Publications by authors named "Declan Murphy"

602 Publications

Self-reported lack of energy or feeling depressed 12 months after treatment in men diagnosed with prostate cancer within a population-based registry.

Psychooncology 2021 Oct 8. Epub 2021 Oct 8.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

Objective: Feeling depressed and lethargic are common side effects of prostate cancer (PCa) and its treatments. We examined the incidence and severity of feeling depressed and lack of energy in patients in a population based PCa registry.

Methods: We included men diagnosed with PCa between 2015 and 2019 in Victoria, Australia, and enrolled in the Prostate Cancer Outcomes Registry. The primary outcome measures were responses to two questions on the Expanded Prostate Cancer Index Composite (EPIC-26) patient reported instrument: problems with feeling depressed and problems with lack of energy 12 months following treatment. We evaluated associations between these and age, cancer risk category, treatment type, and urinary, bowel, and sexual function.

Results: Both outcome questions were answered by 9712 out of 12,628 (77%) men. 981 patients (10%) reported at least moderate problems with feeling depressed; 1563 (16%) had at least moderate problems with lack of energy and 586 (6.0%) with both. Younger men reported feeling depressed more frequently than older men. Lack of energy was more common for treatments that included androgen deprivation therapy than not (moderate/big problems: 31% vs. 13%), irrespective of disease risk category. Both outcomes were associated with poorer urinary, bowel, and sexual functional domain scores.

Conclusions: Self-reported depressive feelings and lack of energy were frequent in this population-based registry. Problems with feeling depressed were more common in younger men and lack of energy more common in men having hormonal treatment. Clinicians should be aware of the incidence of these symptoms in these at-risk groups and be able to screen for them.
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http://dx.doi.org/10.1002/pon.5833DOI Listing
October 2021

The Role of Prostate-specific Membrane Antigen Positron Emission Tomography/Magnetic Resonance Imaging in Primary and Recurrent Prostate Cancer: A Systematic Review of the Literature.

Eur Urol Focus 2021 Sep 15. Epub 2021 Sep 15.

LYX Institute of Urology, Universidad Francisco de Vitoria, Madrid, Spain; Department of Urology, Hospital Universitario Puerta De Hierro-Majadahonda, Madrid, Spain. Electronic address:

Context: Prostate-specific membrane antigen (PSMA) positron emission tomography/magnetic resonance imaging (PET/MRI) is a novel imaging technique with several potential applications in the prostate cancer (PCa) setting.

Objective: To perform a systematic review of the current evidence regarding the diagnostic performance of PSMA PET/MRI in patients with primary and recurrent PCa.

Evidence Acquisition: A comprehensive bibliographic search on the MEDLINE and Cochrane Library databases was performed in October 2020. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Studies were deemed eligible if they assessed patients with primary or recurrent PCa (P) undergoing PSMA PET/MRI (I) with or without comparison with other imaging techniques (C) in order to evaluate its diagnostic performance (O). Retrospective and prospective primary clinical studies were included. Results of previous meta-analyses were reported.

Evidence Synthesis: A total of 23 original articles and three meta-analyses were included. Limited evidence on PSMA PET/MRI is available, especially in the setting of partial gland ablation. PET/MRI can be an effective imaging modality for detecting primary PCa, showing higher accuracy than multiparametric MRI alone. It provides accurate local staging of primary PCa; however, there are contradictory results in this context when its performance is compared with other imaging techniques. PET/MRI also shows high performance for restaging and detecting tumor recurrence, even at low prostate-specific antigen levels.

Conclusions: PSMA PET/MRI could represent a valuable tool in the management of patients with primary and recurrent PCa. No specific recommendations can be provided.

Patient Summary: Encouraging data regarding the benefits of prostate-specific membrane antigen positron emission tomography/magnetic resonance imaging in patients with prostate cancer are emerging from the literature.
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http://dx.doi.org/10.1016/j.euf.2021.08.013DOI Listing
September 2021

A Phase II Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety, and Tolerability of Arbaclofen Administered for the Treatment of Social Function in Children and Adolescents With Autism Spectrum Disorders: Study Protocol for AIMS-2-TRIALS-CT1.

Front Psychiatry 2021 24;12:701729. Epub 2021 Aug 24.

Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Autism Spectrum Disorder (ASD or autism) is characterized by difficulties in social communication and interaction, which negatively impact on individuals and their families' quality of life. Currently no pharmacological interventions have been shown to be effective for improving social communication in autism. Previous trials have indicated the potential of arbaclofen for improving social function among autistic children and adolescents with fluent speech. The AIMS2TRIALS-Clinical Trial 1 (AIMS-CT1) will examine whether arbaclofen is superior to placebo in improving social function and other secondary outcomes over 16 weeks, along with safety and tolerability profiles. AIMS-CT1 is an international, multi-site, double-blind, parallel group Phase II randomized clinical trial. It will include 130 males and females aged 5:0-17:11 years, with a diagnosis of ASD and fluent speech. Eligible participants will be randomized on a ratio of 1:1 for a 16-week treatment period. Medication will be titrated over 5 weeks. The primary outcome is the effect on social function from weeks 0 to 16 measured on the Socialization domain of the Vineland Adaptive Behavior Scales, 3rd edition. Secondary outcome measures include the CGI-S (Clinical Global Impression-Severity), CGI-I (Clinical Global Impression-Improvement), other areas of adaptive function, social communication and other autism symptoms, co-occurring behavior problems and health-related quality of life. Genetic and electrophysiological markers will be examined as potential stratifiers for treatment response. Exploratory novel digital technologies will also be used to measure change, examining simultaneously the validity of digital biomarkers in natural environments. The safety and tolerability of the drug will also be examined. Our protocol is very closely aligned with a parallel Canadian trial of 90 participants (ARBA Study, US NCT number: NCT03887676) to allow for secondary combined analyses. Outcomes will be compared using both an Intent-to-reat and Per Protocol approach. The outcomes of this trial, combined with the parallel Canadian trial, will contribute to the evidence base for medications used to help social difficulties among young autistic individuals; demonstrate the capabilities of the AIMS-2-TRIALS network of academic centers to deliver clinical trials; and support future drug development. EudraCT number: 2018-000942-21 and ClinicalTrials.gov registry number: NCT03682978. Currently under protocol v.7.2, dated 20.11.2020.
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http://dx.doi.org/10.3389/fpsyt.2021.701729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421761PMC
August 2021

Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder.

Am J Psychiatry 2021 Sep 10:appiajp202120050630. Epub 2021 Sep 10.

Department of Child and Adolescent Psychiatry, University Hospital, Goethe University, Frankfurt am Main, Germany (Ecker, Bletsch, Mann, Schaefer, Yousaf, Chiocchetti, Bast, Freitag).

Objective: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions.

Methods: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features.

Results: In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission.

Conclusions: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.
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http://dx.doi.org/10.1176/appi.ajp.2021.20050630DOI Listing
September 2021

The Additive Diagnostic Value of Prostate-specific Membrane Antigen Positron Emission Tomography Computed Tomography to Multiparametric Magnetic Resonance Imaging Triage in the Diagnosis of Prostate Cancer (PRIMARY): A Prospective Multicentre Study.

Eur Urol 2021 Aug 28. Epub 2021 Aug 28.

Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Background: Multiparametric magnetic resonance imaging (MRI) is validated for the detection of clinically significant prostate cancer (csPCa), although patients with negative/equivocal MRI undergo biopsy for false negative concerns. In addition, Ga-PSMA-11 positron emission tomography/computed tomography (prostate-specific membrane antigen [PSMA]) may also identify csPCa accurately.

Objective: This trial aimed to determine whether the combination of PSMA + MRI was superior to MRI in diagnostic performance for detecting csPCa.

Design, Setting, And Participants: A prospective multicentre phase II imaging trial was conducted. A total of 296 men were enrolled with suspected prostate cancer, with no prior biopsy or MRI, recent MRI (6 mo), and planned transperineal biopsy based on clinical risk and MRI. In all, 291 men underwent MRI, pelvic-only PSMA, and systematic ± targeted biopsy.

Outcome Measurements And Statistical Analysis: Sensitivity, specificity, and predictive values (negative predictive value [NPV] and positive predictive value) for csPCa were determined for MRI, PSMA, and PSMA + MRI. PSMA + MRI was defined as negative for PSMA negative Prostate Imaging Reporting and Data System (PI-RADS) 2/3 and positive for either MRI PI-RADS 4/5 or PSMA positive PI-RADS 2/3; csPCa was any International Society of Urological Pathology (ISUP) grade group ≥2 malignancy.

Results And Limitations: Of the patients, 56% (n = 162) had csPCa; 67% had PI-RADS 3-5, 73% were PSMA positive, and 81% were combined PSMA + MRI positive. Combined PSMA + MRI improved NPV compared with MRI alone (91% vs 72%, test ratio = 1.27 [1.11-1.39], p < 0.001). Sensitivity also improved (97% vs 83%, p < 0.001); however, specificity was reduced (40% vs 53%, p = 0.011). Five csPCa cases were missed with PSMA + MRI (four ISUP 2 and one ISUP 3). Of all men, 19% (56/291) were PSMA + MRI negative (38% of PI-RADS 2/3) and could potentially have avoided biopsy, risking delayed csPCa detection in 3.1% men with csPCa (5/162) or 1.7% (5/291) overall.

Conclusions: PSMA + MRI improved NPV and sensitivity for csPCa in an MRI triaged population. Further randomised studies will determine whether biopsy can safely be omitted in men with a high clinical suspicion of csPCa but negative combined imaging.

Patient Summary: The combination of magnetic resonance imaging (MRI) + prostate-specific membrane antigen positron emission tomography reduces false negatives for clinically significant prostate cancer (csPCa) compared with MRI, potentially allowing a reduction in the number of prostate biopsies required to diagnose csPCa.
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http://dx.doi.org/10.1016/j.eururo.2021.08.002DOI Listing
August 2021

The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology.

