Citations

OBJECTIVE Communicating hydrocephalus may occur following stereotactic radiosurgery (SRS) for vestibular schwannomas (VSs), yet identifying individual patient risk factors associated with this post-SRS complication remains a challenge. This study examined predictors of nonobstructive ventricular enlargement and symptomatic communicating hydrocephalus following primary SRS treatment for VS via a single-center institutional cohort review and meta-analysis of the literature. METHODS A retrospective single-institution cohort study and systematic literature review and meta-analysis examining post-SRS communicating hydrocephalus in VS was performed. RESULTS The institutional cohort consisted of 634 patients who received primary SRS as treatment for VS. The cohort was 51.6% female, with a median age of 64 (range 18–89) years. Following SRS treatment, 364 patients (57.4%) experienced tumor shrinkage, 218 (34.4%) had no change in the size of their lesion, and 52 (8.2%) experienced tumor growth. Nonobstructive ventricular enlargement was observed in 23 patients (3.6%) following SRS treatment, of whom 9 (39.1%) remained asymptomatic and 14 (60.9%) required placement of a ventriculoperitoneal (VP) shunt, with a median time to shunt placement of 8 months. In the multivariate analysis, patients ≥ 65 years old (p = 0.038), SRS target volume ≥ 5 cm 3 (p < 0.001), maximum SRS dose ≥ 26 Gy (p = 0.015), and tumor growth at the most recent follow-up (p = 0.002) were associated with an increased risk of post-SRS ventricular enlargement. Similarly, patients with older age (p = 0.049), increased SRS target volume (p = 0.002), and tumor growth (p = 0.016) were at an increased risk of symptomatic communicating hydrocephalus requiring VP shunt placement. Twenty-nine studies, including the cohort in this study, met inclusion criteria in the meta-analysis. Of the pooled 7825 patients, the overall incidence of hydrocephalus following SRS was 5%, and a subanalysis of 7081 patients demonstrated the incidence of symptomatic hydrocephalus requiring a VP shunt to be 4%. In this subanalysis, the overall shunting rate in patients who experienced post-SRS ventriculomegaly was 92%. Among individual studies in the literature, increased tumor size was most commonly found to be a statistically significant risk factor for post-SRS hydrocephalus. CONCLUSIONS Approximately 5% of patients may experience nonobstructive ventricular enlargement following primary SRS treatment for VS. However, not all patients may be symptomatic and require shunting. Patients who are older (≥ 65 years), those with larger tumor volumes, and those with post-SRS tumor growth may be at increased risk of communicating hydrocephalus and may benefit from closer clinical monitoring.

Abstract The genetic contributions of the X chromosome to Alzheimer’s disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE *4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE *4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE *4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.

Background: Several special tests for detecting medial ulnar collateral ligament (MUCL) injuries of the elbow have been described, but data on the clinical utility of these tests are limited. Purpose: To determine the clinical utility of selected elbow special tests to detect MUCL injuries in an athletic population. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 84 consecutive patients with sports-related elbow pain underwent a standardized clinical examination. Overall, 6 special tests (moving valgus stress test, static valgus stress test, modified valgus stress test, milking maneuver, pronation flexion resistance test, and temple/cheek press test) were performed. Sensitivity, specificity, accuracy, positive/negative predictive value, and positive/negative likelihood ratio (LR+ and LR–, respectively) were calculated for individual tests and combinations of tests to detect MUCL injuries. Higher values for the LR+ and lower values for the LR– represent stronger clinical utility. Results: For detecting MUCL injuries, the moving valgus stress test resulted in the highest sensitivity (98%) and accuracy (93%) with the lowest LR– (2%). The milking maneuver had the highest LR+ (5.1) with the second highest sensitivity (77%) and accuracy (79%). The pronation flexion resistance test and the temple/cheek press test had the lowest LR+ (1.5 and 1.8, respectively) and highest LR– (94% and 95%, respectively) in addition to the lowest sensitivity (16% and 9%, respectively) and accuracy (33% and 30%, respectively). No combination of tests resulted in increased clinical utility. Conclusion: The moving valgus stress test and milking maneuver demonstrated acceptable clinical utility in which the moving valgus stress test was better for ruling out MUCL injuries and the milking maneuver was better at ruling in MUCL injuries. There was no added value when combining the 2 tests together or with other maneuvers.

