Abiraterone, Olaparib, or Abiraterone + Olaparib in First-line Metastatic Castration-Resistant Prostate Cancer with DNA Repair Defects (BRCAAway).

PURPOSE: Deleterious germline/somatic homologous recombination-repair mutations (HRRm) are present in ~25% of metastatic castration resistant prostate cancer (mCRPC) patients. Preclinically, PARP-Inhibition demonstrated synergism with ARP-targeted therapy. This trial evaluated efficacy of ARP-Inhibitor versus PARP-Inhibitor versus combination as first-line therapy in mCRPC patients with HRRm. PATIENTS AND METHODS: BRCAAway is a biomarker pre-selected, randomized, phase-2 trial. Patients with BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm1: Abiraterone (1000mg)/prednisone (Abi/pred) (5mg), Arm2: Olaparib (Ola) (300mg), or Arm3: Abiraterone/prednisone + Olaparib (Abi/pred+Ola). Single-agent arms could cross over at progression. Exploratory Arm4 patients with other HRRm received Olaparib alone. The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response, PSA response, and safety. RESULTS: 61/165 eligible patients had BRCA1/2 or ATM mutations: Median age: 67 (IQR 62-73) years. Mutations: BRCA1 n=3, BRCA2 n=46, ATM n=11, multiple n= 1; 33 germline, 28 somatic. Median PFS (95% CI): Abi/pred, 8.6 months (m) (2.9, 17), Ola, 14 m (8.4, 20), Abi/pred+Ola, 39 m (22, NR). There were no G4/5 AEs. 8/19 on Abi/pred crossed over to Ola, and 8/21 vice versa: Median PFS (95% CI) from crossover: Ola-after-Abi/pred, 8.3 m (5.5, 15); Abi/pred-after-Ola, 7.2 m (2.8, NR). Median PFS (95% CI) from randomization: Ola-after-Abi/pred, 16 m (7.8, 25), Abi/pred-after-Ola, 16 m (11, NR). 17/165 patients with other HRRm received olaparib: Median PFS (95% CI): 5.5 m (2, 11). CONCLUSIONS: In mCRPC patients with BRCA1/2 or ATM HRRm, abiraterone/prednisone + olaparib was well tolerated and demonstrated longer PFS versus either agent alone or sequentially.

Clinical Pilot of Bacterial Transcriptional Profiling as a Combined Genotypic and Phenotypic Antimicrobial Susceptibility Test.

Antimicrobial resistance is a growing health threat, but standard methods for determining antibiotic susceptibility are slow and can delay optimal treatment, which is especially consequential in severe infections such as bacteremia. Novel approaches for rapid susceptibility profiling have emerged that characterize either bacterial response to antibiotics (phenotype) or detect specific resistance genes (genotype). GoPhAST-R is a novel assay, performed directly on positive blood cultures, that integrates rapid transcriptional response profiling with detection of key resistance gene transcripts, thereby providing simultaneous data on both phenotype and genotype. Here, we performed the first clinical pilot of GoPhAST-R on 42 positive blood cultures: 26 growing Escherichia coli, 15 growing Klebsiella pneumoniae, and 1 with both. An aliquot of each positive blood culture was exposed to 9 different antibiotics, lysed, then underwent rapid transcriptional profiling on the NanoString® platform; results were analyzed using an in-house susceptibility classification algorithm. GoPhAST-R achieved 95% overall agreement with standard antimicrobial susceptibility testing methods, with the highest agreement for beta-lactams (98%) and the lowest for fluoroquinolones (88%). Epidemic resistance genes including the extended spectrum beta-lactamase bla CTX-M-15 and the carbapenemase bla KPC were also detected within the population. This study demonstrates the clinical feasibility of using transcriptional response profiling for rapid resistance determination, although further validation with larger and more diverse bacterial populations will be essential in future work. GoPhAST-R represents a promising new approach for rapid and comprehensive antibiotic susceptibility testing in clinical settings.

Confirmation of ethanol administration in racing greyhounds by LC-MS-MS.

