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Clinical Genitourinary Cancer Jun 2024Second-generation androgen receptor axis-targeting (ARAT) agents have become a standard treatment for patients with advanced prostate cancer (PC), however much remains... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Second-generation androgen receptor axis-targeting (ARAT) agents have become a standard treatment for patients with advanced prostate cancer (PC), however much remains unknown about the potential cardiovascular toxicities.
PATIENTS AND METHODS
We performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for randomized controlled trials of patients receiving ARAT agents for PC from inception to March 2023. The odds ratios (ORs) of all-grade and high-grade cardiovascular adverse events (CVAEs) for patients treated with and without ARAT agents were pooled for meta-analysis. Subgroup analyses based on PC type and treatment regimen were conducted.
RESULTS
A total of 15 double-blind placebo-controlled phase 3 trials comprising 15,842 patients were included. In addition to hot flush and hypertension of any degree of severity, inclusion of ARAT agents was associated with a significantly higher risk of acute myocardial infarction (OR: 1.96, 95% CI: 1.05-3.68, P = .04), myocardial infarction (OR: 2.44, 95% CI: 1.27-4.66, P = .007) and angina pectoris (OR: 2.00, 95% CI: 1.00-4.02, P = .05). With regard to individual ARAT agents, enzalutamide was associated with a significantly higher risk of acute myocardial infarction (OR: 3.11, 95% CI: 1.17-8.28, P = .02), coronary artery disease (OR: 8.33, 95% CI: 1.54-44.95, P = .01), and high-grade hypertension (OR: 4.94, 95% CI: 1.11-22.06, P = .04), while abiraterone and apalutamide were associated with a significantly higher risk of angina pectoris (OR: 5.48, 95% CI: 1.23-24.33, P = .03) and myocardial infarction (OR: 7.00, 95% CI: 1.60-30.62, P = .01), respectively.
CONCLUSION
The inclusion of ARAT agents was associated with a significantly higher risk of several CVAEs. Clinicians should remain vigilant, both in pre-treatment screening and monitoring for clinical symptoms and signs, when considering ARAT agent particularly for patients with pre-existing risk factors.
Topics: Humans; Male; Randomized Controlled Trials as Topic; Prostatic Neoplasms; Cardiovascular Diseases; Androgen Receptor Antagonists; Receptors, Androgen; Phenylthiohydantoin; Benzamides; Clinical Trials, Phase III as Topic; Nitriles; Thiohydantoins; Androstenes
PubMed: 38584004
DOI: 10.1016/j.clgc.2024.102066 -
JAMA Jun 2024Randomized clinical trials of cancer screening typically use cancer-specific mortality as the primary end point. The incidence of stage III-IV cancer is a potential... (Comparative Study)
Comparative Study Meta-Analysis
IMPORTANCE
Randomized clinical trials of cancer screening typically use cancer-specific mortality as the primary end point. The incidence of stage III-IV cancer is a potential alternative end point that may accelerate completion of randomized clinical trials of cancer screening.
OBJECTIVE
To compare cancer-specific mortality with stage III-IV cancer as end points in randomized clinical trials of cancer screening.
DESIGN, SETTING, AND PARTICIPANTS
This meta-analysis included 41 randomized clinical trials of cancer screening conducted in Europe, North America, and Asia published through February 19, 2024. Data extracted included numbers of participants, cancer diagnoses, and cancer deaths in the intervention and comparison groups. For each clinical trial, the effect of screening was calculated as the percentage reduction between the intervention and comparison groups in the incidence of participants with cancer-specific mortality and stage III-IV cancer.
EXPOSURES
Randomization to a cancer screening test or to a comparison group in a clinical trial of cancer screening.
MAIN OUTCOMES AND MEASURES
End points of cancer-specific mortality and incidence of stage III-IV cancer were compared using Pearson correlation coefficients with 95% CIs, linear regression, and fixed-effects meta-analysis.
