Partial ablation versus radical prostatectomy in intermediate-risk prostate cancer:the PART feasibility RCT

Background Prostate cancer (PCa) is the most common cancer in men in the UK. Patients with intermediate-risk, clinically localised disease are offered radical treatments such as surgery or radiotherapy, which can result in severe side effects. A number of alternative partial ablation (PA) technologies that may reduce treatment burden are available; however the comparative effectiveness of these techniques has never been evaluated in a randomised controlled trial (RCT). Objectives To assess the feasibility of a RCT of PA using high-intensity focused ultrasound (HIFU) versus radical prostatectomy (RP) for intermediate-risk PCa and to test and optimise methods of data capture. Design We carried out a prospective, multicentre, open-label feasibility study to inform the design and conduct of a future RCT, involving a QuinteT Recruitment Intervention (QRI) to understand barriers to participation. Setting Five NHS hospitals in England. Participants Men with unilateral, intermediate-risk, clinically localised PCa. Interventions Radical prostatectomy compared with HIFU. Primary outcome measure The randomisation of 80 men. Secondary outcome measures Findings of the QRI and assessment of data capture methods. Results Eighty-seven patients consented to participate by 31 March 2017 and 82 men were randomised by 4 May 2017 (41 men to the RP arm and 41 to the HIFU arm). The QRI was conducted in two iterative phases: phase I identified a number of barriers to recruitment, including organisational challenges, lack of recruiter equipoise and difficulties communicating with patients about the study, and phase II comprised the development and delivery of tailored strategies to optimise recruitment, including group training, individual feedback and ‘tips’ documents. At the time of data extraction, on 10 October 2017, treatment data were available for 71 patients. Patient characteristics were similar at baseline and the rate of return of all clinical case report forms (CRFs) was 95%; the return rate of the patient-reported outcome measures (PROMs) questionnaire pack was 90.5%. Centres with specific long-standing expertise in offering HIFU as a routine NHS treatment option had lower recruitment rates (Basingstoke and Southampton) – with University College Hospital failing to enrol any participants – than centres offering HIFU in the trial context only. Conclusions Randomisation of men to a RCT comparing PA with radical treatments of the prostate is feasible. The QRI provided insights into the complexities of recruiting to this surgical trial and has highlighted a number of key lessons that are likely to be important if the study progresses to a main trial. A full RCT comparing clinical effectiveness, cost-effectiveness and quality-of-life outcomes between radical treatments and PA is now warranted

Partial ablation versus radical prostatectomy in intermediate-risk prostate cancer: the PART feasibility RCT

Background Prostate cancer (PCa) is the most common cancer in men in the UK. Patients with intermediate-risk, clinically localised disease are offered radical treatments such as surgery or radiotherapy, which can result in severe side effects. A number of alternative partial ablation (PA) technologies that may reduce treatment burden are available; however the comparative effectiveness of these techniques has never been evaluated in a randomised controlled trial (RCT). Objectives To assess the feasibility of a RCT of PA using high-intensity focused ultrasound (HIFU) versus radical prostatectomy (RP) for intermediate-risk PCa and to test and optimise methods of data capture. Design We carried out a prospective, multicentre, open-label feasibility study to inform the design and conduct of a future RCT, involving a QuinteT Recruitment Intervention (QRI) to understand barriers to participation. Setting Five NHS hospitals in England. Participants Men with unilateral, intermediate-risk, clinically localised PCa. Interventions Radical prostatectomy compared with HIFU. Primary outcome measure The randomisation of 80 men. Secondary outcome measures Findings of the QRI and assessment of data capture methods. Results Eighty-seven patients consented to participate by 31 March 2017 and 82 men were randomised by 4 May 2017 (41 men to the RP arm and 41 to the HIFU arm). The QRI was conducted in two iterative phases: phase I identified a number of barriers to recruitment, including organisational challenges, lack of recruiter equipoise and difficulties communicating with patients about the study, and phase II comprised the development and delivery of tailored strategies to optimise recruitment, including group training, individual feedback and ‘tips’ documents. At the time of data extraction, on 10 October 2017, treatment data were available for 71 patients. Patient characteristics were similar at baseline and the rate of return of all clinical case report forms (CRFs) was 95%; the return rate of the patient-reported outcome measures (PROMs) questionnaire pack was 90.5%. Centres with specific long-standing expertise in offering HIFU as a routine NHS treatment option had lower recruitment rates (Basingstoke and Southampton) – with University College Hospital failing to enrol any participants – than centres offering HIFU in the trial context only. Conclusions Randomisation of men to a RCT comparing PA with radical treatments of the prostate is feasible. The QRI provided insights into the complexities of recruiting to this surgical trial and has highlighted a number of key lessons that are likely to be important if the study progresses to a main trial. A full RCT comparing clinical effectiveness, cost-effectiveness and quality-of-life outcomes between radical treatments and PA is now warranted. Future work Men recruited to the feasibility study will be followed up for 36 months in accordance with the protocol. We will design a full RCT, taking into account the lessons learnt from this study. CRFs will be streamlined, and the length and frequency of PROMs and resource use diaries will be reviewed to reduce the burden on patients and research nurses and to optimise data completeness. Trial registration Current Controlled Trials ISRCTN99760303