Ethanol is a prohibited substance in professional animal racing as its administration causes physiological effects such as depression of the central nervous system. Regulation of potential doping agents, including those that inhibit performance, is critical to ensure integrity and animal welfare in greyhound racing, but the detection of ethanol is complicated by dietary and/or environmental exposure. In response, a reliable analytical method capable of detecting recent ethanol administration in greyhound urine samples was validated and implemented. Liquid chromatography-tandem mass spectrometry (LC-MS-MS) was used to investigate the variation in urinary ethanol metabolites; ethyl-ß-D glucuronide (EG; γ ¯ EG $$ {\overline{\gamma}}_{\mathrm{EG}} $$ = 1.0 µg/ml, s EG $$ {s}_{\mathrm{EG}} $$ = 3.3 µg/ml) and ethyl sulfate (ES; γ ¯ ES $$ {\overline{\gamma}}_{\mathrm{ES}} $$ = 0.9 µg/ml, s ES $$ {s}_{\mathrm{ES}} $$ = 1.9 µg/ml) levels from a reference population of 202 racing greyhounds. These were compared to urine samples collected following administration of ethanol to one male and one female greyhound. Results were used to establish a threshold within the national rules of greyhound racing: γ ¯ EG $$ {\overline{\gamma}}_{\mathrm{EG}} $$ and γ ¯ ES $$ {\overline{\gamma}}_{\mathrm{ES}} $$ > 20 µg/ml in urine are defensible criteria to confirm ethanol administration to greyhounds. Case studies of competition samples are provided to demonstrate the forensic translation of this work.

Real-World Incidence and Severity of Hypertension Caused by Abiraterone Acetate in Patients With Metastatic Prostate Cancer.

BACKGROUND: Abiraterone acetate (AA) is used in treatment of patients with metastatic prostate cancer. Despite the survival advantage, AA is associated with hypertension due to mineralocorticoid excess syndrome. OBJECTIVE: We conducted a single-center retrospective analysis to evaluate the real-world incidence and severity of AA-induced hypertension. METHODS: Electronic health records were used to collect baseline characteristics and prostate cancer history. Patient data, including blood pressure at each 4 (±2)-week interval, were collected for 24 weeks after the initiation of AA therapy. The primary endpoint was the incidence and severity of AA-induced hypertension. The secondary endpoints include effect of different prednisone dosing regimens and prostate cancer types on hypertensive incidence and the impact of clinical pharmacists' involvement in managing AA-induced hypertension. RESULTS: A total of 142 patients who met our inclusion criteria received AA for metastatic prostate cancer, 73 (51.4%) with metastatic castration-resistant prostate cancer (mCRPC), and 69 (48.6%) with metastatic castration-sensitive prostate cancer (mCSPC). Of all, 43.7% experienced all-grade hypertension, and 28.2% experienced grade 3-4 hypertension. There was no difference in incidence of hypertension between patients receiving 5 mg of prednisone daily and those receiving 5 mg of prednisone twice daily. All-grade hypertension occurred in 39.7% of mCRPC and 47.8% of mCSPC patients (P = 0.33). Thirty-two percent of patients were actively managed by a clinical pharmacist and had an overall trend of reduced hypertension severity after 12 weeks. CONCLUSION AND RELEVANCE: This single-center, retrospective cohort study found that real-world metastatic prostate cancer patients who received AA had substantially higher incidence and severity of hypertension compared with clinical trials regardless of prednisone dose. In patients with mCRPC and mCSPC, the role of prednisone dose in hypertension incidence and severity warrants further investigation. Overall, results indicate the need for closely monitoring hypertension and optimization of anti-hypertensive therapy by multidisciplinary teams in metastatic prostate cancer patients receiving AA.

Pain and Its Association with Survival for Black and White Individuals with Advanced Prostate Cancer in the United States.

