WUTH publication: Targeted atrial fibrillation (AF) detection in COVID-19 vaccination clinics

Citation: European Heart Journal. 2021 Aug 27, qcab061. Online ahead of print.
Author: Gary A Ford, David Hargroves, Deb Lowe, Nicholas Hicks, Gregory Y H Lip, Guy Rooney, Hannah Oatley 

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WUTH publication: The prevalence of oropharyngeal squamous cell carcinoma in patients admitted with symptoms of peritonsillar abscess or cellulitis: a retrospective multicentre study

Citation: Clinical Otolaryngology. 2021 Aug 18
Author: Andrew S Lau, Kristijonas Milinis, Mila Roode, Stephen P Williams, Colette Cook, Hussein Walijee, Matthew Zammit, Richard Siau, Hannah Emerson, Rosanna Wright, Thomas Hampton 
Abstract: Objectives: Anecdotal evidence suggests that oropharyngeal squamous cell carcinoma (OPSCC) should be suspected in patients presenting with symptoms of peritonsillar abscess (PTA) or cellulitis (PTC). The aim of this study was to estimate the prevalence of OPSCC in patients presenting with symptoms of PTA/PTC. 

Method, setting and participants: We retrospectively identified all adults with a coded diagnosis of PTA or PTC who presented between 2012-2016 inclusive, across six ENT units in Merseyside. Records were compared to that of the centralised regional head and neck cancer database. The clinical records of a subset of patients were reviewed for the purposes of data validation. 

Results: A total of 1975 patients with PTA/PTC were identified. Three patients were subsequently diagnosed with OPSCC. None of the three actually had an objective underlying diagnosis of PTA/PTC on the same side. The prevalence of OPSCC in patients admitted with symptoms of PTA/PTC was 0.15%, or approximately 1:650 admissions. The records of 510 patients who presented over a one-year period (2016) were reviewed in even greater detail. There were 298 patients with PTA (59.4%), 151 with PTC (29.1%) and 61 had an alternative diagnosis (11.9%). High risk features (age ≥40, tonsillar asymmetry or tonsillar lesion) were present in 106 patients (24%). Urgent follow up was expedited for 77 patients (73%). 

Conclusion: This study estimates the risk of OPSCC in patients with peritonsillar symptoms. The prevalence is low, even in a region with a relatively heavy disease burden. Clinicians should, however, retain a high level of suspicion in patients with persistent symptoms. 

Keywords: Peritonsillar abscess; oropharyngeal; peritonsillar cellulitis; risk analysis; squamous cell carcinoma; tonsil.

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WUTH publication: Surgical and radiological predictive factors for ureteric stricture formation in patients treated with ureteroscopy for ureteric stones

Citation: Scandinavian Journal of Urology. 2021, 1-5. Online ahead of print.  
Author: Zuhdi Al-Nabulsi, Yih Chyn Phan, Omer Abdalla, Tomas Austin, George Tanasescu, Peter Osborn, Andreas Auer, Carl Rowbotham, Mohamed Ismail 

Abstract: Background: Ureteric stricture is a potential complication of impacted ureteric stones. This study investigates surgical and radiological factors that could predict ureteric stricture formation after ureteroscopic treatment of impacted ureteric stones. 

Materials and method: Intraoperative and radiological data for patients who underwent ureteroscopic treatment of ureteric stones impaction over a 5-year period were reviewed retrospectively. Patients who had previous ureteroscopic treatment or strictures were excluded. 

Results: Between January 2014 and May 2019, 1,340 patients presented as emergency renal colic secondary to ureteric stones. A total of 297 ureteroscopy procedures were performed for impacted calculi. The mean age was 53 years. The stricture rate was 3.3%. Analysis of radiological and surgical factors revealed that the degree of hydronephrosis, residual fragments and intraoperative ureteric injury were significant predictors for stricture formation (p = 0.018, 0.01 and 0.02, OR = 10, 47 and 1776, respectively). None of the other factors significantly predicted ureteric stricture formation. 

Conclusion: Our study found the presence of severe hydronephrosis, residual stone fragments after surgery and intraoperative ureteric injury are significant predictive factors for ureteric stricture formation. The high-risk patients should be monitored with routine postoperative renal ultrasound. 