RESULTS
The included randomized clinical trials tested benefits of screening for breast (n = 6), colorectal (n = 11), lung (n = 12), ovarian (n = 4), prostate (n = 4), and other cancers (n = 4). Correlation between reductions in cancer-specific mortality and stage III-IV cancer varied by cancer type (I2 = 65%; P = .02). Correlation was highest for trials that screened for ovarian (Pearson ρ = 0.99 [95% CI, 0.51-1.00]) and lung (Pearson ρ = 0.92 [95% CI, 0.72-0.98]) cancers, moderate for breast cancer (Pearson ρ = 0.70 [95% CI, -0.26 to 0.96]), and weak for colorectal (Pearson ρ = 0.39 [95% CI, -0.27 to 0.80]) and prostate (Pearson ρ = -0.69 [95% CI, -0.99 to 0.81]) cancers. Slopes from linear regression were estimated as 1.15 for ovarian cancer, 0.75 for lung cancer, 0.40 for colorectal cancer, 0.28 for breast cancer, and -3.58 for prostate cancer, suggesting that a given magnitude of reduction in incidence of stage III-IV cancer produced different magnitudes of change in incidence of cancer-specific mortality (P for heterogeneity = .004).
CONCLUSIONS AND RELEVANCE
In randomized clinical trials of cancer screening, incidence of late-stage cancer may be a suitable alternative end point to cancer-specific mortality for some cancer types, but is not suitable for others. These results have implications for clinical trials of multicancer screening tests.
Topics: Female; Humans; Male; Early Detection of Cancer; Endpoint Determination; Incidence; Neoplasm Staging; Neoplasms; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 38583868
DOI: 10.1001/jama.2024.5814 -
International Journal of Clinical... Jun 2024Triplet therapy, androgen receptor signaling inhibitors (ARSIs) plus docetaxel plus androgen-deprivation therapy (ADT), is a novel guideline-recommended treatment for... (Meta-Analysis)
Meta-Analysis
Impact of disease volume on survival efficacy of triplet therapy for metastatic hormone-sensitive prostate cancer: a systematic review, meta-analysis, and network meta-analysis.
BACKGROUND
Triplet therapy, androgen receptor signaling inhibitors (ARSIs) plus docetaxel plus androgen-deprivation therapy (ADT), is a novel guideline-recommended treatment for metastatic hormone-sensitive prostate cancer (mHSPC). However, the optimal selection of the patient most likely to benefit from triplet therapy remains unclear.
METHODS
We performed a systematic review, meta-analysis, and network meta-analysis to assess the oncologic benefit of triplet therapy in mHSPC patients stratified by disease volume and compare them with doublet treatment regimens. Three databases and meeting abstracts were queried in March 2023 for randomized controlled trials (RCTs) evaluating patients treated with systemic therapy for mHSPC stratified by disease volume. Primary interests of measure were overall survival (OS). We followed the PRISMA guideline and AMSTAR2 checklist.
RESULTS
Overall, eight RCTs were included for meta-analyses and network meta-analyses (NMAs). Triplet therapy outperformed docetaxel plus ADT in terms of OS in both patients with high-(pooled HR: 0.73, 95%CI 0.64-0.84) and low-volume mHSPC (pooled HR: 0.71, 95%CI 0.52-0.97). There was no statistically significant difference between patients with low- vs. high-volume in terms of OS benefit from adding ARSI to docetaxel plus ADT (p = 0.9). Analysis of treatment rankings showed that darolutamide plus docetaxel plus ADT (90%) had the highest likelihood of improved OS in patients with high-volume disease, while enzalutamide plus ADT (84%) had the highest in with low-volume disease.
CONCLUSIONS
Triplet therapy improves OS in mHSPC patients compared to docetaxel-based doublet therapy, irrespective of disease volume. However, based on treatment ranking, triplet therapy should preferably be considered for patients with high-volume mHSPC while those with low-volume are likely to be adequately treated with ARSI + ADT.
Topics: Humans; Male; Androgen Antagonists; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Network Meta-Analysis; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Tumor Burden
PubMed: 38582807
DOI: 10.1007/s10147-024-02485-4 -
Clinical Radiology Jun 2024Our main goal of this meta-analytical analysis was to evaluate the diagnostic effectiveness of prostate-specific membrane antigen (PSMA) positron emission tomography... (Meta-Analysis)
Meta-Analysis Comparative Study
Head-to-head comparison of prostate-specific membrane antigen positron emission tomography/computed tomography and multiparametric magnetic resonance imaging in the detection of biochemical recurrence of prostate cancer: a systematic review and meta-analysis.