INTRODUCTION: Normalized quality of life represents a crucial long-term treatment goal in Crohn's disease (CD). We evaluated the effect of risankizumab (RZB) vs ustekinumab (UST) on achieving clinically meaningful improvements in patient-reported outcomes in the phase 3b head-to-head SEQUENCE study. METHODS: Adults with moderate-to-severe CD whose previous anti-tumor necrosis factor therapy failed were randomized 1:1 to recommended induction and maintenance doses of RZB or UST. The proportion of patients who achieved Inflammatory Bowel Disease Questionnaire (IBDQ) response, IBDQ remission, and improvements in 36-item short-form health survey physical and mental component summary (physical component summary and mental component summary, respectively) scores was evaluated at weeks 24 and 48. The proportion of patients experiencing improvement in select symptoms of the IBDQ was reported. RESULTS: Analysis included 520 patients (RZB: N = 255; UST: N = 265). At week 24, greater proportions(all P ≤ .01) of RZB- vs UST-treated patients achieved IBDQ response (75.3% vs 64.2%), IBDQ remission (52.5% vs 30.9%), and improvements in 36-item short-form health survey physical component summary (65.9% vs 53.2%). At 24 weeks, lower proportions (all P ≤ .05) of RZB- vs UST-treated patients experienced fatigue (51.4% vs 69.1%), difficulty sleeping (37.7% vs 54.3%), depression (34.1% vs 42.6%), anxiety (34.1% vs 49.8%), and bowel urgency (27.1% vs 40.0%) all of the time to some of the time. Improvements were sustained through week 48. DISCUSSION: RZB was more effective than UST in achieving sustained clinically meaningful patient-reported outcome improvements including IBDQ response and remission, and in reducing frequency of select symptoms of the IBDQ through week 48 among patients with moderate-to-severe CD.

PURPOSE Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Early-stage, high-risk patients with TNBC are treated with chemotherapy and pembrolizumab per the KEYNOTE-522 regimen. This report examines real-world clinical effectiveness and toxicity of this regimen. METHODS This 19-site retrospective analysis included all patients who received at least one dose of the KEYNOTE-522 regimen. Safety, efficacy, and health care encounters were collected. RESULTS 675 patients from 19 sites in the United States who received chemotherapy and pembrolizumab for early-stage TNBC were included. 547 (81.0%) patients underwent surgery and 250 (54.7%) patients had a pathologic complete response (pCR). No baseline characteristics were predictive of pCR status. 224 patients (33.2%) had an adverse drug event resulting in ≥1 dose reduction of chemotherapy and were significantly more likely to have residual disease. Immune-related adverse events (irAEs) were observed in 388 (57.5%) patients and grade 3+ irAEs were observed in 176 (26.1%) patients. There was no difference in pCR status between provider's choice chemotherapy schedules. There was no difference of pCR rate between Black and White patients (55.6% v 51.6%, P = .489). White patients were significantly more likely to have any grade and grade 3+ irAEs. Older patients (age ≥65 years) had similar pCR rates compared with younger patients; however, older patients were significantly more likely to have grade 3+ irAEs. CONCLUSIONS In this multi-institutional real-world cohort, we observed a lower pCR rate, higher rates of toxicity, frequent emergency health care utilization, and the reporting of rare irAEs at higher frequency than the KEYNOTE-522 regimen. These findings have important implications for clinical management of patients with early-stage TNBC and warrant further validation with real-world data sets.

