Citations

AbstractINTRODUCTIONSelf‐reported sex influences brain resilience, but its role in genetic frontotemporal dementia (FTD) remains unclear.METHODSWe analyzed 394 genetic‐FTD patients and 279 controls from the ALLFTD consortium, assessing annual neuropsychological performance and MRI‐based cortical thickness. Clinical characteristics and cortical thickness were compared between sexes. We used the residuals of linear regression models, which predict each participant's cognitive and behavioral performance levels relative to cortical thickness, as a proxy for reserve. We then modeled sex differences in longitudinal trajectories with linear mixed‐effects models.RESULTSSymptomatic females with genetic FTD had lower frontal cortical thickness than males, and the C9orf72 subgroup showed lower‐than‐expected frontal cortical thickness for a given level of executive functioning. Differences in cognitive reserve between sexes peaked near symptom onset but diminished thereafter.DISCUSSIONFemales with genetic FTD showed higher cognitive reserve than males, suggesting that self‐reported sex modulates resilience to frontotemporal neurodegeneration.Highlights Females with genetic FTD showed higher cognitive reserve than males. Those differences were particularly pronounced in the C9orf72 and GRN subgroups. The higher cognitive reserve in females declined as the disease progressed.

AbstractINTRODUCTIONHigher male prevalence in sporadic behavioral variant frontotemporal dementia (bvFTD) has been reported. We hypothesized differences in phenotypes between genetic and sporadic bvFTD females resulting in underdiagnosis of sporadic bvFTD females.METHODSWe included genetic and sporadic bvFTD patients from two multicenter cohorts. We compared behavioral and cognitive symptoms, and gray matter volumes, between genetic and sporadic cases in each sex.RESULTSFemales with sporadic bvFTD showed worse compulsive behavior (p = 0.026) and language impairments (p = 0.024) compared to females with genetic bvFTD (n = 152). Genetic bvFTD females had smaller gray matter volumes than sporadic bvFTD females, particularly in the parietal lobe.DISCUSSIONFemales with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation.Highlights Sex ratio is equal in genetic behavioral variant of frontotemporal dementia (bvFTD), whereas more males are present in sporadic bvFTD. Distinct neuropsychiatric phenotypes exist between sporadic and genetic bvFTD in females. Phenotype might explain the sex ratio difference between sporadic and genetic cases.

Abstract Background: Understanding the spatiotemporal dynamics of the tumor microenvironment (TME) during treatment is crucial for improving outcomes in pancreatic ductal adenocarcinoma (PDAC). This study presents a pre-planned spatiotemporal analysis from a phase II trial evaluating neoadjuvant mFOLFIRINOX in resectable PDAC, aimed at elucidating treatment resistance mechanisms and identifying predictive biomarkers. Methods: This multi-institutional, single-arm phase II trial enrolled treatment-naïve patients with histologically confirmed resectable PDAC (NCT05066802) who underwent six cycles of neoadjuvant mFOLFIRINOX followed by surgery. The primary endpoint was the R0 resection rate. Matched pre-treatment tumor biopsies and post-treatment surgical specimens were analyzed from selected responders (R) and non-responders (NR) using high-resolution spatial transcriptomics (10X Genomics Visium). This approach enabled comprehensive mapping of TME evolution and treatment-induced changes. Results: Between May 2020 and February 2022, 27 patients were enrolled. Of these, 24 patients underwent surgery after neoadjuvant treatment (resection rate: 88.9%), and 23 achieved R0 resection (85.2%), meeting the primary endpoint. However, 20 resected patients (83.3%) recurred. Spatiotemporal analysis was performed on matched samples from four R and four NR. In pre-treatment samples from NR group, clusters dominated by fibroblasts (enriched for ECM, EMT, and CAF phenotypes) and B cell subtypes were distinct compared to R group, which exhibited elevated antibody responses and robust T cell and macrophage activity. NR samples showed increased IgM expression but lacked corresponding Fc receptors, suggesting limited immune effector function. Post-treatment NR surgical specimens displayed elevated expression of MUC5AC and CEACAM6 in malignant ductal cells, alongside genes promoting tumor growth. Neoadjuvant mFOLFIRINOX increased fibroblast, while reducing immune cell components. NR tumors formed distinct "resistance niches" after chemotherapy, marked by ECM production, CAF activation, and RTK signaling. Conversely, R tumors showed enhanced epithelial organization with increased type-I hemidesmosome complexes facilitating epithelial adhesion to the basement membrane. Conclusion: Three months of neoadjuvant mFOLFIRINOX was feasible and tolerable for resectable PDAC but associated with high recurrence rate, emphasizing the need for better patient selection. Spatiotemporal analysis revealed critical differences in TME dynamics according to treatment response, including the emergence of resistance niches and distinct pre-treatment spatial signatures. These findings support the integration of spatial biology into future pancreatic cancer trials to improve stratification and therapy. Citation Format: Choong-kun Lee, Changjin Hong, Ho Kyoung Hwang, Min Hwan Kim, Jean Rene Clemenceau, Seock-Jin Chung, Isabel Barnfather, Sumanth Reddy Nakkireddy, Jeong Hwan Park, Ji-Youn Sung, Minji Kim, Yooho Choi, Inyeop Jang, Sunho Park, Sung Hyun Kim, Chang Moo Kang, Hye Jin Choi, Tae Hyun Hwang. Spatiotemporal evolution of the tumor microenvironment predicts treatment response in phase II trial of neoadjuvant chemotherapy for resectable pancreatic cancer [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 771.

