Virtual LKS Service: A message to all our library users

To all our library members,

We are thinking of all our staff at this very challenging time.

We wanted to put together a post that outlines the services we can provide to support you during the coming months:

• The library space will remain open until otherwise instructed. Medical texts, as well as our fiction and wellbeing collections will all be reference only. Any books that are currently on loan have been extended to 29 May 2020 in the first instance.

• We have a number of online resources to support you:

• Regarding online books:
• Oxford Handbooks Online - Access e-books from the Oxford Handbooks and Emergencies series: http://arrowe.cirqahosting.com/HeritageScripts/Hapi.dll/retrieve2?SearchTerm0=Oxford%20Handbooks%20Online&DataSetName=LIVEDATA
• Cheshire and Wirral Community and Public Health e-book collection: http://arrowe.cirqahosting.com/HeritageScripts/Hapi.dll/retrieve2?SetID=E6F7C0C2-8210-4D38-B6AC-BA11A1962296&LabelText=Community%20and%20Public%20Health%20e-book%20collection&searchterm=Cheshire%20and%20Wirral%20Community%20and%20Public%20Health%20e-book%20collection&Fields=%40&Media=%23&Bool=AND&SearchPrecision=20&DataSetName=LIVEDATA
• Both of these links are available on the library catalogue homepage under ‘Quick links’: http://arrowe.cirqahosting.com/

§  Regarding online resources:

§  Journals and databases that require an OpenAthens account can be found here (click ‘login with your OpenAthens account’ first: https://www.nice.org.uk/about/what-we-do/evidence-services/journals-and-databases

§  To create an OpenAthens account, please click here: https://openathens.nice.org.uk/

§  To have your OpenAthens account transferred from another Trust, please email us at: wuth.lks@nhs.net

§  UpToDate is still available on any Trust computer and also available for you at home via OpenAthens, as well as using the App on your phone or tablet if you have a personal account set up. Reverification for UpToDate has been extended to every 180 days, rather than 90 days.

§  BMJ Best Practice is available via an OpenAthens account and can be found here (under ‘Evidence-based Resources’) or via the app on phone or tablet  if you have a personal account set up. https://www.nice.org.uk/about/what-we-do/evidence-services/journals-and-databases

§  We have many more online resources, which can be found here: https://www.wuth.nhs.uk/choose-us/for-library-and-knowledge-services/search-for-information-or-evidence/online-resources/

• We have lots of help sheets available to help you. Find these listed here or email us if you aren’t sure which one you need: https://www.wuth.nhs.uk/choose-us/for-library-and-knowledge-services/help-and-support/helpsheets/

• We are here to conduct literature searches on your behalf. Please complete this form to request a literature search: https://www.wuth.nhs.uk/choose-us/for-library-and-knowledge-services/literature-search/

• All books currently on loan have been auto-renewed until 29 May 2020 and any fines will be waived.

• We are still offering an interlibrary loan service for electronic articles only. To request an article, please complete this form: https://www.wuth.nhs.uk/choose-us/for-library-and-knowledge-services/document-and-book-supply/

• We’re offering our Searching, Training, Help and Advice services online or via telephone. If you require support, please email wuth.lks@nhs.net

• Our website has lots of further information: https://www.wuth.nhs.uk/choose-us/for-library-and-knowledge-services/

If you need support with something else, please let us know via wuth.lks@nhs.net and we will try our very best to help you as soon as we can.

With our very best wishes,

The LKS team: Carly, Annabel, Linda and Jen x

Health and Well-being Collection

Some of our health and well-being 

books are relaxing on a beanbag 

in our library lounge area.

Come along and browse the 
collection yourself.

CCC publication: Loss of BAP1 Expression Is Associated With an Immunosuppressive Microenvironment in Uveal Melanoma, With Implications for Immunotherapy Development

Citation: The Journal of Pathology. 2020, 250(4), 420-39
Author: Carlos R Figueiredo, Helen Kalirai, Joseph J Sacco, Ricardo A Azevedo, Andrew Duckworth, Joseph R Slupsky, Judy M Coulson, Sarah E Coupland
Abstract: Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour-infiltrating lymphocytes (TILs) within pUM and surrounding mUM - and some evidence of clinical responses to adoptive TIL transfer - strongly suggests that UMs are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA-DR, CD38, and CD74. Further, single-cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumour-associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD-L1, and β-catenin (CTNNB1), suggesting tumour-driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1 - mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Keywords:  CyTOF; NanoString; digital spatial profiling; immune profile; immunotherapy resistance; uveal melanoma.

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CCC publication: CApecitabine Plus Radium-223 (Xofigo™) in Breast Cancer Patients With BONe Metastases (CARBON): Study Protocol for a Phase IB/IIA Randomised Controlled Trial

Citation: Trials. 2020, 21(1), 89
Author: Rob Coleman, Janet Brown, Emma Rathbone, Louise Flanagan, Amber Reid, Jessica Kendall, Sacha Howell, Chris Twelves, Carlo Palmieri, Anjana Anand, Iain MacPherson, Sarah Brown
Abstract: Background:  A substantial proportion of breast cancer patients develop metastatic disease, with over 450,000 deaths globally per year. Bone is the most common first site of metastatic disease accounting for 40% of all first recurrence and 70% of patients with advanced disease develop skeletal involvement. Treatment of bone metastases currently focusses on symptom relief and prevention and treatment of skeletal complications. However, there remains a need for further treatment options for patients with bone metastases. Combining systemic therapy with a bone-targeted agent, such as radium-223, may provide an effective treatment with minimal additional side effects.
Methods/design:  CARBON is a UK-based, open-label, multi-centre study which comprises an initial safety phase to establish the feasibility and safety of combining radium-223 given on a 6-weekly schedule in combination with orally administered capecitabine followed by a randomised extension phase to further characterise the safety profile and provide preliminary estimation of efficacy.
Discussion:  The CARBON study is important as the results will be the first to assess radium-223 with chemotherapy in advanced breast cancer. If the results find acceptable rates of toxicity with a decrease in bone turnover markers, further work will be necessary in a phase II/III setting to assess the efficacy and clinical benefit.
Trial registration:  ISRCTN, ISRCTN92755158, Registered on 17 February 2016.
Keywords:  Bone metastases; Bone turnover markers; Breast cancer; Capecitabine; Radium-223.

