Citations

Importance Primary brain and central nervous system cancer (collectively referred to as CNS cancer) comprises 2% of all human cancers and poses significant health and economic challenges in the United States. Objective To analyze CNS cancer burden in the US, stratified by time, location (state and division), sex, age group, and Sociodemographic Index (SDI). Design, Setting, and Participants This cross-sectional study involved a repeated analysis of Global Burden of Disease Study (GBD) 2021 data in 2024. Using data from 183 sources, CNS cancer metrics in the US were estimated across states and years. US CNS cancer metrics across all sexes and age groups were included in the GBD. Exposure CNS cancer diagnosis. Main Outcomes and Measures Overall and age-standardized estimates of the incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability per 100 000 population, including 95% uncertainty intervals (UIs), and time trends. Results In 2021, for all age groups and sexes across the US, there were 31 780 incident cases (95% UI, 29971.1 to 32843.9). Age-standardized incidence, DALYs, and mortality rates per 100 000 population were 6.91 (95% UI, 6.58 to 7.12), 134.38 (95% UI, 129.83 to 137.95), and 4.1 (95% UI, 3.87 to 4.22), respectively. Despite no significant change observed in the overall incidence between 1990 and 2021, DALY and mortality rates decreased by 15.77% (95% UI, −17.75% to −13.68%) and 8.41% (95% UI, −11.09% to −6.22%), respectively. Substantial geographic variability was noted. Mississippi, Alabama, Kentucky, and Kansas (West North Central and East South Central divisions) and West Virginia faced persistently high burdens over the past 30 years. Sex differences were evident; disease burden was consistently higher in males compared with females. Age-specific estimates showed a bimodal distribution: the youngest group (<5 years) showed a significant decrease in incidence rate (−34.42% to −11.56%), whereas older age groups (>70 years) experienced increasing trends. DALYs and mortality rates were negatively correlated with SDI (ρ = −0.6860 and ρ = −0.6391; P < .001). Conclusions and Relevance These findings provide valuable insights into the CNS cancer burden across the US by age, sex, location, and SDI, enabling better public health status assessments, health care policy restructuring, and resource redistribution for improved care.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

ABSTRACT At the 42nd Annual Meeting of the American Association of Clinical Anatomists (AACA) in Bellevue, Washington, June 2025, two inaugural events—the Clinical Anatomy Fireside Chat (CAFC) and the Clinical Anatomy Symposium: Head and Neck 2025 (CAS)—fostered rich dialogue on the evolving role and operational definition of clinical anatomy. Experts from various clinical and anatomical disciplines explored the meaning of clinical anatomy, highlighting the absence of a universal definition despite its frequent use in education and research. Through these interdisciplinary discussions, a consensus emerged: clinical anatomy is not defined solely by the possession of clinical credentials but by the integration of anatomical knowledge and clinical relevance, achieved most effectively through collaboration. Clinical anatomy education and research require different depths of clinical knowledge depending on the audience and objective, and meaningful collaboration can bridge gaps in expertise. The symposium further illustrated that high‐quality clinical anatomy emerges from mutual respect and reciprocal insight between clinicians and anatomists. This article presents a consensus statement developed by AACA representatives and invited speakers, affirming that collaboration is not only foundational to the practice of clinical anatomy but also fundamental to its definition. These conclusions aim to guide future educational models, research strategies, and interdisciplinary partnerships in the field of clinical anatomy.

