Serum C-reactive protein is associated with earlier mortality across different interstitial lung diseases.

BACKGROUND AND OBJECTIVE: The acute-phase protein C-reactive protein (CRP) is known to be associated with poor outcomes in cancer and cardiovascular disease, but there is limited evidence of its prognostic implications in interstitial lung diseases (ILDs). We therefore set out to test whether baseline serum CRP levels are associated with mortality in four different ILDs. METHODS: In this retrospective study, clinically measured CRP levels, as well as baseline demographics and lung function measures, were collected for ILD patients first presenting to the Royal Brompton Hospital between January 2010 and December 2019. Cox regression analysis was used to determine the relationship with 5-year mortality. RESULTS: Patients included in the study were: idiopathic pulmonary fibrosis (IPF) n = 422, fibrotic hypersensitivity pneumonitis (fHP) n = 233, rheumatoid arthritis associated ILD (RA-ILD) n = 111 and Systemic Sclerosis associated ILD (SSc-ILD) n = 86. Patients with a recent history of infection were excluded. Higher CRP levels were associated with shorter 5-year survival in all four disease groups on both univariable analyses, and after adjusting for age, gender, smoking history, immunosuppressive therapy and baseline disease severity (IPF: HR (95% CI): 1.3 (1.1-1.5), p = 0.003, fHP: 1.5 (1.2-1.9), p = 0.001, RA-ILD: 1.4 (1.1-1.84), p = 0.01 and SSc-ILD: 2.7 (1.6-4.5), p < 0.001). CONCLUSION: Higher CRP levels are independently associated with reduced 5-year survival in IPF, fHP, RA-ILD and SSc-ILD.

EFOMP Malaga Declaration 2023: An updated vision on Medical Physics in Europe.

In 2006, the European Federation of Organisations for Medical Physics (EFOMP) adopted the "Malaga Declaration". The declaration asserted the fundamental role of Medical Physics professionals in the radiation protection of patients, workers, general public, carers and comforters and research participants in hospitals. However, since that time the Medical Physics profession has evolved in Europe and new regulations and documentation have been issued, such as directive 2013/59/Euratom and the "European Guidelines on Medical Physics Expert" (RP174). EFOMP has published updated core-curricula and strived towards the recognition of the profession at the European level. In view of this, an update of the original Malaga Declaration was deemed necessary, to define the future vision that will guide the actions of the Federation in the years to come. This Declaration, which has been approved by the national member organizations of EFOMP in April 2023, is much broader than the original Malaga version. This is expected considering the rapid evolution of medical device technology over the last 17 years. The Radiation Protection Expert in hospital settings should be an MPE, since the latter has the highest level of radiation protection knowledge and training. Given the passion and energy that animated the debate, which led to the updating of the Malaga Declaration, we are confident that it represents a solid basis for the development of our profession in Europe which is in consonance with the aspirations of us all.

EFOMP policy statement 18: Medical physics education for the non-physics healthcare professions.

Although Medical Physics educators have historically contributed to the education of the non-physics healthcare professions, their role was not studied in a systematic manner. In 2009, EFOMP set up a group to research the issue. In their first paper, the group carried out an extensive literature review regarding physics teaching for the non-physics healthcare professions. Their second paper reported the results of a pan-European survey of physics curricula delivered to the healthcare professions and a Strengths-Weaknesses-Opportunities-Threats (SWOT) audit of the role. The group's third paper presented a strategic development model for the role, based on the SWOT data. A comprehensive curriculum development model was subsequently published, whilst plans were laid to develop the present policy statement. This policy statement presents mission and vision statements for Medical Physicists teaching non-physics users of medical devices and physical agents, best practices for teaching non-physics healthcare professionals, a stepwise process for curriculum development (content, method of delivery and assessment), and summary recommendations based on the aforementioned research studies.

MUC5B rs35705950 minor allele associates with older age and better survival in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: The minor T-allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real-world population of European IPF patients. METHODS: In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed. RESULTS: In a multi-variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42-49]) compared to non-carriers (29 months [CI: 26-33]; p = 4 × 10-12 ). CONCLUSION: MUC5B minor allele carriage associates with a better median transplant-free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients.

CTContour: An open-source Python pipeline for automatic contouring and calculation of mean SSDE along the abdomino-pelvic region for CT images; validation on fifteen systems.