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CCC publication: Challenges Conveying Clinical Equipoise and Exploring Patient Treatment Preferences in an Oncology Trial Comparing Active Monitoring With Radiotherapy (ROAM/EORTC 1308)

Citation: The Oncologist. 2020, 25(4), e691-e700. Epub 2020 Feb 11.
Author: Frances C Sherratt, Stephen L Brown, Brian J Haylock, Priya Francis, Helen Hickey, Carrol Gamble, Michael D Jenkinson, Bridget Young
Abstract: Introduction:  Providing balanced information that emphasizes clinical equipoise (i.e., uncertainty regarding the relative merits of trial interventions) and exploring patient treatment preferences can improve informed consent and trial recruitment. Within a trial comparing adjuvant radiotherapy versus active monitoring following surgical resection for an atypical meningioma (ROAM/EORTC-1308), we explored patterns in communication and reasons why health practitioners may find it challenging to convey equipoise and explore treatment preferences.
Materials and methods:  Qualitative study embedded within ROAM/EORTC-1308. Data were collected on 40 patients and 18 practitioners from 13 U.K. sites, including audio recordings of 39 patients' trial consultations, 23 patient interviews, and 18 practitioner interviews. Qualitative analysis drew on argumentation theory.
Results:  Practitioners acknowledged the importance of the research question that the trial aimed to answer. However, they often demonstrated a lack of equipoise in consultations, particularly with eligible patients who practitioners believed to be susceptible to side effects (e.g., cognitive impairment) or inconvenienced by radiotherapy. Practitioners elicited but rarely explored patient treatment preferences, especially if a patient expressed an initial preference for active monitoring. Concerns about coercing patients, loss of practitioner agency, and time constraints influenced communication in ways that were loaded against trial participation.
Conclusions:  We identified several challenges that practitioners face in conveying equipoise and exploring patient treatment preferences in oncology, and particularly neuro-oncology, trials with distinct management pathways. The findings informed communication about ROAM/EORTC-1308 and will be relevant to enhancing trial communication in future oncology trials. Qualitative studies embedded within trials can address difficulties with communication, thus improving informed consent and recruitment. ROAM/EORTC-1308 RCT: ISRCTN71502099.
Implications for practice:  Oncology trials can be challenging to recruit to, especially those that compare treatment versus monitoring. Conveying clinical equipoise and exploring patient treatment preferences can enhance recruitment and patient understanding. This study focused on the challenges that practitioners encounter in trying to use such communication strategies and how practitioners may inadvertently impede patient recruitment and informed decision making. This article provides recommendations to support practitioners in balancing the content and presentation of trial management pathways. The results can inform training to optimize communication, especially for neuro-oncology trials and trials comparing markedly different management pathways.
Keywords:  Clinical equipoise; Clinical trial; Communication; Neuro-oncology; Qualitative; Radiotherapy.

Link to PubMed record

CCC publication: Window of Opportunity Treatment in Breast Cancer

Citation: ANZ journal of Surgery. 2020, 90(1-2), 34-40
Author: Julia Chen, Neshanth Easwaralingam, Sanjay Warrier, Andrew Ong, Emma-Kate Carson, Cindy Mak, Kylie Snook, Kate Middleton, Andrew Parker, Carlo Palmieri, Andrew Spillane , G Bruce Mann, Elgene Lim, Davendra Segara
Abstract: Window of opportunity therapies, which involve short-term administration of systemic therapy between cancer diagnosis and surgery, have raised significant interest in recent years as a mean of assessing the sensitivity of a patient's cancer to therapy prior to surgery. There is now compelling evidence that in patients with early stage hormone-receptor positive breast cancer, a 2-week preoperative treatment with standard hormone therapies in a preoperative window period provides important prognostic information, which in turn helps to aid decision-making regarding treatment options. Changes in short-term biomarker endpoints such as cell proliferation measured by Ki-67 can act as surrogate markers of long-term outcomes. Paired tissues obtained pre- and post-investigational treatment, without having to subject the patient to additional biopsies, can then be used to conduct translational research to investigate predictive biomarkers and pharmacodynamics. In this review, we will examine the utility and challenges of window of opportunities therapies in breast cancer in the current literature, and the current Australian and international trial landscape in this clinical space.
Keywords:  breast cancer; endocrine therapy; window of opportunity therapy.

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CCC publication: Corrigendum to Addition of Docetaxel to Hormonal Therapy in Low- And High-Burden Metastatic Hormone Sensitive Prostate Cancer: Long-Term Survival Results From the STAMPEDE Trial: Ann Oncol 2019; 30: 1992-2003

Citation: Annals of Oncology. 2020, 31(3), 442
Author: N W Clarke, A Ali, F C Ingleby, A Hoyle, C L Amos, G Attard, C D Brawley, J Calvert, S Chowdhury, A Cook, W Cross, D P Dearnaley, H Douis, D Gilbert, S Gillessen, R J Jones, R E Langley, A MacNair, Z Malik, M D Mason, D Matheson, R Millman, C C Parker, A W S Ritchie, H Rush, J M Russell, J Brown, S Beesley, A Birtle, L Capaldi, J Gale, S Gibbs, A Lydon, A Nikapota, A Omlin, J M O'Sullivan, O Parikh, A Protheroe, S Rudman, N N Srihari, M Simms, J S Tanguay, S Tolan, J Wagstaff, J Wallace, J Wylie, A Zarkar, M R Sydes, M K B Parmar, N D James, STAMPEDE investigators

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CCC publication: Audit of safety and tolerability of combination platinum-pemetrexed-pembrolizumab in advanced non-squamous NSCLC in the real-world setting of a UK Cancer Centre

Citation: Lung Cancer. 2020, 139
Author: Bhalla N.; Ghoz H.