Bone pain is a well-known quality-of-life detriment for individuals with prostate cancer and is associated with survival. This study expands previous work into racial differences in multiple patient-reported dimensions of pain and the association between baseline and longitudinal pain and mortality. This is a prospective cohort study of individuals with newly diagnosed advanced prostate cancer enrolled in the International Registry for Men with Advanced Prostate Cancer (IRONMAN) from 2017 to 2023 at U.S. sites. Differences in four pain scores at study enrollment by race were investigated. Cox proportional hazards models and joint longitudinal survival models were fit for each of the scale scores to estimate HRs and 95% confidence intervals (CI) for the association with all-cause mortality. The cohort included 879 individuals (20% self-identifying as Black) enrolled at 38 U.S. sites. Black participants had worse pain at baseline compared with White participants, most notably a higher average pain rating (mean 3.1 vs. 2.2 on a 10-point scale). For each pain scale, higher pain was associated with higher mortality after adjusting for measures of disease burden, particularly for severe bone pain compared with no pain (HR, 2.47; 95% CI: 1.44-4.22). The association between pain and all-cause mortality was stronger for participants with castration-resistant prostate cancer compared with those with metastatic hormone-sensitive prostate cancer and was similar among Black and White participants. Overall, Black participants reported worse pain than White participants, and more severe pain was associated with higher mortality independent of clinical covariates for all pain scales. SIGNIFICANCE: Black participants with advanced prostate cancer reported worse pain than White participants, and more pain was associated with worse survival. More holistic clinical assessments of pain in this population are needed to determine the factors upon which to intervene to improve quality of life and survivorship, particularly for Black individuals.

Quality of life in the year after new diagnosis with advanced prostate cancer for Black and White individuals living in the US.

PURPOSE: To assess differences in baseline and longitudinal quality of life among Black and White individuals in the US with advanced prostate cancer. METHODS: Secondary analysis of data from the International Registry for Men with Advanced Prostate Cancer (IRONMAN) including US participants newly diagnosed with advanced prostate cancer and identifying their race as Black or White from 2017 to 2023. Participants completed the EORTC QLQ-C30 Quality of Life (QoL) Survey at study enrollment and every 3 months thereafter for up to 1 year of follow-up reporting 15 scale scores ranging from 0 to 100 (higher functioning and lower symptom scores represent better quality of life). Linear mixed effects models with race and month of questionnaire completion were fit for each scale, and model coefficients were used to assess differences in baseline and longitudinal QoL by race. RESULTS: Eight hundred and seventy-nine participants were included (20% identifying as Black) at 38 US sites. Compared to White participants at baseline, Black participants had worse constipation (mean 6.3 percentage points higher; 95% CI 2.9-9.8), financial insecurity (5.7 (1.4-10.0)), and pain (5.1 (0.9-9.3)). QoL decreased over time similarly by race; most notably, role functioning decreased by 0.7 percentage points (95% CI -0.8, -0.5) per month. CONCLUSION: There are notable differences in quality of life at new diagnosis of advanced prostate cancer for Black and White individuals, and quality of life declines similarly in the first year for both groups. Interventions that address specific aspects of quality of life in these patients could meaningfully improve the overall survivorship experience.

Waldenström macroglobulinemia with secondary pure red cell aplasia in a patient with metastatic castrate resistant prostate cancer receiving an immune checkpoint inhibitor: a case report.

BACKGROUND: Hypoproliferative anemia is a frequently encountered adverse event in cancer patients receiving immune checkpoint inhibitors (ICI). Secondary pure red cell aplasia (PRCA) is a rare but recognized immune related adverse event. With the burgeoning use of ICIs, the association of secondary PRCA with an underlying lymphoproliferative disorder is often overlooked. CASE PRESENTATION: We report a case of a 67-year-old non-Hispanic Caucasian male with metastatic castrate resistant prostate cancer, who developed severe transfusion dependent anemia with reticulocytopenia while receiving treatment with olaparib and pembrolizumab. His bone marrow findings demonstrated erythroid hypoplasia, in addition to a CD5-negative, CD10-negative monotypic B-cell population and a somatic MYD88L265P mutation. With a presence of an IgM-paraprotein, he was diagnosed with Waldenström macroglobulinemia (WM) with secondary PRCA and treated with 6 cycles of bendamustine and rituximab. He achieved a complete response with this regimen and was transfusion independent. CONCLUSION: In this case, underlying WM was uncovered through systematic investigation of anemia caused by ICI therapy. This report highlights the possibility of a lymphoproliferative disorder in patients with concerns for PRCA with prior ICI exposure. If identified, treating the underlying lymphoproliferative disorder is highly efficacious in the management of the secondary PRCA.