PURPOSE: Calculation of the Size Specific Dose Estimate (SSDE) requires accurate delineation of the skin boundary of patient CT slices. The AAPM recommendation for SSDE evaluation at every CT slice is too time intensive for manual contouring, prohibiting real-time or bulk processing; an automated approach is therefore desirable. Previous automated delineation studies either did not fully disclose the steps of the algorithm or did not always manage to fully isolate the patient. The purpose of this study was to develop a validated, freely available, fast, vendor-independent open-source tool to automatically and accurately contour and calculate the SSDE for the abdomino-pelvic region for entire studies in real-time, including flagging of patient-truncated images. METHODS: The Python tool, CTContour, consists of a sequence of morphological steps and scales over multiple cores for speed. Tool validation was achieved on 700 randomly selected slices from abdominal and abdomino-pelvic studies from public datasets. Contouring accuracy was assessed visually by four medical physicists using a 1-5 Likert scale (5 indicating perfect contouring). Mean SSDE values were validated via manual calculation. RESULTS: Contour accuracy validation produced a score of four of five for 98.5 % of the images. A 300 slice exam was contoured and truncation flagged in 6.3 s on a six-core laptop. CONCLUSIONS: The algorithm was accurate even for complex clinical scenarios and when artefacts were present. Fast execution makes it possible to automate the calculation of SSDE in real time. The tool has been published on GitHub under the GNU-GPLv3 license.

Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476).

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10-9 ) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group.

Early career medical physicist groups in Europe: An EFOMP survey.

INTRODUCTION: Training, educating, and fostering of young professionals are key requisites for the progress of any profession. The young medical physicists (MPs) of today are the medical physics professionals and leaders of tomorrow. It is, therefore, essential that they learn to work collectively and in a coordinated manner at both national and European levels at an early stage in their career. In view of this, EFOMP is planning to create a special interest group (SIG) encompassing early career MPs from across Europe. METHODS: A survey was developed by EFOMP and circulated to all National Member Organisations (NMOs) to gather information on the status of early career groups in their respective societies and on the interest to partake in such group within the Federation. RESULTS: Of the 36 NMOs that are part of EFOMP, 32 responded to the survey. Only 9 NMOs have established early career MPs groups within their NMOs, while the remaining countries are either considering setting up young MPs groups in the future (15 NMOs) or do not show such interest (8 NMOs). Of all responders, 59% expressed interest in the creation of the EFOMP SIG, 34% remained neutral towards this issue by not answering the question and for two NMOs the SIG idea had no appeal. CONCLUSION: Most NMOs showed interest in the creation of an early career MPs group within EFOMP and offered constructive feedbacks on the roles they envisage for the group. EFOMP will use and implement this information when establishing the special interest group.

Short-term lung function changes predict mortality in patients with fibrotic hypersensitivity pneumonitis.

BACKGROUND AND OBJECTIVE: A proportion of patients with fibrotic hypersensitivity pneumonitis (fHP) follow a progressive disease course despite immunosuppressive treatment. Little is known about predictors of mortality in fHP. We aimed to investigate the impact of short-term lung function changes in fHP on mortality. METHODS: Baseline demographics for 145 consecutive patients with a multi-disciplinary team diagnosis of fHP, as well as baseline and 1-year follow-up of lung function, baseline echocardiographic findings, bronchoalveolar lavage (BAL) cellularity and all-cause mortality were recorded. Changes in forced vital capacity (FVC) ≥ 5% and ≥10%, and diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 10% and ≥15% at 1 year were calculated. Cox proportional hazards analysis was performed to test for associations with mortality. RESULTS: Baseline lung function severity, age, presence of honeycombing on computed tomography (CT) and echocardiographic pulmonary arterial systolic pressure (PASP) ≥ 40 mm Hg were associated with early mortality, while BAL lymphocytosis was associated with improved survival. A decline in FVC ≥ 5% (hazard ratio [HR]: 3.10, 95% CI: 2.00-4.81, p < 0.001), FVC ≥ 10% (HR: 3.11, 95% CI: 1.94-4.99, p < 0.001), DLCO ≥ 10% (HR: 2.80, 95% CI: 1.78-4.42, p < 0.001) and DLCO ≥ 15% (HR: 2.92, 95% CI: 1.18-4.72, p < 0.001) at 1 year was associated with markedly reduced survival on univariable and multivariable analyses after correcting for demographic variables, disease severity, honeycombing on CT and treatment, as well as BAL lymphocytosis and PASP ≥ 40 mm Hg on echocardiography, in separate models. CONCLUSION: Worsening in FVC and DLCO at 1 year, including a marginal decline in FVC ≥ 5% and DLCO ≥ 10%, is predictive of markedly reduced survival in fHP.