CCC publication: The use of atezolizumab combination therapy in the EGFR+ metastatic non-squamous NSCLC setting: practical guidance based on early clinical experience

Citation: Lung Cancer. 2020, 139
Author: Geldart T.; Belitei P.; Benepal T.; Mehta A.; Baijal S.; Denton A.; Escriu C.; Chitnis M.; Bennett M.; Popat S.

CCC publication: ADSCaN: a randomised phase II study of accelerated, dose escalated, sequential chemoradiotherapy in non-small cell lung cancer (NSCLC)

Citation: Lung Cancer. 2020, 139
Author: Lawless C.; Shaw A.; McCartney E.; Hatton M.; Faivre-Finn C.; Pope A.; Peedell C.; Simoes R.
Abstract: Introduction: Lung cancer is the most common cause of cancer mortality in the UK, and NSCLC accounts for approximately 87% of all UK lung cancers. Most patients present with inoperable disease therefore radiotherapy plays a major role in treatment. However, a large portion of patients are not suitable for gold standard treatment (concurrent chemo-radiotherapy) due to performance status and comorbidities. Novel strategies integrating radiotherapy advances and radiobiological knowledge need to be evaluated in patients treated with sequential chemo-radiotherapy. Four separate accelerated dose escalated radiotherapy schedules have been completed in the UK (CHART-ED, IDEAL-CRT, I-START and Isotoxic IMRT). ADSCaN will compare these schedules with a UK standard sequential chemo-radiotherapy schedule. A combined randomized phase II screening/'pick the winner' approach will identify the best schedule to take into a randomised phase III study against conventionally fractionated radiotherapy. Method(s): Suitable patients will have histologically/cytologically confirmed, stage III NSCLC and be able to undergo chemo-radiotherapy treatment. The study will recruit 360 patients; 130 on the standard arm and 60 on each experimental arm. Patients will complete 2-4 cycles of platinum based chemotherapy before being randomised to one of the radiotherapy schedules. Logistic/capacity challenges make it impractical for sites to open all experimental trial arms; a novel trial design allows centres to select upfront the experimental arms they are able to participate in and all will offer the standard arm. Result(s): CRUK is funding this multicentre study which is being coordinated by the CRUK CTU Glasgow. The study includes a tailored QA programme through the UK RTTQA Group. Conclusion(s): Current Status: The study opened to recruitment on 22/08/2017 with planned recruitment lasting 3 years 8 months. 20/36 sites are opened to recruitment with further sites in set up. 51 patients have been randomised to date. Disclosure: C. Peedell: honoraria for talks and presentations from Elekta; the remaining authors have declared no conflicts of interest. Figure Presented Copyright © 2020 Elsevier B.V.

CCC publication: Thoracic re-irradiation dose constraints: early results from a literature review

Citation: Lung Cancer. 2020, 139
Author: Rulach R.; Harrow S.; Fenwick J.
Abstract: Introduction: Radical re-irradiation for lung cancer is indicated for local recurrence after radical radiotherapy or the development of a new lung primary. We estimate approximately 900 patients annually in the UK may be eligible for re-irradiation. Retrospective studies have shown the expected overall survival from re-treatment is 17 months, but a grade 3 or above toxicity rate of 5-20% and a mortality rate of 3%. There is no high level evidence regarding cumulative dose constraints for thoracic re-irradiation. The aim of this project is to generate putative re-irradiation dose constraints using published data. Method(s): A literature search was conducted using MEDLINE and the Glasgow University search engine, identifying any English language studies from 01/01/1970 to 01/10/2018 which included adult humans who had two courses of radiotherapy for malignancy, where both the dose given to a given organ/tumour and the toxicity encountered were published. Animal models were excluded. Data were collected for the following organs at risk (OARs): aorta, oesophagus, spinal cord, bronchial tree, lungs, heart, skin and brachial plexus. The cumulative doses to the OARs were calculated as the equivalent dose in 2-Gray fractions (EQD2) using the alpha/beta ratios in Table 1. Result(s): 244 studies were screened and 90 papers had sufficient data for analysis. Data from 2400 patients were included. The cumulative EQD2 listed in Table 1 represents the cumulative maximum dose (Dmax) received by each OAR before toxicity was first observed. There was inadequate dose/volume information in the literature to create dose/volume constraints. Conclusion(s): These are crude estimates of the maximum cumulative doses thorax OARs can tolerate at re-irradiation. This Dmax data is relevant to serial OARs, but not useful for parallel organs. There is no data regarding cardiac re-irradiation. Further research is ongoing to model dose/volume constraints and better quantify the risk of toxicity at a given dose. Disclosure: All authors have declared no conflicts of interest. Table Presented Copyright © 2020 Elsevier B.V.