AIM
Our main goal of this meta-analytical analysis was to evaluate the diagnostic effectiveness of prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) against multiparametric magnetic resonance imaging (mpMRI) in the context of identifying biochemical recurrence in patients with prostate cancer (PCa).
MATERIALS AND METHODS
A thorough search covering articles published until March 2023 was carried out across major databases such as PubMed, Embase, and Web of Science. Studies examining the direct comparison of PSMA PET/CT and mpMRI in patients with PCa suffering biochemical recurrence were included in the inclusion criteria. Using the renowned Quality Assessment of Diagnostic Performance Studies-2 technique, each study's methodological rigor was assessed.
RESULTS
We analyzed data from six eligible studies involving 290 patients in total. The combined data showed that for PSMA PET/CT and mpMRI, respectively, the pooled overall detection rates for recurrent PCa after definitive treatment were 0.69 (95% confidence interval [CI]: 0.45-0.89) and 0.70 (95% CI: 0.44-0.91). The detection rates for local recurrence were specifically 0.52 (95% CI: 0.39-0.65) and 0.62 (95% CI: 0.31-0.89), while they were 0.50 (95% CI: 0.26-0.74) and 0.32 (95% CI: 0.18-0.48) for lymph node metastasis. Notably, there was no discernible difference between the two imaging modalities in terms of the overall detection rate (P = 0.95). The detection rates for local recurrence and lymph node metastasis did not differ statistically significantly (P = 0.55, 0.23).
CONCLUSION
The performance of PSMA PET/CT and mpMRI in identifying biochemical recurrence in PCa appears to be comparable. However, the meta-analysis' findings came from research with modest sample sizes. In this context, more extensive research should be conducted in the future.
Topics: Humans; Male; Prostatic Neoplasms; Positron Emission Tomography Computed Tomography; Multiparametric Magnetic Resonance Imaging; Neoplasm Recurrence, Local; Glutamate Carboxypeptidase II; Prostate-Specific Antigen; Prostate; Antigens, Surface
PubMed: 38582633
DOI: 10.1016/j.crad.2024.02.008 -
JAMA Oncology Jun 2024Prostate magnetic resonance imaging (MRI) is increasingly integrated within the prostate cancer (PCa) early detection pathway. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Prostate magnetic resonance imaging (MRI) is increasingly integrated within the prostate cancer (PCa) early detection pathway.
OBJECTIVE
To systematically evaluate the existing evidence regarding screening pathways incorporating MRI with targeted biopsy and assess their diagnostic value compared with prostate-specific antigen (PSA)-based screening with systematic biopsy strategies.
DATA SOURCES
PubMed/MEDLINE, Embase, Cochrane/Central, Scopus, and Web of Science (through May 2023).
STUDY SELECTION
Randomized clinical trials and prospective cohort studies were eligible if they reported data on the diagnostic utility of prostate MRI in the setting of PCa screening.
DATA EXTRACTION
Number of screened individuals, biopsy indications, biopsies performed, clinically significant PCa (csPCa) defined as International Society of Urological Pathology (ISUP) grade 2 or higher, and insignificant (ISUP1) PCas detected were extracted.
MAIN OUTCOMES AND MEASURES
The primary outcome was csPCa detection rate. Secondary outcomes included clinical insignificant PCa detection rate, biopsy indication rates, and the positive predictive value for the detection of csPCa.
DATA SYNTHESIS
The generalized mixed-effect approach with pooled odds ratios (ORs) and random-effect models was used to compare the MRI-based and PSA-only screening strategies. Separate analyses were performed based on the timing of MRI (primary/sequential after a PSA test) and cutoff (Prostate Imaging Reporting and Data System [PI-RADS] score ≥3 or ≥4) for biopsy indication.
