Citations

Abstract Background Instruments to assess patient-reported outcomes (PRO) should generate high-quality evidence. Reliable PRO evidence is essential to policymakers, in conjunction with outcomes such as survival and radiological response, to understand the net clinical benefit of antitumor treatments. This study aimed to establish the content validity of 215 identified PRO measures used in patients with brain tumors. Methods A survey (n = 148 items) was developed reflecting aspects of the WHO International Classification of Functioning, Disability, and Health (ICF) framework. Patients with brain tumors, their proxies, and healthcare professionals (HCPs) were asked to rate each survey item on relevance. An item was considered a relevant issue if ≥25% of the patients or proxies or ≥50% of the HCPs considered that item to be an issue. Next, all items in the identified PRO measures were linked to ICF and relevant items in the survey, and the percentage of content coverage was calculated. Results In total, 114 patients, 71 proxies, and 65 HCPs from different countries completed the survey. Fifty-six of 148 (37.8%) items in the survey were considered relevant. The most important aspects mentioned by both patients and proxies were difficulty concentrating, difficulty remembering, multitasking, and handling stress. Depending on the definition, between 35% and 49% of PRO measures were considered to have sufficient content validity (≥80% coverage). Conclusion The content validity was insufficient in more than half of the identified PRO measures, particularly multidimensional measures. Future research should investigate whether different approaches to PRO assessment better meet the needs of all stakeholders.

ImportanceThe safety and effectiveness of combining surgical peripheral iridectomy (SPI) with goniosynechialysis (GSL) and goniotomy (GT) vs trabeculectomy for intraocular pressure (IOP) reduction remains unknown.ObjectiveTo investigate the safety and effectiveness at 1 year of SPI + GSL + GT vs trabeculectomy in advanced primary angle-closure glaucoma (PACG) without cataract.Design, Setting, and ParticipantsThis noninferiority randomized clinical trial was conducted at 8 tertiary eye centers in China. A total of 88 Chinese patients (88 eyes) with advanced PACG without cataract were enrolled from January 2022 to July 2023. Data were analyzed from August 2024 to September 2024. Mean (SD) patient age was 60.3 (7.3) years, and 52 patients (59.1%) were female. Forty-three patients were randomized to SPI + GSL + GT and 45 were randomized to trabeculectomy; 86 patients (97.7%) completed the 12-month follow-up.InterventionsParticipants were randomized 1:1 to receive SPI + GSL + GT or trabeculectomy.Main Outcomes and MeasuresThe primary outcome was IOP at 12 months (noninferior margin: 4 mm Hg). Secondary outcomes included surgical success (IOP: 5-18 mm Hg, ≥20% reduction from baseline, with or without antiglaucoma medications); postoperative complications and interventions, including bleb massage, suture lysis, or releasable sutures; and number of antiglaucomatous medications prescribed.ResultsAt 12 months, the SPI + GSL + GT group had a mean (SD) IOP of 15.6 (4.0) mm Hg vs 14.9 (4.2) mm Hg in the trabeculectomy group (difference, 0.5 mm Hg; 95% CI, −1.2 to 2.2; P = .55), which was within the 4-mm Hg noninferiority margin. Qualified success rates were 38 of 43 participants (88.4%) for SPI + GSL + GT and 42 of 45 participants (93.3%) for trabeculectomy (difference, −5.0%; 95% CI, −19.6% to 8.5%; P = .48). However, complete success rates were lower in the SPI + GSL + GT group (26 participants [60.5%]) vs the trabeculectomy group (37 participants [82.2%]; difference, −21.8%; 95% CI, −40.2% to −2.4%; P = .03). Postoperative complications were present for 8 participants (18.6%) in the SPI + GSL + GT group vs 9 participants (20.0%) in the trabeculectomy group (difference, −1.4%; 95% CI, −17.9% to 15.1%; P = .71). Postoperative interventions were lower in the SPI + GSL + GT group (3 participants [7.0%] vs 25 participants [55.6%]; difference, 48.6%; 95% CI, 32.2%-65.0%; P < .001). Median (IQR) numbers of medications used decreased from 2 (0-3) to 0 (0-1) in the SPI + GSL + GT group and from 2 (2-3) to 0 (0-0) in the trabeculectomy group (difference, −0.81; 95% CI, −1.36 to −0.26; P = .004).Conclusions and RelevanceIn this randomized clinical trial among patients with advanced PACG without cataract, SPI + GSL + GT demonstrated noninferiority (4-mm Hg margin) to trabeculectomy for IOP at 12 months, with fewer interventions (including bleb massage, suture lysis, or releasable sutures) but no difference in postoperative medication use. This suggests SPI + GSL + GT as a potential alternative to trabeculectomy for similar cases, pending validation in larger sample sizes with smaller noninferiority margins.Trial RegistrationClinicalTrials.gov Identifier: NCT05163951

