Abstract Purpose 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. Patients and methods NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. Results Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. Conclusion NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. Trial registration Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240.

Background The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel. Methods In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL). Results High dose CRT did not improve OS (16.9 (60% confidence interval, CI 16.2-17.7) vs. 15.6 (60%CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60%CI 0.91-1.40; p=0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60%CI 9.9-10.2) vs. 11.1 (60%CI 10.3-12.8) months; adjusted HR 1.71 (60%CI 1.38-2.12; p=0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n=11/46 (23.9%) vs. n=15/45 (33.3%)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment. Conclusions Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS.

OBJECTIVE:To compare the effectiveness of molnupiravir, nirmatrelvir-ritonavir, and sotrovimab with no treatment in preventing hospital admission or death in higher-risk patients infected with SARS-CoV-2 in the community. DESIGN:Retrospective cohort study of non-hospitalized adult patients with COVID-19 using the Secure Anonymised Information Linkage (SAIL) Databank. SETTING:A real-world cohort study was conducted within the SAIL Databank (a secure trusted research environment containing anonymised, individual, population-scale electronic health record (EHR) data) for the population of Wales, UK. PARTICIPANTS:Adult patients with COVID-19 in the community, at higher risk of hospitalization and death, testing positive for SARS-CoV-2 between 16th December 2021 and 22nd April 2022. INTERVENTIONS:Molnupiravir, nirmatrelvir-ritonavir, and sotrovimab given in the community by local health boards and the National Antiviral Service in Wales. MAIN OUTCOME MEASURES:All-cause admission to hospital or death within 28 days of a positive test for SARS-CoV-2. STATISTICAL ANALYSIS:Cox proportional hazard model with treatment status (treated/untreated) as a time-dependent covariate and adjusted for age, sex, number of comorbidities, Welsh Index of Multiple Deprivation, and vaccination status. Secondary subgroup analyses were by treatment type, number of comorbidities, and before and on or after 20th February 2022, when omicron BA.1 and omicron BA.2 were the dominant subvariants in Wales. RESULTS:Between 16th December 2021 and 22nd April 2022, 7013 higher-risk patients were eligible for inclusion in the study. Of these, 2040 received treatment with molnupiravir (359, 17.6%), nirmatrelvir-ritonavir (602, 29.5%), or sotrovimab (1079, 52.9%). Patients in the treatment group were younger (mean age 53 vs 57 years), had fewer comorbidities, and a higher proportion had received four or more doses of the COVID-19 vaccine (36.3% vs 17.6%). Within 28 days of a positive test, 628 (9.0%) patients were admitted to hospital or died (84 treated and 544 untreated). The primary analysis indicated a lower risk of hospitalization or death at any point within 28 days in treated participants compared to those not receiving treatment. The adjusted hazard rate was 35% (95% CI: 18-49%) lower in treated than untreated participants. There was no indication of the superiority of one treatment over another and no evidence of a reduction in risk of hospitalization or death within 28 days for patients with no or only one comorbidity. In patients treated with sotrovimab, the event rates before and on or after 20th February 2022 were similar (5.0% vs 4.9%) with no significant difference in the hazard ratios for sotrovimab between the time periods. CONCLUSIONS:In higher-risk adult patients in the community with COVID-19, those who received treatment with molnupiravir, nirmatrelvir-ritonavir, or sotrovimab were at lower risk of hospitalization or death than those not receiving treatment.

Introduction: Having an appropriate sample size is important when developing a clinical prediction model. We aimed to review how sample size is considered in studies developing a prediction model for a binary outcome.Methods: We searched PubMed for studies published between 01/07/2020 and 30/07/2020 and reviewed the sample size calculations used to develop the prediction models. Using the available information, we calculated the minimum sample size that would be needed to estimate overall risk and minimise overfitting in each study and summarised the difference between the calculated and used sample size.Results: Nine out of 119 included studies provided sample size justification (8%). The recommended minimum sample size could be calculated for 94 studies: 73% used sample sizes lower than required to estimate overall risk and minimise overfitting (median deficit:75 events [IQR: 234 lower to 7 higher]); 26% used sample sizes lower than required to estimate overall risk; and 75% did not meet the ≥10 EPV rule of thumb.Conclusion: Prediction models are often developed with no sample size calculation, as a consequence many are too small to precisely estimate the overall risk. We encourage researchers to justify, perform and report sample size calculations when developing a prediction model.