Burnout in healthcare workers in COVID-19-dedicated hospitals.

BACKGROUND: Considering the prolongation of the COVID-19 pandemic, the lack of studies on burnout, particularly in healthcare workers, needs to be addressed. This report aimed to identify the risk factors of burnout by comparing the level of burnout between nurses in general wards and those in COVID-19-dedicated wards in a national university hospital. METHODS: A survey based on the Korean version of Burnout Assessment Tool (BAT-K) was conducted on nurses between 10 January and 31 January 2022. The BAT-K consists of exhaustion, mental distance, cognitive impairment, emotional impairment and secondary symptoms. RESULTS: A total of 165 nurses, including 81 nurses from the COVID-19-dedicated ward, completed the questionnaire. The percentage of general-ward nurses with an emotional impairment score above the clinical cutoff was higher than that of COVID-19 ward nurses. General ward compared to the COVID-19 ward increased the risk of presenting with total-core symptoms. Two factors increased the risk regarding mental distance: short career length and underlying disease. CONCLUSIONS: In contrast to previous studies, the risk of burnout in the COVID-19-ward nurses was lower than that of the general ward nurses. The risk regarding mental distance was correlated with short career length and presence of an underlying disease.

Assessment of left ventricular geometry in normotensive type II diabetic patients.

Background: Abnormalities of glucose metabolism are associated with abnormal left ventricular geometry (LV) independent of atherosclerosis. Abnormal LV geometry, a predictor of premature cardiovascular events, indicates presence of subclinical target organ damages. Screening for abnormal LV geometry in diseases of abnormal glucose metabolism is desirable as part of their management protocol. Aim: To assess the left ventricular geometry in normotensive type II diabetic patients. Cross-sectional, descriptive, hospital-based study. One hundred normotensive type II diabetic patients drawn from the Endocrinology and Family Medicine Clinics of a tertiary hospital were age- and gender-matched with 100 apparently healthy controls. Participants meeting the criteria and informed consent proceeded for clinical evaluation, biochemical assessment, electrocardiography, and echocardiography using the American Society of Echocardiography guideline. Materials and Methods: Data were analyzed using the Statistical Package for Social Sciences [SPSS] version 25.0 (Chicago Illinois, USA). Results: Mean age of study and control groups was (55.56 ± 9.89 versus 55.47 ± 10.7) years (χ2 = 0.062, P = 0.951). The mean duration of diabetes illness was 6.57 ± 6.26 years. Prevalence of abnormal LV geometry was 51% (study) versus 18% (control) FT, P < 0.001). Concentric remodeling was the predominant geometry in 36% of study versus 11% of controls, followed by eccentric hypertrophy in 11% (study) versus 4% (control) and concentric hypertrophy in 4% (study) versus 3% (control). Geometry was normal in 49% of study against 82% in the controls (FT, P < 0.001). Significant association existed between LV geometry and duration of diabetes (χ2 = 10.793, P = 0.005). Conclusion: Abnormal LV geometry is highly prevalent in normotensive diabetic patients.

Feasibility of home-based exercise training in men with metastatic castration-resistant prostate cancer.

BACKGROUND: Home-based training increases accessibility to exercise and mitigates the side effects of hormone therapy for prostate cancer (PC). However, it is unknown if men with more advanced disease are willing to partake in such interventions. PURPOSE: To determine the feasibility of a home-based exercise intervention in men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: mCRPC patients on androgen receptor signaling inhibitors (ARSI) were prescribed a 12-week, home-based exercise intervention using resistance bands and walking. Feasibility was assessed using recruitment, retention, adherence, and outcome capture. Physiological changes and patient reported outcomes were assessed before and after the intervention. RESULTS: Of the 62 referrals, 47 were eligible with 22 men performing baseline testing (47% recruitment rate) and 16 completing the intervention (73% retention). Task completion was >86% for all physiological tests. Walking adherence was 80% and resistance training was 63%, the latter falling short of the study target (75%). Training increased thigh muscle cross-sectional area by 22%, time to exhaustion by 19% (both p < 0.05) and peak oxygen uptake by 6% (p = 0.057). Improvements in short physical performance battery scores and 400 m walk demonstrated moderate effect sizes that did not reach significance. CONCLUSIONS: Home-based exercise is feasible during ARSI treatment for mCRPC. Greater endurance capacity and localized hypertrophy appear as the primary improvements following training. These preliminary findings suggest home-based training may increase exercise accessibility, with important lessons that will inform subsequent trials investigating the efficacy of home-based exercise interventions during mCRPC.

