Multimodal Mass Spectrometry Imaging of an Osteosarcoma Multicellular Tumour Spheroid Model to Investigate Drug-Induced Response.

A multimodal mass spectrometry imaging (MSI) approach was used to investigate the chemotherapy drug-induced response of a Multicellular Tumour Spheroid (MCTS) 3D cell culture model of osteosarcoma (OS). The work addresses the critical demand for enhanced translatable early drug discovery approaches by demonstrating a robust spatially resolved molecular distribution analysis in tumour models following chemotherapeutic intervention. Advanced high-resolution techniques were employed, including desorption electrospray ionisation (DESI) mass spectrometry imaging (MSI), to assess the interplay between metabolic and cellular pathways in response to chemotherapeutic intervention. Endogenous metabolite distributions of the human OS tumour models were complemented with subcellularly resolved protein localisation by the detection of metal-tagged antibodies using Imaging Mass Cytometry (IMC). The first application of matrix-assisted laser desorption ionization-immunohistochemistry (MALDI-IHC) of 3D cell culture models is reported here. Protein localisation and expression following an acute dosage of the chemotherapy drug doxorubicin demonstrated novel indications for mechanisms of region-specific tumour survival and cell-cycle-specific drug-induced responses. Previously unknown doxorubicin-induced metabolite upregulation was revealed by DESI-MSI of MCTSs, which may be used to inform mechanisms of chemotherapeutic resistance. The demonstration of specific tumour survival mechanisms that are characteristic of those reported for in vivo tumours has underscored the increasing value of this approach as a tool to investigate drug resistance.

Prostate Cancer Survivorship Essentials for men with prostate cancer on androgen deprivation therapy: protocol for a randomised controlled trial of a tele-based nurse-led survivorship care intervention (PCEssentials Hormone Therapy Study).

INTRODUCTION: Androgen deprivation therapy (ADT) is commonly used to treat men with locally advanced or metastatic prostate cancer. Men receiving ADT experience numerous side effects and frequently report unmet supportive care needs. An essential part of quality cancer care is survivorship care. To date, an optimal effective approach to survivorship care for men with prostate cancer on ADT has not been described. This protocol describes a randomised trial of tele-based nurse-led survivorship that addresses this knowledge gap: (1) determine the effectiveness of a nurse-led survivorship care intervention (PCEssentials), relative to usual care, for improving health-related quality of life (HR-QoL) in men with prostate cancer undergoing ADT and (2) evaluate PCEssentials implementation strategies and outcomes, including cost-effectiveness, compared with usual care. METHODS AND ANALYSIS: This is an effectiveness-implementation hybrid (type 1) trial with participants randomised to one of two arms: (1) minimally enhanced usual care and (2) nurse-led prostate cancer survivorship essentials (PCEssentials) delivered over four tele-based sessions, with a booster session 5 months after session 1. Eligible participants are Australian men with prostate cancer commencing ADT and expected to be on ADT for a minimum of 12 months. Participants are followed up at 3, 6 and 12 months postrecruitment. Primary outcomes are HR-QoL and self-efficacy. Secondary outcomes are psychological distress, insomnia, fatigue and physical activity. A concurrent process evaluation with participants and study stakeholders will be undertaken to determine effectiveness of delivery of PCEssentials. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Metro South Health HREC (HREC/2021/QMS/79429). All participants are required to provide written informed consent. Outcomes of this trial will be published in peer-reviewed journals. The findings will be presented at conferences and meetings, local hospital departments, participating organisations/clinical services, and university seminars, and communicated at community and consumer-led forums. TRIAL REGISTRATION NUMBER: ACTRN12622000025730.

A scoping review of active, participant centred, digital adverse events following immunization (AEFI) surveillance of WHO approved COVID-19 vaccines: A Canadian immunization Research Network study.