Abstract Background Having an appropriate sample size is important when developing a clinical prediction model. We aimed to review how sample size is considered in studies developing a prediction model for a binary outcome. Methods We searched PubMed for studies published between 01/07/2020 and 30/07/2020 and reviewed the sample size calculations used to develop the prediction models. Using the available information, we calculated the minimum sample size that would be needed to estimate overall risk and minimise overfitting in each study and summarised the difference between the calculated and used sample size. Results A total of 119 studies were included, of which nine studies provided sample size justification (8%). The recommended minimum sample size could be calculated for 94 studies: 73% (95% CI: 63–82%) used sample sizes lower than required to estimate overall risk and minimise overfitting including 26% studies that used sample sizes lower than required to estimate overall risk only. A similar number of studies did not meet the ≥ 10EPV criteria (75%, 95% CI: 66–84%). The median deficit of the number of events used to develop a model was 75 [IQR: 234 lower to 7 higher]) which reduced to 63 if the total available data (before any data splitting) was used [IQR:225 lower to 7 higher]. Studies that met the minimum required sample size had a median c-statistic of 0.84 (IQR:0.80 to 0.9) and studies where the minimum sample size was not met had a median c-statistic of 0.83 (IQR: 0.75 to 0.9). Studies that met the ≥ 10 EPP criteria had a median c-statistic of 0.80 (IQR: 0.73 to 0.84). Conclusions Prediction models are often developed with no sample size calculation, as a consequence many are too small to precisely estimate the overall risk. We encourage researchers to justify, perform and report sample size calculations when developing a prediction model.

Background The COVID-19 pandemic has directly and indirectly had an impact on health service provision owing to surges and sustained pressures on the system. The effects of these pressures on the management of long-term or chronic conditions are not fully understood. Aim To explore the effects of COVID-19 on the recorded incidence of 17 long-term conditions. Design and setting This was an observational retrospective population data linkage study on the population of Wales using primary and secondary care data within the Secure Anonymised Information Linkage (SAIL) Databank. Method Monthly rates of new diagnosis between 2000 and 2021 are presented for each long-term condition. Incidence rates post-2020 were compared with expected rates predicted using time series modelling of pre-2020 trends. The proportion of annual incidence is presented by sociodemographic factors: age, sex, social deprivation, ethnicity, frailty, and learning disability. Results A total of 5 476 012 diagnoses from 2 257 992 individuals are included. Incidence rates from 2020 to 2021 were lower than mean expected rates across all conditions. The largest relative deficit in incidence was in chronic obstructive pulmonary disease corresponding to 343 (95% confidence interval = 230 to 456) undiagnosed patients per 100 000 population, followed by depression, type 2 diabetes, hypertension, anxiety disorders, and asthma. A GP practice of 10 000 patients might have over 400 undiagnosed long-term conditions. No notable differences between sociodemographic profiles of post- and pre-2020 incidences were observed. Conclusion There is a potential backlog of undiagnosed patients with multiple long-term conditions. Resources are required to tackle anticipated workload as part of COVID-19 recovery, particularly in primary care.

Background and Objectives: When developing a clinical prediction model, assuming a linear relationship between the continuous predictors and outcome is not recommended. Incorrect specification of the functional form of continuous predictors could reduce predictive accuracy. We examine how continuous predictors are handled in studies developing a clinical prediction model. Methods: We searched PubMed for clinical prediction model studies developing a logistic regression model for a binary outcome, published between July 01, 2020, and July 30, 2020.Results: In total, 118 studies were included in the review (18 studies (15%) assessed the linearity assumption or used methods to handle nonlinearity, and 100 studies (85%) did not). Transformation and splines were commonly used to handle nonlinearity, used in 7 (n = 7/18, 39%) and 6 (n = 6/18, 33%) studies, respectively. Categorization was most often used method to handle continuous predictors (n = 67/118, 56.8%) where most studies used dichotomization (n = 40/67, 60%). Only ten models included nonlinear terms in the final model (n = 10/ 18, 56%).Conclusion: Though widely recommended not to categorize continuous predictors or assume a linear relationship between outcome and continuous predictors, most studies categorize continuous predictors, few studies assess the linearity assumption, and even fewer use methodology to account for nonlinearity. Methodological guidance is provided to guide researchers on how to handle continuous predictors when developing a clinical prediction model. & COPY; 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

This work was supported by the Wales COVID-19 Evidence Centre, funded by Health and Care Research Wales.

