Citations

Abstract Background Neurofibromatosis type 1 (NF1) is a multisystem genetic condition. Up to 50% of individuals with NF1 develop plexiform neurofibromas (PN) that can cause pain and significant morbidity, impairing quality of life. As of December 2025, only a limited number of countries have an approved medical treatment for adults with NF1-PN. A systematic literature review (PROSPERO CRD42023463980) was conducted to better understand disease burden and unmet need in this population. Methods An evidence prioritization strategy identified studies reporting on NF1-PN populations with ≥50% adults from database searches conducted between 1988 and July 20, 2023. Studies published in the last 15 years were extracted. Results Of 3242 identified sources, 57 publications (53 unique studies) were included. The proportion of adults with NF1 who had PN ranged from 11.8% to 84.9% (n = 9 studies). Annual median change in untreated PN volume was −3.7% to +8.3% (n = 5 articles). Pain was the most common PN-related manifestation (32.0%–38.4% of patients; n = 12 articles). Malignant PN transformation occurred in 2.0%–4.1% of patients (n = 5 cohorts); 3 shorter-term studies reported no transformation. Surgery was performed in 69.5% of patients (n = 7 cohorts); post-operative complications occurred in 13.0%–30.0% (n = 3 articles). Analgesia was the most reported pharmacological treatment (37.9% of patients; n = 7 articles). Limited data indicated that PN monitoring and surgery cause substantial resource use. No studies reported on caregiver burden, healthcare costs, or transition from pediatric to adult care. Conclusions Adults with NF1-PN experience high disease burden. Data gaps exist for epidemiology, transition of care, caregiver burden, healthcare cost, and resource use.

635 Background: [ 212 Pb]VMT-a-NET is an alpha therapy agent targeting somatostatin receptor subtype 2 (SSTR2)-expressing tumors. Here, we report the results of a prospective, open-label, Phase I/IIa trial (NCT05636618), assessing safety, tolerability, pharmacokinetics, and preliminary efficacy of [ 212 Pb]VMT-a-NET in patients with advanced neuroendocrine tumors (NETs). Methods: Adults with well-differentiated unresectable or metastatic SSTR2-expressing NETs, who are peptide receptor radionuclide therapy (PRRT) naïve, and who progressed on at least one prior line of systemic therapy, are eligible. Participants can receive up to four cycles of [ 212 Pb]VMT-a-NET at the assigned dose level. Participants are followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy is evaluated by investigators according to RECIST criteria v1.1. Results: As of 16-Aug-2025 (data cut-off [DCO]) a total of 48 participants were enrolled into cohorts 1 and 2 and received at least one dose of [ 212 Pb]VMT-a-NET (n=2 in Cohort 1, and n=46 in Cohort 2 at a dose level of 92.5 MBq and 185 MBq, respectively). Among all participants treated with at least one dose of [ 212 Pb]VMT-a-NET (n=48), no DLTs, no grade 4 or 5 adverse events (AEs), and no treatment-related discontinuations, were observed. Median follow-up time was 28 weeks (range: 6-93). Nine participants were followed for DLT observation (n=2 in cohort 1 and n=7 in cohort 2).Seven of these patients were with no progression as of the DCO. Three out of the seven participants enrolled at the dose level of 185 MBq achieved a confirmed partial response (PR). Median follow-up time for participants included in the efficacy group was 72 weeks (range: 6-93). Cohort 3, at a dose level of 222 MBq, has recently been opened for enrollment. At the DCO, 4 participants were enrolled in this cohort. Updated safety outcome for all participants along with updated efficacy findings for participants in Cohort 1 and 2 with sufficient maturity, will be presented during the congress. Conclusions: [ 212 Pb]VMT-a-NET showed a favorable safety profile and promising clinical benefit for patients with advanced SSTR2-expressing NETs treated at the dose levels of 92.5 MBq and 185 MBq. The study is ongoing with Cohort 3 (222 MBq) currently open for enrollment. Clinical trial information: NCT05636618 .