Nat Commun 2021 08 19;12(1):5049. Epub 2021 Aug 19.

Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.

Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide. The PDXs represent the clinico-pathological and genomic spectrum of prostate cancer, from treatment-naïve primary tumors to castration-resistant metastases. Inter- and intra-tumor heterogeneity in adenocarcinoma and neuroendocrine phenotypes is evident from bulk and single-cell RNA sequencing data. Organoids can be cultured from PDXs, providing further capabilities for preclinical studies. Using a 1 x 1 x 1 design, we rapidly identify tumors with exceptional responses to combination treatments. To govern the distribution of PDXs, we formed the Melbourne Urological Research Alliance (MURAL). This PDX collection is a substantial resource, expanding the capacity to test and prioritize effective treatments for prospective clinical trials in prostate cancer.
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http://dx.doi.org/10.1038/s41467-021-25175-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376965PMC
August 2021

Imputing the Number of Responders from the Mean and Standard Deviation of CGI-Improvement in Clinical Trials Investigating Medications for Autism Spectrum Disorder.

Brain Sci 2021 Jul 9;11(7). Epub 2021 Jul 9.

Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, 81675 Munich, Germany.

Introduction: Response to treatment, according to Clinical Global Impression-Improvement (CGI-I) scale, is an easily interpretable outcome in clinical trials of autism spectrum disorder (ASD). Yet, the CGI-I rating is sometimes reported as a continuous outcome, and converting it to dichotomous would allow meta-analysis to incorporate more evidence.

Methods: Clinical trials investigating medications for ASD and presenting both dichotomous and continuous CGI-I data were included. The number of patients with at least much improvement (CGI-I ≤ 2) were imputed from the CGI-I scale, assuming an underlying normal distribution of a latent continuous score using a primary threshold θ = 2.5 instead of θ = 2, which is the original cut-off in the CGI-I scale. The original and imputed values were used to calculate responder rates and odds ratios. The performance of the imputation method was investigated with a concordance correlation coefficient (CCC), linear regression, Bland-Altman plots, and subgroup differences of summary estimates obtained from random-effects meta-analysis.

Results: Data from 27 studies, 58 arms, and 1428 participants were used. The imputation method using the primary threshold (θ = 2.5) had good performance for the responder rates (CCC = 0.93 95% confidence intervals [0.86, 0.96]; β of linear regression = 1.04 [0.95, 1.13]; bias and limits of agreements = 4.32% [-8.1%, 16.74%]; no subgroup differences χ = 1.24, -value = 0.266) and odds ratios (CCC = 0.91 [0.86, 0.96]; β = 0.96 [0.78, 1.14]; bias = 0.09 [-0.87, 1.04]; χ = 0.02, -value = 0.894). The imputation method had poorer performance when the secondary threshold (θ = 2) was used.

Discussion: Assuming a normal distribution of the CGI-I scale, the number of responders could be imputed from the mean and standard deviation and used in meta-analysis. Due to the wide limits of agreement of the imputation method, sensitivity analysis excluding studies with imputed values should be performed.
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http://dx.doi.org/10.3390/brainsci11070908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305379PMC
July 2021

The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project design and methodologies: a dimensional approach to understanding neurobiological and genetic aetiology.

Mol Autism 2021 08 5;12(1):55. Epub 2021 Aug 5.

Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, 18 Innovation Walk, Melbourne, VIC, 3800, Australia.

Background: ASD and ADHD are prevalent neurodevelopmental disorders that frequently co-occur and have strong evidence for a degree of shared genetic aetiology. Behavioural and neurocognitive heterogeneity in ASD and ADHD has hampered attempts to map the underlying genetics and neurobiology, predict intervention response, and improve diagnostic accuracy. Moving away from categorical conceptualisations of psychopathology to a dimensional approach is anticipated to facilitate discovery of data-driven clusters and enhance our understanding of the neurobiological and genetic aetiology of these conditions. The Monash Autism-ADHD genetics and neurodevelopment (MAGNET) project is one of the first large-scale, family-based studies to take a truly transdiagnostic approach to ASD and ADHD. Using a comprehensive phenotyping protocol capturing dimensional traits central to ASD and ADHD, the MAGNET project aims to identify data-driven clusters across ADHD-ASD spectra using deep phenotyping of symptoms and behaviours; investigate the degree of familiality for different dimensional ASD-ADHD phenotypes and clusters; and map the neurocognitive, brain imaging, and genetic correlates of these data-driven symptom-based clusters.

Methods: The MAGNET project will recruit 1,200 families with children who are either typically developing, or who display elevated ASD, ADHD, or ASD-ADHD traits, in addition to affected and unaffected biological siblings of probands, and parents. All children will be comprehensively phenotyped for behavioural symptoms, comorbidities, neurocognitive and neuroimaging traits and genetics.