Keywords: Hydronephrosis; impacted ureteric stones; residual stone fragments; ureteric stricture; ureteroscopy. 

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WUTH publication: Localised Darier's disease: 3 cases of type 1 segmental mosaicism

Citation: Clinical and experimental dermatology. 2021 Aug 4. Online ahead of print. 
Author: D Phillips, K Gumparthy, W C W Farrar, R Karumanchery, B B Tan 
Abstract: Darier's Disease (DD) is an autosomal dominant acantholytic dermatosis with an estimated prevalence of 1:30000-1000001 . Onset is during childhood or adolescence2 and is characterised keratotic, crusted red-brown papules in a seborrhoeic distribution, nail changes (longitudinal erythronychia, longitudinal ridges and distal breakage with V-shaped notches) and palmar/plantar pits1 . 

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CCC publication: Characterization of liver function tests (LFTs) following tebentafusp (tebe) in previously treated (2L+) metastatic uveal melanoma (mUM) patients (pts)

Citation: Journal of Clinical Oncology. 2021, 39(15)

Author: Sato T.; Carvajal R.D.; Sacco J.J.; Shoushtari A.N.; Hassel J.C.; Ikeguchi A.; Hernandez-Aya L.F.; Nathan P.; Rioth M.; Hamid O.; Piulats J.M.; Luke J.J.; Johnson D.B.; Leyvraz S.; Espinosa E.; Abdullah S.E.; Sum D.; Lockwood S.; Mendez P.; Butler M.O. 

CCC publication: Outcomes of immune checkpoint inhibitor-mediated colitis: Multicenter cohort study

Citation: Journal of Clinical Oncology. 2021, 39(15) 
Author: Abu-Sbeih H.; Tang T.; Faleck D.M.; Dougan M.L.; Olsson-Brown A.; Johnson D.B.; Owen D.H.; Warner D.E.; Philipp A.B.; Powell N.; Daniels E.; Philpott J.; Weppler A.M.; Pinato D.J.; Wang Y.

CCC publication: Co-primary endpoint of overall survival for tebentafusp (tebe)- induced rash in a phase 3 randomized trial comparing tebe versus investigator's choice (IC) in first-line metastatic uveal melanoma

Citation: Journal of Clinical Oncology. 2021, 39(15) 
Author: Hassel J.C.; Rutkowski P.; Baurain J.-F.; Butler M.O.; Schlaak M.; Sullivan R.; Ochsenreither S.; Dummer R.; Kirkwood J.M.; Joshua A.M.; Sacco J.J.; Shoushtari A.N.; Orloff M.; Carvajal R.D.; Hamid O.; Abdullah S.E.; Holland C.; Goodall H.; Nathan P.; Piperno-Neumann S. 

CCC publication: Overall survival in patients who received checkpoint inhibitors after completing tebentafusp in a phase 3 randomized trial of firstline metastatic uveal melanoma

Citation: Journal of Clinical Oncology. 2021, 39(15)
Author: Orloff M.; Carvajal R.D.; Shoushtari A.N.; Sacco J.J.; Schlaak M.; Watkins C.; Abdullah S.E.; Goodall H.; Butler M.O.

CCC publication: Characterization of cytokine release syndrome (CRS) following treatment with tebentafusp in patients (pts) with previously treated (2L+) metastatic uveal melanoma (mUM)

Citation: Journal of Clinical Oncology. 2021, 39(15)
Author: Carvajal R.D.; Sato T.; Butler M.O.; Sacco J.J.; Shoushtari A.N.; Hassel J.C.; Ikeguchi A.; Hernandez-Aya L.F.; Rioth M.; Hamid O.; Piulats J.M.; Luke J.J.; Johnson D.B.; Leyvraz S.; Espinosa E.; Collins L.; McCully M.L.; Lockwood S.; Abdullah S.E.; Nathan P. 

CCC publication: Real-world outcomes in older adults treated with immunotherapy: A United Kingdom multicenter series of 2,049 patients

Citation: Journal of Clinical Oncology. 2021, 39(15)
Author: Olsson-Brown A.C.; Baxter M.; Dobeson C.; Feeney L.; Lee R.; Maynard A.; Mirza S.; Parikh S.; Rodgers L.J.; Salawu A.; Shotton R.; Tinsley N.; Heseltine J.; Cotton J.; Hughes D.; Zhao S.; Parry J.; Jones C.; Rowe M.; Tivey A.