CCC publication: Treatment patterns in patients with advanced non-small cell lung cancer (aNSCLC): real-world data from the United Kingdom

Citation: Lung Cancer. 2020, 139
Author: Lester J.; Powell C.; Khan S.; Escriu C.; Hudson E.; Conn A.; Mansy T.; Chan S.; Brock J.; Zhuo X.; Zhang X.; Pawar V.; Durand A.
Abstract: Introduction: There are limited data regarding the current treatment patterns for aNSCLC in the United Kingdom. This study aims to overcome this gap by evaluating data from 8 UK hospitals (representing approximately 10% of all UK patients with aNSCLC). To our knowledge, this is the first large-scale UK-based real-world study in this patient population. Method(s): This retrospective study used electronic prescribing records (EPRs) and chart review of treatment-naive patients with aNSCLC starting first-line (1L) treatment between June 2016 and March 2018 (follow-up until December 2018). Line of treatment was defined by the treating physician within the EPRs. Data presented are from interim analyses (IA) and are descriptive. Result(s): A total of 1113 patients initiated 1L treatment: 814 (73.1%) received chemotherapy, 186 (16.7%) received immunotherapy (IO; all monotherapy), and 113 (10.2%) received targeted therapy (TT; ALK and EGFR inhibitors). Median age at diagnosis was 68.0 years (range, 29-93; among 613 patients with age information available at IA), and 54.1% were male. 1L IO therapy usage increased from 3% in June 2016 to 21% in March 2018, while chemotherapy usage decreased from 78% to 70%. Among the patients who advanced to 2L (n=385), 188 (48.8%) received chemotherapy, 123 (31.9%) received IO therapy, and 74 (19.2%) received TT. For the subgroup who initiated 1L chemotherapy or IO therapy, chemotherapy was the most commonly used 2L treatment, whereas most patients receiving TT in 1L (89.2%) continued TT in 2L (Table 1). Conclusion(s): As a percentage of total 1L treatment, IO therapy usage has increased in recent years. However, the majority of the patients with aNSCLC were treated with 1L chemotherapy regimens. Among patients who received 2L treatment, most received chemotherapy or IO therapy. Future analyses should focus on evaluating clinical outcomes in patients with aNSCLC by choice of 1L treatment and treatment sequencing. Disclosure: J. Lester: honoraria, sponsorship, advisory board participation from Roche, AstraZeneca, Pfizer, Boehringer-Ingelheim, MSD, BMS, and Lilly; S. Khan and J. Brock: no relevant conflict of interest to declare; C. Powell: received sponsorship to conferences from Boehringer-Ingelheim and Roche and honoraria for talks/session chairing from Boehringer-Ingelheim and Bristol-Myers-Squibb (but not within the last 12 months); C. Escriu: travel grants from MSD, Roche, AstraZeneca and Boehringer-Ingelheim, consultancy fees from MSD, AstraZeneca and Boehringer-Ingelheim, lecturer fees from Pfizer, AstraZeneca and Roche; E. Hudson: Advisory Board work for Roche and Tesaro; A. Conn: educational grants from Lilly, AstraZeneca, Boehringer-Ingelheim; T. Mansy: honorarium and congress travel funding from: MSD, Bristol-Myers-Squibb, PharmaMar, AstraZeneca, Roche, Tesaro, Amgen; S. Chan: honoraria for presentation from Bristol-Myers-Squibb; X. Zhuo: employee of Merck KgaA employee when the analysis was conducted; A. Durand: employee of Merck Serono Limited; X. Zhang and V. Pawar: employee of EMD Serono Inc. Table Presented Copyright © 2020 Elsevier B.V.

CCC publication: Does travel time for SABR treatment, impact upon the management of early-stage inoperable NSCLC?

Citation: Lung Cancer. 2020, 139
Author: Brown S.; Mee T.; Kirkby N.; Kirkby K.; Faivre-Finn C

CCC publication: Molecular MRD Status and Outcome After Transplantation in NPM1-mutated AML

Citation: Blood. 2020, 135(9), 680-88
Author: Richard Dillon, Robert Hills, Sylvie Freeman, Nicola Potter, Jelena Jovanovic, Adam Ivey, Anju Shankar Kanda, Manohursingh Runglall, Nicola Foot, Mikel Valganon, Asim Khwaja, Jamie Cavenagh, Matthew Smith, Hans Beier Ommen, Ulrik Malthe Overgaard, Mike Dennis, Steven Knapper, Harpreet Kaur, David Taussig, Priyanka Mehta, Kavita Raj, Igor Novitzky-Basso, Emmanouil Nikolousis, Robert Danby, Pramila Krishnamurthy, Kate Hill, Damian Finnegan, Samah Alimam, Erin Hurst, Peter Johnson, Anjum Khan, Rahuman Salim, Charles Craddock, Ruth Spearing, Amanda Gilkes, Rosemary Gale, Alan Burnett, Nigel H Russell, David Grimwade
Abstract: Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABL in the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P < .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P = .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P < .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P = .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P = .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).

Link to PubMed record

CCC publication: Reply To: Considerations on "Impact of Centralization of Services on Outcomes in a Rare Tumour: Retroperitoneal Sarcomas"

Citation: European Journal of Surgical Oncology. 2020, 46(4 Pt A), 708
Author: R Kalaiselvan, A K Malik, R Rao, K Wong, N Ali, M Griffin, C R Chandrasekar, S F Fenwick, G J Poston, H Malik

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CCC publication: PIVOTALboost Trial contouring RTQA

Citation: Journal of Clinical Oncology. 2020, 38(6)
Author: Syndikus I.; Tree A.; Staffurth J.; Mayles H.; Naismith O.F.; Montazeri A.; Hall E.
Abstract: Background: Asymptomatic meningioma is a common incidental finding with no consensus on the optimal management strategy. We aimed to develop a prognostic model to guide personalized monitoring of incidental meningioma patients. Method(s): A prognostic model of disease progression was developed in a retrospective cohort (2007-2015), defined as: symptom development, meningioma-specific mortality, meningioma growth or loss of window of curability. Secondary endpoints included non-meningioma-specific mortality and intervention. Result(s): Included were 441 patients (459 meningiomas). Over a median of 55 months (interquartile range, 37-80), 44 patients had meningioma progression and 57 died (non-meningioma-specific). Forty-four had intervention (at presentation, n = 6; progression, n = 20; nonprogression, n = 18). Model parameters were based on statistical and clinical considerations and included: increasing meningioma volume (hazard ratio [HR] 2.17; 95% CI: 1.53-3.09), meningioma hyperintensity (HR 10.6; 95% CI: 5.39-21.0), peritumoral signal change (HR 1.58; 95% CI: 0.65-3.85), and proximity to critical neurovascular structures (HR 1.38; 95% CI: 0.74-2.56). Patients were stratified based on these imaging parameters into low-, medium- and high-risk groups and 5-year disease progression rates were 3%, 28%, and 75%, respectively. After 5 years of follow-up, the risk of disease progression plateaued in all groups. Patients with an age-adjusted Charlson comorbidity index >=6 (eg, an 80-year-old with chronic kidney disease) were 15 times more likely to die of other causes than to receive intervention at 5 years following diagnosis, regardless of risk group. Conclusion(s): The model shows that there is little benefit to rigorous monitoring in low-risk and older patients with comorbidities. Risk-stratified follow-up has the potential to reduce patient anxiety and associated health care costs. Copyright © 2019 The Author(s).