RESULTS
Data were synthesized from 80 114 men from 12 studies. Compared with standard PSA-based screening, the MRI pathway (sequential screening, PI-RADS score ≥3 cutoff for biopsy) was associated with higher odds of csPCa when tests results were positive (OR, 4.15; 95% CI, 2.93-5.88; P ≤ .001), decreased odds of biopsies (OR, 0.28; 95% CI, 0.22-0.36; P ≤ .001), and insignificant cancers detected (OR, 0.34; 95% CI, 0.23-0.49; P = .002) without significant differences in the detection of csPCa (OR, 1.02; 95% CI, 0.75-1.37; P = .86). Implementing a PI-RADS score of 4 or greater threshold for biopsy selection was associated with a further reduction in the odds of detecting insignificant PCa (OR, 0.23; 95% CI, 0.05-0.97; P = .048) and biopsies performed (OR, 0.19; 95% CI, 0.09-0.38; P = .01) without differences in csPCa detection (OR, 0.85; 95% CI, 0.49-1.45; P = .22).
CONCLUSION AND RELEVANCE
The results of this systematic review and meta-analysis suggest that integrating MRI in PCa screening pathways is associated with a reduced number of unnecessary biopsies and overdiagnosis of insignificant PCa while maintaining csPCa detection as compared with PSA-only screening.
Topics: Humans; Male; Prostatic Neoplasms; Magnetic Resonance Imaging; Early Detection of Cancer; Prostate-Specific Antigen
PubMed: 38576242
DOI: 10.1001/jamaoncol.2024.0734 -
Journal of Geriatric Oncology Jun 2024Older patients are often deemed ineligible for clinical research, and many frequently-used endpoints and outcome measures are not as relevant for older patients for... (Review)
Review
INTRODUCTION
Older patients are often deemed ineligible for clinical research, and many frequently-used endpoints and outcome measures are not as relevant for older patients for younger ones. This systematic review aimed to present an overview of outcomes used in clinical research regarding patients over the age of 65 years with prostate cancer.
MATERIALS AND METHODS
PubMed and Embase were systematically searched to identify studies on prostate cancer (treatment) in patients aged ≥65 between 2016 and 2023. Data on title, study design, number of participants and age, stage of disease, treatment, and investigated outcomes were synthesized and descriptively analyzed.
RESULTS
Sixty-eight studies were included. Of these most included patients over 65 years, while others used a higher age. Overall, 39 articles (57.3%) reported on survival-related outcomes, 22 (32.4%) reported on progression of disease and 38 (55.9%) used toxicity or adverse events as an outcome measure. Health-related quality of life and functional outcomes were investigated in 29.4%, and cognition in two studies. The most frequently investigated survival-related outcomes were overall and cancer-specific survival (51.3%); however, 38.5% only studied overall survival.
DISCUSSION
The main focus of studies included in this review remains survival and disease progression. There is limited attention for health-related quality of life and functional status, although older patients often prioritize the latter. Future research should incorporate outcome measures tailored to the aged population to improve care for older patients with prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms; Aged; Quality of Life; Aged, 80 and over; Disease Progression; Outcome Assessment, Health Care; Age Factors
PubMed: 38575500
DOI: 10.1016/j.jgo.2024.101763 -
Radiology. Artificial Intelligence Jul 2024Purpose To investigate the accuracy and robustness of prostate segmentation using deep learning across various training data sizes, MRI vendors, prostate zones, and...
Purpose To investigate the accuracy and robustness of prostate segmentation using deep learning across various training data sizes, MRI vendors, prostate zones, and testing methods relative to fellowship-trained diagnostic radiologists. Materials and Methods In this systematic review, Embase, PubMed, Scopus, and Web of Science databases were queried for English-language articles using keywords and related terms for prostate MRI segmentation and deep learning algorithms dated to July 31, 2022. A total of 691 articles from the search query were collected and subsequently filtered to 48 on the basis of predefined inclusion and exclusion criteria. Multiple characteristics were extracted from selected studies, such as deep learning algorithm performance, MRI vendor, and training dataset features. The primary outcome was comparison of mean Dice similarity coefficient (DSC) for prostate segmentation for deep learning algorithms versus diagnostic radiologists. Results Forty-eight studies were included. Most published deep learning algorithms for whole prostate gland segmentation (39 of 42 [93%]) had a DSC at or above expert level (DSC ≥ 0.86). The mean DSC was 0.79 ± 0.06 (SD) for peripheral zone, 0.87 ± 0.05 for transition zone, and 0.90 ± 0.04 for whole prostate gland segmentation. For selected studies that used one major MRI vendor, the mean DSCs of each were as follows: General Electric (three of 48 studies), 0.92 ± 0.03; Philips (four of 48 studies), 0.92 ± 0.02; and Siemens (six of 48 studies), 0.91 ± 0.03. Conclusion Deep learning algorithms for prostate MRI segmentation demonstrated accuracy similar to that of expert radiologists despite varying parameters; therefore, future research should shift toward evaluating segmentation robustness and patient outcomes across diverse clinical settings. MRI, Genital/Reproductive, Prostate Segmentation, Deep Learning Systematic review registration link: osf.io/nxaev © RSNA, 2024.