Observation of γγ → ττ in proton-proton collisions and limits on the anomalous electromagnetic moments of the τ lepton

The production of a pair of τ leptons via photon–photon fusion, γγ → ττ, is observed for the f irst time in proton–proton collisions, with a significance of 5.3 standard deviations. This observation is based on a data set recorded with the CMS detector at the LHC at a center-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 138 fb−1. Events with a pair of τ leptons produced via photon–photon fusion are selected by requiring them to be back-to-back in the azimuthal direction and to have a minimum number of charged hadrons associated with their production vertex. The τ leptons are reconstructed in their leptonic and hadronic decay modes. The measured fiducial cross section of γγ → ττ is σfid obs = 12.4+3.8 −3.1 fb. Constraints are set on the contributions to the anomalous magnetic moment (aτ) and electric dipole moments (dτ) of the τ lepton originating from potential effects of new physics on the γττ vertex: aτ = 0.0009+0.0032 −0.0031 and |dτ| < 2.9×10−17ecm (95% confidence level), consistent with the standard model

Abstract PD14-08: Effectiveness of aromatase inhibitors versus tamoxifen in lobular compared to ductal carcinoma: Individual patient data meta-analysis of 9328 women with central histopathology, and 7654 women with e-Cadherin status

Abstract Background: In post-menopausal women with hormone receptor (HR) positive early breast cancer, aromatase inhibitors (AIs) are more effective than tamoxifen as endocrine therapy. However, some trial reports indicate greater benefit from AIs in lobular than ductal cancers. Invasive lobular cancer can be identified using conventional microscopy and/or immunohistochemistry for e-Cadherin status. We performed an individual patient data meta-analysis to explore possible differential treatment benefits for AI vs tamoxifen in women with lobular vs ductal hormone receptor positive breast cancer. Methods: Individual patient data were collected from three randomised controlled trials (BIG 01-98, TEAM and ATAC) of AI vs tamoxifen for postmenopausal women with estrogen receptor positive breast cancer, as well as results of central pathology review and e-Cadherin expression. Central pathology and e-Cadherin data were available on 9328 and 7654 women. Local pathology data was available for TEAM, BIG 01-98. Data were analysed using the same methodology as the previous EBCTCG meta-analysis of AI vs tamoxifen: results of different methods of diagnosing ductal vs lobular cancer were cross tabulated, and outcomes analysed using log-rank methods, yielding event rate ratios (RR) and confidence intervals. Interactions were evaluated using standard tests for heterogeneity; the primary outcomes were time to any invasive breast cancer recurrence, and time to distant recurrence. Results: Rates of lobular cancer were higher when assessed by central pathology (BIG 01-98 16%; ATAC 16%; TEAM 12%) than e-Cadherin (15% vs 14% vs 9%). Methods agreed in over 80% of cases classified as ductal using either pathology or e-Cadherin, while the agreement rate for lobular cancers was only about 50%. A similar pattern was seen comparing local pathology with either central pathology or e-Cadherin. Consequently, analyses were stratified by pathology and e-Cadherin both separately and together. Consistent with the previous meta-analysis there was a significant reduction in recurrence for AI compared to tamoxifen (RR 0.73 (0.61-0.87) p=0.0004). Exploration of interaction found no evidence of heterogeneity of treatment effect on recurrence by pathology (ductal HR 0.76 (0.64-0.89); lobular HR 0.76 (0.50-1.15) interaction p&amp;gt0.99; nor by