Abstract Introduction: Despite treatment advances, ovarian cancer (OC) remains the deadliest gynecological cancer, with a ∼70% mortality rate. OCs initially respond to platinum chemotherapy but often develop resistance. While PARP inhibitors improve relapse-free survival in responsive cases, they do not extend overall survival. This underscores the need for effective combination therapies beyond BRCA status. The lysosomal protein cathepsin L (CTSL) can traffic to the nucleus, where it can regulate DNA repair and serve as a chromatin modifier. We found that nucleoside analog clofarabine (CLF) induces CTSL nuclear trafficking in OC cells. Here we tested the hypothesis that accumulation nuclear CTSL (nCTSL) is a biomarker of sensitivity to DNA damaging therapy in OCs for improved therapeutic options. Methods: To determine the role of CLF induced nuclear CTSL in DNA damage and its synergy with PARP and CRM1 inhibitors in PARP inhibitor–sensitive and –resistant ovarian cancer (OC) cell lines, ex vivo cultures of ascites-derived patient OC cells (OVA-3D spheroids), primary ovarian tumors, and patient-derived xenograft (PDX) models and validated by colony formation assays. Nuclear CTSL localization was determined in subcellular fractionated lysates by western blots and immunofluorescence cytometry (IFC). Tumor regression was determined in vivo using ex vivo cultures of PDX derived cells. Results: In ovarian cancer (OC) cell lines, CLF monotherapy induced nuclear CTSL (nCTSL) in a subset of models classified as CLF-responsive (CLF-r), sensitizing them to the PARP inhibitors olaparib and rucaparib. In CLF-non-responsive (CLF-nr) models, nCTSL induction and therapeutic synergy were observed only with the CLF+olaparib combination. Synergy was detected in 47% of CLF-r and 24% of CLF-nr patient-derived ascites samples (OVA). Mechanistically, CLF induced nuclear import of CTSL via KPNB1 in CLF-r cells, while this import was triggered by the CLF+olaparib combination in CLF-nr cells. CLF also downregulated the nuclear export protein CRM1 (XPO1) in both groups. Knockdown of CTSL in either CLF-r or CLF-nr cells abrogated sensitivity to the combination. Notably, in 29% of OVA samples classified as CLF-resistant (CLF-Res), CLF failed to suppress CRM1 expression. In these cases, CRM1 inhibition with KPT8602 restored CLF+PARP inhibitor synergy. In vivo, CLF-r and CLF-nr PDX models treated with the combination exhibited increased DNA damage, reduced tumor burden, and extended survival. Conclusion: These findings identify nuclear CTSL (nCTSL) induction as a potential biomarker of response to DNA-damaging therapies. The combination of CLF and olaparib represents a promising strategy to overcome drug resistance in ovarian cancer by promoting CTSL nuclear localization and enhancing DNA damage. Citation Format: Prabhu Thirusangu, Ling Jin, Upasana Ray, Anya Zhao, Julie Staub, Xinyan Wu, Xiaonan Hou, Jamison L. VanBlaricom, Syed Mohamed Musheer Aalam, Sun-Hee Lee, Ann Oberg, Nagarajan Kannan, John Weroha, Jeremy Chien, Scott H. Kaufmann, Jamie N. Bakkum-Gamez, Viji Shridhar. Role of drug induced nuclear CTSL (nCTSL) in DNA damage response in cancer- therapeutic implications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A050.

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Abstract Background Disruption of the blood–brain barrier (BBB) in high-grade brain tumors is characterized by contrast accumulation on diagnostic imaging. This window of opportunity study correlates contrast imaging features with the tumor distribution of BBB-permeable (levetiracetam) and -impermeable (cefazolin) drugs. Methods Patients with a clinical diagnosis of a high-grade brain tumor underwent MRI for surgical planning. Cefazolin and levetiracetam were administered prior to skin incision, and serial plasma and image-registered tumor samples were collected during the operation. Drug levels were measured by LC-MS/MS, tissue drug levels were corrected for residual blood, and tumor-to-plasma concentration ratios were calculated. Intraoperative microdialysis was performed in a subset of patients to measure the same two drugs. Results Tumor (n = 125) and plasma (n = 261) samples were available for analysis from 42 operative cases. Across all samples, the tumor-to-plasma ratio was significantly lower for cefazolin (marginal mean [MM]: 0.15, 95% CI: 0.11–0.19) as compared to levetiracetam (MM: 0.70, 95% CI: 0.64–0.75; P < .001). When compared between contrast-enhancing and non-enhancing regions, tumor-to-plasma ratios for cefazolin varied by 4.4-fold (0.27, 95% CI: 0.20–0.35 vs. 0.06, 95% CI: 0.04–0.08, respectively; P < .001), and varied for levetiracetam by 1.4-fold (0.88, 95% CI: 0.78–0.97 vs. 0.61, 95% CI: 0.55–0.66, respectively; P < .001). These results were confirmed with the intra-operative microdialysis and a population pharmacokinetic analysis. Conclusions This study demonstrates significant inter- and intra-tumoral heterogeneity in drug delivery for both levetiracetam and cefazolin within high-grade brain tumors that is not necessarily predicted by clinical MR imaging and may reflect tumor-induced changes in both perfusion and BBB integrity.