CCC publication: Eight-year outcomes of a phase III randomized trial of conventional versus hypofractionated high-dose intensity modulated radiotherapy for prostate cancer (CRUK/06/016): Update from the CHHiP Trial

Citation: Journal of Clinical Oncology. 2020, 38(6)
Author: Dearnaley D.P.; Griffin C.; Syndikus I.; Khoo V.; Birtle A.J.; Choudhury A.; Ferguson C.; Graham J.; O'Sullivan J.; Panades M.; Rimmer Y.L.; Scrase C.D.; Staffurth J.; Cruickshank C.; Hassan S.; Pugh J.
Abstract: Background: CHHiP is a non-inferiority trial to determine efficacy and safety of hypofractionated radiotherapy for localised prostate cancer (PCa). Five year results indicated that moderate hypofractionation of 60 Gray (Gy)/20 fractions (f) was non-inferior to 74Gy/37f (Lancet Oncology, 2016). Moderate hypofractionation is now an international standard of care but with patients remaining at risk of recurrence for many years, information on long-term outcomes is important. Here we report pre-planned analysis of 8 year outcomes. Method(s): Between October 2002 and June 2011, 3216 men with node negative T1 b-T3a localised PCa with risk of seminal vesical involvement <30% were randomised (1:1:1 ratio) to 74Gy/37f (control), 60Gy/20f or 57Gy/19f. Androgen deprivation began at least 3 months prior to radiotherapy (RT) and continued until end of RT. The primary endpoint was time to biochemical failure (Phoenix consensus guidelines) or clinical failure (BCF). The non-inferiority design specified a critical hazard ratio (HR) of 1.208 for each hypofractionated schedule compared to 74Gy/37f. Late toxicity was assessed at 5 years by RTOG and LENT-SOM scales. Analysis was by intention-to-treat. Result(s): With a median follow up of 9.2 years, 8 year BCF-free rates (95% CI) were 74Gy: 80.6% (77.9%, 83.0%); 60Gy: 83.7% (81.2% 85.9%) and 57Gy: 78.5% (75.8% 81.0%). For 60Gy/20f, non-inferiority was confirmed: HR60=0.84 (90% CI 0.71, 0.99). For 57Gy/19f, non-inferiority could not be declared: HR57=1.17 (90% CI 1.00, 1.37). Clinician assessments of late toxicity were similar across groups. At 5 years, RTOG grade>2 (G2+) bowel toxicity was observed in 14/879 (1.6%), 18/908 (2.0%) and 17/904 (1.9%) of the 74Gy, 60Gy and 57Gy groups respectively. RTOG G2+ bladder toxicity was observed in 17/879 (1.9%), 14/908 (1.5%) and 17/904 (1.9%) of the 74Gy, 60Gy and 57Gy groups respectively. Conclusion(s): With BCF rates over 80%, long-term follow-up confirms that 60Gy/20f is non-inferior to 74Gy/37f. Late side effects were very low across all groups. These results support the continued use of 60Gy/20f as standard of care for men with localised PCa.

CCC publication: Outcomes of advanced plasmacytoid urothelial carcinoma receiving systemic therapy

Citation: Journal of Clinical Oncology. 2020, 38(6)
Author: Andrews E.; Curran C.; Grivas P.; Diamantopoulos L.N.; Drakaki A.; Jain R.K.; Tandon A.; Agarwal N.; Tripathi A.; Santos V.S.; Hussain S.A.; Sonpavde G.
Abstract: Background: Plasmacytoid urothelial carcinoma (pUC) is an aggressive variant with poor outcomes reported in small retrospective studies. Patients (pts) with plasmacytoid-predominant tumor histology have generally been excluded from clinical trials. Given the lack of systematic data regarding outcomes in metastatic pUC, we conducted a retrospective multicenter study to broadly examine outcomes. Method(s): Pts who underwent any systemic therapy for metastatic pUC were eligible from collaborating institutions. Data were collected for demographics, clinical and pathological variables. Descriptive statistics were reported to examine tumor regression, time to treatment discontinuation or failure (TTF), and overall survival (OS). Result(s): 52 pts with metastatic pUC were evaluable from 7 institutions. The ECOG-PS ranged from 0-3 (median 1 ), median age was 65 (range 46 - 85), and 14 pmts (26.9%) were female. The histology consisted of predominant urothelial, predominant plasmacytoid, and pure plasmacytoid carcinoma in 35 (67.3%), 14 (26.9%) and 3 (5.8%) pts, respectively. The median OS for evaluable pts according to histology were 234 (n=21 ), 203 (n=11 ), and 12 (n=1 ) days (d), respectively. The sites of metastasis (mets) were liver +/- other, non-liver visceral +/- soft tissue/lymph node (ST/LN), and ST/LN only in 5 (9.6%), 36 (69.2%), and 11 (21.2%) pts, respectively. Cisplatin-based chemotherapy (cis-chemo), PD1/L1 inhibitor (i), or other non-cis-chemo was administered in 20 (41 .7%), 13 (27.1%), and 15 (31.3%) pts, respectively (therapy unknown in 4 pts). Overall best response PR, CR, SD, and PD were seen in 3 (7%), 3 (7%), 7 (16.3%), and 30 (69.8%) pts, respectively. The overall median TTF and median OS were 91 and 232 d, respectively. The median TTF for cisplatin-based chemo, non-cisplatin based chemo and PD1/L1 inhibitors was 96.5, 122.5 and 73.5 d, respectively and the median OS was 236 (n=12), 221 (n=12) and 161 (n=8) d, respectively. Conclusion(s): The clinical outcomes of pts with metastatic pUC are dismal and appear worse than conventional UC without plasmacytoid component. Further progress will be possible only with better understanding of tumor biology and rational drug development.

