Citations

Neoadjuvant immune checkpoint inhibition (Neo-ICI) in melanoma is an emerging therapeutic strategy that induces pathologic responses with significant prognostic implications for survival. Tumor burden in nonresectable melanoma has a major impact on immunotherapy efficacy, yet little is known on its impact in the Neo-ICI setting. We evaluated the association between tumor burden, measured by the sum of diameters (SoD), and pathological response in melanoma patients treated with Neo-ICI. A meta-analysis of published trials in resectable stage III/IV melanoma was conducted, extracting data on patient characteristics, treatment regimens, pathological response, and survival outcomes. A total of 451 patients were included in the meta-analysis. The pooled pathological complete response (pCR) rate was 47% (95% confidence interval: 35–58%; P < 0.001). Meta-regression demonstrated a significant association between SoD and pCR (moderator = −0.36; P = 0.032), with greater tumor burden associated with lower pCR rates. No significant association was observed between SoD and recurrence-free survival (RFS). This study identifies higher tumor burden as a potential risk factor for lower pathologic response rates to neoadjuvant therapy, underscoring the need to incorporate tumor burden into future clinical research and potentially clinical decision-making.

Cellular senescence is a heterogeneous phenotype characterized primarily in mesenchymal cells, but the extent to which immune cells differ in their senescence phenotype, or “senotype,” is unclear. Here, we applied single-cell approaches alongside both global and cell-specific genetic senolytic mouse models to evaluate the senotype of immune cells in the bone marrow of aging mice. We found that myeloid-lineage cells exhibited the highest expression of p16 and senescence-associated secretory phenotype markers among all immune cell types. In contrast with clearance of p16 + senescent mesenchymal cells, targeted clearance of p16 + myeloid cells in aged mice had only minor effects on age-related bone loss in male mice, with no effects in females. In more detailed analyses, p16 + myeloid cells were only acutely cleared, being repopulated back to basal levels within a short time. This led to a lack of long-lasting reduction in senescent cell burden, unlike when targeting bone mesenchymal cells. In vitro, myeloid-lineage cells differed markedly from mesenchymal cells in the development of a senescent phenotype. Collectively, our findings indicate that aged bone marrow myeloid cells do not achieve the fully developed senescent phenotype originally described in mesenchymal cells, justifying further characterization of senotypes of immune cells across tissues.

Abstract Objective Despite being safe and effective, surgery for pediatric epilepsy is underutilized. Social determinants of health (SDoH) are important to consider when examining this treatment gap. This study examined the potential systemic inequities at three different stages in the journey toward epilepsy surgery across the Pediatric Epilepsy Research Consortium (PERC). Methods Any youth in the PERC prospective surgery database (≤18 years) was eligible and included if sociodemographic factors were also available. We examined if there were differences in disparity factors in: (1) referral to Phase I evaluation, (2) offering of surgery, and (3) completion of surgery. Results Of 1309 patients, the majority were male (53%, p = .04), White (82.2%, p < .001), not Hispanic or Latino (84.3%, p < .001), and privately insured (56.3%, p < .001). Of the youth who were offered surgical treatment ( n = 1103, 84.3%), there were no significant differences in race/ethnicity or sex. Those with a structural lesion were more likely to be offered surgery, and historically marginalized youth were more likely to have a lesion. Of patients who completed surgery ( n = 927, 84.0%), White patients were 1.88 times (95% confidence interval [CI]: 1.14–3.04) more likely than Black patients to complete surgery ( p = .01). Significance Youth who began surgery evaluation are not representative of the demographics of those with epilepsy in the United States, with greater representation of White, non‐Hispanic male individuals. In addition, youth who began surgery evaluation disproportionally have private insurance. At the next stage of offering surgery, there were no differences based on SDoH. However, there is evidence that underrepresented youth that were magnetic resonance negative were less likely to be referred for surgical workup and that Black youth were less likely to undergo surgery. Therefore, efforts to provide equitable opportunity for all youth with refractory epilepsy should be concentrated at the referral for surgery evaluation point of care; however, additional efforts are also needed at later stages.

ABSTRACT The limited efficacy of current therapies against cholangiocarcinoma (CCA) necessitates the development of novel treatment strategies. Src family kinases (SFKs) contribute significantly to tumor progression and resistance in CCA. Therefore, we investigated the novel, first-in-class SFK ‘OFF’ inhibitor NXP900 in diverse preclinical CCA models, including those with acquired resistance. This study evaluated the therapeutic effects of NXP900 and detailed adaptive molecular responses to SFK inhibitor therapy. We also aimed to identify biomarkers predictive of drug sensitivity using integrated multiomic profiling and develop strategies to overcome resistance. NXP900 inhibited YAP activity through direct inhibition of tyrosine phosphorylation and indirect activation of the Hippo pathway via LATS. These effects were associated with decreased tumor cell viability in CCA cell lines and several in vivo models. Notably, IDH -mutant patient-derived xenograft CCA models were particularly sensitive to NXP900. NXP900 also synergized with gemcitabine/cisplatin chemotherapy, enhancing antitumor efficacy in both in vitro and in vivo models. Multiomic analyses combining transcriptomics, global proteomics, and phosphoproteomics identified molecular features associated with primary response and acquired resistance. IL13RA-AKT signaling was upregulated in resistant models; NXP900 sensitivity could be restored with AKT or IL13RA2 inhibition. Together, these findings demonstrate the therapeutic potential of NXP900 as a novel YAP inhibitor in CCA and support further investigation in a clinical trial. Graphical Abstract