This scoping review examines the role of digital solutions in active, participant-centered surveillance of adverse events following initial release of COVID-19 vaccines. The goals of this paper were to examine the existing literature surrounding digital solutions and technology used for active, participant centered, AEFI surveillance of novel COVID-19 vaccines approved by WHO. This paper also aimed to identify gaps in literature surrounding digital, active, participant centered AEFI surveillance systems and to identify and describe the core components of active, participant centered, digital surveillance systems being used for post-market AEFI surveillance of WHO approved COVID-19 vaccines, with a focus on the digital solutions and technology being used, the type of AEFI detected, and the populations under surveillance. The findings highlight the need for customized surveillance systems based on local contexts and the lessons learned to improve future vaccine monitoring and pandemic preparedness.

Redefining online biology education: a study on interactive branched video utilisation and student learning experiences.

This study evaluated the use of interactive, branched videos compared with traditional passive linear delivery for enhancing student engagement and learning in online courses. Undergraduate biology students were provided with either branched decision-based or linear videos on cell biology and protein purification as self-guided or consolidation activities. While the interactive branched videos did not improve learning gains, thematic analysis revealed that students found them more enjoyable and preferable for revision. However, most students felt linear passive videos were more logically structured for core content delivery. In a revised format, with clearer scaffolding, the interactive branched videos were perceived as significantly more engaging and useful when utilised for a problem-solving activity. Students welcomed the autonomy of directing their learning path but desired support to avoid missing critical information. Overall, thoughtfully designed branched videos can increase student motivation, but their utility depends on context. Our findings indicate the importance of balancing interactivity, clear organisation and purpose when incorporating these innovative formats into online learning. Branched videos show promise for increasing engagement but require intentional instructional design tailored to learning objectives.

Benefits and harms of prostate specific antigen testing according to Australian guidelines.

Guidelines for prostate specific antigen (PSA) testing in Australia recommend that men at average risk of prostate cancer who have been informed of the benefits and harms, and who decide to undergo regular testing, should be offered testing every 2 years from 50 to 69 years. This study aimed to estimate the benefits and harms of regular testing in this context. We constructed Policy1-Prostate, a discrete event microsimulation platform of the natural history of prostate cancer and prostate cancer survival, and PSA testing patterns and subsequent management in Australia. The model was calibrated to pre-PSA (before 1985) prostate cancer incidence and mortality and validated against incidence and mortality trends from 1985 to 2011 and international trials. The model predictions were concordant with trials and Australian observed incidence and mortality data from 1985 to 2011. Out of 1000 men who choose to test according to the guidelines, 36 [21-41] men will die from prostate cancer and 126 [119-133] men will be diagnosed with prostate cancer, compared with 50 [47-54] and 94 [90-98] men who do not test, respectively. During the 20 years of active PSA testing, 32.3% [25.6%-38.8%] of all PSA-test detected cancers are overdiagnosed cases that is, 30 [21-42] out of 94 [83-107] PSA-test detected cancers. Australian men choosing to test with PSA every two years from 50 to 69 will reduce their risk of ever dying from prostate cancer and incur a risk of overdiagnosis: for every man who avoids dying from prostate cancer, two will be overdiagnosed with prostate cancer between 50 and 69 years of age. Australian men, with health professionals, can use these results to inform decision-making about PSA testing.

Effect of exercise interventions on hospital length of stay and admissions during cancer treatment: a systematic review and meta-analysis.

OBJECTIVE: To assess the effect of participating in an exercise intervention compared with no exercise during cancer treatment on the duration and frequency of hospital admissions. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, PEDro and Cochrane Central Registry of Randomized Controlled Trials. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised studies published until August 2023 evaluating exercise interventions during chemotherapy, radiotherapy or stem cell transplant regimens, compared with usual care, and which assessed hospital admissions (length of stay and/or frequency of admissions). STUDY APPRAISAL AND SYNTHESIS: Study quality was assessed using the Cochrane Risk-of-Bias tool and Grading of Recommendations Assessment, Development and Evaluation assessment. Meta-analyses were conducted by pooling the data using random-effects models. RESULTS: Of 3918 screened abstracts, 20 studies met inclusion criteria, including 2635 participants (1383 intervention and 1252 control). Twelve studies were conducted during haematopoietic stem cell transplantation regimens. There was a small effect size in a pooled analysis that found exercise during treatment reduced hospital length of stay by 1.40 days (95% CI: -2.26 to -0.54 days; low-quality evidence) and lowered the rate of hospital admission by 8% (difference in proportions=-0.08, 95% CI: -0.13 to -0.03, low-quality evidence) compared with usual care. CONCLUSION: Exercise during cancer treatment can decrease hospital length of stay and admissions, although a small effect size and high heterogeneity limits the certainty. While exercise is factored into some multidisciplinary care plans, it could be included as standard practice for patients as cancer care pathways evolve.