CCC publication: Tivozanib as first-line treatment of metastatic renal cell carcinoma: A real-world outcome review in North-West of England, United Kingdom

Citation: Journal of Clinical Oncology. 2020, 38(6)
Author: Wong S.; Prasad K.; Waddell T.; Charnley N.; Wong H.; Law A.; Parikh O.; Pillai M.; Griffiths R.; Chow S.
Abstract: Background: Tivozanib is a selective tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor and has been shown to offer PFS and tolerance advantage compared to sorafenib among patients with mRCC. In this retrospective review, we aim to investigate the real world efficacy and tolerance of tivozanib delivered in four cancer hospital in the Northwest of England. Method(s): mRCC patients started tivozanib in first line setting were identified and reviewed. Primary outcomes of interest include overall response rate (ORR), survival (OS, PFS where possible) and treatment tolerance. Result(s): A total of 113 patients were identified between March 2017 and May 2019. Median follow up was 200 days (15-792). 26% were switched from other prior TKI due to intolerance. 28%, 48% and 24% had Favourable (F), Intermediate (I) and Poor(P) IMDC risk category respectively. ORR was 29% (CR 0%, PR29%, SD38%, PD26%, NE 7%). Median PFS (after 53 events) was 9 months (F = NR, I = 7 months, P = 3 months p value < 0.0001 ) with estimated 6 and 12 months OS of 80% and 67 % respectively. At cut-off, 26/32 with F IMDC risk remaining on treatment cf. 24/54 (I) and 6/27 (P). Median treatment received was 5 cycles and 65% still on full dose at end of observation. Dose reduction was necessary in 31 % while treatment was stopped in 15% due to toxicity. 46% received subsequent therapy post- progression. The commonest adverse events were fatigue (32%, G3 0%), diarrhoea (15%, G3 1.7%), mucositis (15% G3 < 1%), and anorexia (7% G3 1.7%). Conclusion(s): Preliminary findings from this review suggests similar clinical efficacy of tivozanib compared to agents such as pazopanib or sunitinib in real-world setting particularly among patient with Favourable IMDC category however longer follow up is required to fully evaluate this. Treatment is well tolerated with low incidence of severe grade toxicities and may be a good monotherapy option in patient of Favourable IMDC category unsuitable for combination therapies.

CCC publication: A phase I/II feasibility study of cetuximab with 5FU and mitomycin C or cisplatin with concurrent radiotherapy in muscle invasive bladder cancer

Citation: Journal of Clinical Oncology. 2020, 38(6)

Author: James N.D.; Pirrie S.; Liu W.; Ford D.; Zarkar A.; Southgate E.; Desai A.; Hussain S.A.

Abstract: Background: Chemoradiotherapy (cRT) with 5FU and Mitomycin C (5FU/MMC) is an accepted standard of care for muscle invasive bladder cancer. Cetuximab is an approved radio-sensitiser in head and neck cancer and EGFR is over-expressed in bladder cancer. We report a phase 1/2 trial of the addition of cetuximab to standard cRT. Method(s): Phase 1/2 single-arm, multicentre, open-label study conducted in 5 UK centres. Treatment: RT: 64 Gy/32 fractions, 5FU 2.5g/m2 over days 1-5 & 22-26, MMC 12g/m2 day 1, cetuximab 400mg/m2 day -8, 200mg/m2 day 1 and weekly x7. Main inclusion criteria: T2-4aN0M0 urothelial cancer, PS 0-1; prior neoadjuvant therapy permitted. Endpoints: Phase 1; feasibility and safety of cRT with cetuximab + 5FU/MMC in combination. Phase 2; local control (LC) at 3 months. Secondary Outcomes: invasive loco-regional progression free survival (LPFS), noninvasive LPFS, metastasis free survival (MFS), overall survival (OS) & patient reported outcomes (PROMs). Sample size; phase 1 between 6 and 18, phase 2 up to 45 including those recruited in phase 1. Result(s): Between Sept 2012 and Oct 2016, 33 patients were recruited; 7 in phase 1 26 in phase 2. Median age 70.1 (IQR 65.4-80.2) yrs, 60.6% WHO Performance Status 0; 81.8% male, 26/33 neoAd chemotherapy. 3 patients ineligible post registration. 30 evaluable pts started RT, 1 patient didn't complete RT due to serious adverse event (interstitial pneumonitis), 3 with delays. Phase 1, 6/7 pts completed Cetux therapy, 1 omitted 1 dose for grade 3 rash. LC was 77% (95% CI 58, 90). Overall median dose intensities Cetux 100%, MMC 99% 5FU 99.8%. 8 pts developed recurrence; 2 MIBC. The 6 & 12 month muscle-invasive LPFS was 93 non-invasive LPFS 97% & 85% MFS 90% & 90% OS 97% & 87%. PROMs showed a transient dip at 1 mo, back to baseline at 3 mo. Conclusion(s): Phase 1 data demonstrate it's feasible and safe to add cetuximab to cRT with 5FU/MMC with high delivered dose intensities. Although recruitment failed to reach the pre-specified target for phase 2 exploratory analysis indicate the 3 month bladder control rates and recurrence rates are above those reported in BC2001 with good PROMs provides evidence to consider further evaluation of cetuximab.