CCC publication: CORONET; COVID-19 in Oncology evaluatiON Tool: Use of machine learning to inform management of COVID-19 in patients with cancer

Citation: Journal of Clinical Oncology. 2021, 39(15)

Author: Lee R.; Wysocki O.; Zhou C.; Calles A.; Eastlake L.; Ganatra S.; Harrison M.; Horsley L.; Huddar P.; Khan K.; Mckenzie H.; Palmieri C.; Revuelta J.R.; Thomas A.; Wilson C.; Cooksley T.; Dive C.; Freitas A.; Armstrong A.C. 

CCC publication: CAcTUS: A parallel arm, biomarker driven, phase II feasibility trial to determine the role of circulating tumor DNA in guiding a switch between targeted therapy and immune therapy in patients with advanced cutaneous melanoma

Citation: Journal of Clinical Oncology. 2021, 39(15)
Author: Lee R.; Rothwell D.G.; Chow S.; May Shaw H.; Turajlic S.; Smith N.; Clipson A.; Clarke H.; Kelso N.; Mitchell J.; Sutton C.; Sylvestre G.; Nathan P.D.; Larkin J.; Corrie P.G.; Plummer E.R.; Marais R.; Dive C.; Lorigan P. 

CCC publication: Efficacy of enobosarm, a selective androgen receptor (AR) targeting agent, correlates with the degree of AR positivity in advanced AR+/estrogen receptor (ER)+ breast cancer in an international phase 2 clinical study

Citation: Journal of Clinical Oncology. 2021, 39(15)

Author: Palmieri C.; Linden H.M.; Birrell S.; Lim E.; Schwartzberg L.S.; Rugo H.S.; Cobb P.W.; Jain K.; Vogel C.L.; O'Shaughnessy J.; Johnston S.R.D.; Getzenberg R.H.; Barnette K.G.; Steiner M.S.; Brufsky A.; Overmoyer B

CCC publication: Less chemotherapy for equal survival: Enhanced supportive care in hepatobiliary cancer

Citation: Supportive Care in Cancer. 2021, 29

Author: Monnery D.; Benson S.; Wong H.; Olsson-Brown A. 

CCC publication: P-123 The impact of external carotid artery ligation on oropharyngeal bleeding following transoral laser surgery for oropharyngeal squamous cell cancer

Citation: Oral Oncology. 2021, 118, 2-2
Author: Dalton; Milinisa, Kristijonas; Houghton, David; Ridley, Paul; Davies, Katharine; Haridass, Anoop; Brammer, Caroline; Husband, David; Shenoy, Aditya; Loh, Christopher; Roland, Nicholas J.; Bekiroglu, Fazilet; Tandon, Sankalap; Lancaster, Jeffrey; Jones, Terence M.

CCC publication: P-109 CYTOFLOC: Evaluation of a non-endoscopic immunocytological device (Cytosponge™) for post-chemo-radiotherapy surveillance in patients with oesophageal cancer – a feasibility study,

Citation: Annals of Oncology. 2021, 32(Sup 3), S135-6
Author: S. Mukherjee, H. O'Connor, R. Harman, M. O'Donovan, I. Debiram-Beecham, B. Alias, A. Bailey, A. Bateman, J. de Caestecker, T. Crosby, S. Falk, S. Gollins, M. Hawkins, S. Levy, G. Radhakrishna, R. Roy, R. Sripadam, R. Fitzgerald

CCC publication: Beyond the lessons learned from the Covid19 pandemic: Opportunities to optimize clinical trial implementation in oncology