Descriptive analysis of prostate cancer pathology data from diagnosis and surgery in men from the 45 and Up Study.

Information available from the New South Wales Cancer Registry (NSWCR) about the aggressiveness of prostate cancer is limited to the summary stage variable 'degree of spread', which contains a high proportion of cases defined as 'unknown'. In this study we demonstrate the feasibility of obtaining and analysing prostate cancer pathology data from stored pathology records. Pathology data were extracted from stored pathology records of incident prostate cancer cases in men participating in the 45 and Up Study, a large Australian prospective cohort study, who were diagnosed between January 2006 and December 2013. Baseline questionnaires from the 45 and Up Study were linked to the NSWCR. Demographic and pathology items were tabulated and associations described. We evaluated the completeness of pathological characteristics by degree of spread of cancer at diagnosis. Among the 123,921 men enrolled in the 45 and Up Study, 5,091 had incident prostate cancer and 5,085 were linked to a pathology record. The most complete variables included grade group of diagnostic (85.8%) and surgical (99.8%) specimens, margin status (98.1%), extraprostatic extension (95.1%) and seminal vesicle invasion (96.8%). Most diagnostic specimens were grade group 1 (26.6%) or 2 (23.5%). Of the 5,085 cases, 30.8% were classified by the NSWCR with unknown degree of spread; a pathology record could be extracted for 99.4% of these. The unknown degree of spread cases had similar levels of completeness and distribution of diagnostic and surgical pathology features to those with a localised degree of spread. This study demonstrated the feasibility of obtaining and analysing data derived from pathology reports from centralised state-based cancer registry notifications. Supplementing degree of spread information with pathology data from diagnosis and surgery will improve both the quality of research and policy aimed at improving the lives of men with prostate cancer.

Disease mapping: Geographic differences in population rates of interventional treatment for prostate cancer in Australia.

BACKGROUND: Treatment decisions for men diagnosed with prostate cancer depend on a range of clinical and patient characteristics such as disease stage, age, general health, risk of side effects and access. Associations between treatment patterns and area-level factors such as remoteness and socioeconomic disadvantage have been observed in many countries. OBJECTIVE: To model spatial differences in interventional treatment rates for prostate cancer at high spatial resolution to inform policy and decision-making. METHODS: Hospital separations data for interventional treatments for prostate cancer (radical prostatectomy, low dose rate and high dose rate brachytherapy) for men aged 40 years and over were modelled using spatial models, generalised linear mixed models, maximised excess events tests and k-means statistical clustering. RESULTS: Geographic differences in population rates of interventional treatments were found (p<0.001). Separation rates for radical prostatectomy were lower in remote areas (12.2 per 10 000 person-years compared with 15.0-15.9 in regional and major city areas). Rates for all treatments decreased with increasing socioeconomic disadvantage (radical prostatectomy 19.1 /10 000 person-years in the most advantaged areas compared with 12.9 in the most disadvantaged areas). Three groups of similar areas were identified: those with higher rates of radical prostatectomy, those with higher rates of low dose brachytherapy, and those with low interventional treatment rates but higher rates of excess deaths. The most disadvantaged areas and remote areas tended to be in the latter group. CONCLUSIONS: The geographic differences in treatment rates may partly reflect differences in patients' physical and financial access to treatments. Treatment rates also depend on diagnosis rates and thus reflect variation in investigation rates for prostate cancer and presentation of disease. Spatial variation in interventional treatments may aid identification of areas of under-treatment or over-treatment.

Guidelines for genetic testing in prostate cancer: a scoping review.

