Imperial Prostate-4 Comparative Healthcare Research Outcomes of Novel Surgery in Prostate Cancer (Ip4-Chronos): Early Feasibility, Safety and Functional Outcomes from a Pilot Rct

INTRODUCTION AND OBJECTIVE: Randomised comparative outcomes are unavailable for focal therapy in localised prostate cancer. IP4 CHRONOS is an RCT aimed to optimise recruitment of patients dependent upon clinician and patient equipoise. METHOD(S): Patients with clinically significant localised prostate cancer could opt for IP4-CHRONOS-A or IP4-CHRONOS-B. IP4- CHRONOS-A randomised patients 1:1 between focal therapy(HIFU or cryotherapy) versus radical therapy(radiation or prostatectomy). Using a multi-arm-multistage(MAMS)design, IP4-CHRONOS-B randomised between focal alone(FTA) and focal combined with neoadjuvant medication (12 weeks of finasteride [FTF] or bicalutamide [FTB]). We report the pilot phase outcomes on feasibility of randomisation, early safety outcomes relative to treatment and genito-urinary functional outcomes following over 12 months treatment in IP4-CHRONOS-B. IP4-CHRONOS had ethics committee approval and was registered(ISRCTN17796995). RESULT(S): Following COVID-19 adjustments, IP4-CHRONOSA did not meet its feasibility target. Having randomised 36 patients via10 sites with a recruitment rate (95% CI) of 18% (13-23) & randomisation rate of 97%(86-100). IP4-CHRONOS-B did meet its target, randomising 64 patients across 7 sites with a recruitment rate of 43% (35-52) &randomisation rate of 100%(94-100). The only patients to withdraw were randomised to the radical arm of IP4-CHRONOS-A(4 [22%]) All patients in IP4-CHRONOS-B were compliant with neoadjuvant treatment.Only 1 patient reported CTCAE V4.0 grade>=3 adverse event(AE) in IP4-CHRONOS-A following radical treatment, another patient in each arm reported a serious adverse event(SAE) following treatment. 1 &3 patients reported an AE &SAE following FTB. 2 and 3 patients reported an AE &SAE following FTA. No patients reported any AE or SAE event following FTF. Figure 1 demonstrates generally well preserved genito-urinary function following focal treatment+/-neoadjuvant treatment. CONCLUSION(S): IP4-CHRONOS evaluated patient and physician equipoise regarding focal therapy. Traditional randomisation was not feasible due to strong patient preferences, while a MAMS RCT investigating the role of neoadjuvant agents combined with focal therapy was.