Being an excellent scientist is not enough to succeed! Soft skills for medical physicists.

PURPOSE: To provide a review of the literature and commentary regarding soft skills for Medical Physicists. METHOD: A comprehensive search in PubMed was carried out using the searchwords 'medical physics' coupled separately ('AND', both in Title) with each of the following terms: leadership, teamwork, communication, pedagog*, teach*, marketing, conflict resolution, negotiat*, qualitative research, organizational psychology. RESULTS: The total number of PubMed references was extremely low (total 6 relevant articles for all of leadership, communication, pedagog*, teach*, with the rest of the searchwords giving zero hits) which is quite disturbing. For an improved perspective, we compared the search for 'leadership AND medical physics' to 'leadership AND medical' and 'leadership AND nursing' we only had 4 hits for Medical Physics as opposed to 564 for 'leadership AND medical' and 1419 for 'leadership AND nursing'. CONCLUSIONS: It seems that Medical Physicists give an extremely low priority to soft skills as opposed to scientific skills. In a world of austerity economics and sometimes over commoditization such a situation is not only disturbing it is actually very risky for the profession. Medical Physicists must learn to provide strategic and robust leadership, be able to market their profession to all stakeholders (in particular to decision makers, other health care professions and the general public), be able to communicate their role, negotiate effectively for their profession, and boost their abilities for teambuilding and conflict resolution. The setting up of education programmes to overcome this soft skill deficit among medical physicists by national, regional and international medical physics organizations must be given priority.

CX-5461 Sensitizes DNA Damage Repair-proficient Castrate-resistant Prostate Cancer to PARP Inhibition.

Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) with defects in homologous recombination (HR) DNA repair. New treatments are required for the remaining tumors, and an emerging strategy is to combine PARP inhibitors with other therapies that induce DNA damage. Here we tested whether PARP inhibitors are effective for HR-proficient CRPC, including androgen receptor (AR)-null tumors, when used in combination with CX-5461, a small molecule that inhibits RNA polymerase I transcription and activates the DNA damage response, and has antitumor activity in early phase I trials. The combination of CX-5461 and talazoparib significantly decreased in vivo growth of patient-derived xenografts of HR-proficient CRPC, including AR-positive, AR-null, and neuroendocrine tumors. CX-5461 and talazoparib synergistically inhibited the growth of organoids and cell lines, and significantly increased the levels of DNA damage. Decreased tumor growth after combination therapy was maintained for 2 weeks without treatment, significantly increasing host survival. Therefore, combination treatment with CX-5461 and talazoparib is effective for HR-proficient tumors that are not suitable for monotherapy with PARP inhibitors, including AR-null CRPC. This expands the spectrum of CRPC that is sensitive to PARP inhibition.

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

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.

Education, training and registration of Medical Physics Experts across Europe.

From its inception, EFOMP has pursued a policy to improve and coordinate education and training of medical physicists across all its participating European countries. Several EFOMP policy statements on education and training have been published and surveys have been held to get an overview of the actual situation. At the beginning of 2020 a new survey was distributed amongst the 36 National Member Organizations (NMOs), in which questions were based on recommendations published in the most recent policy statements. Thirty-three of the NMOs (91%) responded, of which 22 indicated having a National Registration Scheme (NRS) for Medical Physics Experts (MPEs) in place. Another 6 indicated considering such a scheme. Results of the questionnaire showed that there was good correspondence between education and training programmes, i.e. a division between a BSc phase, an MSc phase and a clinical phase after completion of the MSc. Differences between NRSs were primarily seen in the availability and composition of a supervising committee and in the availability of guidelines for handling professional misconduct. In addition, some differences were seen in the topics that were part of the education and training programme. The goal of a universal (registered) MPE accepted by all European countries is still far away despite the progress being made. The new procedure for approving an existing NRS, which fulfils all EFOMP criteria is seen as an important step forward. Exchange of experience, knowledge, ideas and, above all, MPE trainees between European countries is seen as the best approach to achieve this goal.

Telomeres in Interstitial Lung Disease.