198 Background: The Hedgehog (Hh) signaling pathway regulates tissue patterning, growth and differentiation, including within gastrointestinal tract. Mammalian homologs include Sonic (SHH), Indian (IHH) and Desert (DHH) Hedgehog, which signal through PTCH and SMO and the GLI transcription factors. In the digestive tract, both SHH and IHH are expressed, but the functional role of Hh signaling in mCRC remains incompletely defined. Methods: We analyzed 433 mCRC patients treated with either bevacizumab (bev = 226) or cetuximab (cet = 207) plus first line chemotherapy in CALGB/SWOG 80405 (NCT00265850). RNA expression (Illumina HiSeq 2500) of 9 Hh pathway genes (SHH, IHH, DHH, PTCH1, PTCH2, SMO, GLI1, GLI2, GLI3) was evaluated. Median overall survival (mOS) and progression free survival (mPFS) in months (mo) were compared across expression tertiles (low [L], medium [M], high [H]). Likelihood ratio tests, hazard ratios and 95% confidence intervals were computed from multivariable Cox proportional hazards models, adjusting for age, sex, ethnicity, ECOG PS, tumor location, number of metastatic sites, KRAS , microsatellites instability status and treatment. Prognostic effects were modeled as marginal terms; predictive effects were modeled as multiplicative interactions. Results: Overall, IHH and GLI2 demonstrated prognostic value for OS after adjusting for multiple testing (Benjamini-Hochberg False Discovery Rate (FDR) < 0.05). High IHH expression (H group, n = 143) correlated with improved mOS (H: 36.0 mo vs M: 32.8 mo vs L: 23.5 mo; p= 0.031), whereas low GLI2 expression (L group, n = 145) was associated with longer mOS (H: 25.6 mo vs M: 33.9 mo vs L: 33.7 mo; p= 0.0016). Moreover, IHH showed predictive value for cet benefit in both OS (mOS H: 38.1 mo vs M: 34.0 mo vs L: 18.4 mo; p= 0.0032) and PFS (mPFS H: 12.6 mo vs M: 12.9 mo vs L: 8.8 mo; p= 0.0025) with significant treatment interaction for OS and PFS (p= 0.0046 and p= 0.0049, respectively; FDR< 0.05). No significant associations were found in bev treated pts. No other Hh genes showed significant prognostic or predictive effects after FDR correction. Conclusions: These results highlight a dual role of Hh pathway in mCRC. Consistent with prior preclinical evidence, reduced IHH expression appears to mark poor prognosis, likely reflecting the loss of IHH-mediated restraint on Wnt signaling, which drives proliferation and dedifferentiation. Conversely, low GLI2, a downstream transcription factor, was linked with favorable outcomes, underscoring context-specific effects of Hh signaling. The strong predictive association of IHH with cet efficacy supports its potential as a biomarker in RAS wild type mCRC. These results suggest that Hh pathway modulation, particularly IHH signaling, may influence disease biology and treatment response. Validation in independent cohorts and mechanistic studies is warranted to clarify implications.

179 Background: Neuroligins are a family of postsynaptic cell adhesion molecules that play a crucial role in synapse formation and function. Recent studies suggest Neuroligin family genes (NLGN1,2,3,4X) may promote cancer cell growth and metastasis in various cancers, including colorectal cancer. Here, we investigated the association between neuroligin family gene expression and first-line treatment outcomes in mCRC. Methods: We evaluated the expression of 4 genes in the neuroligin family (NLGN1, NLGN2, NLGN3 and NLGN4X) on treatment outcomes of 433 pts with mCRC treated with either bevacizumab (Bev, n = 226) or cetuximab (Cet, n = 207) in combination with first-line chemotherapy within the CALGB/SWOG 80405 trial. mRNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by low expression (Q1) (≤25 percentile), medium expression (Q2-3) (25th-75th percentile) and high expression (Q4)(>75th percentile) of NLGN family genes. The associations between gene expression and clinical outcomes were assessed via the multivariable Cox model and plotted with Kaplan-Meier curve. Treatment-gene interactions were evaluated using the likelihood ratio test. False discovery rate (FDR) was controlled through the Benjamini-Hochberg procedure. Results: High NLGN2 expression was associated with shorter PFS (median 10.0 mos, 95% CI (8.3, 11.3)) and OS (median 25.2mos, 95%CI (20.9, 30.0)) compared to low NLGN2 expression (PFS: median 11.2mos, 95% CI (9.8,14.3))(HR 1.41, 95% CI (1.06, 1.89)), P = 0.029). (OS: (median 31.8mos, 95%CI (26.8, 37.5)( HR 1.49, 95% CI (1.10, 2.01) P =0.0095) in multivariate analysis. Patients treated in the cetuximab arm(n=207), high HLGN2 expression significantly associated with shorter PFS (median 8.0 vs 13.4, HR 2.02, 95% CI (1.35, 3.03), P = 0.0021) and OS (median19.6 vs 36.3, HR 2.30, 95% CI (1.50, 3.53), P =8.3e-05). High NLGN3 expression was associated with shorter OS (23.9 vs 36.0 mos, P =0.0083) in cetuximab treatment arms, no significance found in PFS. We found significant treatment interaction for OS with NLGN2 and NLGN3 favoring cetuximab. In pts treated with cetuximab, High NLGN2 expression was significantly associated with shorter OS (median 29.1vs 36.3) (p=0.024) compared to pts treated with bevacizumab. For NLGN3, pts treated with cetuximab, high NLGN3 expression was significantly associated with shorter OS (median 25.0 vs 36.0) (p=0.018) compared to pts treated with bevacizumab. No significant association was found in NLGN1 and NLGN4X. Conclusions: Our results suggest NLGN2/3 gene expression may predict mCRC treatment outcomes. Potential therapeutic drug target NLGN in combination with anti-EGFR treatment in mCRC is warranted.