This multicenter, single-arm, phase 1/2 study evaluated the safety and efficacy of CD19-directed allogeneic chimeric-antigen-receptor (CAR) immunotherapy CTX110 in adult patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (NHL). Patients received 1 or 2 treatment courses: standard lymphodepletion, followed by 1 CTX110 infusion at dose levels (DLs) 1-4 (3-60 × 107 CAR T-cells; dose escalation, N=32), or 2 infusions at DL4 on days 1 and 35 (cohort expansion, N=31). Primary endpoints in dose escalation and cohort expansion were incidence of dose-limiting toxicities and objective response rate, respectively. CTX110 was administered to 63 heavily pretreated patients: 59% primary refractory, 43% with ≥3 prior treatment lines. Among 57 patients whose first infusion was DL≥3, rates of objective and complete response (CR) were 65% and 39%, respectively. Among 22 patients achieving CR, 5 (23%) had ongoing CR at data cutoff, with 15-50 (median 34) months follow-up. The 2-infusion regimen appeared to prolong response duration compared to 1 infusion (hazard ratio 0.65). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 54% and 13% of treated patients, respectively, including 2 grade ≥3 cases each. The most common grade ≥3 adverse events were neutropenia (59%), and anemia and thrombocytopenia (35% each). Serious adverse events occurred in 32% of treated patients, including CRS (14%), ICANS (8%), and febrile neutropenia (6%). In this r/r NHL population, CTX110 was well-tolerated, resulting in clinically meaningful responses at DL≥3, with a second infusion demonstrating evidence of further clinical benefit. This trial (NCT04035434) was registered at www.clinicaltrials.gov.

Importance Allogeneic hematopoietic cell transplant (HCT) is curative for hematologic cancers, yet access remains inequitable for racially and ethnically underrepresented and socioeconomically disadvantaged populations, making the goal of having a suitable donor for every patient who needs a transplant challenging. The ACCESS trial broadened access by enrolling patients without matched donors, who instead received an HCT from a mismatched unrelated donor. Objective To compare baseline characteristics of ACCESS trial participants with participants enrolled in a similar clinical trial and a patient-reported outcome (PRO) protocol cohort. Design, Setting, and Participants This cross-sectional study included adult participants (aged ≥18 years) from 3 cohorts—the ACCESS trial (2021-2024), BMT CTN 1703 trial (2019-2021), and Center for International Blood and Marrow Transplant Research (CIBMTR) PRO Protocol observational study (2020-2025)—who completed a baseline PRO survey. The ACCESS and PRO Protocol cohorts were stratified by conditioning intensity (myeloablative [MAC] vs reduced-intensity and nonmyeloablative [RIC/NMA]); all BMT CTN 1703 participants received RIC/NMA. Exposure Hematopoietic cell transplant. Main Outcomes and Measures Racial and ethnic diversity, insurance type, education, and income were compared among cohorts using counts and percentages, and socioeconomic and structural disadvantage were measured using the Social Vulnerability Index and Comprehensive Score for Financial Toxicity–Functional Assessment of Chronic Illness Therapy. Results Baseline surveys were completed by 208 participants in the ACCESS trial (median [range] age at transplant, 62.3 [20.4-78.9] years; 108 male [51.9%]), 122 participants in the PRO Protocol study (median [range] age at transplant, 63.9 [21.1-78.0] years; 67 male [54.9%]), and 342 participants in the BMT CTN 1703 trial (median [range] age at transplant, 66.9 [20.7-78.6] years; 218 male [63.7%]). Participants in ACCESS were more racially and ethnically diverse, with 15 (7.2%), 25 (12.1%), 46 (22.2%), 110 (53.1%), and 11 (5.3%) of Asian, Black or African American, Hispanic or Latino, White, and other race and ethnicity, respectively, compared with 4 (3.3%), 2 (1.6%), 8 (6.6%) 104 (85.2%), and 4 (3.3%), respectively, in the PRO Protocol and 10 (3.0%), 0, 16 (4.8%), 302 (91.0%), and 4 (1.2%), respectively, in the BMT CTN 1703 trial. Participants in ACCESS were more likely to have Medicaid (36 [18.1%]) vs PRO Protocol (8 [6.7%]) and BMT CTN 1703 (16 [5.1%]) participants and reported lower education (some college or an associate’s degree: 103 [49.5%] vs 73 [59.8%] in the PRO Protocol; postcollege education: 34 [17.3%] vs 35 [29.2%] in the PRO Protocol) and household income (&amp;lt;$40 000 annually: 25 [24.0%] vs 8 [11.6%] in the PRO Protocol and 7 [38.9%] in the BMT CTN 1703 trial). Median Social Vulnerability Index scores were highest among participants in the ACCESS MAC group (median [range], 0.72 [0.01-0.97] vs 0.61 [0.16-0.78] in the PRO Protocol MAC group), and 16 participants [27.6%] in the ACCESS MAC group reported moderate to severe financial toxicity. The ACCESS participants lived closer to transplant centers, especially in the RIC/NMA group (median [IQR], 28 [14-75] miles vs 47 [16-96] miles for BMT CTN 1703 participants and 49 [21-104] miles for PRO Protocol participants). Conclusions and Relevance This cross-sectional study of clinical trial participants and a clinical cohort found that the ACCESS trial enrolled a more racially and ethnically diverse and socioeconomically disadvantaged population. Trial designs that broaden eligibility could expand access to HCT, highlighting the need for systemic interventions to ensure equity.