BACKGROUND: Genetic testing, to identify pathogenic or likely pathogenic variants in prostate cancer, is valuable in guiding treatment decisions for men with prostate cancer and to inform cancer prevention and early detection options for their immediate blood relatives. There are various guidelines and consensus statements for genetic testing in prostate cancer. Our aim is to review genetic testing recommendations across current guidelines and consensus statements and the level of evidence supporting those recommendations. METHODS: A scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping review (PRISMA-ScR) guidelines. Electronic database searches and manual searches of grey literature, including websites of key organisations were conducted. Using the Population, Concept, Context (PCC) framework, this scoping review included: men with prostate cancer or men at high risk of prostate cancer and their biological families; existing guidelines and consensus statements with supporting evidence for genetic testing of men with prostate cancer from any geographical location worldwide. RESULTS: Of the 660 citations identified, 23 guidelines and consensus statements met the inclusion criteria for the scoping review. Based on different levels of evidence about who should be tested and how, a diverse range of recommendations were identified. There was general consensus among the guidelines and consensus statements that men with metastatic disease be offered genetic testing; however, there was less consensus in relation to genetic testing in localised prostate cancer. While there was some consensus in relation to which genes to test, recommendations varied regarding who to test, testing methods and implementation. CONCLUSION: While genetic testing in prostate cancer is routinely recommended and numerous guidelines exist, there is still considerable lack of consensus regarding who should be tested and how they should be tested. Further evidence is needed to inform value-based genetic testing strategies for implementation in practice.

Comparing the Use of a Mobile App and a Web-Based Notification Platform for Surveillance of Adverse Events Following Influenza Immunization: Randomized Controlled Trial.

BACKGROUND: Vaccine safety surveillance is a core component of vaccine pharmacovigilance. In Canada, active, participant-centered vaccine surveillance is available for influenza vaccines and has been used for COVID-19 vaccines. OBJECTIVE: The objective of this study is to evaluate the effectiveness and feasibility of using a mobile app for reporting participant-centered seasonal influenza adverse events following immunization (AEFIs) compared to a web-based notification system. METHODS: Participants were randomized to influenza vaccine safety reporting via a mobile app or a web-based notification platform. All participants were invited to complete a user experience survey. RESULTS: Among the 2408 randomized participants, 1319 (54%) completed their safety survey 1 week after vaccination, with a higher completion rate among the web-based notification platform users (767/1196, 64%) than among mobile app users (552/1212, 45%; P<.001). Ease-of-use ratings were high for the web-based notification platform users (99% strongly agree or agree) and 88.8% of them strongly agreed or agreed that the system made reporting AEFIs easier. Web-based notification platform users supported the statement that a web-based notification-only approach would make it easier for public health professionals to detect vaccine safety signals (91.4%, agreed or strongly agreed). CONCLUSIONS: Participants in this study were significantly more likely to respond to a web-based safety survey rather than within a mobile app. These results suggest that mobile apps present an additional barrier for use compared to the web-based notification-only approach. TRIAL REGISTRATION: ClinicalTrials.gov NCT05794113; https://clinicaltrials.gov/show/NCT05794113.

Alcohol consumption and socioeconomic status associated with the risk of kidney cancer in a large Australian cohort study.

PURPOSE: Studies have shown an inverse association between alcohol consumption and kidney cancer risk. We postulate that this inverse association may be further influenced by other risk factors. METHODS: We used an Australian cohort, the 45 and Up Study, recruited between 2005 and 2009 to investigate the association between alcohol consumption, and other potential risk factors and kidney cancer incidence. The median follow-up was 5.4 years. RESULTS: Of the 267,357 participants aged ≤45 years living in New South Wales, 497 were diagnosed with kidney cancer. There was a significant inverse association between alcohol consumption and risk of kidney cancer (P = .027), and a significant inverse dose-response relationship (P = .011). There was a significant interaction between alcohol consumption and socioeconomic status (P interaction = .001). Participants residing in higher socioeconomic areas (the two most advantaged quintiles) who consumed 8-10 drinks or greater than 10 drinks per week, respectively, had a lower risk of kidney cancer compared to the group who consumed 1-4 drinks per week (hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.15-0.76, HR 0.51, 95% CI 0.31-0.83) with a dose-response trend of HR 0.62 (95% CI 0.42-0.93) per 7 drink increase in weekly alcohol consumption. CONCLUSIONS: There could be an inverse association between alcohol consumption and risk in those residents in higher socioeconomic areas.