Topics: Humans; Deep Learning; Magnetic Resonance Imaging; Male; Prostatic Neoplasms; Prostate; Image Interpretation, Computer-Assisted
PubMed: 38568094
DOI: 10.1148/ryai.230138 -
Pediatric Blood & Cancer Jun 2024Approximately one third of children with rhabdomyosarcoma relapse or have refractory disease. Treatment approaches include a combination of systemic therapies and local... (Review)
Review
Approximately one third of children with rhabdomyosarcoma relapse or have refractory disease. Treatment approaches include a combination of systemic therapies and local therapies, directed at tumour site(s). This review was conducted to evaluate the effectiveness and safety of the combination of surgery and brachytherapy as local therapy for treating children and young people with relapsed/refractory rhabdomyosarcoma. This review identified studies based on a previous systematic review looking at the treatments for children and young people under 18 years old with relapsed/refractory rhabdomyosarcoma. Studies conducted after 2000 were included. Survival outcomes, relapse rates, adverse events and functional outcomes were extracted. From 16,965 records identified in the baseline systematic review, 205 included the words 'AMORE' or 'brachytherapy', and were screened for eligibility in this substudy. Thirteen studies met the inclusion criteria for Local-REFoRMS, including over 55 relapsed and refractory rhabdomyosarcoma patients. Most studies were retrospective cohort studies conducted within Europe. Most patients had embryonal disease within the head and neck or bladder/prostate regions, and received local therapy for first relapse. Approximately one quarter of patients relapsed following surgery and brachytherapy, with local relapses occurring more than metastatic relapse. Adverse events and functional outcomes were infrequently reported, but related to the site of surgery and brachytherapy. Study quality was limited by inconsistent reporting and potential selection bias. Outcomes following surgery and brachytherapy for a selected group of relapsed and refractory rhabdomyosarcoma show reasonable benefits, but reporting was often unclear and based on small sample sizes.
Topics: Humans; Brachytherapy; Rhabdomyosarcoma; Child; Adolescent; Neoplasm Recurrence, Local; Combined Modality Therapy; Male; Child, Preschool; Female
PubMed: 38566349
DOI: 10.1002/pbc.30952 -
Radiotherapy and Oncology : Journal of... Jun 2024High-level evidence on hypofractionated proton therapy (PT) for localized and locally advanced prostate cancer (PCa) patients is currently missing. The aim of this study... (Meta-Analysis)
Meta-Analysis
BACKGROUND
High-level evidence on hypofractionated proton therapy (PT) for localized and locally advanced prostate cancer (PCa) patients is currently missing. The aim of this study is to provide a systematic literature review to compare the toxicity and effectiveness of curative radiotherapy with photon therapy (XRT) or PT in PCa.
METHODS
PubMed, Embase, and the Cochrane Library databases were systematically searched up to April 2022. Men with a diagnosis of PCa who underwent curative hypofractionated RT treatment (PT or XRT) were included. Risk of grade (G) ≥ 2 acute and late genitourinary (GU) OR gastrointestinal (GI) toxicity were the primary outcomes of interest. Secondary outcomes were five-year biochemical relapse-free survival (b-RFS), clinical relapse-free, distant metastasis-free, and prostate cancer-specific survival. Heterogeneity between study-specific estimates was assessed using Chi-square statistics and measured with the I2 index (heterogeneity measure across studies).