Background The COVID-19 pandemic has resulted in delayed diagnosis and treatment for cancer patients and increases in elective surgery waiting lists. The impact on other ‘long-term’ conditions (LTCs) is unclear. We examined the effects of the pandemic on the recorded incidence of 20 LTCs to inform decisions on treatment pathways and resource allocation. Approach We included Welsh residents diagnosed with any of 20 LTCs for the first time between 2000-2021. Data were accessed and analysed within the Secure Anonymised Information Linkage (SAIL) Databank. The primary aim was to assess the impact of the COVID-19 pandemic on trends in recorded incidence. Secondarily we examined incidence by socio-demographic and clinical subgroups: age, sex, deprivation quintile, ethnicity, frailty score and learning disability. Incidence were presented as monthly rates for each LTC. We performed interrupted time series analyses to estimate; the immediate and long-term change in rates following the pandemic; and the size of the undiagnosed population. Results We included 2,206,070 individuals diagnosed with at least one LTC. An immediate reduction in recording of new diagnoses was observed in April 2020 across all 20 LTCs, followed by a gradual recovery towards pre-pandemic levels over the next 18 months, though at different rates across conditions. The largest difference between observed and expected (as predicted using pre-pandemic trends) incidence between January 2020 and June 2021 were in the diagnoses of COPD (-43%, 95% CI (-50%, -34%)), Asthma, Hypertension and Depression and the smallest difference was in Type 1 diabetes, dementia, stroke and TIA (-8%, 95% CI (-19% ,5%)). Differences in the proportions of incidence by socio-demographic and clinical subgroups in the years preceding and following the pandemic have also been analysed (results to be finalised). Conclusion There was an abrupt reduction in the observed incidence of all 20 LTCs after March 2020 followed by a gradual recovery over consequent months towards pre-pandemic levels. Of 20 LTCs, 15 strongly indicate a reservoir of yet undiagnosed patients. The results from this study will have implications in resource allocation.

OBJECTIVE:Malignant Pleural Mesothelioma (MPM) has a poor prognosis and high symptom burden. RESPECT-Meso was a multicenter randomized study examining the role of early specialist palliative care (SPC) on quality of life (QoL) with MPM. This is a post-hoc exploratory analysis of the symptom burden and unmet needs identified from RESPECT-Meso participants.METHODS:Exploratory analysis from 174 participants using the General Health Status (GHS) measure (from the EORTC QLQ-C30 QoL questionnaire) and 87 participants using validated assessment questionnaires in those randomized to SPC. Eligibility for the study included confirmed MPM with diagnosis <6 weeks prior, performance score (PS) 0 or 1, no significant physical or psychological comorbidity. Cox proportional hazards models were derived to examine for relationships with survival. Free text was assessed using content analysis, looking for common themes and words.RESULTS:Participants were predominantly male (79.9%), mean age 72.8 years, PS was 0 in 38%, 78% of MPM was epithelioid. At least 3 symptoms were reported in 69.8% of participants, including fatigue (81%), dyspnea (73.3%), pain (61.2%), weight loss (59.3%). Anxiety was reported by 54.7% of participants, 52.3% low mood and 48.8% anhedonia symptoms. After multivariable adjustment, only pain remained statistically significant with a hazard ratio (HR) 2.9 (95% CI 1.3-6.7; p = 0.01). For each 1 unit increase in GHS score, the HR for death was 0.987 (0.978-0.996; p = 0.006), indicating a worse reported QoL is related to shorter survival. Unmet needs were common: 25.9% wanted more information about their condition, 24.7% about their care and 21.2% about their treatment. 79.1% were concerned about the effect of their illness on family.CONCLUSION:There is a high symptom burden in mesothelioma despite good baseline performance status. A worse QoL is associated with a worse survival. Unmet needs are common, perhaps highlighting a need for improved communication and information sharing.