Unusual Myositis of the Temporalis Muscle Occurring with Acute Covid-19

Background. SARS-CoV-2 infection can be accompanied by neuromuscular disorders. Rhabdomyolysis and Guillain-Barre syndrome have been described repeatedly. There are case reports of inflammatory myopathies manifesting during COVID-19, presenting as dermatomyositis, polymyositis or immune-mediated necrotizing myopathy, with dermatomyositis-like presentations most commonly reported. Larger cases series are from postmortem examinations of COVID-19 patients, where variable inflammatory pathology of the skeletal muscle has been found frequently but without local detection of the actual virus. Thus, autoimmune mechanisms or the systemic interferon response are discussed as causes. We report a case of focal inflammatory myopathy with perimysial pathology of the temporalis muscle occurring with acute, but mild COVID-19. Methods. Case report of clinical observations, cranial MRI, histopathological, and laboratory findings. 3T cranial MRI was performed with gadolinium contrast. Open temporalis muscle biopsy was performed. The sample underwent standard cryohistological studies as well as immunohistochemistry with antibodies against MHC-I and II, CD3, CD4, CD19, CD68, anti-MAC, p62 and MxA. Testing for auto-antibodies was based on immunoblots or ELISA. RT-PCR for SARS-CoV-2 was run with RNA extracted from cryopreserved muscle. Results. A Caucasian woman in her 60s with no history of autoimmune or muscle complaints developed swelling and pain of the right jaw musculature five days after testing positive for SARS-CoV-2 due to respiratory tract symptoms. In addition, she experienced trismus, but no further neuromuscular complaints. The course of respiratory tract symptoms stayed mild. She had been vaccinated previously with single shot SARS-CoV-2 vector vaccine. Due to persistent swelling and complaints, giant cells arteritis was excluded by unresponsiveness to five days oral steroids and sonography of the temporal artery. Cranial MRI was performed nearly four weeks after the SARS-CoV-2 infection and showed marked swelling and oedema of the temporalis muscle. Its biopsy showed numerous CD68 and acid phosphatase positive cells infiltrating from perimysial perivascular foci towards the endomysium with perimysial damage but little damage of adjacent, perifascicular muscle fibres. Muscle fibres did not react with anti-MHC-II, anti-MAC or -MxA. Capillaries did not react with anti-MAC or -MxA. SARS-CoV-2 RNA was not detected in muscle tissue. Serum creatine kinase was not elevated in the subacute phase. Slightly elevated ANA titre led to detection of autoantibodies against proliferating cell nuclear antigen (PCNA). No pathological results for other autoantibodies, including myositis-specific antibodies and anti-ds-DNA, were found in blood. Neither were antibodies against hepatitis C and B viruses. Retesting 15 weeks after infection, anti-PCNA immunoblot was still positive, but ELISA did not indicate a pathologic titre. The swelling, myalgia and trismus regressed spontaneously a month after onset, yet the latter still persists at the time of reporting. Conclusion. Our case diverges from the majority of COVID-19 associated my-ositis reports in the unusual location of the focal myositis and the histopathological pattern of predominantly perimysial damage and histiocytic infiltration. It concurs with the literature as no SARS-CoV2 RNA could be detected in the muscle. Anti-PCNA is associated very rarely with myositis. Other associated disorder (systemic lupus erythematosus, chronic viral hepatitis B or C) were not found. Increased levels of autoantibodies are reported in COVID-19 and mostly attributed to loss of self-tolerance during the acute disease phase. Interestingly, the structural protein M of SARS-CoV-2 appears to interact notably with PCNA in infected cells. Still, the causal connection between the myositis and COVID-19 in this case is based on the close temporal association in the absence of alternative, competing explanations from the medical history and findings.

PACE-A: An international phase 3 randomised controlled trial (RCT) comparing stereotactic body radiotherapy (SBRT) to surgery for localised prostate cancer (LPCa)-Primary endpoint analysis