Abstract Background Parkinson's disease (PD) represents a growing global health challenge, with prevalence doubling from 2.5 million cases in 1990 to 6.1 million in 2016, and projections suggesting it will exceed 12 million by 2040. This exponential growth has been termed the "Parkinson's pandemic." China and the United States, which together account for nearly half of the global PD population, have developed markedly different approaches to end-of-life (EOL) care, shaped by their distinct healthcare systems and cultural contexts. Understanding these differences is crucial for developing effective global strategies. This systematic review and meta-analysis comprehensively compares advanced-stage PD care between these two nations to quantify disparities and inform evidence-based policy interventions. Methods We conducted a rigorous systematic review following PRISMA 2020 guidelines, searching six databases (PubMed, Embase, Scopus, Web of Science, CNKI, Wanfang) from January 2015 to October 2025. The timeframe was selected to capture contemporary care patterns following major healthcare reforms in both countries (Affordable Care Act implementation in the US; Healthy China 2030 initiative). Inclusion criteria encompassed peer-reviewed studies reporting on advanced PD (Hoehn-Yahr stage ≥ 3) with outcome measures including survival, quality of life (QoL), palliative care access, caregiver burden, rehabilitation utilization, or healthcare costs. The sample size threshold (n ≥ 100) balanced statistical power with inclusivity. Two independent reviewers screened 3,847 records with excellent agreement (Cohen's κ = 0.82–0.89). Quality assessment employed the Newcastle-Ottawa Scale (NOS ≥ 8 indicating high quality) and ROBINS-I for observational studies, with GRADE criteria determining evidence certainty. Meta-analyses utilized random-effects models with comprehensive heterogeneity assessment (I² statistics, meta-regression) and publication bias evaluation (Egger's test, trim-and-fill analysis). Sensitivity analyses included high-quality studies only and examined the influence of large database studies. Results Our analysis of 42 high-quality studies encompassing over 125,000 patients revealed profound and systematic cross-national disparities across multiple domains. In terms of care access, US patients demonstrated significantly higher hospice enrollment rates (28–35% vs. <1% in China, p < 0.001; HIGH certainty evidence) and greater access to specialized neuropalliative programs (15% of US centers vs. <1% in China). These differences translated into measurable quality of life disparities, with Chinese patients scoring 17.6 points worse on the PDQ-39 scale (95% CI 14.2–21.0; MODERATE certainty, I²=68%), a difference exceeding the minimal clinically important difference nearly four-fold. The burden on families showed equally striking patterns: Chinese families provided 94% of EOL care compared to 61% in the US, resulting in significantly higher caregiver depression rates (47% vs. 32%, OR = 1.89, 95% CI 1.45–2.47) and burden scores (Zarit difference: 10.2 points, 95% CI 7.8–12.6). Access to interventions revealed additional gaps, with only 9.2% of Chinese patients receiving physical therapy versus 14.4% in the US (OR = 0.61, 95% CI 0.49–0.76), and a 5.25-fold disparity in deep brain stimulation access (4.2% vs. 0.8%). Economic analysis demonstrated substantial out-of-pocket burden differences: Chinese families paid 58% of total costs ($4,200 annually) versus 12% for US families ($2,800). Meta-regression identified healthcare system characteristics as the primary driver of these disparities (R²=0.42, p < 0.001). Conclusions This comprehensive analysis reveals that systematic differences in healthcare infrastructure, insurance coverage, and cultural care models produce markedly divergent EOL experiences for PD patients in China versus the United States. These findings have immediate policy implications. For China, we recommend: (1) establishing pilot neuropalliative programs in tertiary centers with phased national expansion; (2) developing caregiver support infrastructure including respite care and training programs; (3) leveraging telemedicine platforms to address urban-rural disparities. For the United States, priorities include: (1) addressing racial disparities in rehabilitation access through culturally competent outreach; (2) expanding Medicare coverage for maintenance therapy; (3) earlier integration of neuropalliative care. Implementation science research is urgently needed to test culturally adapted interventions. As global PD prevalence accelerates, lessons from this bilateral comparison provide a framework for other nations confronting similar challenges in neurological care delivery.