OBJECTIVE Core outcome sets (COSs) are needed to promote data consistency across studies as well as data synthesis and comparability. The aim of the current study was to use a modified Delphi process to develop a COS for lateral femoral cutaneous neuropathy (LFCN), hereafter COS-LFCN. METHODS A 5-stage approach was used to develop the COS-LFCN: 1) consortium development, 2) literature review to identify potential outcome measures, 3) Delphi survey to develop consensus on outcomes for inclusion, 4) Delphi survey to develop definitions, and 5) consensus meeting to finalize the COS and definitions. This study followed the Core Outcome Set - STAndards for Development, (COS-STAD) recommendations. RESULTS The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 25 participants, all neurological surgeons, representing 14 countries. The final COS-LFCN consisted of 41 factors and outcomes covering domains of demographics, diagnostics, patient-reported outcomes, motor/sensory outcomes, and complications. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 12 months, with the consensus optimal time points for assessment being preoperatively and 3, 6, and 12 months postoperatively. CONCLUSIONS The COINS Consortium developed a consensus COS for LFCN and provided definitions, methods of implementation, and time points for assessment. The COS-LFCN should serve as the minimum data to be collected in all future neurosurgical studies on LFCN. Incorporation of this COS will help improve consistency in reporting, data synthesis and comparability, and minimize outcome reporting bias.

Abstract Objective This study aimed to evaluate how differences in case complexity affect information-processing burden, as measured by eye-tracking, as well as the efficiency of electronic health record (EHR) use among healthcare providers in the intensive care unit. Materials and Methods This cross-sectional study recruited providers from 4 U.S. medical centers that use 2 prominent EHR systems (Epic and Oracle). After reporting demographic information, participants reviewed 2 complex cases and 2 standard cases in their institution’s EHR system and then responded to 5 questions about each case, yielding a performance score. Information-processing burden was assessed by measuring the number of eye fixations via eye-tracking software. The efficiency of EHR use was assessed by measuring the task completion time, number of mouse clicks per minute, number of EHR screens viewed, and performance score. Results Eighty-one providers were included for analysis. Providers exhibited significantly more eye fixations (P &lt; .001) and longer task completion times (P &lt; .001) for complex cases than for standard cases. There were also significantly fewer mouse clicks per minute during complex cases (P &lt; .001). Reviewing a complex case first led to significantly more eye fixations (P = .015) and longer task completion times (P &lt; .01) than when a standard case was presented first. Case complexity did not significantly affect performance scores or the number of EHR screens viewed. Discussion Higher case complexity was shown to be associated with greater information-processing burden and less efficient EHR use. These findings have implications for enhancing the efficiency of EHR use, thereby leading to improved clinical decision-making and patient safety. Furthermore, reviewing complex cases first led to a greater information-processing burden, suggesting that providers could benefit from “warming up” with standard cases before reviewing complex cases.

Abstract Background The cerebellar dentate is a known site of iron accumulation and tau deposition in progressive supranuclear palsy (PSP); however, detailed iron distribution and localized volume and shape changes remain unclear across PSP clinical variants. Objective The study aimed to clarify details about regional susceptibility distribution, volume, and shape deformation in the cerebellar dentate across PSP clinical variants. Methods Sixty‐seven PSP patients, including 31 PSP‐Richardson syndrome, 12 PSP‐parkinsonism, 10 PSP‐progressive gait freezing, and 14 PSP‐cortical variants (PSP‐frontal, PSP‐speech/language, and PSP‐corticobasal syndrome), and 31 healthy controls underwent 3 Tesla magnetic resonance imaging to reconstruct quantitative susceptibility maps. Manual dentate segmentation was performed to extract magnetic susceptibility and volume adjusted for total intracranial volume. Shape deformation was assessed using Deformetrica atlas construction. Group comparisons were evaluated with Kruskal–Wallis tests and receiver operating characteristic analysis. Results Patients with PSP‐Richardson syndrome, PSP‐parkinsonism, and PSP‐cortical variants showed significantly increased dentate susceptibility compared with controls ( P < 0.05). Patients with PSP‐progressive gait freezing showed no significant susceptibility differences. Volume loss was most prominent in PSP‐cortical variants, bilaterally, and PSP‐Richardson syndrome, left hemisphere only ( P < 0.05). Shape analysis revealed subregion‐specific deformation patterns, especially in the anterior and posterior deformation in PSP‐progressive gait freezing and the ventroanterior deformation in PSP‐cortical variants. Conclusions The PSP clinical variants had different patterns of susceptibility, volume, and shape metrics, reflecting distinct neurodegenerative patterns of the cerebellar dentate. These findings contribute to our understanding of the neurobiology of PSP and may help to improve phenotypic differentiation of PSP clinical variants. © 2026 International Parkinson and Movement Disorder Society.