Background: People presenting with early-stage LPCa have several treatment options. There is therapeutic equipoise with lack of randomised evidence for superiority of radiotherapy or surgery. PACE-A aimed to determine if there is improved quality of life (QoL) following SBRT compared to surgery. Method(s): PACE (NCT01584258) is a phase 3 open-label multiple-cohort RCT. In PACE-A, people with LPCa, T1-T2, Gleason<=3+4, PSA<=20ng/mL & suitable for surgery were randomised (1:1) to SBRT or surgery. SBRT dose was 36.25Gy/5 fractions in 1-2 weeks;surgery was laparoscopic or robotically assisted prostatectomy. Androgen deprivation was not permitted. Co-primary endpoints were patient reported outcomes (PROs) of Expanded Prostate Index Composite (EPIC-26) questionnaire number of absorbent pads per day & EPIC bowel subdomain score at 2 years. Target sample size was 234 participants (pts) to detect 9% difference in urinary incontinence (80% power, 5% 2-sided alpha) & 5-point difference in mean bowel subdomain score (90% power, 5% 2-sided alpha) with higher EPIC score (range 0-100) indicating better QoL. Secondary endpoints included clinician reported toxicity and additional PROs (1% significance level). Analysis is by treatment received. Result(s): From Aug 2012 to Feb 2022, 123 men from 10 UK centres were randomised. The IDMC advised stopping recruitment after a 2-year gap in during COVID. Pts had median age 66years (IQR: 61, 69), median PSA 8ng/ml (6, 11) with 52% tumours >=T2b and 79% Gleason 3+4;93% pts were of white race. 58/63 pts received SBRT as allocated (2 received surgery, 2 unknown, 1 withdrawn);48/60 received surgery as allocated (1 received SBRT, 3 received CRT, 2 unknown, 6 withdrawn). 8 laparoscopic and 42 robotic assisted operations were performed. Median follow-up is 50 months (IQR 41, 74). At 2 years, fewer SBRT pts reported use of urinary pads: 2/43 (4.5%) vs 15/32 (46.9%), p<0.001. SBRT pts had significantly worse bowel subdomain score (mean (SD) 88.4 (12.7) vs 97.3 (5.5), p<0.001). 7/45 (15.6%) SBRT and 0/31 (0%) surgery pts reported moderate/big problem with bowel symptoms (p=0.04). SBRT pts reported less EPIC sexual subdomain score (58.0 (31.9) vs 29.3 (20.5), p<0.001);there was no evidence of a difference in urinary subdomain score (85.5 (19.8) vs 80.5 (20.8), p=0.29). At 2 years, CTCAE genitourinary grade 2 or higher(G2+) toxicity was seen in 5/54 (9.3%) SBRT vs 4/42 (9.5%) surgery pts (p=0.97);there was no G2+ gastrointestinal (GI) events seen in either group. Conclusion(s): PACE-A contributes the first randomised data to the comparison of SBRT with surgery in LPCa providing PRO data relevant to informed decision making. Compared to surgery, pts receiving SBRT had better urinary continence & sexual bother score;clinician reported GI toxicity was low but SBRT pts reported more bowel bother at 2 years.

Short vs. Long Symptom Duration Prior to Remdesivir for Hospitalized Patients with COVID-19

Background. Remdesivir (RDV) has been a mainstay of COVID-19 therapy for hospitalized patients. Impact of RDV timing in relationship to symptom-onset in hospitalized patients remains unclear, though early treatment is theorized to improve antiviral activity and clinical outcomes. Methods. This was a single-center retrospective study of adult patients hospitalized for severe COVID-19 treated with RDV. Patient charts were reviewed by 2 independent investigators to determine disease course and outcomes. Patients were stratified based on time from symptom-onset to RDV (short: <=7 vs. long: >7 days). The primary outcome was time to clinical recovery within 28 days. Secondary outcomes were proportion of patients recovered and proportion discharged from the hospital within 10, 14, and 28 days;and mortality within 28 days. Time to recovery was analyzed using the Kaplan-Meier method and the significance was tested by log rank tests. Cox's proportional hazards models were used to estimate hazard ratios (HR). Fisher's exact test was used to compare recovery rates between groups. Results. Overall, 405 patient charts were reviewed, and 337 met the inclusion criteria. On the first day of RDV, 178 (53%) of patients had symptoms for <7 days, while 159 (47%) of patients had symptoms for >7 days. Patients in the short symptom duration group were slightly older (66.5 vs. 59 years, p=0.004) and had more comorbidities. Median time to recovery was 7 (95% CI 5-9) in the short- vs. 5 (95% CI 4-6) days in the long-symptom duration groups, respectively, p=0.066. By day 10, 111 (62%) vs. 116 (73%) patients met the clinical recovery definition (p=0.048), and 113 (63%) vs. 119 (75%) patients were discharged from the hospital (p=0.026) in the short- vs. long-symptom duration groups, respectively. In the Cox's proportional hazards model, age, disease severity, and co-morbidities (kidney, liver, chronic respiratory diseases, and type II diabetes mellitus) were associated with longer recovery times. Conclusion. In this cohort, long duration of symptoms ( >7 days) prior to initiation of RDV therapy was not associated with longer recovery time or longer hospitalization. Additional studies are needed to elucidate benefits of RDV therapy in relationship to the time course of severe COVID-19 in hospitalized patients.