Conclusion: The MAGNET project will be the first large-scale family study to take a transdiagnostic approach to ASD-ADHD, utilising deep phenotyping across behavioural, neurocognitive, brain imaging and genetic measures.
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http://dx.doi.org/10.1186/s13229-021-00457-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340366PMC
August 2021

The application of theranostics in different stages of prostate cancer.

Future Oncol 2021 Sep 6;17(27):3637-3644. Epub 2021 Jul 6.

Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne 3000, Australia.

Despite the remarkable achievements in treating metastatic prostate cancer over the last two decades, castrate-resistant status is still considered the lethal stage of the disease. Theranostics combines a targeting compound (ligand) with a therapeutic radioisotope (radioactive particle) injected into the blood to target the cancer cells. The most studied radioligand is Lu-PSMA-617, which targets PSMA, a protein found in prostate cancer cells. This new approach has shown promising results in treating metastatic castration-resistant prostate cancer. Currently, many trials are using PSMA-targeting radioligands in combination with conventional therapies in advanced prostate cancer or even in the earlier stages of the disease. Other preclinical trials are exploring the possibility of using newer ligands or radioisotopes to treat prostate cancer to increase the specificity and efficacy of this treatment.
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http://dx.doi.org/10.2217/fon-2020-1209DOI Listing
September 2021

Modulation of striatal functional connectivity differences in adults with and without autism spectrum disorder in a single-dose randomized trial of cannabidivarin.

Mol Autism 2021 07 1;12(1):49. Epub 2021 Jul 1.

Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 16 De Crespigny Park, London, SE5 8AF, UK.

Background: Autism spectrum disorder (ASD) has a high cost to affected individuals and society, but treatments for core symptoms are lacking. To expand intervention options, it is crucial to gain a better understanding of potential treatment targets, and their engagement, in the brain. For instance, the striatum (caudate, putamen, and nucleus accumbens) plays a central role during development and its (atypical) functional connectivity (FC) may contribute to multiple ASD symptoms. We have previously shown, in the adult autistic and neurotypical brain, the non-intoxicating cannabinoid cannabidivarin (CBDV) alters the balance of striatal 'excitatory-inhibitory' metabolites, which help regulate FC, but the effects of CBDV on (atypical) striatal FC are unknown.

Methods: To examine this in a small pilot study, we acquired resting state functional magnetic resonance imaging data from 28 men (15 neurotypicals, 13 ASD) on two occasions in a repeated-measures, double-blind, placebo-controlled study. We then used a seed-based approach to (1) compare striatal FC between groups and (2) examine the effect of pharmacological probing (600 mg CBDV/matched placebo) on atypical striatal FC in ASD. Visits were separated by at least 13 days to allow for drug washout.

Results: Compared to the neurotypicals, ASD individuals had lower FC between the ventral striatum and frontal and pericentral regions (which have been associated with emotion, motor, and vision processing). Further, they had higher intra-striatal FC and higher putamenal FC with temporal regions involved in speech and language. In ASD, CBDV reduced hyperconnectivity to the neurotypical level.

Limitations: Our findings should be considered in light of several methodological aspects, in particular our participant group (restricted to male adults), which limits the generalizability of our findings to the wider and heterogeneous ASD population.

Conclusion: In conclusion, here we show atypical striatal FC with regions commonly associated with ASD symptoms. We further provide preliminary proof of concept that, in the adult autistic brain, acute CBDV administration can modulate atypical striatal circuitry towards neurotypical function. Future studies are required to determine whether modulation of striatal FC is associated with a change in ASD symptoms.

Trial Registration: clinicaltrials.gov, Identifier: NCT03537950. Registered May 25th, 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03537950?term=NCT03537950&draw=2&rank=1 .
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http://dx.doi.org/10.1186/s13229-021-00454-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252312PMC
July 2021

Autism symptoms in anorexia nervosa: a comparative study with females with autism spectrum disorder.

Mol Autism 2021 06 30;12(1):47. Epub 2021 Jun 30.

Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, 103 Denmark Hill, London, SE5 8AZ, UK.

Background: Recent research suggests a link between autism spectrum disorder (ASD) and anorexia nervosa (AN). Individuals with AN show high scores on measures of ASD symptoms, relative to individuals without AN, however, there are currently no studies directly comparing women with AN to women with ASD. The aim of the current study was to examine profiles of ASD symptoms in young women in the acute and recovered stages of AN, women with ASD, and typically developing controls (TD), on both self-report and clinical interview measures.

Methods: Four groups of participants aged 12-30 years were included (n = 218): AN, recovered AN (REC), ASD, and TD. Group differences on the Social Responsiveness Scale, 2nd edition (SRS-2), 10-item Autism Quotient (AQ-10), and the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2) were examined. To explore similarities and differences in specific symptom profiles associated with AN and ASD, individual item endorsement on the ADOS-2 was also examined in AN, REC, and ASD.

