Citations

Importance The role and safety of transcranial electrical stimulation (tES) for treating depressive disorders remain under evaluation. Objective To evaluate tES treatment in patients with major depressive disorder (MDD) and comorbid depressive conditions. Data Sources A search of MEDLINE, Embase, Cochrane, APA PsycINFO, and Scopus databases was conducted from inception to September 17, 2024. Study Selection Randomized clinical trials (RCTs) of adults with MDD, depression with psychiatric comorbidities (DPC), or depression with medical comorbidities (DMC), treated with transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), or transcranial random noise stimulation (tRNS), compared with sham or other treatments were included. Data Extraction and Synthesis Independent reviewers extracted data in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, with random-effects meta-analysis used for pooling. Main Outcomes and Measures Primary outcomes were depression severity, response and remission rates, and adverse events. Standardized mean differences (SMDs) were reported for continuous outcomes, and odds ratios (ORs) were reported for categorical outcomes. Quality of evidence (QOE) was assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria. Results The meta-analysis included 5522 participants from 114 study groups from 88 RCTs (3198 female [58.9%]; mean [range] age, 43.1 [19.4-76.9] years). Most studies (104 study groups from 79 RCTs [91.2%]) evaluated tDCS, while 7 study groups from 6 RCTs (6.1%) evaluated tACS, and 3 study groups from 3 RCTs (2.7%) evaluated tRNS. tES was associated with reduced depressive symptoms (SMD = −0.59; 95% CI, −0.83 to −0.35; low QOE) and improvement in DMC (SMD = −1.05; 95% CI, −1.67 to −0.43; low QOE) and DPC (SMD = −0.78; 95% CI, −1.27 to −0.29; low QOE) compared with MDD (SMD = −0.22; 95% CI, −0.44 to 0.01; low QOE). tDCS was associated with reduced depression in DMC (SMD = −1.05; 95% CI, −1.70 to −0.40; very low QOE) and DPC (SMD = −0.88; 95% CI, −1.40 to −0.36; low QOE) but not MDD. tACS was associated with improved MDD symptoms (SMD = −0.58; 95% CI, −0.96 to −0.20; high QOE) and response rates (OR, 2.07; 95% CI, 1.34 to 3.19; high QOE). Combined tDCS and medication was associated with reduced symptoms (SMD = −0.51; 95% CI, −0.90 to −0.13; moderate QOE) and increased response (OR, 2.25; 95% CI, 1.08 to 4.65; high QOE) in MDD. tDCS combined with psychotherapy was not associated with improvement. Subgroup analysis showed that anodal left dorsolateral prefrontal cortex DCS was associated with improved outcomes. Mild to moderate adverse events were more frequent in tES groups. Conclusions and Relevance In this systematic review and meta-analysis, tDCS was associated with improvement in depression among patients with DMC and DPC (with smaller benefits in MDD), tACS was associated with improved MDD outcomes (while tRNS had insufficient evidence) in smaller samples, and combined tDCS and medication was associated with improvement in depression. These findings suggest that tES is well-tolerated overall, with only mild to moderate adverse events, and that future research should optimize stimulation parameters and individualize tES interventions.