PURPOSE Manual extraction of treatment outcomes from unstructured oncology clinical notes is a significant challenge for real-world evidence (RWE) generation. This study aimed to develop and evaluate a robust natural language processing (NLP) system to automatically extract cancer treatments and their associated RECIST-based response categories (complete response, partial response, stable disease, and progressive disease) from non–small cell lung cancer (NSCLC) clinical notes. METHODS This retrospective NLP development and validation study used a corpus of 250 NSCLC oncology notes from University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, annotated by physician experts. An end-to-end NLP pipeline was designed, integrating a rule-based module for entity extraction (treatments and responses) and a machine learning module using biomedical clinical bidirectional encoder representations from transformers for relation classification. The system's performance was evaluated on a held-out test set, with partial external validation for relation extraction on a Mayo Clinic data set. RESULTS The NLP system achieved high overall accuracy. On the UPMC test set (64 notes), the relation classification model attained an area under the receiver operating characteristic curve of 0.94 and an F1 score of 0.92 for linking treatments with documented responses. The rule-based entity extraction demonstrated a macro-averaged F1 score of 0.87 (precision 0.98, recall 0.81). Although precision was high for chemotherapy and most response types (1.00), recall for cancer surgery was 0.45. External validation at Mayo Clinic showed moderate relation extraction F1 scores (range: 0.51-0.64). CONCLUSION The proposed NLP system can reliably extract structured treatment and response information from unstructured NSCLC oncology notes with high accuracy. This automated approach can assist in abstracting critical cancer treatment outcomes from clinical narrative text, thereby streamlining real-world data analysis and supporting the generation of RWE in oncology.

Abstract Background The incidence of type 2 diabetes mellitus among young adults has been increasing over the past few decades. There are limited data on contemporary national cardiovascular mortality rates in young adults with diabetes mellitus (DM). Methods We queried the Centers for Disease Control and Prevention's Wide‐Ranging Online Data for Epidemiologic Research database for patients aged 15 to 44 years from 1999 to 2019 in the primary analysis. A secondary analysis included data from 2020 to 2022 to examine the effect of the COVID‐19 pandemic. We analysed patients in whom cardiovascular diseases (CVD) were listed as the main cause of death and DM as a contributing cause of death. In calculating age‐adjusted mortality rates (AAMR) per 100 000 individuals, we used CVD mortality in young adults with comorbid diabetes as the numerator and the overall population as the denominator. We determined temporal trends by estimating the average annual percent change (AAPC) using the Joinpoint regression program. Results Among 3 309 079 individuals aged 15–44 years who died, 30 978 deaths were due to CVD with comorbid DM listed as a contributing cause. The overall AAMR increased from 1.08 per 100 000 individuals in 1999 to 1.23 per 100 000 individuals in 2019, with an average APC of 0.75 (95% CI, 0.31–1.20). Compared with 1999, the percentage increase in CVD deaths in 2019 among young adults with comorbid DM was +6.2%, whereas a decrease of 19.9% was observed among those without comorbid DM. Males had a higher AAMR than females (1.60 vs. 0.97). Non‐Hispanic Black individuals and non‐Hispanic American Indian/Alaska Native individuals had the highest AAMRs of 2.99 and 2.89, respectively. The AAMR was higher in rural regions compared to urban areas (1.63 vs. 1.23). The overall AAMR increased markedly from 1.23 in 2019 to 1.60 in 2022, with a similar pattern observed across demographic subgroups. Conclusion Our study reveals a rising trend in CVD mortality in young adults with DM as a contributing cause. Males, non‐Hispanic Black individuals, and individuals from rural regions had higher AAMR than their counterparts. This warrants the development of specific healthcare policies aimed at these at‐risk populations. Lay summary Our study shows that cardiovascular disease (CVD) deaths are increasing in young adults with diabetes mellitus listed as a contributing cause.