Results: Across measures, women with ASD showed the highest scores, and TDs the lowest. Generally, individuals with AN and REC showed intermediate levels of ASD symptoms, scoring between the other two groups. However, AN and ASD did not differ on restricted interests and repetitive behaviour subscales. The ADOS-2 item 'quality of social response' adequately discriminated between ASD and non-ASD participants.

Limitations: A full diagnostic assessment for ASD was not provided for participants with AN/REC, nor were eating disorders assessed in the ASD group. Therefore, some diagnostic overlap between groups is possible. The cross-sectional design is another limitation.

Conclusions: The results suggest similarities in scores on both self-report and clinical interview measures in AN and ASD. However, individual ADOS-2 item analyses also revealed subtle differences, particularly in reciprocal social interaction. ASD symptoms may be a combination of both state and trait features in AN.
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http://dx.doi.org/10.1186/s13229-021-00455-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247081PMC
June 2021

Assessment and management of haematuria in the general practice setting.

Aust J Gen Pract 2021 07;50(7):467-471

MBBCh, BaO, FRACS, FRCS Urol, Director of Genitourinary Oncology, Peter MacCallum Cancer Centre, Vic.

Background: The presence of haematuria may be a singular symptom signalling underlying urological pathology, either benign or malignant. However, a large proportion of patients with haematuria will have no identifiable cause found. Appropriate early investigation and management of haematuria in the primary care setting is important for timely referral of patients suspected of having serious underlying pathology while avoiding over-investigation in those patients prone to transient and benign causes.

Objective: The aim of this article is to provide a summary of the aetiology, investigation and management of haematuria in the primary care setting, with a focus on urological assessment and outcomes.

Discussion: The approach to the diagnosis and investigation of haematuria differs depending on whether the haematuria is macro- or microscopic. In both cases, clinicians should begin by obtaining a careful patient history to include specific risk factors for urological malignancy, as often the decision for further work-up requires a risk-stratified approach.
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http://dx.doi.org/10.31128/AJGP-03-21-5892DOI Listing
July 2021

Drug development for Autism Spectrum Disorder (ASD): Progress, challenges, and future directions.

Eur Neuropsychopharmacol 2021 Jul 19;48:3-31. Epub 2021 Jun 19.

Department of Psychiatry, Columbia University, New York, NY, United States.

In 2017, facing lack of progress and failures encountered in targeted drug development for Autism Spectrum Disorder (ASD) and related neurodevelopmental disorders, the ISCTM with the ECNP created the ASD Working Group charged to identify barriers to progress and recommending research strategies for the field to gain traction. Working Group international academic, regulatory and industry representatives held multiple in-person meetings, teleconferences, and subgroup communications to gather a wide range of perspectives on lessons learned from extant studies, current challenges, and paths for fundamental advances in ASD therapeutics. This overview delineates the barriers identified, and outlines major goals for next generation biomedical intervention development in ASD. Current challenges for ASD research are many: heterogeneity, lack of validated biomarkers, need for improved endpoints, prioritizing molecular targets, comorbidities, and more. The Working Group emphasized cautious but unwavering optimism for therapeutic progress for ASD core features given advances in the basic neuroscience of ASD and related disorders. Leveraging genetic data, intermediate phenotypes, digital phenotyping, big database discovery, refined endpoints, and earlier intervention, the prospects for breakthrough treatments are substantial. Recommendations include new priorities for expanded research funding to overcome challenges in translational clinical ASD therapeutic research.
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http://dx.doi.org/10.1016/j.euroneuro.2021.05.010DOI Listing
July 2021

A Quantitative Analysis Investigating the Prevalence of "Manels" in Major Urology Meetings.

Eur Urol 2021 Oct 4;80(4):442-449. Epub 2021 Jun 4.

Department of Urology, Hospital Clinic, University of Barcelona, Barcelona, Spain.

Background: Female representation in urological meetings is important for gender equity.

Objective: Our objective was to examine the prevalence of "manels" or all-male speaking panels at urological meetings.

Design, Setting, And Participants: Urology meetings organized by major urological associations/societies from December 2019 to November 2020 were reviewed. Meeting information and details of the faculty were retrieved.

Outcome Measurements And Statistical Analysis: Primary outcomes were: (1) the percentage of male faculty in all included sessions and (2) the overall proportion of manels. We made further comparisons between manel and multigender sessions. Male and female faculty were stratified by quartiles of publications, citations, and H-index, and their mean numbers of sessions were compared.

Results And Limitations: Among 285 meeting sessions, 181 (63.5%) were manels. The mean percentage of male faculty was 86.9%. Male representation was very high in urology meetings for most disciplines and urological associations/societies, except for female urology meeting sessions and those organized by the International Continence Society. Nonmanel sessions had higher numbers of chairs/moderators (p = 0.027), speakers (p < 0.001), and faculty (p < 0.001) than manel sessions. A total of 1037 faculty members were included, and 900 of them (86.8%) were male. Male faculty had longer mean years of practice (23.8 vs 17.7 yr, p < 0.001) and was more likely to include professors (43.2% vs 17.5%, p < 0.001) than female faculty. Male faculty within the first quartile (ie, lower quartile) of publications and H-index had a significantly higher number of sessions than female faculty within the same quartile.