Among patients with treatment-naive hepatocellular carcinoma, glass microsphere radiation segmentectomy before liver transplant achieved high rates of complete pathologic necrosis, which was positively associated with the number of optimized treatment parameter thresholds.

Abstract INTRODUCTION : Despite expanding use of plasma biomarkers for Alzheimer's disease (AD), minimal examination has been undertaken in early‐onset AD (EOAD). Prior analyses assessed criterion and convergent validity of common plasma biomarkers in a well‐characterized sample with sporadic EOAD. METHODS : Plasma amyloid beta (Aβ) 42/40, tau phosphorylated at threonine 231 (p‐tau231), glial fibrillary acidic protein (GFAP), and neurofilament light change (NfL) levels were obtained for 189 EOAD, 52 early‐onset non‐AD (EOnonAD), and 83 cognitively normal (CN) participants. Diagnostic group differences, convergence with imaging biomarkers, and the capacity to predict specific cognitive domains were investigated. RESULTS : After controlling for cognitive status, EOAD participants exhibited more pathologic levels of Aβ42/40, p‐tau231, and GFAP relative to EOnonAD participants. However, NfL displayed the greatest sensitivity to non‐amnestic cognitive impairment across the sample. DISCUSSION : These results establish criterion and convergent validity of plasma biomarkers in sporadic EOAD and highlight complementary roles that AD‐specific and non‐specific plasma markers may play across the course of AD care.

Abstract INTRODUCTION Naturalistic driving provides real‐world behavioral indicators of early cognitive and functional changes. This study integrated naturalistic driving GPS trajectories collected from in‐vehicle sensors with points of interest (POIs) to quantify daily environmental engagement among older adults who were cognitively normal at enrollment. METHODS Data from 438 participants enrolled in the Driving Real‐world in‐Vehicle Evaluation System Project were used to generate daily POI share vectors and model latent engagement patterns using a logistic‐normal hidden Markov model (HMM). Thirteen latent states described distinct modes of environmental interaction. From each participant's inferred state sequence, we derived mobility features – state occupancy, dwell time, transition entropy, and self‐transition probability – and examined their differences across clinical status groups and associations with Preclinical Alzheimer's Cognitive Composite (PACC) performance. RESULTS Transition entropy and several state‐specific occupancy and dwelling metrics differed across clinical groups, but none of the mobility features were significantly associated with PACC scores. DISCUSSION Mobility‐derived behavioral features differentiate clinical status groups and may reflect early functional changes preceding cognitive decline.