BACKGROUND AND OBJECTIVES: Aneurysm risk prediction remains an imprecise science that places patients at risk for either over or undertreatment. Machine learning (ML) models may improve clinical practice by adding precision to risk assessment. This study aims to comprehensively assess the current landscape of ML applications in predicting the risk of aneurysm rupture and compare the performance with the widely used PHASES score. METHODS: A systematic review of PubMed, Scopus, and Web of Science was conducted. All studies using ML tools to predict the rupture risk of intracranial aneurysms were included. Meta-analysis was conducted with consideration to the ML algorithms and compared with the PHASES score. RESULTS: Thirty-six studies involving 22 462 patients were included in the final analysis. ML techniques, including 124 models using 25 algorithms, were employed. Among various ML models, while they had comparable diagnostic performance, deep learning exhibited a slightly better performance profile (sensitivity = 0.792, specificity = 0.788, and accuracy = 0.778 in external validation). Based on our analysis, ML, regardless of the algorithm, provides comparable sensitivity (0.743 vs 0.771, P = .60) and higher specificity (0.763 vs 0.507, P < .01) compared with the PHASES score. Consistently, pooling the area under the receiver operating characteristic curve (AUC) for 60 ML models and 5 PHASES score data, ML models exhibited higher AUC (0.84 vs 0.64, P < .01). Using hemodynamic parameters as input for models improved specificity ( P < .01) in the test sets without any significant changes in the sensitivity. The later improvement was not observed in the external validation sets. CONCLUSION: ML techniques have the potential to enhance the prediction of intracranial aneurysm rupture compared with traditional approaches, like the PHASES score. Incorporating hemodynamic parameters may further enhance the accuracy of ML models. Feature prospective studies are required to validate the utility of ML models for clinical integration.

Abstract Objective To examine the effectiveness of treatment strategies for medication‐overuse headache (MOH) in children and adolescents. Background There are no guidelines for the treatment of adult or pediatric patients with MOH. However, research pertaining to MOH in adults is far outpacing research in children and adolescents. Methods A systematic review of evidence on treatment for MOH in children and adolescents was performed via PubMed, Embase, Web of Science, PsycINFO, and Cochrane from database inception to October 2024 for articles with the subject headings and keywords for MOH and pediatric, children, and/or adolescent. Inclusion criteria were: (i) randomized controlled trials and retrospective and prospective observational studies, (ii) children and adolescents aged <18 years with chronic headaches and with medication overuse (MO) or MOH, and (iii) interventions addressing MO or MOH, including pharmacologic and behavioral interventions. At least two independent reviewers screened citations and full‐text articles independently. Results A total of 16 studies (one randomized control trial, six prospective observational studies and nine retrospective observational studies) were identified as meeting final inclusion criteria, resulting in 7978 total participants with a subset of those having MO, MOH or probable MOH. Participants ranged in mean age from 10 to 14.7 years, with 7.1%–46.2% male participants. All the studies recruited patients from an outpatient setting. Interventions used in the studies included withdrawal of the overused acute medication, initiation of preventive medication, patient education, physiotherapy and psychological treatment, and motivational interviewing. Multimodal therapy was studied more than single therapeutic intervention. There was vast heterogeneity across the studies, including study design, diagnostic criteria, intervention type, and outcomes. Conclusion From the data available, there does not seem to be a singular superior treatment approach. Accordingly, the most appropriate treatment modality will need to be tailored to the patient and their caregivers. Further research is required regarding management of MOH in children and adolescents.

ABSTRACT Erectile dysfunction (ED) is a prevalent condition severely impacting men's quality of life. While micronutrient balance is critical for sexual health, observational studies on micronutrient and ED remain inconclusive. The objective of this study was to evaluate the causal role of circulating levels of copper and other micronutrients in ED risk by Mendelian randomization (MR). We conducted bidirectional two‐sample MR using summary statistics from European‐ancestry cohorts involving thirteen micronutrients. Inverse‐variance weighted (IVW) MR was complemented by sensitivity analyses, including MR‐Egger and MR‐PRESSO, and pooled analysis of two GWAS‐based datasets was performed to substantiate the findings of MR. In this study, circulating copper levels significantly increased ED risk in the discovery (OR = 1.129, 95% CI: 1.004–1.27, p = 0.042) and replication (OR = 1.115, 95% CI: 1.001–1.242, p = 0.0476) stages, as well as pooled analyses (OR = 1.122, 95% CI: 1.036–1.214, p = 0.0046). Sensitivity analyses reinforced the robustness of these findings, with no significant heterogeneity or directional pleiotropy observed. Reverse MR found no causal effect of ED on micronutrients. In summary, this study provides robust genetic evidence that elevated circulating copper levels are a modifiable risk factor for ED. Personalized management of copper intake, guided by genetic predisposition, may mitigate ED risk and improve sexual health outcomes. These findings highlight the clinical relevance of copper homeostasis in ED prevention and underscore the need for targeted nutritional interventions.