Comparative healthcare research outcomes of novel Surgery in prostate cancer (IP4-CHRONOS): Pilot RCT assessing feasibility of randomization for focal therapy in localized prostate cancer

Background: Randomised comparative data is lacking for focal therapy in localised prostate cancer. Imperial Prostate 4 CHRONOS (IP4-CHRONOS) is an RCT designed to reflect patient and physician equipoise to maximise acceptance to randomisation. Methods: Patients and physicians could opt for CHRONOS-A or CHRONOS-B. CHRONOS-A randomised between focal therapy (HIFU/cryotherapy) and radical therapy (radiation/prostatectomy). Using a multi-arm-multistage design, CHRONOS-B randomised between focal and focal combined with neoadjuvant medication (3 months of either finasteride or bicalutamide). We report the pilot phase outcomes on feasibility of randomisation. IP4-CHRONOS had ethics committee approval and was registered (ISRCTN17796995). Results: Due to impact of COVID-19, the target for CHRONOS-A was modified from 60 to 36;36 patients were randomised over 24 months from 7 sites (Nov/2019-Nov/2021). CHRONOS-B randomised 64 patients over 14 months across 6 sites (Dec/2019-Feb/2021). Median (IQR) age and PSA (ng/ml) for CHRONOS-A were 69 (65-72) years and 6 (5-7) and for 66 (60.5-70) years and 6 (4-7) for CHRONOS-B, respectively. 34/36 (94%) and 60/64 (94%) had ISUP Grade Group > / = 2, respectively. 4/18 (22%) randomised to radical in CHRONOS-A withdrew consent;1/22 (5%) randomised to focal withdrew. In CHRONOS-B, only 1/21 (5%) randomised to focal alone, and another randomised to focal with neoadjuvant bicalutamide withdrew. A qualitative recruitment intervention partially improved accrual to CHRONOS-A. Conclusions: IP4-CHRONOS evaluated patient and physician equipoise regarding focal therapy. Randomising between focal and radical therapy is not feasible due to strong patient preferences. A multi-arm, multi-stage RCT investigating the role of neoadjuvant agents combined with focal therapy is feasible.

Case Study: Impact of Diurnal Variations and Stormwater Dilution on SARS-CoV-2 RNA Signal Intensity at Neighborhood Scale Wastewater Pumping Stations

Wastewater based epidemiology (WBE) has emerged as a tool to track the spread of SARS-CoV-2. However, sampling at wastewater treatment plants (WWTPs) cannot identify transmission hotspots within a city. Here, we sought to understand the diurnal variations (24 h) in SARS-CoV-2 RNA titers at the m A neighborhood level, using pump stations that serve vulnerable communities (e.g., essential workers, more diverse communities). Hourly composite samples were collected from wastewater pump stations located in (i) a residential area and (ii) a shopping district. In the residential area, SARS-CoV-2 RNA concentration (N1, N2, and E assays) varied by up to 42-fold within a 24 h period. The highest viral load was observed between 5 and 7 am, when viral RNA was not diluted by stormwater. Normalizing peak concentrations during this time window with nutrient concentrations (N and P) enabled correcting for rainfall to connect sewage to clinical cases reported in the sewershed. Data from the shopping district pump station were inconsistent, probably due to the fluctuation of customers shopping at the mall. This work indicates pump stations serving the residential area offer a narrow time period of high signal intensity that could improve the sensitivity of WBE, and tracer compounds (N, P concentration) can be used to normalize SARS-CoV-2 signals during rainfall.

Multi-Modal Economic Analysis of the COVID-19 Pandemic Exogenous Shock

No abstract available.