Citation: ESMO Open. 2021
Author: Luis Castelo-Branco, Ahmad Awada, George Pentheroudakis, Jose Luis Perez-Garcia, Joaquin Mateo, Giuseppe Curigliano, Susana Banerjee, Rosa Giuliani, Florian Lordick, Andres Cervantes, Josep Tabernero, Solange Peters
Abstract: The COVID-19 pandemic affected millions of people globally with lasting effects on society, patients, investigators and health institutions. Clinical trials, our best tool to improve cancer treatment for patients through testing the clinical value of a new treatment, have been affected by the pandemic. The pandemic footprint represents both a risk of compromising development of new therapies and an opportunity to elicit discussion over a portfolio of broader reforms, applicable irrespective of pandemics, in order to improve the design and implementation of clinical trials in oncology. The administrative load should be reduced, without affecting the quality of research and principles of good clinical practice. Cancer centres are encouraged to adapt their research/operational structures to the requirements of molecular oncology and embrace novel trial designs. Technological and methodological leaps in telemedicine can convert physical to virtual visits while routine examinations may be performed in local institutions (co-research centres), maintaining adherence to good clinical and research practices. The adoption of broader inclusion criteria and clinically significant endpoints (survival, quality of life) should be promoted, co-existing with pathways for fast-track “conditional” drug approvals in areas of unmet need, based on surrogate endpoints that are linked to strict post-approval validation requirements. The utility of Real World Data as part of these validation requirements should be actively investigated. Lessons learnt from the SARS Cov2 pandemic can be developed in order to expand equitable access to clinical trials of a real world population, in a simplified and methodologically robust modus operandi, for the benefit of all our patients.

CCC publication: USP9X Is Required to Maintain Cell Survival in Response to High-LET Radiation

Citation: Frontiers in oncology. 2021, 11, 671431. eCollection 2021.
Author: Catherine M Nickson, Maria Rita Fabbrizi, Rachel J Carter, Jonathan R Hughes, Andrzej Kacperek, Mark A Hill, Jason L Parsons 
Abstract: Ionizing radiation (IR) principally acts through induction of DNA damage that promotes cell death, although the biological effects of IR are more broad ranging. In fact, the impact of IR of higher-linear energy transfer (LET) on cell biology is generally not well understood. Critically, therefore, the cellular enzymes and mechanisms responsible for enhancing cell survival following high-LET IR are unclear. To this effect, we have recently performed siRNA screening to identify deubiquitylating enzymes that control cell survival specifically in response to high-LET α-particles and protons, in comparison to low-LET X-rays and protons. From this screening, we have now thoroughly validated that depletion of the ubiquitin-specific protease 9X (USP9X) in HeLa and oropharyngeal squamous cell carcinoma (UMSCC74A) cells using small interfering RNA (siRNA), leads to significantly decreased survival of cells after high-LET radiation. We consequently investigated the mechanism through which this occurs, and demonstrate that an absence of USP9X has no impact on DNA damage repair post-irradiation nor on apoptosis, autophagy, or senescence. We discovered that USP9X is required to stabilize key proteins (CEP55 and CEP131) involved in centrosome and cilia formation and plays an important role in controlling pericentrin-rich foci, particularly in response to high-LET protons. This was also confirmed directly by demonstrating that depletion of CEP55/CEP131 led to both enhanced radiosensitivity of cells to high-LET protons and amplification of pericentrin-rich foci. Our evidence supports the importance of USP9X in maintaining centrosome function and biogenesis and which is crucial particularly in the cellular response to high-LET radiation.

Keywords: DNA damage; DNA repair; USP9X; centrosome; ionizing radiation; protons; ubiquitin.

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CCC publication: A multi-centre survey reveals variations in the standard treatments and treatment modifications for head and neck cancer patients during Covid-19 pandemic

Citation: Clinical and translational radiation oncology.  2021, 30, 50-9. Epub 2021 Jun 30.
Author: Ifigenia Vasiliadou, David Noble, Andrew Hartley, Rafael Moleron, Paul Sanghera, Teresa Guerrero Urbano, Stefano Schipani, Dorothy Gujral, Bernie Foran, Shree Bhide, Anoop Haridass, Kannon Nathan, Andriana Michaelidou, Mehmet Sen, Konstantinos Geropantas, Mano Joseph, Lorcan O'Toole, Matthew Griffin, Laura Pettit, Jonathan Chambers, Petra Jankowska, Emma De Winton, Rebecca Goranova, Niveditha Singh, Ketan Shah, Anthony Kong Conceptualisation
Abstract: Background: The onset of the COVID-19 pandemic necessitated rapid changes to the practice of head and neck oncology in UK. There was a delay between the onset of the pandemic and the release of guidelines from cancer societies and networks, leading to a variable response of individual centres. This survey was conducted to assess the pre-Covid-19 pandemic standard of practice for head and neck oncology patients and the treatment modifications introduced during the first wave of the pandemic in UK.