Changes in prostate specific antigen (PSA) "screening" patterns by geographic region and socio-economic status in Australia: Analysis of medicare data in 50-69 year old men.

BACKGROUND: While it is known that national PSA testing rates have decreased in Australia since 2007, it is not known whether these trends are consistent by broad geographical areas, nor whether previously reported area-specific differences have remained in more recent time periods. METHODS: Population-based cohort study of Australian men (n = 2793,882) aged 50-69 who received at least one PSA test (Medicare Benefit Schedule item number 66655) during 2002-2018. Outcome measures included age-standardised participation rate, annual percentage change using JoinPoint regression and indirectly standardised participation rate ratio using multivariable Poisson regression. RESULTS: During 2005-09, two thirds (68%) of Australian men aged 50-69 had at least one PSA test, reducing to about half (48%) during 2014-18. In both periods, testing rates were highest among men living in major cities, men aged 50-59 years, and among men living in the most advantaged areas. Nationally, the Australian PSA testing rate increased by 9.2% per year between 2002 and 2007, but then decreased by 5.0% per year to 2018. This pattern was generally consistent across States and Territories, and socio-economic areas, however the magnitude of the trends was less pronounced in remote and very remote areas. CONCLUSIONS: The decreasing trends are consistent with a greater awareness of the current guidelines for clinical practice in Australia, which recommend a PSA test be done only with the informed consent of individual men who understand the potential benefits and risks. However, given there remain substantial geographical disparities in prostate cancer incidence and survival in Australia, along with the equivocal evidence for any benefit from PSA screening, there remains a need for more effective diagnostic strategies for prostate cancer to be implemented consistently regardless of where men live.

Cutaneous melanoma, prostate-specific antigen testing and the subsequent risk of prostate cancer diagnosis: a prospective analysis of the 45 and Up Study.

BACKGROUND: The association between cutaneous melanoma and subsequent risk of prostate cancer (PC) was examined in a large population-based cohort study. METHODS: Male participants in the Sax Institute's 45 and Up Study (Australia) were recruited between 2006 and 2009. Questionnaire data and linked administrative health data from the Centre for Health Record Linkage and Services Australia identified melanomas diagnosed between 1/1/1994 and 12 months before Study recruitment (i.e., between 2005 and 2008), incident PCs, primary healthcare utilisation and prostate-specific antigen (PSA) tests. Men were excluded from the current analyses if they had a recorded PC or other cancer diagnosis other than melanoma and non-melanoma skin cancer prior to recruitment. Multivariable Cox regression was used to estimate hazard ratios (HRs) adjusting for PSA-testing frequency before PC diagnosis. RESULTS: Of 96,548 eligible men, 1899 were diagnosed with melanoma during the melanoma diagnosis period and 3677 incident PC diagnosed during follow-up (latest date 31/12/2013). Men with melanoma diagnosis had increased risk of a subsequent PC diagnoses (vs. no melanoma; fully adjusted HR = 1.32; 95% CI: 1.09-1.60). There was weak evidence of higher risks of a subsequent PC diagnosis for men diagnosed with more than one melanoma compared to men diagnosed with only one melanoma (p = 0.077), and if first melanoma diagnosis was 10 to 15 years before Study recruitment (fully adjusted HR = 2.05; 95% CI [1.35, 3.12]). CONCLUSION: Melanoma diagnosis was associated with increased risk of subsequent PC diagnosis, after adjusting for PSA testing and primary healthcare utilisation. While our ability to adjust for PC screening reduced risk of detection bias, we acknowledge that residual confounding from increased medical surveillance after melanoma diagnoses cannot be entirely ruled out.

Propagation of Parkinson's disease by extracellular vesicle production and secretion.