Background This study aimed to evaluate outcomes of different antibiotic durations in patients with severe diverticulitis. Methods Initial electronic medical record review identified 2437 adult patients who underwent sigmoid colectomy. Manual chart review identified 133 patients who underwent sigmoid resection and proximal diversion for Hinchey stage 3 or 4 diverticulitis. Patients who received a short antibiotic course (SAC, ≤5 days) were compared with those who received a long antibiotic course (LAC, >5 days). The primary composite outcome included superficial, incisional, organ-space infections or death within 30 days post procedure. Results A total of 53 SAC patients and 55 LAC patients were identified. The composite outcome occurred more frequently in LAC patients than in SAC patients (40% vs 15%; P = .005). Organ-space infection occurred more frequently in LAC patients than in SAC patients (31% vs 13%; P = .04). Conclusions Extended duration of antibiotics after adequate source control does not improve outcomes even in the setting of extensive intra-abdominal contamination.

Asymptomatic aortic regurgitation (AR) has traditionally been managed conservatively until symptom onset or overt left ventricular systolic dysfunction. However, adverse myocardial remodeling—detected by myocardial strain, volumetric cardiac magnetic resonance, and fibrosis imaging—often precedes current guideline thresholds for interventions and may be irreversible. Advances in multimodal imaging now enable earlier risk stratification beyond conventional metrics. In parallel, intervention strategies are evolving, including valve repair, valve-sparing root replacement, Ross procedure, and transcatheter aortic valve replacement in selected high-risk patients. This narrative review summarizes contemporary advances in imaging and intervention for asymptomatic AR, while critically appraising current evidentiary and technical limitations that constrain earlier intervention. The review is based on a narrative synthesis of the contemporary literature, drawing from recent clinical studies, imaging advances, and guideline documents rather than a systematic evidence search.

Acute myocardial infarction (AMI) is a significant factor leading to the death of patients with coronary heart disease. Both AMI and reperfusion therapy after AMI cause myocardial cell death, which plays a significant role in heart failure. Following the restoration of blood flow during reperfusion, myocardial cells generate a large amount of oxygen free radicals, causing various forms of myocardial ischemia–reperfusion (IR) injury (IRI), ultimately leading to multiple types of myocardial cell death, among which apoptosis and necroptosis are the two major types. Given the extremely limited regenerative capacity of myocardium, inhibiting myocardial cell apoptosis and necroptosis is a key strategy for reducing mortality in patients with AMI. Both apoptosis and necroptosis are regulated by the BCL2 family of proteins, which were modulated by multiple signaling pathways, converging at BAK/BAX-mediated mitochondrial outer membrane permeabilization (MOMP), as well as mitochondrial inner membrane permeabilization (MIMP). BAK/BAX double knock out (DKO) mice showed reduced cell apoptosis, necroptosis, and infarct size in AMI animal models compared to wild type. This review describes the role of BCL2 family proteins in regulating apoptotic and necroptotic myocardial cell death during AMI and IR, explores the upstream pathways modulating apoptosis and necroptosis, and summarizes the recent advances in targeting BAK and/or BAX for cardiac protection. In addition, targeted delivery of BAK/BAX inhibitors to cardiomyocytes during AMI or myocardial IR has the potential to reduce myocardial cell death and therefore lower the mortality and enhance long-term prognosis for myocardial infarction patients.