Management of patients with advanced prostate cancer—metastatic and/or castration-resistant prostate cancer: report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022

Background: Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. Objective: To present the voting results of the APCCC 2022. Design, setting, and participants: The experts voted on controversial questions where high- level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration- resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. Outcome measurements and statistical analysis: The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration- resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. Results and limitations: The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. Conclusions: These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. Patient summary: The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. Twitter summary: Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. Take-home message: At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration- resistant prostate cancer is summarised here

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error

Abstract: Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia

Multi-trait genome-wide association study identifies new loci associated with optic disc parameters

A new avenue of mining published genome-wide association studies includes the joint analysis of related traits. The power of this approach depends on the genetic correlation of traits, which reflects the number of pleiotropic loci, i.e. genetic loci influencing multiple traits. Here, we applied new meta-analyses of optic nerve head (ONH) related traits implicated in primary open-angle glaucoma (POAG); intraocular pressure and central corneal thickness using Haplotype reference consortium imputations. We performed a multi-trait analysis of ONH parameters cup area, disc area and vertical cup-disc ratio. We uncover new variants; rs11158547 in PPP1R36-PLEKHG3 and rs1028727 near SERPINE3 at genome-wide significance that replicate in independent Asian cohorts imputed to 1000 Genomes. At this point, validation of these variants in POAG cohorts is hampered by the high degree of heterogeneity. Our results show that multi-trait analysis is a valid approach to identify novel pleiotropic variants for ONH

Attributional style and depressive symptoms in a male prison sample

The reformulated learned helplessness model proposes that people who tend to make internal, stable, and global attributions in response to uncontrollable aversive events are more likely to develop depression. The present study sought to investigate the nature of the relationship between attributional style and depression in a male prison sample. One hundred and one adult male prisoners from four medium security prisons in Ireland completed the Attributional Style Questionnaire and measures of depression (BDI-II) and anxiety (BAI). Severity of self-reported depressive symptoms in the present sample was comparable to other prison and clinical samples, but higher than community samples. Participants were more severely affected by depressive symptoms than anxiety. The original attributional dimensions (i.e. internal, stable, and global) predicted a significant amount of variance in depression, but the model was not significant after controlling for anxiety. A subsequent regression model, comprising attributional dimensions for both negative events and positive events including a measure of \u27uncontrollability\u27, accounted for 35% of the variance in depression and the model retained significance while controlling for anxiety. An attributional model of depression may be relevant to the prison population and could provide a valid insight into the development and treatment of depressive symptoms in prisoners. The findings are interpreted in relation to previous research and implications for theory, clinical practice, and rehabilitation are discussed

Attributional style and depressive symptoms in a male prison sample

<div><p>The reformulated learned helplessness model proposes that people who tend to make internal, stable, and global attributions in response to uncontrollable aversive events are more likely to develop depression. The present study sought to investigate the nature of the relationship between attributional style and depression in a male prison sample. One hundred and one adult male prisoners from four medium security prisons in Ireland completed the Attributional Style Questionnaire and measures of depression (BDI-II) and anxiety (BAI). Severity of self-reported depressive symptoms in the present sample was comparable to other prison and clinical samples, but higher than community samples. Participants were more severely affected by depressive symptoms than anxiety. The original attributional dimensions (i.e. internal, stable, and global) predicted a significant amount of variance in depression, but the model was not significant after controlling for anxiety. A subsequent regression model, comprising attributional dimensions for both negative events and positive events including a measure of ‘uncontrollability’, accounted for 35% of the variance in depression and the model retained significance while controlling for anxiety. An attributional model of depression may be relevant to the prison population and could provide a valid insight into the development and treatment of depressive symptoms in prisoners. The findings are interpreted in relation to previous research and implications for theory, clinical practice, and rehabilitation are discussed.</p></div

Frequency distributions for the qualitative categories on the beck inventories.

<p>Frequency distributions for the qualitative categories on the beck inventories.</p

Results of the hierarchical regression attributional model of depression.

<p>Results of the hierarchical regression attributional model of depression.</p

Improved Neutralisation of the SARS-CoV-2 Omicron Variant following a Booster Dose of Pfizer-BioNTech (BNT162b2) COVID-19 Vaccine

In late November 2021, the World Health Organization declared the SARS-CoV-2 lineage B.1.1.529 the fifth variant of concern, Omicron. This variant has acquired over 30 mutations in the spike protein (with 15 in the receptor-binding domain), raising concerns that Omicron could evade naturally acquired and vaccine-derived immunity. We utilized an authentic virus, multicycle neutralisation assay to demonstrate that sera collected one, three, and six months post-two doses of Pfizer-BioNTech BNT162b2 had a limited ability to neutralise SARS-CoV-2. However, four weeks after a third dose, neutralising antibody titres were boosted. Despite this increase, neutralising antibody titres were reduced fourfold for Omicron compared to lineage A.2.2 SARS-CoV-2

Co-infection with SARS-COV-2 Omicron and Delta Variants Revealed by Genomic Surveillance

We identified the co-infection of the SARS-CoV-2 Omicron and Delta variants in two epidemiologically unrelated patients with chronic kidney disease requiring haemodialysis. Both SARS-CoV-2 variants were co-circulating locally at the time of detection. Amplicon- and probe-based sequencing using short- and long-read technologies identified and quantified Omicron and Delta subpopulations in respiratory samples from the two patients. These findings highlight the importance of genomic surveillance in vulnerable populations