Purpose To evaluate the clinical outcomes of lower trapezius tendon (LTT) transfer using an Achilles tendon allograft in patients with failed superior capsular reconstruction (SCR). Methods A retrospective therapeutic review was conducted on patients who underwent LTT transfer using an Achilles tendon allograft after SCR failure between January 2018 and May 2020. The inclusion criteria encompassed both structural and functional failures of SCR in patients with minimal glenohumeral arthritis and a minimum follow‐up of 2 years. Exclusion criteria were insufficient clinical data or loss to follow‐up. Clinical outcomes were assessed preoperatively and at final follow‐up using the visual analog scale (VAS), subjective shoulder value (SSV), Constant score, American Shoulder and Elbow Surgeons (ASES) score, and range of motion (ROM). Results Eighteen patients were included, with a mean follow‐up of 42.5 months (range: 24‐62 months). All outcome measures demonstrated statistically significant improvement: VAS scores improved from 5.9 ± 1.3 to 1.8 ± 1.4; SSV scores improved from 18.0 ± 9.1 to 61.4 ± 18.5; Constant score improved from 33.3 ± 5.3 to 65.5 ± 17.4; and ASES score improved from 38.5 ± 5.2 to 67.1 ± 17.7 (all P < .001). On the basis of the minimal clinically important difference (MCID) using a 0.5 SD distribution‐based method, clinically meaningful improvements were observed in 88.9% of patients for VAS and ASES scores, and 94.4% for Constant and SSV scores. ROM gains included forward elevation (73° to 120°), abduction (57° to 93°), and external rotation (−22° to 40°). At final follow‐up, 77.8% of patients had resumed occupational activities, and 61.1% returned to sports. Four patients (22.2%) required conversion to reverse shoulder arthroplasty. Conclusions LTT transfer using an Achilles tendon allograft following failed SCR yields significant improvements in pain relief, functional outcomes, and ROM. LTT transfer using an Achilles tendon allograft following failed SCR may offer a potential treatment option, particularly in younger, active patients who seek to preserve native shoulder anatomy and function. Level of Evidence Level IV retrospective case series.

ABSTRACT Determining an appropriate sample size in human cadaveric studies remains a long‐standing and unresolved challenge. Unlike other basic science fields, anatomical research is constrained by factors such as limited human donor availability, cultural considerations, and ethical restrictions. Despite these limitations, researchers are often asked to justify sample sizes, yet no standardized guidelines currently exist. To quantitatively assess sample sizes in recent human cadaveric studies and propose evidence‐based recommendations for future research, a PubMed search was conducted on February 26, 2024, using the term human cadaveric study . The articles published in 2023 and 2024 were screened, yielding 770 eligible studies. Data extracted included the total sample size, number of classified groups, and journal impact factor (IF). Descriptive statistics, linear regression, and correlation analyses were performed. Continuous variables were summarized using medians and interquartile ranges (IQR). The median sample size was 11.5 (IQR: 7–20), and 47.9% of studies used 10 or fewer specimens. The median number of classified groups was 3 (IQR: 2–4). Linear regression showed that studies dividing specimens into 2–6 groups often failed to meet the recommended sample size per group based on regression modeling. No significant correlation was found between sample size and journal IF ( r = −0.062, p = 0.115). Most cadaveric studies rely on small sample sizes due to inherent constraints, yet many still attempt a subgroup analysis without sufficient statistical power. Although flexibility is essential in anatomical research, we recommend a minimum total sample size of 10 for basic studies and at least five samples per group for those involving classification. Cadaveric sample size alone does not predict journal impact, highlighting the importance of methodological rigor over quantity.

Objectives: Novel biomechanics of the exhalation delivery system can deliver fluticasone (EDS-FLU; XHANCE) to sinonasal areas above the inferior turbinate, especially sinus drainage pathways not reached by standard nasal sprays. This study aimed to evaluate the effectiveness of EDS-FLU in treating chronic rhinosinusitis (CRS). Methods: Studies were retrieved from PubMed, SCOPUS, Embase, Web of Science, and Cochrane databases up to April 2024. We analyzed 5 studies that compared EDS-FLU with a control group (exhalation delivery system with placebo) on various outcomes, including the 22-item Sinonasal Outcome Test (SNOT-22), nasal symptom scores (congestion, facial pain, olfactory dysfunction, and rhinorrhea), nasal polyp scores, surgical indication rate, and the incidence of adverse effects. Results: Five studies with 2129 patients were included. EDS-FLU significantly improved SNOT-22 score (−20.9657 [−23.5639; −18.3674]) and the polyp score (−1.5099 [−1.7810; −1.2388]) after 6 months. The incidence of epistaxis was significantly higher in the treatment group compared to the control group (OR = 5.7954 [2.1004; 15.9909]). Effects of EDS-FLU on polyp score (−0.6497 [−0.8186; −0.4807]), responder rate (OR = 2.1755 [1.2784; 3.7020]), complete responder rate (OR = 2.0423 [1.0109; 4.1262]), surgical indication rate (OR = 0.7313 [0.5459; 0.9797]), and SNOT-22 score (−6.1513 [−11.3054; −0.9972]) were significantly higher in the treatment group than in the control group. Conclusions: This study demonstrated that EDS-FLU (372 µg twice daily) produced statistically significant improvements compared to EDS-placebo in multiple subjective and objective outcomes, although some adverse effects, such as epistaxis, may occur.