The anti-cancer activity of 5-FU requires conversion to its active metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP) to inhibit thymidylate synthase (TS), a critical enzyme in de novo nucleotide synthesis and cell survival. Although 5-FU based chemotherapies remain the cornerstone of cancer treatment, their clinical utility is limited by resistance mechanisms including conversion to FUDR-MP, catabolism by DPD and short plasma half-life. NUC-3373, a phosphoramidate transformation of FUDR-MP, is designed to bypass these mechanisms and enhance TS inhibition.

Abstract Purpose: Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non–small cell lung cancer (NSCLC). Patients and Methods: Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed. Results: Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change −28% [95% confidence interval (CI), −58.2 to −4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, −6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%–74%) lower in cohort 1 compared with cohort 2 (P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported. Conclusions: This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.

Tumor hypoxia confers profound resistance to radiation. An emerging strategy to tackle hypoxia is by reprogramming tumor metabolism. The antimalarial drug atovaquone inhibits oxidative phosphorylation (OXPHOS) and preclinically has been shown to reduce tumor cell oxygen consumption and alleviate tumor hypoxia resulting in radiosensitization. We conducted a translational clinical trial to determine whether atovaquone reduces tumor hypoxia in patients with non-small cell lung cancer (NSCLC). Patients with NSCLC scheduled for surgical resection were recruited sequentially into two cohorts. Cohort 1 received oral atovaquone 750mg bd until the day before surgery. Cohort 2 received no treatment. Tumor hypoxia imaging with 18F-FMISO or 18F-FAZA PET-CT was undertaken at baseline and repeated just prior to resection. Tumor hypoxic volume (HV) was defined using tumor-to-blood tracer uptake ratio ≥1.4, with ≥10% reduction in HV classed a response to treatment. Patients with <1.5 mL HV at baseline were deemed not evaluable for HV analysis and were replaced. Perfusion CT (pCT) and shMOLLI T1 map MRI were undertaken at the same timepoints to assess for changes in tumor perfusion and biochemistry, respectively. An inter-cohort comparison of hypoxia metagene expression signatures obtained by RNA sequencing was conducted from multiple regions per resected tumor. Adverse event monitoring (CTCAE v4.0) was performed until surgery. Forty-six patients were recruited with 30 (15 per cohort) evaluable for paired HV analysis. Patient and tumor characteristics were similar between cohorts. Median duration of atovaquone treatment between imaging timepoints was 12 days. The median change in HV in atovaquone-treated patients was -28% (95% CI: -58.2, -4.4), with 11 (73.3%) patients classed as responders. In contrast, the median change in untreated patients was +15.5% (95% CI: -6.5, +35.5). Using linear regression with pre-surgery HV as outcome adjusting for cohort and baseline HV and tumor volume (log-transformed), the expected geometric mean HV was 60% (95% CI: 30%, 70%) lower for treated patients (p = 0.004). Transcriptomic analysis revealed significantly decreased expression of multiple hypoxia metagene signatures in treated tumors. Altered expression of OXPHOS related pathways was also observed suggesting wider metabolic reprogramming. pCT and MRI results did not show altered tumor perfusion or suggest change in cellularity, respectively, in keeping with an OXPHOS-dependent mechanism of action. No adverse events related to atovaquone were reported. This the first clinical study to investigate whether an OXPHOS inhibitor reduces tumor hypoxia. The data presented supports our pre-clinical finding that atovaquone rapidly reduces tumor hypoxia through decreased oxygen consumption in NSCLC. We will shortly commence phase I clinical testing combining atovaquone with radical chemoradiotherapy in NSCLC.