Methodology: The UK National Cancer Research Institute (NCRI) Head and Neck Clinical Studies Group initiated a multi-centre survey using questionnaire to investigate the effect on feeding tube practice, radiotherapy (RT) fractionation and volumes, use of chemotherapy in the neo-adjuvant, concurrent and palliative setting, the use of immunotherapy in the palliative setting, access to radiology and histopathology services, and availability of surgical procedures.

Results: 30 centres were approached across UK; 23 (76.7%) centres responded and were included in the survey. There were differences in the standard practices in feeding tube policy, RT dose and fractionation as well as concurrent chemotherapy use. 21 (91%) participating centres had at least one treatment modification. 15 (65%) centres initiated a change in radical RT; changing to either a hypofractionation or acceleration schedule. For post-operative RT 10 centres (43.5%) changed to a hypofractionation schedule. 12 (52.2%) centres stopped neo-adjuvant chemotherapy for all patients; 13 (56.5%) centres followed selective omission of chemotherapy in concurrent chemo-radiotherapy patients, 17 (73.9%) centres changed first-line chemotherapy treatment to pembrolizumab (following NHS England's interim guidance) and 8 (34.8%) centres stopped the treatment early or offered delays for patients that have been already on systemic treatment. The majority of centres did not have significant changes associated with surgery, radiology, histopathology and dental screening.

Conclusion: There are variations in the standard of practice and treatment modifications for head and neck cancer patients during Covid-19 pandemic. A timely initiative is required to form a consensus on head and neck cancer management in the UK and other countries.

Keywords: COVID-19 pandemic; Chemotherapy; Feeding tube; Head and neck cancers; Immunotherapy; Radiotherapy; SARS-CoV-2; Survey; Treatment modifications.

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CCC publication: Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphom

Citation: Haematologica. 2021 Jul 1. Online ahead of print.
Author: Johannes Duell, Kami J Maddocks, Eva González-Barca, Wojciech Jurczak, Anna Marina Liberati, Sven De Vos, Zsolt Nagy, Aleš Obr, Gianluca Gaidano, Pau Abrisqueta, Nagesh Kalakonda, Marc André, Martin Dreyling, Tobias Menne, Olivier Tournilhac, Marinela Augustin, Andreas Rosenwald, Maren Dirnberger-Hertweck, Johannes Weirather, Sumeet Ambarkhane, Gilles Salles 
Abstract: Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study (NCT02399085) of autologous stem-cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). To assess long-term outcomes, we report an updated analysis with ≥35 months' follow-up. Patients were aged >18 years, had 1-3 prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression (PD). The primary endpoint was best objective response rate (ORR). After ≥35 months' follow-up (data cut-off: October 30, 2020), ORR was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). Median duration of response (DoR) was 43.9 months (95% CI: 26.1-not reached [NR]); median overall survival (OS) was 33.5 months (18.3-NR); and median progression-free survival was 11.6 months (6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most patient subgroups. This extended L-MIND follow-up confirms the long DoR, meaningful OS, and welldefined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in ASCT-ineligible patients with R/R DLBCL.

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CCC publication: Second-line FOLFOX chemotherapy for advanced biliary tract cancer - Authors' reply

Citation: The Lancet. Oncology. 2021, 22(7), e288-e289
Author: Angela Lamarca, Daniel H Palmer, Harpreet Singh Wasan, Paul J Ross, Yuk Ting Ma, Arvind Arora, Stephen Falk, Roopinder Gillmore, Jonathan Wadsley, Kinnari Patel, Alan Anthoney, Anthony Maraveyas, Tim Iveson, Justin S Waters, Claire Hobbs, Safia Barber, W David Ryder, John Ramage, Linda M Davies, John A Bridgewater, Juan W Valle, Advanced Biliary Cancer Working Group

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CCC publication: Clinically Applicable Segmentation of Head and Neck Anatomy for Radiotherapy: Deep Learning Algorithm Development and Validation Study