Parkinson's disease (PD) is a common neurodegenerative condition affecting a significant number of individuals globally, resulting in the presentation of debilitating motor and non-motor symptoms, including bradykinesia, resting tremor, as well as mood and sleep disorders. The pathology of PD has been observed to spread through the central nervous system resulting in progressive brain degeneration and a poor prognosis. Aggregated forms of the protein α-synuclein, particularly intermediary aggregates, referred to as oligomers, or preformed fibrils, have been implicated as the causative agent in the degeneration of neuronal processes, including the dysfunction of axonal transport, mitochondrial activity, and ultimately cellular death. Extracellular vesicles (EVs) have been strongly implicated in the propagation of PD pathology. Current observations suggest that aggregated α-synuclein is transported between neurons via small EVs in a series of exocytosis and endocytosis cellular processes leading to the observed spread of neurotoxicity and cellular death. Despite some understanding of the role of EVs in neurodegeneration, the exact mechanism by which these lipidic particles participate in the progression of Parkinson's pathology is not entirely understood. Here we review the current understanding of the role of EVs in the propagation of PD and explore their potential as a therapeutic target.

Comparative Analysis of the Relative Fragmentation Stabilities of Polymorphic Alpha-Synuclein Amyloid Fibrils.

The division of amyloid fibril particles through fragmentation is implicated in the progression of human neurodegenerative disorders such as Parkinson's disease. Fragmentation of amyloid fibrils plays a crucial role in the propagation of the amyloid state encoded in their three-dimensional structures and may have an important role in the spreading of potentially pathological properties and phenotypes in amyloid-associated diseases. However, despite the mechanistic importance of fibril fragmentation, the relative stabilities of different types or different polymorphs of amyloid fibrils toward fragmentation remain to be quantified. We have previously developed an approach to compare the relative stabilities of different types of amyloid fibrils toward fragmentation. In this study, we show that controlled sonication, a widely used method of mechanical perturbation for amyloid seed generation, can be used as a form of mechanical perturbation for rapid comparative assessment of the relative fragmentation stabilities of different amyloid fibril structures. This approach is applied to assess the relative fragmentation stabilities of amyloid formed in vitro from wild type (WT) α-synuclein and two familial mutant variants of α-synuclein (A30P and A53T) that generate morphologically different fibril structures. Our results demonstrate that the fibril fragmentation stabilities of these different α-synuclein fibril polymorphs are all highly length dependent but distinct, with both A30P and A53T α-synuclein fibrils displaying increased resistance towards sonication-induced fibril fragmentation compared with WT α-synuclein fibrils. These conclusions show that fragmentation stabilities of different amyloid fibril polymorph structures can be diverse and suggest that the approach we report here will be useful in comparing the relative stabilities of amyloid fibril types or fibril polymorphs toward fragmentation under different biological conditions.

Socioeconomic differences in prostate cancer treatment: A systematic review and meta-analysis.

BACKGROUND: Since the 1990s, most nations have had a reduction or stabilisation in prostate cancer mortality. However, socioeconomic differences in disease specific mortality and survival have persisted. This has been partially attributed to differences in treatment choices. The aim of this systematic review and meta-analysis was to describe and quantify socioeconomic differences in use of prostate cancer treatment in the literature. METHODS: MEDLINE, CINAHL and Embase were searched from 01 January 2000-01 April 2021 to identify articles that reported use of prostate cancer treatment by socioeconomic status. Random effects meta-analysis was used to analyse socioeconomic differences in treatment where there was more than one study for treatment type. A modified version of the Newcastle-Ottawa Scale was used to assess risk of bias. RESULTS: Out of 7267 articles identified, eight met the inclusion criteria and six were analysed using meta-analysis. Meta-analysis could only be completed for non-active treatment (watchful waiting/active surveillance). Lower education was associated with non-active treatment (OR=0.90, [95% CI 0.83-0.98], p=0.02, I2=67%), however, level of income was not (OR=0.87, [CI 0.75-1.02], p=0.08, I2=94%). Sensitivity analysis of studies where active surveillance was the outcome (n=3), indicated no associations with level of income (OR=0.91, [95% CI 0.82-1.01], p=0.08, I2=52%) or education (OR=0.88, [95% CI 0.70-1.10], p=0.25, I2=79%). All studies were assessed as high-risk of bias. DISCUSSION: The relationship between socioeconomic status and prostate cancer treatment depended on the socioeconomic variable being used, the treatment type and how it was defined in research. Considerable methodological limitations were identified. Further research should improve on previous findings and address current gaps.