CCC publication: Patterns of use of chemotherapy with radiotherapy in the treatment of muscle-invasive bladder cancer: Data from the RAIDER randomized trial of adaptive radiotherapy

Citation: Journal of Clinical Oncoloogy. 2020, 38(6)
Author: Huddart R.A.; Lewis R.; Griffin C.; Alonzi R.; Birtle A.J.; Choudhury A.; Cresswell J.; Foroudi F.; Hafeez S.; Henry A.; Hindson B.; McLaren D.; Mitra A.; Nikapota A.; Parikh O.; Rimmer Y.L.; Syndikus I.; Varughese M.A.; Hall E.
Abstract: Background: Level 1 evidence exists for the use of both neoadjuvant chemotherapy (NAC) and concomitant radiosensitization (CRS) to improve outcomes in patients receiving radical radiotherapy (RT) for muscle invasive bladder cancer, but uptake has been patchy. We report here the current patterns of usage in an ongoing trial of adaptive radiotherapy. Method(s): RAIDER is an international randomized phase II trial recruiting patients with unifocal T2-T4a urothelial carcinoma of the bladder suitable for RT (ISCRTN:26779187). Patients are randomized in a 1:1:2 ratio to one of 3 arms: Standard whole bladder RT (control); Standard dose adaptive tumour focused RT; Dose escalated (DE) adaptive tumour boost RT. Standard dose patients are treated to either 64Gy/32f or 55Gy/20f and DE patients to 70Gy in 32f or 60Gy in 20f. Patients are encouraged to receive NAC and CRS. The primary endpoint is the rate of late toxicity 6-18 months post treatment in arm 3, with secondary endpoints of patient reported and disease related outcomes. Result(s): To August 2019, 285 patients had been recruited. Median age is 72 years (IQR 67-79). Stage of disease is T2 79%, T3 19%, T4 2%; 19% have hydronephrosis. Patients receiving NAC were more likely to be PS 0 at trial entry (70% v 45%). Variation in frequency of CRS use is seen across sites, with some offering to >90% of participants and some <50%. Data on NAC and CRS use is available for 249 patients recruited to date is shown in table. Conclusion(s): In this ongoing clinical trial the majority of patients are receiving NAC and/or CRS. However, uptake is not universal with ~30% of patients not receiving low dose CRS, including some who have received NAC.

CCC publication: The Efficacy and Safety of Venetoclax Therapy in Elderly Patients With Relapsed, Refractory Chronic Lymphocytic Leukaemia

Citation: British Journal of Haematology. 2020, 188(6), 918-23
Author: Toby A Eyre, Lindsey E Roeker, Christopher P Fox, Satyen H Gohill, Renata Walewska, Harriet S Walter, Francesco Forconi, Angus Broom, Arvind Arumainathan, Danielle M Brander, John N Allan, Stephen J Schuster, Brian T Hill, Frederick Lansigan, Bruce D Cheson, Nicole Lamanna, Catherine C Coombs, Paul M Barr, Alan P Skarbnik, Mazyar Shadman, Chaitra S Ujjani, Laurie Pearson, John M Pagel, Ryan Jacobs, Anthony R Mato
Abstract: Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.
Keywords:  BCL2; chronic lymphocytic leukaemia; elderly; venetoclax.

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CCC publication: Two Distinct Clinical Patterns of Checkpoint Inhibitor-Induced Thyroid Dysfunction

Citation: Endocrine Connections. 2020, 9(4), 318-25. 2020 Mar 1[Online ahead of print]
Author: Anna Olsson-Brown, Rosemary Lord, Joseph Sacco, Jonathan Wagg, Mark Coles, Munir Pirmohamed
Abstract: Intoduction: Immune checkpoint inhibitors can lead to thyroid dysfunction. However the understanding of the clinical phenotype of ICI-induced thyroid dysfunction in the real-world population is limited. The purpose of this study was to characterise the clinical patterns of dysfunction and evaluate the demographic, biochemical and immunological features associated with this patient cohort.
Materials and methods:  To characterise the longitudinal clinical course of thyroid dysfunction in patients from a single, UK regional cancer centre a retrospective review of patients was conducted. Inclusion criteria included all patients treated with antiPD-1 checkpoint inhibitors (ICI), either as monotherapy (pembrolizumab/nivolumab) or in combination with a CTLA-4 inhibitor (ipilimumab). Patterns of toxicity were evaluated together with assessment of antibody titres.
Results:  Over 16 months, thyroid dysfunction was seen in 13/90 and 3/13 patients treated with anti-PD1 monotherapy, and in combination with the anti-CTLA4 ICI ipilimumab, respectively. Patients either developed hyperthyroidism followed by hypothyroidism 12/16 or de novo hypothyroidism 4/16. Most patients were female (n=11). All patients required thyroid replacement therapy. There was no relationship between clinical pattern of dysfunction and the presence of thyroid autoantibodies.
Conclusions:  There are two distinct patterns of thyroid dysfunction in ICI-treated patients. Patients with thyroiditis develop subsequent hypothyroidism in the vast majority of cases. The potential benefit from steroids or other therapy to manage the hyperthyroid phase remains unclear. Early detection of these patients through appropriate monitoring will improve clinical management and early hormone replacement reducing the symptomatic burden of hypothyroidism.