Citation: Journal of Medical Internet Research. 2021, 23(7), e26151 
Author: Stanislav Nikolov, Sam Blackwell, Alexei Zverovitch, Ruheena Mendes, Michelle Livne, Jeffrey De Fauw, Yojan Patel, Clemens Meyer, Harry Askham, Bernadino Romera-Paredes, Christopher Kelly, Alan Karthikesalingam, Carlton Chu, Dawn Carnell, Cheng Boon, Derek D'Souza, Syed Ali Moinuddin, Bethany Garie, Yasmin McQuinlan, Sarah Ireland, Kiarna Hampton, Krystle Fuller, Hugh Montgomery, Geraint Rees, Mustafa Suleyman, Trevor Back, Cían Owen Hughes, Joseph R Ledsam, Olaf Ronneberger 

Abstract: Background: Over half a million individuals are diagnosed with head and neck cancer each year globally. Radiotherapy is an important curative treatment for this disease, but it requires manual time to delineate radiosensitive organs at risk. This planning process can delay treatment while also introducing interoperator variability, resulting in downstream radiation dose differences. Although auto-segmentation algorithms offer a potentially time-saving solution, the challenges in defining, quantifying, and achieving expert performance remain.

Objective: Adopting a deep learning approach, we aim to demonstrate a 3D U-Net architecture that achieves expert-level performance in delineating 21 distinct head and neck organs at risk commonly segmented in clinical practice.

Methods: The model was trained on a data set of 663 deidentified computed tomography scans acquired in routine clinical practice and with both segmentations taken from clinical practice and segmentations created by experienced radiographers as part of this research, all in accordance with consensus organ at risk definitions.

Results: We demonstrated the model's clinical applicability by assessing its performance on a test set of 21 computed tomography scans from clinical practice, each with 21 organs at risk segmented by 2 independent experts. We also introduced surface Dice similarity coefficient, a new metric for the comparison of organ delineation, to quantify the deviation between organ at risk surface contours rather than volumes, better reflecting the clinical task of correcting errors in automated organ segmentations. The model's generalizability was then demonstrated on 2 distinct open-source data sets, reflecting different centers and countries to model training.

Conclusions: Deep learning is an effective and clinically applicable technique for the segmentation of the head and neck anatomy for radiotherapy. With appropriate validation studies and regulatory approvals, this system could improve the efficiency, consistency, and safety of radiotherapy pathways.

Keywords: UNet; artificial intelligence; contouring; convolutional neural networks; machine learning; radiotherapy; segmentation; surface DSC.

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CCC publication: Effect of Celecoxib vs Placebo as Adjuvant Therapy on Disease-Free Survival Among Patients With Breast Cancer: The REACT Randomized Clinical Trial

Citation: JAMA Oncology. 2021 Jul 15, e212193. Online ahead of print.
Author: R Charles Coombes, Holly Tovey, Lucy Kilburn, Janine Mansi, Carlo Palmieri, John Bartlett, Jonathan Hicks, Andreas Makris, Abigail Evans, Sibylle Loibl, Carsten Denkert, Elisabeth Murray, Robert Grieve, Robert Coleman, Annabel Borley, Marcus Schmidt, Beate Rautenberg, Catarina Alisa Kunze, Uwe Rhein, Keyur Mehta, Kelly Mousa, Tessa Dibble, Xiao Lou Lu, Gunter von Minckwitz, Judith M Bliss, Randomized European Celecoxib Trial (REACT) Trial Management Group and Investigators
Abstract: Importance: Patients with breast cancer remain at risk of relapse after adjuvant therapy. Celecoxib has shown antitumor effects in preclinical models of human breast cancer, but clinical evidence is lacking.

Objective: To evaluate the role of celecoxib as an addition to conventional therapy for women with ERBB2 (formerly HER2)-negative primary breast cancer.

Design, setting, and participants: The Randomized European Celecoxib Trial (REACT) was a phase 3, randomized, double-blind study conducted in 160 centers across the UK and Germany testing 2 years of adjuvant celecoxib vs placebo among 2639 patients recruited between January 19, 2007, and November 1, 2012, with follow-up 10 years after treatment completion. Eligible patients had completely resected breast cancer with local and systemic therapy according to local practice. Patients with ERBB2-positive or node-negative and T1, grade 1 tumors were not eligible. Randomization was in a 2:1 ratio between celecoxib or placebo. Statistical analysis was performed from May 5, 2019, to March 5, 2020.