Aims: The use of diffusion-weighted magnetic resonance imaging (DW-MRI) as a prognostic marker of treatment response would enable early individualisation of treatment. We aimed to quantify the changes in mean apparent diffusion coefficient (Delta ADC(mean)) between a DW-MRI at diagnosis and on fraction 8-10 of chemoradiotherapy (CRT) as a biomarker for cellularity, and correlate these with anal squamous cell carcinoma recurrence. Materials and methods: This prospective study recruited patients with localised anal cancer between October 2014 and November 2017. DW-MRI was carried out at diagnosis and after fraction 8-10 of radical CRT. A region of interest was delineated for all primary tumours and any lymph nodes >2 cm on high-resolution T-2-weighted images and propagated to the ADC map. Routine clinical follow-up was collected from Nation Health Service electronic systems. Results: Twenty-three of 29 recruited patients underwent paired DW-MRI scans. Twenty-six regions of interest were delineated among the 23 evaluable patients. The median (range) tumour volume was 13.6 cm(3) (2.8-84.9 cm(3)). Ten of 23 patients had lesions with Delta ADC(mean) < 20%. With a median follow-up of 41.2 months, four patients either failed to have a complete response to CRT or subsequently relapsed. Three of four patients with disease relapse had lesions demonstrating Delta ADC(mean) <= 20%, the other patient with persistent disease had Delta ADC(mean) of 20.3%. Conclusions: We demonstrated a potential correlation between patients with Delta ADC(mean) <20% and disease relapse. Further investigation of the prognostic merit of DW-MRI change is needed in larger, prospective cohorts. Crown Copyright (C) 2020 Published by Elsevier Ltd on behalf of The Royal College of Radiologists. All rights reserved.

Background Anal Squamous Cell Carcinoma (ASCC) is radically treated by chemoradiotherapy (CRT). The use of DW-MRI as a predictive marker of outcome would enable early individualisation of treatment. We aimed to quantify the changes in mean apparent-diffusion-coefficient (ADCMean) between a DW-MRI at diagnosis and on fraction 8-10 of CRT as a biomarker for cellularity, and correlate these with outcome. Methods This prospective study recruited patients with ASCC between October 2014 and November 2017. DW-MRI was performed at diagnosis and after fraction 8-10 of radical CRT. A region of interest (ROI) was delineated for all primary tumours and any lymph nodes >2 cm on high-resolution T2 –weighted images and propagated to the ADC map. A pre-defined cut-off for percentage change in ADCMean (ΔADC) was set at Results Twenty-three of 29 recruited patients underwent paired DW-MRI scans. The median (range) tumour volume was 13.6 cm3 (2.8 cm3 to 84.9 cm3). The median ΔADCMean between scans was 20.7% (95% CI: 12.7%, 34.1%). Nine of 23 (43%) patients had a change of ADCMean Conclusions In a subset of patients, Clinical trial identification NCT02145416. Legal entity responsible for the study University of Oxford. Funding CRUK EPSRC Cancer Imaging Centre in Oxford, the CRUK Oxford Centre and the NIHR.M Hawkins is supported by Medical Research Council grant MC_UU_00001/2. Disclosure R. Muirhead: Honoraria (self), Fee for lecture: Boehringer Ingelheim. V. Goh: Research grant / Funding (self): Siemens. All other authors have declared no conflicts of interest.

PurposeMalignant pleural mesothelioma (MPM) has a high symptom burden and poor survival. Evidence from other cancer types suggests some benefit in health-related quality of life (HRQoL) with early specialist palliative care (SPC) integrated with oncological services, but the certainty of evidence is low.MethodsWe performed a multicentre, randomised, parallel group controlled trial comparing early referral to SPC versus standard care across 19 hospital sites in the UK and one large site in Western Australia. Participants had newly diagnosed MPM; main carers were additionally recruited. Intervention: review by SPC within 3 weeks of allocation and every 4 weeks throughout the study. HRQoL was assessed at baseline and every 4 weeks with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30. Primary outcome: change in EORTC C30 Global Health Status 12 weeks after randomisation.ResultsBetween April 2014 and October 2016, 174 participants were randomised. There was no significant between group difference in HRQoL score at 12 weeks (mean difference 1.8 (95% CI −4.9 to 8.5; p=0.59)). HRQoL did not differ at 24 weeks (mean difference −2.0 (95% CI −8.6 to 4.6; p=0.54)). There was no difference in depression/anxiety scores at 12 weeks or 24 weeks. In carers, there was no difference in HRQoL or mood at 12 weeks or 24 weeks, although there was a consistent preference for care, favouring the intervention arm.ConclusionThere is no role for routine referral to SPC soon after diagnosis of MPM for patients who are cared for in centres with good access to SPC when required.Trial registration numberISRCTN18955704.

The authors wish to point out that L. Coughlan and S. Sridhar were both at the Jenner Institute, University of Oxford, OX3 7DQ, UK, when the work for the paper was completed. Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy AdultsA two dose heterologous vaccination regimen of MVA/ChAdOx1 NP + M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A. Full-Text PDF Open Access