Abstract Background Robotic Whipple holds the promise to overcome safety concerns associated with laparoscopy, paving the way for widespread implementation of minimal-invasive surgery in this complex procedure. However, randomized data comparing robot vs. open Whipple demonstrate more pancreas-specific complications and R1-resections in the robotic arm. Recent international consensus identified establishing benchmarks as critical to ensure safe adoption of the robot. Benchmarking is a validated quality improvement tool, enabling comparison of surgical performance. Aims The aim was to define benchmarks for outcome parameters in robotic Whipple. Methods We analyzed consecutive patients undergoing robotic Whipple from January 2020 until December 2023 in 11 centers across 4 continents, with a minimum one-year follow-up. Centers had to perform ≥15 cases/year and have mounted their learning curve. Benchmark criteria included benign or resectable malignant disease without neoadjuvant therapy, arterial resection, major co-morbidities, or significant previous abdominal surgery. Medians across centers represented benchmark cutoffs. Results Eleven centers performed 1’037 Whipple procedures, of which 603 (58%) were benchmark cases. One third (n=192) were pancreatic ductal adenocarcinoma (PDAC) patients. Key benchmarks at 6 months included ≤1.2% mortality, ≤24.2% major complications, and ≤ 8.7 points Comprehensive Complication Index®. Pancreas-specific cutoffs included ≤13.0% postoperative pancreatic fistula (POPF) B/C and ≤3.4% post-pancreatectomy hemorrhage B/C, with 100% R0-resection and ≥19 harvested lymph nodes in PDAC patients. One-year actuarial overall and recurrence-free survival was 87% and 77%. In the entire cohort POPF B/C occurred in 16% (n=195). Independent POPF predictors included duct diameter ≤4mm (OR 1.79 95%CI [1.27-2.55]), anticoagulation (OR 3.68 95%CI [2.14-6.24]), and indication other than PDAC (OR 3.17, 95%CI [2.13-4.85]). Conclusion This study establishes benchmarks for key outcomes in robotic Whipple, demonstrating oncologic adequacy and morbidity comparable to open surgery. Risk factors for POPF in open surgery also hold true in the robotic approach.

Abstract Context Primary aldosteronism (PA) is a leading endocrine cause of secondary hypertension. Objective To support the development of the Endocrine Society Clinical Practice Guideline on managing PA. Data Source MEDLINE, Embase, Scopus, and others were searched on October 4, 2024. Study Selection Studies were selected by pairs of independent reviewers. Data Extraction Data were extracted and appraised by pairs of independent reviewers. Data Synthesis We included 95 studies (7 randomized trials and 88 observational studies). We did not identify trials that evaluated the outcomes of PA screening. One observational study suggested that screening was associated with higher rates of using PA-specific medical therapies and better blood pressure control. Patients managed with adrenal venous sampling (vs computed tomography alone) may have a better post-adrenalectomy biochemical cure rate, but with an increased risk of adrenal hemorrhage. Two small observational studies suggested that PA-specific medical or surgical therapy was likely associated with better blood pressure control than nonspecific therapy. Small randomized trials suggested that surgical therapy may be associated with better blood pressure control than medical therapy, with a lower number and dosage of antihypertensive medications. Compared to eplerenone, spironolactone may be associated with better control of hypokalemia and a lower number and dosage of antihypertensive agents. Unsuppressed plasma renin activity was associated with better control of hypokalemia, while suppression was associated with higher risk of mortality, atrial fibrillation, and stroke (very low certainty). Conclusion This systematic review addresses various aspects of managing PA and will support the development of the Endocrine Society guidelines.