RESULTS
A total of 230 studies matched inclusion criteria and, due to overlapped populations, 160 were included in the present analysis. Significant lower rates of G ≥ 2 acute GI incidence (2 % vs 7 %) and improved 5-year biochemical relapse-free survival (95 % vs 91 %) were observed in the PT arm compared to XRT. PT benefits in 5-year biochemical relapse-free survival were maintained for the moderate hypofractionated arm (p-value 0.0122) and among patients in intermediate and low-risk classes (p-values < 0.0001 and 0.0368, respectively). No statistically relevant differences were found for the other considered outcomes.
CONCLUSION
The present study supports that PT is safe and effective for localized PCa treatment, however, more data from RCTs are needed to draw solid evidence in this setting and further effort must be made to identify the patient subgroups that could benefit the most from PT.
Topics: Humans; Male; Photons; Prostatic Neoplasms; Proton Therapy; Radiation Dose Hypofractionation
PubMed: 38561122
DOI: 10.1016/j.radonc.2024.110264 -
JAMA Network Open Mar 2024Multiple strategies integrating magnetic resonance imaging (MRI) and clinical data have been proposed to determine the need for a prostate biopsy in men with suspected... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Multiple strategies integrating magnetic resonance imaging (MRI) and clinical data have been proposed to determine the need for a prostate biopsy in men with suspected clinically significant prostate cancer (csPCa) (Gleason score ≥3 + 4). However, inconsistencies across different strategies create challenges for drawing a definitive conclusion.
OBJECTIVE
To determine the optimal prostate biopsy decision-making strategy for avoiding unnecessary biopsies and minimizing the risk of missing csPCa by combining MRI Prostate Imaging Reporting & Data System (PI-RADS) and clinical data.
DATA SOURCES
PubMed, Ovid MEDLINE, Embase, Web of Science, and Cochrane Library from inception to July 1, 2022.
STUDY SELECTION
English-language studies that evaluated men with suspected but not confirmed csPCa who underwent MRI PI-RADS followed by prostate biopsy were included. Each study had proposed a biopsy plan by combining PI-RADS and clinical data.
DATA EXTRACTION AND SYNTHESIS
Studies were independently assessed for eligibility for inclusion. Quality of studies was appraised using the Quality Assessment of Diagnostic Accuracy Studies 2 tool and the Newcastle-Ottawa Scale. Mixed-effects meta-analyses and meta-regression models with multimodel inference were performed. Reporting of this study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline.
MAIN OUTCOMES AND MEASURES
Independent risk factors of csPCa were determined by performing meta-regression between the rate of csPCa and PI-RADS and clinical parameters. Yields of different biopsy strategies were assessed by performing diagnostic meta-analysis.
RESULTS
The analyses included 72 studies comprising 36 366 patients. Univariable meta-regression showed that PI-RADS 4 (β-coefficient [SE], 7.82 [3.85]; P = .045) and PI-RADS 5 (β-coefficient [SE], 23.18 [4.46]; P < .001) lesions, but not PI-RADS 3 lesions (β-coefficient [SE], -4.08 [3.06]; P = .19), were significantly associated with a higher risk of csPCa. When considered jointly in a multivariable model, prostate-specific antigen density (PSAD) was the only clinical variable significantly associated with csPCa (β-coefficient [SE], 15.50 [5.14]; P < .001) besides PI-RADS 5 (β-coefficient [SE], 9.19 [3.33]; P < .001). Avoiding biopsy in patients with lesions with PI-RADS category of 3 or less and PSAD less than 0.10 (vs <0.15) ng/mL2 resulted in reducing 30% (vs 48%) of unnecessary biopsies (compared with performing biopsy in all suspected patients), with an estimated sensitivity of 97% (vs 95%) and number needed to harm of 17 (vs 15).
CONCLUSIONS AND RELEVANCE
These findings suggest that in patients with suspected csPCa, patient-tailored prostate biopsy decisions based on PI-RADS and PSAD could prevent unnecessary procedures while maintaining high sensitivity.
Topics: Male; Humans; Magnetic Resonance Imaging; Prostatic Neoplasms; Prostate-Specific Antigen; Prostate; Biopsy
PubMed: 38551559
DOI: 10.1001/jamanetworkopen.2024.4258