e-Cadherin status (interaction p=0.9). No significant interactions were seen on other endpoints. Conclusion: Analyses of three large trials of adjuvant AI vs tamoxifen found discordance in identifying patients with lobular carcinoma by local or central pathology or e-Cadherin status, indicating variability in the consistency of diagnosis. The trials included showed a benefit for AI over tamoxifen in line with the previous meta-analysis, but with no evidence of differential efficacy in lobular compared to ductal carcinomas, however measured. These data cannot rule out smaller quantitative interactions or differences in site of recurrence: however, in contrast to earlier reports, this meta-analysis of the totality of the data does not identify ductal/lobular cancer as a predictive marker for differential endocrine treatment benefit. Citation Format: Robert K Hills, Steffi Oesterreich, Otto Metzger, David Dabbs, Hongchao Pan, Jeremy Braybrooke, Richard Gray, Richard Peto, Rosie Bradley, Ewan Straiton, Richard Berry, Daniel Rea, David Cameron, Jack Cuzick, Meredith Regan, Mitch Dowsett, Ivana Sestak, Jonas Bergh, Sandra M Swain, John Bartlett, Early Breast Cancer Trialists' Collaborative Group. Effectiveness of aromatase inhibitors versus tamoxifen in lobular compared to ductal carcinoma: Individual patient data meta-analysis of 9328 women with central histopathology, and 7654 women with e-Cadherin status [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-08.</jats:p

Long-Term Persistence of Spike Protein Antibody and Predictive Modeling of Antibody Dynamics After Infection With Severe Acute Respiratory Syndrome Coronavirus 2

Abstract Background Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been shown to neutralize the virus in vitro and prevent disease in animal challenge models on reexposure. However, the current understanding of SARS-CoV-2 humoral dynamics and longevity is conflicting. Methods The COVID-19 Staff Testing of Antibody Responses Study (Co-Stars) prospectively enrolled 3679 healthcare workers to comprehensively characterize the kinetics of SARS-CoV-2 spike protein (S), receptor-binding domain, and nucleoprotein (N) antibodies in parallel. Participants screening seropositive had serial monthly serological testing for a maximum of 7 months with the Meso Scale Discovery Assay. Survival analysis determined the proportion of seroreversion, while 2 hierarchical gamma models predicted the upper and lower bounds of long-term antibody trajectory. Results A total of 1163 monthly samples were provided from 349 seropositive participants. At 200 days after symptoms, &amp;gt;95% of participants had detectable S antibodies, compared with 75% with detectable N antibodies. S antibody was predicted to remain detectable in 95% of participants until 465 days (95% confidence interval, 370–575 days) using a “continuous-decay” model and indefinitely using a “decay-to-plateau” model to account for antibody secretion by long-lived plasma cells. S-antibody titers were correlated strongly with surrogate neutralization in vitro (R2 = 0.72). N antibodies, however, decayed rapidly with a half-life of 60 days (95% confidence interval, 52–68 days). Conclusions The Co-Stars data presented here provide evidence for long-term persistence of neutralizing S antibodies. This has important implications for the duration of functional immunity after SARS-CoV-2 infection. In contrast, the rapid decay of N antibodies must be considered in future seroprevalence studies and public health decision-making. This is the first study to establish a mathematical framework capable of predicting long-term humoral dynamics after SARS-CoV-2 infection. Clinical Trials Registration NCT04380896. </jats:sec