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CCC publication: Phase I Trial of WEE1 Inhibition With Chemotherapy and Radiotherapy as Adjuvant Treatment, and a Window of Opportunity Trial With Cisplatin in Patients With Head and Neck Cancer: The WISTERIA Trial Protocol

Citation: BMJ Open. 2020, 10(3), e033009
Author: Anthony Kong, James Good, Amanda Kirkham, Joshua Savage, Rhys Mant, Laura Llewellyn, Joanna Parish, Rachel Spruce, Martin Forster, Stefano Schipani, Kevin Harrington, Joseph Sacco, Patrick Murray, Gary Middleton, Christina Yap, Hisham Mehanna
Abstract: Introduction:  Patients with head and neck squamous cell carcinoma with locally advanced disease often require multimodality treatment with surgery, radiotherapy and/or chemotherapy. Adjuvant radiotherapy with concurrent chemotherapy is offered to patients with high-risk pathological features postsurgery. While cure rates are improved, overall survival remains suboptimal and treatment has a significant negative impact on quality of life.Cell cycle checkpoint kinase inhibition is a promising method to selectively potentiate the therapeutic effects of chemoradiation. Our hypothesis is that combining chemoradiation with a WEE1 inhibitor will affect the biological response to DNA damage caused by cisplatin and radiation, thereby enhancing clinical outcomes, without increased toxicity. This trial explores the associated effect of WEE1 kinase inhibitor adavosertib (AZD1775).
Methods and analysis:  This phase I dose-finding, open-label, multicentre trial aims to determine the highest safe dose of AZD1775 in combination with cisplatin chemotherapy preoperatively (group A) as a window of opportunity trial, and in combination with postoperative cisplatin-based chemoradiation (group B).Modified time-to-event continual reassessment method will determine the recommended dose, recruiting up to 21 patients per group. Primary outcomes are recommended doses with predefined target dose-limiting toxicity probabilities of 25% monitored up to 42 days (group A), and 30% monitored up to 12 weeks (group B). Secondary outcomes are disease-free survival times (groups A and B). Exploratory objectives are evaluation of pharmacodynamic (PD) effects, identification and correlation of potential biomarkers with PD markers of DNA damage, determine rate of resection status and surgical complications for group A; and quality of life in group B.
Ethics and dissemination:  Research Ethics Committee, Edgbaston, West Midlands (REC reference 16/WM/0501) initial approval received on 18/01/2017. Results will be disseminated via peer-reviewed publication and presentation at international conferences.
Trial registration number:  ISRCTN76291951 and NCT03028766.
Keywords:  TITE-CRM; chemoradiation; head and neck squamous cell carcinoma; wee1 inhibitor; window of opportunity study; wisteria.

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WUTH publication: Outcome of revision surgery in recurrent dislocation of primary total hip arthroplasty

Citation: Hip International. 2020 Mar [Epub ahead of print]
Author: Mehta N, Selvaratnam V, Alsousou J, Donnachie N, Carroll FA
Abstract: BACKGROUND: The cause of recurrent dislocation following primary total hip arthroplasty (THA) is multifactorial. A re-dislocation rate of up-to 34% following revision is reported. The aim of this study was to determine the re-dislocation rates following revision for recurrent THR dislocation.
METHODOLOGY: Patients who underwent revision for recurrent dislocation between January 2008 and January 2015 were identified. We identified the date and type of primary implant, overall number and reasons for dislocation, revision implant details and complication data.
RESULTS: Over an 8-year period, 24 patients underwent revision. The median age was 77 (68-85) years, median time to first dislocation was 78 (23-160) months and median number of dislocations was 3 (2-4) with a mean follow-up of 18 months. Socket Mal-Orientation (10) and Abductor deficiency (5) were the main causes of recurrent dislocation. 21 patients (88%) underwent revision of both components, 1 patient underwent isolated cup revision and 2 patients had revision of acetabular component with insertion of a BioBall. There were no dislocations within 90 days of revision surgery. 4 patients had late dislocations (3 recurrent, 1 isolated). There was no significant increase risk of dislocation after revision surgery in the neck of femur group (p = 0.467).
CONCLUSIONS: We report favourable outcomes for revision of both components for recurrent dislocation with no dislocations within 90 days. The overall late dislocation rate was 16.7%, however, these patients have settled following closed reduction. Due to its multifactorial aetiology, both component revision can be considered in this patient population.
KEYWORDS: Both components; recurrent dislocation; revision

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WUTH publication: The development of a robotic gynaecological surgery training curriculum and results of a delphi study

Citation: BMC Medical Education. 2020, 20(1), 66
Author: Ismail A, Wood M, Ind T, Gul N, Moss E
Abstract: BACKGROUND: Technology for minimal access surgery is rapidly progressing in all surgical specialities including Gynaecology. As robotic surgery becomes established in increasing numbers of hospitals, there is no set curriculum for training in robotic gynaecological surgery or the assistant role in use in the UK. The purpose of this study was to determine a list of competencies that could be used as the basis of a core robotic gynaecological surgery curriculum, to explore its acceptability and the level of interest in undertaking training in robotics among obstetrics & gynaecology (O&G) trainees.
METHODS: A four-round Delphi study was conducted using members and associates of British & Irish Association of Robotic Gynaecological Surgeons (BIARGS). In Round 1 respondents were asked to propose standards that could be used in the curriculum. In the following three rounds, the respondents were asked to score each of the standards according to their opinion as to the importance of the standard. Items that scored a mean of 80% or above were included in the final proposed curriculum. Following this, a national survey was conducted to explore the interest among O&G trainees in undertaking a formal robotic training for the first assistant and console surgeon roles.
RESULTS: The items proposed were divided into three separate sections: competencies for a medical first assistant; competencies for a console surgeon; continued professional development for trained console surgeons. From the national survey; 109 responses were received of which 60% were interested in undertaking a formal training for the first assistant role, and 68% are expressing interest in training for the console surgeon role.
CONCLUSION: Undertaking a Delphi exercise to determine a core gynaecological robotic training curriculum has enabled consensus to be achieved from the opinions of BIARGS members/associates. There is interest among O&G trainees at all levels of training to gain experience and develop their skills in robotic surgery by undertaking a formal training in robotic surgery at both the first assistant and console surgeon level.
KEYWORDS: Console surgeon; Gynaecological surgery; Minimally invasive surgery; Robotic-assisted surgery; Surgical training

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