Can we have our steak and eat it: The impact of breeding for lowered environmental impact on yield and meat quality in sheep.

Global agreements in place to reduce methane emissions in livestock are a potential threat to food security. Successful but independent breeding strategies for improved production and lower methane are in place. The unanswered questions are whether these strategies can be combined and how they impact one another, physically and economically. The New Zealand economy is largely dependent on pastoral agriculture from grazing ruminants. The sheep industry produces ∼20 million lamb carcasses for export each year primarily from grass. Methane emitted from the fermentation of forage by grazing ruminants accounts for one-third of all New Zealand's greenhouse gas emissions. Here, we use sheep selection lines bred for divergent methane production and large numbers of their relatives to determine the genetic and phenotypic correlations between enteric methane emissions, carcass yield, and meat quality. The primary objectives were to determine whether previously shown physiological differences between methane selection lines (differing by ∼12% in methane) result in a negative impact on meat production and quality by measuring close relatives. The results show no negative effects of breeding for lowered methane on meat and carcass quality. Gross methane emissions were highly correlated with liveweight and measures of carcass weight and negatively correlated with dressing-out percentage and fat yield (GR). Trends were similar but not significant for methane yield (g CH4/kg DMI). Preliminary evidence, to date, shows that breeding for low methane may result in animals with higher lean yields that are economically favorable even before carbon costs and environmental benefits are taken into account. These benefits were seen in animals measured for methane on fixed intakes and require validation on intakes that are allowed to vary.

Advances in organ-on-a-chip systems for modelling joint tissue and osteoarthritic diseases.

Joint-on-a-chip (JOC) models are powerful tools that aid in osteoarthritis (OA) research. These microfluidic devices apply emerging organ-on-a-chip technology to recapitulate a multifaceted joint tissue microenvironment. JOCs address the need for advanced, dynamic in vitro models that can mimic the in vivo tissue environment through joint-relevant biomechanical or fluidic integration, an aspect that existing in vitro OA models lack. There are existing review articles on OA models that focus on animal, tissue explant, and two-dimensional and three-dimensional (3D) culture systems, including microbioreactors and 3D printing technology, but there has been limited discussion of JOC models. The aim of this article is to review recent developments in human JOC technology and identify gaps for future advancements. Specifically, mechanical stimulation systems that mimic articular movement, multi-joint tissue cultures that enable crosstalk, and systems that aim to capture aspects of OA inflammation by incorporating immune cells are covered. The development of an advanced JOC model that captures the dynamic joint microenvironment will improve testing and translation of potential OA therapeutics.

Critical links between biodiversity and health in wild bee conservation.

Wild bee populations are declining due to human activities, such as land use change, which strongly affect the composition and diversity of available plants and food sources. The chemical composition of food (i.e., nutrition) in turn determines the health, resilience, and fitness of bees. For pollinators, however, the term 'health' is recent and is subject to debate, as is the interaction between nutrition and wild bee health. We define bee health as a multidimensional concept in a novel integrative framework linking bee biological traits (physiology, stoichiometry, and disease) and environmental factors (floral diversity and nutritional landscapes). Linking information on tolerated nutritional niches and health in different bee species will allow us to better predict their distribution and responses to environmental change, and thus support wild pollinator conservation.

Results of a single-arm pilot study of 32P microparticles in unresectable locally advanced pancreatic adenocarcinoma with gemcitabine/nab-paclitaxel or FOLFIRINOX chemotherapy.

BACKGROUND: Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 (32P) microparticles, combined with standard-of-care chemotherapy. PATIENTS AND METHODS: In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks. RESULTS: Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively. CONCLUSIONS: Endoscopic ultrasound-guided 32P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining 32P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC.

Correction: A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer.

[This corrects the article DOI: 10.1371/journal.pone.0253021.].