Interventions: Patients received celecoxib, 400 mg, or placebo once daily for 2 years.

Main outcomes and measures: The primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population using Cox proportional hazards regression and log-rank analysis. Follow-up is complete.

Results: A total of 2639 patients (median age, 55.2 years [range, 26.8-86.0 years]) were recruited; 1763 received celecoxib, and 876 received placebo. Most patients' tumors (1930 [73%]) were estrogen receptor positive or progesterone receptor positive and ERBB2 negative. A total of 1265 patients (48%) had node-positive disease, and 1111 (42%) had grade 3 tumors. At a median follow-up of 74.3 months (interquartile range, 61.4-93.6 years), DFS events had been reported for 487 patients (19%): 18% for those who received celecoxib (n = 323; 5-year DFS rate = 84%) vs 19% for those who received placebo (n = 164; 5-year DFS rate = 83%); the unadjusted hazard ratio was 0.97 (95% CI, 0.80-1.17; log-rank P = .75). Rates of toxic effects were low across both treatment groups, with no evidence of a difference.

Conclusions and relevance: In this randomized clinical trial, patients showed no evidence of a DFS benefit for 2 years' treatment with celecoxib compared with placebo as adjuvant treatment of ERBB2-negative breast cancer. Longer-term treatment or use of a higher dose of celecoxib may lead to a DFS benefit, but further studies would be required to test this possibility.

Trial registration: ClinicalTrials.gov Identifier: NCT02429427 and isrctn.org Identifier: ISRCTN48254013.

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CCC publication: Genome-wide association studies of toxicity to oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab in 1800 patients with advanced colorectal cancer

Citation: International Journal of Cancer. 2021 Jul 16. Online ahead of print.
Author: Katie Watts, Christopher Wills, Ayman Madi, Claire Palles, Timothy S Maughan, Richard Kaplan, Nada A Al-Tassan, Rachel Kerr, David Kerr, Victoria Gray, Hannah West, Richard S Houlston, Valentina Escott-Price, Jeremy P Cheadle 
Abstract: Chemotherapies administered at normal therapeutic dosages can cause significant side-effects and may result in early treatment discontinuation. Inter-individual variation in toxicity highlights the need for biomarkers to personalise treatment. We sought to identify such biomarkers by conducting 40 genome-wide association studies, together with gene and gene set analyses, for any toxicity and 10 individual toxicities in 1800 patients with advanced colorectal cancer treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab from the MRC COIN and COIN-B trials (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). Single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome-wide or suggestive significance were validated in independent patient groups. We found that MROH5 was significantly associated with neutropenia in MAGMA gene analyses in patients treated with XELOX (P = 6.6 × 10-7 ) and was independently validated in those receiving XELOX + cetuximab; pooled P = 3.7 × 10-7 . rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (odds ratio = 5.0, 95% confidence interval = 3.0-8.3, P = 9.8 × 10-10 ) but was not independently replicated. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five of these were independently validated (rs6030266 with diarrhoea, rs1546161 with hand-foot syndrome, rs9601722 with neutropenia, rs13413764 with lethargy and rs4600090 with nausea; all with pooled P's < 5.0 × 10-6 ). In conclusion, the association of MROH5 with neutropenia and five other putative biomarkers warrant further investigation for their potential clinical utility. Despite our comprehensive genome-wide analyses of large, well-characterised, clinical trials, we found a lack of common variants with modest effect sizes associated with toxicities.

Keywords: GWAS; chemotherapy; colorectal cancer; toxicity.

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CCC publication: A multi-centre analysis of adjuvant contact x-ray brachytherapy (CXB) in rectal cancer patients treated with local excision - preliminary results of the CONTEM1 study

Citation: Radiotherapy and Oncology. 2021 Jul 27. Online ahead of print.
Author: A Dhadda, A Sun Myint, B Thamphya, I Hunter, M Hershman, J Gerard
Abstract: Introduction: Early rectal cancers are increasingly diagnosed through screening programmes and are often treated using local excision (LE). In the case of adverse pathological features completion total mesorectal excision surgery (TME) is the standard recommendation. The morbidity and mortality risks of TME have stimulated the use of adjunctive treatments following LE to achieve organ preservation.