Conclusions: Our study showed that manels are prevalent in urology meetings. There is evidence showing that males received more opportunities than females. A huge gender imbalance exists in urology meetings; urological associations and societies should actively strive for greater gender parity.

Patient Summary: Women are under-represented in urology meetings. Urological associations and societies should play an active role to ensure a more balanced gender representation.
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http://dx.doi.org/10.1016/j.eururo.2021.05.031DOI Listing
October 2021

Ga-PSMA-PET screening and transponder-guided salvage radiotherapy to the prostate bed alone for biochemical recurrence following prostatectomy: interim outcomes of a phase II trial.

World J Urol 2021 Jun 2. Epub 2021 Jun 2.

Epworth HealthCare, Richmond, VIC, Australia.

Purpose: To evaluate outcomes for men with biochemically recurrent prostate cancer who were selected for transponder-guided salvage radiotherapy (SRT) to the prostate bed alone by Ga-labelled prostate-specific membrane antigen positron emission tomography (Ga-PSMA-PET).

Methods: This is a single-arm, prospective study of men with a prostate-specific antigen (PSA) level rising to 0.1-2.5 ng/mL following radical prostatectomy. Patients were staged with Ga-PSMA-PET and those with a negative finding, or a positive finding localised to the prostate bed, continued to SRT only to the prostate bed alone with real-time target-tracking using electromagnetic transponders. The primary endpoint was freedom from biochemical relapse (FFBR, PSA > 0.2 ng/mL from the post-radiotherapy nadir). Secondary endpoints were time to biochemical relapse, toxicity and patient-reported quality of life (QoL).

Results: Ninety-two patients (median PSA of 0.18 ng/ml, IQR 0.12-0.36), were screened with Ga-PSMA-PET and metastatic disease was found in 20 (21.7%) patients. Sixty-nine of 72 non-metastatic patients elected to proceed with SRT. At the interim (3-year) analysis, 32 (46.4%) patients (95% CI 34.3-58.8%) were FFBR. The median time to biochemical relapse was 16.1 months. The rate of FFBR was 82.4% for ISUP grade-group 2 patients. Rates of grade 2 or higher gastrointestinal and genitourinary toxicity were 0% and 15.2%, respectively. General health and disease-specific QoL remained stable.

Conclusion: Pre-SRT Ga-PSMA-PET scans detect metastatic disease in a proportion of patients at low PSA levels but fail to improve FFBR. Transponder-guided SRT to the prostate bed alone is associated with a favourable toxicity profile and preserved QoL.

Trial Registration Number: ACTRN12615001183572, 03/11/2015, retrospectively registered.
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http://dx.doi.org/10.1007/s00345-021-03735-0DOI Listing
June 2021

Infographic: Positioning In Macular hole Surgery (PIMS) trial.

Eye (Lond) 2021 May 26. Epub 2021 May 26.

Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.

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http://dx.doi.org/10.1038/s41433-021-01559-1DOI Listing
May 2021

Maternal depression during pregnancy alters infant subcortical and midbrain volumes.

J Affect Disord 2021 08 14;291:163-170. Epub 2021 May 14.

Sackler Institute for Translational Neurodevelopment, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK; NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King's College London, UK.

Background: Maternal depression in pregnancy increases the risk for adverse neurodevelopmental outcomes in the offspring. The reason for this is unknown, however, one plausible mechanism may include the impact of maternal antenatal depression on infant brain. Nevertheless, relatively few studies have examined the brain anatomy of infants born to clinically diagnosed mothers.

Methods: A legacy magnetic resonance imaging (MRI) dataset was used to compare regional brain volumes in 3-to-6-month-old infants born to women with a clinically confirmed diagnosis of major depressive disorder (MDD) during pregnancy (n = 31) and a reference sample of infants born to women without a current or past psychiatric diagnosis (n = 33). A method designed for analysis of low-resolution scans enabled examination of subcortical and midbrain regions previously found to be sensitive to the parent-child environment.

Results: Compared with infants of non-depressed mothers, infants exposed to maternal antenatal depression had significantly larger subcortical grey matter volumes and smaller midbrain volumes. There was no association between gestational medication exposure and the infant regional brain volumes examined in our sample.

Limitations: Our scanning approach did not allow for an examination of fine-grained structural differences, and without repeated measures of brain volume, it is unknown whether the direction of reported associations are dependent on developmental stage.

Conclusions: Maternal antenatal depression is associated with an alteration in infant brain anatomy in early postnatal life; and that this is not accounted for by medication exposure. However, our study cannot address whether anatomical differences impact on future outcomes of the offspring.
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http://dx.doi.org/10.1016/j.jad.2021.05.008DOI Listing
August 2021

Self-harm and Mental Health Characteristics of Prisoners with elevated rates of autistic traits.

Res Dev Disabil 2021 Jul 15;114:103987. Epub 2021 May 15.

King's College London, United Kingdom.