Prostate pathway embedded comparative trial: The ip3-prospect study

Introduction & Objectives: The strength of evidence to support much of how we treat localized prostate cancer can be underwhelming. This is not due to a lack of trying. We have attempted many trials to assess interventions for localized prostate cancer which have unfortunately failed to accrue. There have been admirable exceptions, but many others have struggled. There are multiple reasons for this including a lack of equipoise to clinical questions posed amongst clinicians, or potential participants not wanting to sacrifice their health autonomy when joining trials. A further factor may be our reliance on the head-to-head Randomised Controlled Trial (RCT). We aimed to determine whether level-one evidence might be gathered using a novel trial design. Materials & Methods: IP3-PROSPECT (NCT04400656) is a cohort multiple RCT, designed to test multiple prostate cancer interventions from eligible men in one cohort. The design is based on the Zelen randomisation concept in which participants are randomised before consent in an effort to address accrual rates and to reduce potential bias of participants to control treatments. To address the ethical implications using of Zelen, the cmRCT design uses two points of consent. First, at point-of-consent 1, participants on invitation to the cohort, consent to being randomly invited in future to consider interventions for which they might be eligible. Later, at point-of-consent 2, participants are then randomly invited to consider interventions they are eligible for, and consent only to those they wish to. To include as broad a group of participants as possible our inclusion criteria are deliberately broad. These comprise those aged >/=18 years with a life expectancy of >/=5 years, who are referred for clinical suspicion of prostate cancer, or those in whom there is already a diagnosis of prostate cancer referred for specialist treatment. Acceptability and feasibility will be measured by a combination of quantitative and qualitative methods. The primary outcome is the rate of consent to inclusion to the IP3-PROSPECT cohort. Secondary outcomes include the completeness of data collection at sites and return rates of patient reported outcome measures using validated questionnaires. We will also interview patients and healthcare professionals to explore their thoughts on the implementation, practicality and efficiency of IP3-PROSPECT. Results: Enrolment to IP3-PROSPECT began in September 2020 and is recruiting to schedule despite the global COVID19 pandemic. 26 patients have been recruited at two centres, and four further sites are expected to open in the first half of 2021. Conclusions: The trial reports a good pace of recruitment and expects to complete in the third quarter of 2021. Interest amongst men referred for investigations of prostate cancer is high and we expect to demonstrate the feasibility of developing a cmRCT cohort of men referred for investigations of prostate cancer within the study period.

Identifying men affected by changes in PSA screening in the COVID-19 pandemic

Introduction & Objectives: The COVID19 pandemic has had enormous impacts on the health of our population. With health services under significant strain, prostate cancer was subject to strict changes in referral criteria. In our network the PSA thresholds for cancer referral criteria were raised, to >10ng/mL and >20ng/mL for those aged <70 years and 70-75 years respectively, for 3 months. Materials & Methods: We modelled the effects of these restricted referral criteria on patients, applying them to our prospective multicentre database of consecutive men referred to our cancer network from 04/2017-07/2020. We calculated the total numbers and proportions of significant cancers - by grade or T-stage - that may have been missed when these restrictions were applied. Four definitions of ‘significance’ were used;Gleason 3+4, 4+3, UCL1 (>/=4+3 OR maximum cancer core length (MCCL) >/=6mm) and UCL2 (>/=3+4 OR MCCL >/=4mm). Results: 2107/3014 (69.9%) of patients would not have been referred under the restricted referral criteria, including 199 (9.4%) and 486 (23.1%) significant cancers depending on the definition of significance. During the restricted period, this represents an expected 162 men who would not have been referred, including between 15 and 37 significant cancers by grade, and 1 and 7 by T-stage. Conclusions: The COVID19 pandemic had significant impact on our prostate cancer pathways. Potentially, up to 1 in 4 men who ordinarily would have had curable disease identified early, and treated, will not have done. Efforts must be made to identify these men before they represent with disease states of poorer prognosis.