Family history, obesity, urological factors and diabetic medications and their associations with risk of prostate cancer diagnosis in a large prospective study.

BACKGROUND: Prostate cancer (PC) aetiology is unclear. PC risk was examined in relation to several factors in a large population-based prospective study. METHODS: Male participants were from Sax Institute's 45 and Up Study (Australia) recruited between 2006 and 2009. Questionnaire and linked administrative health data from the Centre for Health Record Linkage and Services Australia were used to identify incident PC, healthcare utilisations, Prostate Specific Antigen (PSA) testing reimbursements and dispensing of metformin and benign prostatic hyperplasia (BPH) prescriptions. Multivariable Cox and Joint Cox regression analyses were used to examine associations by cancer spread, adjusting for various confounders. RESULTS: Of 107,706 eligible men, 4257 developed incident PC up to end 2013. Risk of PC diagnosis increased with: PC family history (versus no family history of cancer; HRadjusted = 1.36; 95% CI:1.21-1.52); father and brother(s) diagnosed with PC (versus cancer-free family history; HRadjusted = 2.20; 95% CI:1.61-2.99); severe lower-urinary-tract symptoms (versus mild; HRadjusted = 1.77; 95% CI:1.53-2.04) and vasectomy (versus none; HRadjusted = 1.08; 95% CI:1.00-1.16). PC risk decreased with dispensed prescriptions (versus none) for BPH (HRadjusted = 0.76; 95% CI:0.69-0.85) and metformin (HRadjusted = 0.57; 95% CI:0.48-0.68). Advanced PC risk increased with vasectomy (HRadjusted = 1.28; 95% CI:1.06-1.55) and being obese (versus normal weight; HRadjusted = 1.31; 95% CI:1.01-1.69). CONCLUSION: Vasectomy and obesity are associated with an increased risk of advanced PC. The reduced risk of localised and advanced PC associated with BPH, and diabetes prescriptions warrants investigation.

Changes in prostate cancer incidence, mortality and survival in relation to prostate specific antigen testing in New South Wales, Australia.

BACKGROUND: To examine changes in prostate cancer incidence and mortality rates, and 5-year relative survival, in relation to changes in the rate of prostate specific antigen (PSA) screening tests and the use of radical prostatectomy (RP) in the Australian population. METHODS: Prostate cancer stage-specific incidence rates, 5-year relative survival and mortality rates were estimated using New South Wales Cancer Registry data. PSA screening test rates and RP/Incidence ratios were estimated from Medicare Benefits Schedule claims data. We used multiple imputation to impute stage for cases with "unknown" stage at diagnosis. Annual percentage changes (APC) in rates were estimated using Joinpoint regression. RESULTS: Trends in the age-standardized incidence rates for localized disease largely mirrored the trends in PSA screening test rates, with a substantial 'spike' in the rates occurring in 1994, followed by a second 'spike' in 2008, and then a significant decrease from 2008 to 2015 (APC -6.7, 95% CI -8.2, -5.1). Increasing trends in incidence rates were observed for regional stage from the early 2000s, while decreasing or stable trends were observed for distant stage since 1993. The overall RP/Incidence ratio increased from 1998 to 2003 (APC 9.6, 95% CI 3.8, 15.6), then remained relatively stable to 2015. The overall 5-year relative survival for prostate cancer increased from 58.4% (95% CI: 55.0-61.7%) in 1981-1985 to 91.3% (95% CI: 90.5-92.1%) in 2011-2015. Prostate cancer mortality rates decreased from 1990 onwards (1990-2006: APC -1.7, 95% CI -2.1, -1.2; 2006-2017: APC -3.8, 95% CI -4.4, -3.1). CONCLUSIONS: Overall, there was a decrease in the incidence rate of localized prostate cancer after 2008, an increase in survival over time and a decrease in the mortality rate since the 1990s. This seems to indicate that the more conservative use of PSA screening tests in clinical practice since 2008 has not had a negative impact on population-wide prostate cancer outcomes.