Background: Prevalence studies among prisoners have found rates of 1-4% for autism spectrum disorder (ASD) or autistic traits. However, little is known about those prisoners with high levels of autistic traits.

Aim: This aim of this study was to compare the mental health characteristics of prisoners with autistic traits with neurotypical prisoners not screening positive for neurodevelopmental disorders.

Method: The study recruited 240 male prisoners from a London prison and screened for autism spectrum disorder using the Autism Quotient (AQ) 20 and 10, and Autism Diagnostic Observation Schedule (ADOS). The Mini International Neuropsychiatric Interview was used to assess for depression, anxiety, self-harm behavior and suicide.

Results: Screening using the AQ identified 46 prisoners with significant autistic traits, with 12 meeting the diagnostic threshold for ASD using the ADOS. Those screening positive with autistic traits were significantly more likely to have thought about self-harm and suicide in the past month than neurotypical prisoners and have a comorbid mental disorder. They were also significantly more likely to report having attempted suicide during their lifetime compared to neurotypical peers at a rate of 64.9 % compared to 11.6 % for the neurotypical prisoners.

Conclusion: Prisoners with elevated levels of autistic traits were more likely to report self-harm, suicidal thoughts and were more vulnerable to a range of mental disorders than neurotypical prisoners. There is a need for more evidence on the experience of autistic prisoners to inform how pathways should work to improve health outcomes through increased awareness and access to screening and subsequent diagnosis which currently prisons are currently not set up for.
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http://dx.doi.org/10.1016/j.ridd.2021.103987DOI Listing
July 2021

COVID-19 health and social care access for autistic people: European policy review.

BMJ Open 2021 05 17;11(6):e045341. Epub 2021 May 17.

Department of Forensic and Neurodevelopmental Sciences, King's College London, London, UK.

Background: The global COVID-19 pandemic has had an unprecedented impact on European health and social care systems, with demands on testing, hospital and intensive care capacity exceeding available resources in many regions. This has led to concerns that some vulnerable groups, including autistic people, may be excluded from services.

Methods: We reviewed policies from 15 European member states, published in March-July 2020, pertaining to (1) access to COVID-19 tests; (2) provisions for treatment, hospitalisation and intensive care units (ICUs); and (3) changes to standard health and social care. In parallel, we analysed survey data on the lived experiences of 1301 autistic people and caregivers.

Results: Autistic people experienced significant barriers when accessing COVID-19 services. First, despite being at elevated risk of severe illness due to co-occurring health conditions, there was a lack of accessibility of COVID-19 testing. Second, many COVID-19 outpatient and inpatient treatment services were reported to be inaccessible, predominantly resulting from individual differences in communication needs. Third, ICU triage protocols in many European countries (directly or indirectly) resulted in discriminatory exclusion from lifesaving treatments. Finally, interruptions to standard health and social care left over 70% of autistic people without everyday support.

Conclusions: The COVID-19 pandemic has further exacerbated existing healthcare inequalities for autistic people, probably contributing to disproportionate increases in morbidity and mortality, mental health and behavioural difficulties, and reduced quality of life. An urgent need exists for policies and guidelines on accessibility of COVID-19 services to be updated to prevent the widespread exclusion of autistic people from services, which represents a violation of international human rights law.
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http://dx.doi.org/10.1136/bmjopen-2020-045341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130751PMC
May 2021

Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry.

Commun Biol 2021 05 14;4(1):574. Epub 2021 May 14.

Roche Pharma Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Roche Innovation Center Basel, Basel, Switzerland.

Social-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97-99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry.
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http://dx.doi.org/10.1038/s42003-021-02015-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121854PMC
May 2021

Differences in treatment choices for localised prostate cancer diagnosed in private and public health services.

Med J Aust 2021 06 11;214(10):486-486.e1. Epub 2021 May 11.

Peter MacCallum Cancer Centre, Melbourne, VIC.

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http://dx.doi.org/10.5694/mja2.51074DOI Listing
June 2021

Musculoskeletal Responses to Exercise Plus Nutrition in Men with Prostate Cancer on Androgen Deprivation: A 12-Month RCT.

Med Sci Sports Exerc 2021 Oct;53(10):2054-2065

Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, AUSTRALIA.

Purpose: Androgen deprivation therapy (ADT) for prostate cancer has multiple adverse effects on musculoskeletal health. This 12-month randomized controlled trial aimed to assess the effects of multicomponent exercise training combined with whey protein, calcium and vitamin D supplementation on bone mineral density (BMD), structure and strength, body composition, muscle strength, and physical function in ADT-treated men.

Methods: Seventy ADT-treated men were randomized to exercise plus supplementation (Ex + Suppl; n = 34) or usual care (control; n = 36). Ex + Suppl involved thrice weekly progressive resistance training plus weight-bearing impact exercise with daily multinutrient supplementation. Primary outcomes were DXA hip and spine areal BMD. Secondary outcomes included the following: tibia and radius pQCT volumetric BMD, bone structure and strength, DXA body composition, pQCT muscle and fat cross-sectional area and muscle density, and muscle strength and physical function.