Abstract Tumor cells develop various strategies to evade immune surveillance, one of which involves altering the metabolic state of the tumor microenvironment. In response to metabolic stress in the tumor microenvironment, several tumor-infiltrating immune subsets upregulate CD36 to take up lipids. This leads to impaired antitumor immunity, as intratumoral regulatory T cells exhibit increased survival and suppressive activity, whereas CD8+ T cells become more susceptible to ferroptosis and exhaustion. In this study, we develop a humanized anti-CD36 IgG4 antibody, PLT012, against the lipid-binding domain of CD36 with excellent safety and favorable pharmacokinetic features in mice and cynomolgus monkeys. PLT012 alone or in combination with PD-L1 blockade or standard-of-care immunotherapy results in robust antitumor immunity in both immunotherapy-sensitive and -resistant hepatocellular carcinomas (HCC). Notably, PLT012 also reprograms the immune landscape of human HCC ex vivo. Our findings provide proof-of-concept evidence that PLT012 reprograms antitumor immunity in HCC, positioning it as a first-in-class immunotherapy targeting CD36. Significance: Despite the success of cancer immunotherapies, like immune checkpoint inhibitors, many patients still fail to demonstrate significant responses because of metabolic constraints in tumors. PLT012 rejuvenates antitumor immunity by targeting metabolic pathways to reprogram the immune landscape of liver cancer and liver metastasis, with potential to influence future HCC immunotherapy.

Abstract Background and Objective: Bladder cancer is the 9th most diagnosed cancer worldwide with high incidences reported in Europe and the United States. Here, we evaluated the real-world performance of a commercially available multiplex immunoassay Oncuria-Detect that detects bladder cancer by simultaneously measuring a panel of 10 biomarker proteins in naturally voided urine samples. Methods: We tested prospectively collected urine samples from a real-world cohort of 1, 002 patients presenting to five USA centers, one European center and one Japanese center with hematuria. Assay results were collated with patient clinical data and a cancer diagnosis was defined by biopsy and pathology. The prevalence of bladder cancer in the cohort was 15.9%. Results: In a training set (n=684), the Oncuria-Detect assay correctly identified bladder cancer in 94/109 cases, representing a sensitivity of 91.8%, specificity of 71.6% (AUC 0.885; 95% CI 0.843 - 0.927) and with improved performance for high-grade bladder cancer and muscle-invasive bladder cancer (sensitivity 93.6% and 92.1%, respectively). In a test cohort of n =339 the AUC for detecting bladder cancer was 0.850 (95% CI 0.779-0.920). Conclusions and Implications: The multiplex Oncuria-Detect assay identified bladder cancer with high sensitivity and NPV, for low-grade and high-grade tumors alike. Oncuria-Detect’s high NPV could effectively rule out 66% of patients from requiring subsequent cystoscopy. Citation Format: Ian Pagano, Zhen Zhang, Sergei Tikhonenkov, Florence Le Calvez-Kelm, Steve Goodison, Toru Sakatani, Kaoru Murakami, Takashi Kobayashi, Howard Kim, Riko Lee, Sunao Tanaka, Charles J. Rosser, Hideki Furuya. Performance of the Oncuria-detect bladder cancer test for evaluating patients presenting with hematuria: results from a real-world clinical setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5919.

Non-ST-segment elevation myocardial infarction (NSTEMI) can be managed by ischemia guide strategies or early invasive strategies. Here, we present the findings of an updated contemporary analysis regarding the use of intracoronary imaging (ICI)-guided PCI versus angiography-guided PCI and in-hospital mortality in patients with NSTEMI in the United States using the NIS database from 2016 to 2021. ICI use increased by nearly threefold between 2016 and 2021, without a significant difference in in-hospital mortality, though interestingly, mortality rates compared with angiography guidance were similar and relatively low. In this study, the use of ICI was associated with lower adjusted odds of in-hospital mortality, cardiogenic shock, and cardiac arrest, but with a longer length of stay and cost of hospitalization.