambulatory, Medicine, Primary spontaneous pneumothorax, business

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::cf7070e738901071feb843028c1ecd12Test
https://doi.org/10.1183/13993003.congress-2020.3799Test