Results: Sixty men (86%) completed the study. Mean exercise and supplement adherence were 56% and 77%, respectively. There were no effects of the intervention on bone or body composition outcomes. Ex + Suppl improved leg muscle strength (net difference, (95% confidence interval, or CI), 14.5% (-0.2 to 29.2); P = 0.007) and dynamic mobility (four-square-step test time, -9.3% (-17.3 to -1.3), P = 0.014) relative to controls. Per-protocol analysis of adherent participants (≥66% exercise, ≥80% supplement) showed Ex + Suppl preserved femoral neck aBMD (1.9% (0.1 to 3.8), P = 0.026) and improved total body lean mass (1.0 kg (-0.23 to 2.22), P = 0.044) relative to controls.

Conclusions: Exercise training combined with multinutrient supplementation had a limited effect on ameliorating the adverse musculoskeletal consequences of ADT, likely related to the modest intervention adherence.
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http://dx.doi.org/10.1249/MSS.0000000000002682DOI Listing
October 2021

Positron Emission Tomography and Whole-body Magnetic Resonance Imaging for Metastasis-directed Therapy in Hormone-sensitive Oligometastatic Prostate Cancer After Primary Radical Treatment: A Systematic Review.

Eur Urol Oncol 2021 Mar 6. Epub 2021 Mar 6.

Nuclear Medicine Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, University of Bologna, Bologna, Italy.

Context: Next-generation imaging includes positron emission tomography (PET) imaging and whole-body magnetic resonance imaging (wbMRI) including diffusion-weighted imaging. Accurate quantification of oligometastatic disease using next-generation imaging is important to define the role and value of metastasis-directed therapy (MDT).

Objective: To perform a review of next-generation imaging modalities in the detection of recurrent oligometastatic hormone-sensitive prostate cancer in men who received prior radical treatment for localized disease.

Evidence Acquisition: MEDLINE, Scopus, Cochrane Libraries, and Web of Science databases were systematically searched for studies reporting next-generation imaging and oncological outcomes. An expert panel of urologists, radiation oncologists, radiologists, and nuclear medicine physicians performed a nonsystematic review of strengths and limitations of currently available imaging options for detecting the presence and extent of recurrent oligometastatic disease.

Evidence Synthesis: From 370 articles identified, three clinical trials and 21 observational studies met the following inclusion criteria: metachronous oligometastatic recurrence after radical treatment for prostate cancer, MDT, and hormone-sensitive patients. Androgen deprivation therapy (ADT) was allowed before MDT. Next-generation imaging modalities included PET/computed tomography and/or PET/MRI with the following tracers: choline (n = 1), NaF (n = 1), and prostate-specific membrane antigen (PSMA; n = 1) for clinical trials; choline (n = 7) or PSMA (n = 11) or both (n = 3) for observational studies. The number of metastases ranged from two to five lesions in most studies. In PSMA-based studies, progression-free survival ranged from 19% to 100%, whereas in studies employing choline, progression-free survival ranged from 16% to 93%. Overall, ADT-free survival ranged from 48% to 79%, while local control was reported as 75-100% and prostate-specific antigen response as 23-94%. Among the different PET tracers and wbMRI, PSMA PET is emerging as the most accurate imaging technique in defining the oligometastatic status.

Conclusions: PSMA and choline PET contribute to guiding MDT in men with hormone-sensitive oligometastatic prostate cancer. Further studies are warranted to ascertain their role and optimize the timing of imaging for such patients.

Patient Summary: We looked at the evidence regarding the use of modern imaging techniques to direct additional treatments in men with early spread of prostate cancer after they receive their initial radical treatment. We found that next-generation imaging, in particular prostate-specific membrane antigen and choline positron emission tomography, can successfully guide metastasis-directed therapies, and further trials should evaluate which modalities are best suited to improve outcomes for our patients.
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http://dx.doi.org/10.1016/j.euo.2021.02.003DOI Listing
March 2021

Role of PSMA PET/CT imaging in the diagnosis, staging and restaging of prostate cancer.

Future Oncol 2021 Jun 16;17(17):2225-2241. Epub 2021 Mar 16.

Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, 3000, Australia.

Prostate-specific membrane antigen (PSMA) PET/CT is a novel imaging technique for the detection and staging of either primary or recurrent prostate cancer. Early studies demonstrated its improved sensitivity and specificity over and in combination with other currently employed imaging techniques, such as multiparametric MRI, bone scan, PET and CT. However, the lack of strength and confidence in these studies has meant incorporation of PSMA PET/CT into clinical guidelines and practice has been limited to date. In response, a number of high-quality prospective studies have recently emerged and reflect exciting results seen in preceding publications. Here we recount some of the key earlier publications, report results from the latest studies and look to the future discussing some of the eagerly awaited ongoing clinical trials.
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http://dx.doi.org/10.2217/fon-2020-1293DOI Listing
June 2021
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