Material and methods: Patients treated with adjuvant CXB following local excision between 2004-2017 in three centres were identified (Clatterbridge, Hull, Nice). All patients had adverse pathological features including: lymphovacular invasion, Sm2-3 Kikuchi level, tumour budding, pT2, positive resection margins (R1). CXB was performed with the Papillon50 tm machine to a dose of 40 to 60 Gy in 2 or 3 fractions over 2 to 4 weeks preceding/following external beam chemo/radiotherapy. Kaplan Meier survival estimates were used for outcomes measures.

Results: 194 patients were identified. Median age was 70 years. pT staging was: pT1:143, pT2:45, pT3:6. CXB alone was given in 24 pts and combined with EBRT in 170. Median follow-up time was 77 months (range 7-122 months). Local relapse rate was 8% and distant metastases 9%. Organ preservation was achieved in 95%. 6 year local recurrence free and overall survival was 91% and 81% respectively. Cancer specific survival was 97%. No treatment related mortality was seen.

Conclusion: This large multi-centre cohort study using adjuvant CXB following local excision suggests excellent oncological outcomes for these patients without completion TME. This treatment approach can be considered as an alternative for selective patients compliant with long term follow up.

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CCC publication: Proton beam therapy in rectal cancer: A systematic review and meta-analysis

Citation: Surgical Oncology. 2021, 38, 101638. Online ahead of print.
Author: Matthew Fok, Steven Toh, Jeremy Easow, Hayley Fowler, Rachael Clifford, Jason Parsons, Dale Vimalachandran
Abstract: Introduction: Locally advanced rectal cancer is often treated with neoadjuvant chemoradiotherapy and surgery. Radiotherapy carries significant risk of toxicity to organs at risk (OAR). Proton beam therapy (PBT) has demonstrated to be effective in other cancers, delivering equivalent dosimetric radiation but with the benefit of improved sparing of OAR. This review compares dosimetric irradiation of OAR and oncological outcomes for PBT versus conventional photon-based radiotherapy in locally advanced rectal cancer.

Methods: An electronic literature search was performed for studies with comparative cohorts receiving proton beam therapy and photon-based radiotherapy for rectal cancer.

Results: Eight articles with a total of 127 patients met the inclusion criteria. There was significantly less irradiated small bowel with PBT compared to three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) (MD -17.01, CI [-24.06, -9.96], p < 0.00001 and MD -6.96, CI [-12.99, -0.94], p = 0.02, respectively). Similar dosimetric results were observed for bladder and pelvic bone marrow. Three studies reported clinical and oncological results for PBT in recurrent rectal cancer with overall survival reported as 43 %, 68 % and 77.2 %, and one study in primary rectal cancer with 100 % disease free survival.

Conclusion: PBT treatment plans revealed significantly less irradiation of OAR for rectal cancer compared to conventional photon-based radiotherapy. Trials for recurrent rectal cancer and PBT have shown promising results. There are currently no ongoing clinical trials for primary rectal cancer and PBT. More research is required to validate its potential role in dose escalation, higher complete response rate and organ preservation without increasing toxicity.

Keywords: Chemoradiotherapy; Neoadjuvant; Photon radiotherapy; Proton beam therapy; Radiotherapy; Rectal cancer.

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WUTH publication: Hematopoietic stem and progenitor cells directly participate in host immune response

Citation: American Journal of Stem Cells. 2021, 10(2), 18-27. eCollection
Author: Olusola Jumoke Daramola, Stephen Osasan, Hebah Ali, Perpetua Emeagi 
Abstract: The properties of hematopoietic stem and progenitor cells (HSPCs), including self-renewal and pluripotency, have been extensively studied. These features have been explored in the management of several haematological disorders and malignancies. Although their role as precursors of innate immune cells is well understood, little is known about their direct participation in host immune response. In this review, we explicate the direct role of HSPCs in the host immune response and highlight therapeutic options for the infectious disease burden that is currently ravaging the world, including COVID-19. 

Keywords: Hematopoietic; haematopoiesis; immune; progenitor cells; stem cells. 

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