ImportanceIntraocular pressure (IOP) reduction with phacogoniotomy (phacoemulsification plus goniosynechialysis plus goniotomy) was not less than that of phacotrabeculectomy for advanced primary angle-closure glaucoma (PACG) with cataract at 1-year follow-up, but longer-term outcomes are needed.ObjectiveTo investigate if phacogoniotomy is noninferior to phacotrabeculectomy for advanced PACG with cataract at 2 years.Design, Setting, and ParticipantsThis multicenter, noninferiority, randomized clinical trial took place in 7 ophthalmology centers in China. The trial started May 31, 2021, and 2-year follow-up ended May 31, 2024. Included in this analysis were patients with advanced PACG and cataract. Study data were analyzed from September 2024 to January 2025.InterventionsRandom assignment (1:1) to phacogoniotomy or phacotrabeculectomy.Main Outcomes and MeasuresThe primary outcome measure was reduction in IOP from baseline to the 2-year visit with a noninferiority margin of 4 mm Hg.ResultsA total of 124 participants (124 eyes) were randomized (mean [SD] age, 66.4 [8.6] years; 67 female [54.0%]), 65 (52.4%) to the phacogoniotomy group and 59 (47.6%) to the phacotrabeculectomy group. A total of 59 patients (90.7%) in the phacogoniotomy group and 52 patients (88.1%) in the phacotrabeculectomy group completed 2-year visits. All participants were Chinese. Mean (SD) IOP reduction was −25.6 (10.2) mm Hg and −24.7 (9.4) mm Hg in the phacogoniotomy and phacotrabeculectomy groups, respectively, and the upper boundary of the CI for difference in change between groups was lower than the 4-mm Hg noninferiority margin (mean difference, −0.5 mm Hg; 97.5% CI, −1.7 mm Hg to 0.8 mm Hg; P = .42). The mean difference for complete success for phacogoniotomy vs phacotrabeculectomy was −6.7% (95% CI, −21.4% to 8.8%; P = .47) and for qualified success was 1.4% (95% CI, −11.0% to 14.3%, P = .30). Median (IQR) number of antiglaucomatous medication was 0 (0) vs 0 (0; Hodges-Lehmann estimate of location shift, 0; 95% CI, 0; P =.12) with phacogoniotomy vs phacotrabeculectomy, respectively (mean difference, 0.13; 95% CI, −0.36 to 0.63; P = .60).Conclusions and RelevanceMean IOP reduction with phacogoniotomy was noninferior to phacotrabeculectomy for advanced PACG and cataract at 2-year follow-up with no differences detected in complete or qualified success or mean number of antiglaucomatous medications. These findings support phacogoniotomy as an alternative to phacotrabeculectomy for patients with advanced PACG and cataract.Trial registrationClinicalTrials.gov Identifier: NCT04878458

Précis: 240-degree and 360-degree goniotomy (GT) demonstrated similar efficacy in intraocular pressure (IOP) reduction, both outperforming 120-degree GT in patients with juvenile open angle glaucoma (JOAG) at postoperative 6-month follow-up. Objective: To compare the surgical efficacy and safety of 120-degree, 240-degree, and 360-degree GT for patients with JOAG. Patients and Methods: This multicenter retrospective study included 102 eyes of 102 patients with JOAG, who underwent GT with a follow-up of at least 6 months. Patients were categorized into 3 groups: (1) 120-degree GT, (2) 240-degree GT, and (3) 360-degree GT. IOP, glaucoma medications, and complications were recorded at baseline and the final visit. Complete success and qualified success were defined as a postoperative IOP ≤21 mm Hg without and with medications, respectively. Results: Mean age of the participants was 24.4 ± 7.9 years. After a mean follow-up of 8.1 ± 2.7 months, complete success rates were similar between the 240-degree GT (45.2%) and the 360-degree GT (63.2%; P = 0.135), and both were superior to 120-degree GT (18.2%; P < 0.05). Qualified success rates among patients in the 120-degree, 240-degree, and 360-degree GT groups were 93.9%, 96.8%, and 100%, respectively, and showed no statistically significant difference (P = 0.292). 360-degree GT required fewer medications than 240-degree GT and 120-degree GT (P < 0.05), with no significant difference in medications between 120-degree GT and 240-degree GT (P > 0.05). Hyphema was the most common postoperative complication, with a significantly higher incidence in the 360-degree GT (68.4%) compared with the 240-degree GT (41.9%) and 120-degree GT (33.3%; P < 0.05). Conclusions: 240-degree and 360-degree GT showed similar efficacy in IOP reduction and were superior to 120-degree GT. More extensive GT may provide better outcomes in JOAG.