Interstitial lung diseases (ILD) encompass a group of conditions involving fibrosis and/or inflammation of the pulmonary parenchyma. Telomeres are repetitive DNA sequences at chromosome ends which protect against genome instability. At each cell division, telomeres shorten, but the telomerase complex partially counteracts progressive loss of telomeres by catalysing the synthesis of telomeric repeats. Once critical telomere shortening is reached, cell cycle arrest or apoptosis are triggered. Telomeres progressively shorten with age. A number of rare genetic mutations have been identified in genes encoding for components of the telomerase complex, including telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), in familial and, less frequently, in sporadic fibrotic ILDs. Defects in telomerase result in extremely short telomeres. More rapidly progressive disease is observed in fibrotic ILD patients with telomere gene mutations, regardless of underlying diagnosis. Associations with common single nucleotide polymorphisms in telomere related genes have also been demonstrated for various ILDs. Shorter peripheral blood telomere lengths compared to age-matched healthy individuals are found in a proportion of patients with fibrotic ILDs, and in idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (HP) have been linked to worse survival, independently of disease severity. Greater susceptibility to immunosuppressant-induced side effects in patients with short telomeres has been described in patients with IPF and with fibrotic HP. Here, we discuss recent evidence for the involvement of telomere length and genetic variations in the development, progression, and treatment of fibrotic ILDs.

Serum markers of pulmonary epithelial damage in systemic sclerosis-associated interstitial lung disease and disease progression.

BACKGROUND AND OBJECTIVE: The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable, and accurate prognostic markers are needed. KL-6 is a mucin-like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21-1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury. METHODS: Serum KL-6 and CYFRA 21-1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed-effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis. RESULTS: In both cohorts, KL-6 and CYFRA 21-1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL-6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc-ILD, serum KL-6, but not CYFRA 21-1, was significantly associated with DLCO decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL-6 remained predictive of decline in DLCO in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage. CONCLUSION: Our results suggest serum KL-6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc-ILD.

ESTABLISHING LOCAL AND NATIONAL DIAGNOSTIC AND INTERVENTIONAL CARDIOLOGY AND RADIOLOGY REFERENCE LEVELS IN A SMALL EUROPEAN STATE: THE CASE OF MALTA.

European Directive 2013/59/EURATOM requires the establishment and use of diagnostic reference levels (DRLs) for diagnostic and interventional procedures. The purpose of this study was to establish local DRLs for a major tertiary public hospital. As the hospital is the only such hospital in Malta, the same data collected for setting local DRLs can also be used for setting national DRLs, making local DRLs de facto national DRLs. A retrospective survey of cumulative kerma-area product (KAP) and fluoroscopy time data from the cardiac catheterisation laboratory and interventional radiology suites was carried out. The effect of system upgrades on cumulative KAP was also assessed. Local DRLs were set for common cardiology and interventional radiology procedures. All DRLs compare favourably with those in European literature. A Philips Allura Clarity upgrade to the cardiac catheterisation laboratories led to significant reductions in cumulative KAP (p â‰ª  0.05) for most procedures.

Interaction between the promoter MUC5B polymorphism and mucin expression: is there a difference according to ILD subtype?

The MUC5B promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in MUC5B rs35705950 T-carriers is specific to IPF.

Defining genetic risk factors for scleroderma-associated interstitial lung disease : IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease.

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), pcorr = 0.015) and rs10488631 (OR 1.48 (1.14-1.92), pcorr = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), pcorr = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), pcorr = 0.0098), and rs2004640 (OR 1.39 (1.11-1.75), pcorr = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), pcorr = 6.6 × 10-6). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), pcorr = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.

Early Post-treatment Prostate-specific Antigen at 4 Weeks and Abiraterone and Enzalutamide Treatment for Advanced Prostate Cancer: An International Collaborative Analysis.

BACKGROUND: Declines in prostate-specific antigen (PSA) levels at 12wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study. OBJECTIVE: To evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term. RESULTS AND LIMITATIONS: We identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4wk, and 948 at both 4 and 12wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21-25) compared with no change (median: 17; 95% CI: 15-18) and progression (median: 13; 95% CI: 10-15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio=0.57; 95% CI=0.48-0.67; p<0.001). PSA4w30 strongly correlated with PSA12w30 (ρ=0.91; 95% CI=0.90-0.92; p<0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4wk had a PSA12w30 (1% of the overall population). CONCLUSIONS: PSA changes in the first 4wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions. PATIENT SUMMARY: Prostate-specific antigen changes at 4wk after abiraterone/enzalutamide treatment are important to determine patients' outcome and should be taken into consideration in clinical practice.