Background and Aims: Clinical hepatology research often faces limited data availability, underrepresentation of minority groups, and complex data-sharing regulations. Synthetic data—artificially generated patient records designed to mirror real-world distributions—offers a potential solution. We hypothesized that diffusion models, a state-of-the-art generative technique, could produce synthetic liver transplant waitlist data from the United Network for Organ Sharing database that maintains statistical fidelity, replicates clinical correlations and survival patterns, and ensures robust privacy protection. Approach and Results: Diffusion models were used to generate synthetic patient cohorts mirroring the United Network for Organ Sharing liver transplant waitlist database between the years 2019 and 2023. Statistical fidelity was assessed using maximum mean discrepancy (MMD) and Wasserstein distance, correlation analysis, and variable-level metrics. Clinical utility was evaluated by comparing transplant-free survival via Kaplan–Meier curves and the MELD score performance. Privacy was quantified using the Distance to Closest Record (DCR) and attribute disclosure risk assessments. The synthetic dataset was nearly indistinguishable from the original dataset (MMD=0.002, standardized Wasserstein distance <1.0), preserving clinically relevant correlations and survival patterns as evidenced by similar median survival times (110 vs. 101 days) and 5-year survival rates (22.2% vs. 22.8%). MELD-based 90-day mortality prediction was maintained (original AUC=0.839 vs. synthetic AUC=0.844). Privacy metrics indicated no identifiable patient matches, and mean DCR values ensured that synthetic individuals were not direct replicas of real patients. Conclusion: Artificial intelligence–generated synthetic data derived from diffusion models can faithfully replicate complex hepatology datasets, maintain key clinical signals, and ensure strong privacy safeguards. This approach can help address data scarcity, enhance model generalizability, foster multi-institutional collaboration, and accelerate progress in hepatology research.

Importance High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. Objective To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). Design, Setting, and Participants The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (&amp;lt;60 years vs ≥60 years) and disease duration (&amp;lt;6 months vs ≥6 months). Interventions A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. Main Outcomes and Measures The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. Results A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). Conclusions and Relevance Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Importance Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. Objective To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Design, Setting, and Participants Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Intervention Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Main Outcomes and Measures Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Results Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (&amp;lt;60 years or ≥60 years) and disease duration (recent [&amp;lt;6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P &amp;gt;.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months ( P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). Conclusions and Relevance One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Abstract Background Despite advances in our understanding of the molecular underpinnings of meningioma progression and innovations in systemic and local treatments, recurrent meningiomas remain a substantial therapeutic challenge. The objective of this systematic review and meta-analysis is to provide a historical baseline, contemporary analysis, and propose a “rate of probable interest” to inform future clinical trial design and development on behalf of the Response Assessment in Neuro-Oncology meningioma group. Methods PubMed, ClinicalTrials.gov, and ASCOpubs databases were screened for clinical trials evaluating the activity of systemic therapies for adults with recurrent meningiomas. The pooled progression-free survival at 6-months and 1-year (PFS-6 and PFS-1 year) values were calculated using the random effects technique with I2 indices. Results The pooled PFS-6 and PFS-1 year rates for recurrent WHO grade 1 meningiomas were 43.6% (95% CI: 22.7-67.0%, I2 = 80%) and 21.7% (95% CI: 6.2-53.9%, I2 = 76%), and for grades 2-3 meningiomas, the PFS-6 was 38.0% (95% CI: 28.3-48.8%, I2 = 68%). In the targeted therapy group, PFS-6 and PFS-1 year rates stood at 62.0% (I2 = 58%) and 49.0% (I2 = 63%) for grade 1, while for grades 2-3 tumors, the PFS-6 rates with targeted therapy and immunotherapy were 42.1% (I² = 60%) and 46.0% (I² = 0%), respectively. The benchmarks were set at 67% and 54% for PFS-6 and PFS-1 year for grade 1 tumors, and PFS-6 of 49% for grades 2-3 tumors. Conclusions Several studies have reported outcomes in patients with recurrent meningiomas testing a variety of agents with modest, but variable and progressively increasing activity. In this context, we recommend new benchmarks for future trials to define efficacy of future investigational therapies.

Importance Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions and hospital systems. This is in large part because there is a persistent reluctance among third-party payers to cover molecular testing. The objective of this Review is to describe why comprehensive molecular biomarker testing is now required for the accurate diagnosis and grading and prognostication of CNS tumors and, in so doing, to justify more widespread use by clinicians and coverage by third-party payers. Observations The 5th edition of the World Health Organization (WHO) classification system for CNS tumors incorporates specific molecular signatures into the essential diagnostic criteria for most tumor entities. Many CNS tumor types cannot be reliably diagnosed according to current WHO guidelines without molecular testing. The National Comprehensive Cancer Network also incorporates molecular testing into their guidelines for CNS tumors. Both sets of guidelines are maximally effective if they are implemented routinely for all patients with CNS tumors. Moreover, the cost of these tests is less than 5% of the overall average cost of caring for patients with CNS tumors and consistently improves management. This includes more accurate diagnosis and prognostication, clinical trial eligibility, and prediction of response to specific treatments. Each major group of CNS tumors in the WHO classification is evaluated and how molecular diagnostics enhances patient care is described. Conclusions and Relevance Routine advanced multidimensional molecular profiling is now required to provide optimal standard of care for patients with CNS tumors.