Abstract Background: Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are the most common lung cancer subtypes. SCC is traditionally resistant to anti-angiogenic therapies, though the mechanisms remain unclear. Nintedanib, a multi-angiokinase receptor inhibitor, is approved for treating ADC in combination with docetaxel, based on selective efficacy in the LUME-1 trial. It is also FDA-approved for idiopathic pulmonary fibrosis due to its antifibrotic properties. Both ADC and SCC feature fibrotic stroma rich in activated tumor-associated fibroblasts (TAFs). Our prior work showed Nintedanib has stronger antifibrotic effects on ADC-TAFs than SCC-TAFs. However, its impact on TAF-driven angiogenesis and the role of TAFs in SCC resistance to multi-angiokinase inhibitors remain unexplored. Methods: The pro-angiogenic activity of TAFs secretome from ADC and SCC patients was assessed. TAFs were stimulated with TGF-β1 to mimic their activated phenotype, then treated with Nintedanib. Conditioned media from treated TAFs was used to assess endothelial cell migration and vascular network formation. Pro-angiogenic factor secretion was analyzed using antibody arrays, and functional roles of selected proteins were validated in vitro and in vivo using genetic approaches. Results: Nintedanib inhibited the pro-angiogenic effects of ADC-TAF secretome but paradoxically enhanced angiogenesis in SCC-TAFs, increasing endothelial cell migration in vitro and in vivo. Notably, Nintedanib selectively upregulated CXCL-1 secretion in SCC-TAFs. Silencing CXCL-1 using siRNA in SCC-TAFs abrogated the Nintedanib-induced angiogenesis. Similar findings with other multi-angiokinase inhibitors suggest aberrant CXCL-1 production in SCC-TAFs may drive universal resistance to these therapies. Conclusion: SCC-TAFs are resistant to the anti-angiogenic effects of Nintedanib, which paradoxically promotes angiogenesis via CXCL-1 upregulation. This study provides the first mechanistic insight into SCC resistance to anti-angiogenic therapies and underscores the critical role of TAFs in modulating therapeutic responses. Targeting CXCL-1 or TAF-mediated pathways may inform alternative anti-angiogenic strategies in SCC, potentially in combination with immune checkpoint inhibitors. Citation Format: Natalia Isabel Diaz Valdivia, Paula Duch, Alejandro Bernardo, Marselina Arshakyan, Noemi Reguart, Derek Radisky, Oriol Casanovas, Jordi Alcaraz. Intrinsic resistance mechanism of squamous cell lung carcinomas to the multiangiokinase receptor inhibitor Nintedanib through CXCL-1 upregulation in tumor associated fibroblasts [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 5554.

The importance of having region-specific data when planning health interventions has become evident in recent years. Nonetheless, several world regions, including Latin America and the Caribbean (LAC), still face significant challenges. These regions need to develop strategies specifically designed to consider the inherent characteristics of their population composite and sociodemographic characteristics. More than 20% of the global cancer incidence arises in LAC. Yet, treatment, prevention, and follow-up guidelines in the area are frequently based on studies that mainly include patients from North America, Europe, and Asia. As personalized approaches become ubiquitous in medical practice, the amount of information emerging from LAC has risen considerably. In this review, we seek to present a comprehensive summary of the frequency of germline genetic variants in hereditary cancer syndromes in patients from LAC. The data highlight relevant differences in variants associated with LAC patients, including founder and recurrent variants, while showcasing potential features that might be relevant in oncology practices.

Abstract Background The Global Leadership Initiative on Malnutrition (GLIM) introduced an approach for malnutrition diagnosis in 2019 that comprised screening followed by assessment of three phenotypic criteria (weight loss, low body mass index [BMI], and low muscle mass) and two etiologic criteria (reduced food intake/assimilation and inflammation/disease burden). This planned update reconsiders the GLIM framework based on published knowledge and experience over the past 5 years. Methods A working group ( n = 43 members) conducted a literature search spanning 2019–2024 using the keywords “Global Leadership Initiative on Malnutrition or GLIM.” Prior GLIM guidance activities for using the criteria on muscle mass and inflammation were reviewed. Successive rounds of revision and review were used to achieve consensus. Results More than 400 scientific reports were published in peer‐reviewed journals, forming the basis of 10 systematic reviews, some including meta‐analyses of GLIM validity that indicate strong construct and predictive validity. Limitations and future priorities are discussed. Working group findings suggest that assessment of low muscle mass should be guided by experience and available technological resources. Clinical judgment may suffice to evaluate the inflammation/disease burden etiologic criterion. No revisions of the weight loss, low BMI, or reduced food intake/assimilation criteria are suggested. After two rounds of review and revision, the working group secured 100% agreement with the conclusions reported in the 5‐year update. Conclusion Ongoing initiatives target priorities that include malnutrition risk screening procedures, GLIM adaptation to the intensive care setting, assessment in support of the reduced food intake/assimilation criterion, and determination of malnutrition in obesity.

Abstract Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel–Lindau disease, desirable personalized surveillance programs are lacking due to insufficient data on genotype-specific risk profiles of individual mutations. To describe neoplastic risk profiles for carriers of pathogenic and likely pathogenic VHL germline mutations, our observational study recruited 1,350 participants from 40 centers worldwide. 432 different VHL germline mutations were observed, with p.Asn78Ser, p.Arg161Ter, p.Arg161Gln, p.Arg167Gln, p.Arg167Trp and p.Tyr98His being the six most frequent, occurring in a total of 493 carriers (36.5%) and in ≥30 patients each. Age-related penetrance risks for retinal hemangioblastoma, central nervous system hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma in carriers of the most frequent VHL mutations were assessed. In addition, the number of organs affected, the frequency of surgery and the outcome are reported. Pairwise comparisons of the age-dependent tumor penetrance of these six mutations showed that 47 out of 90 pairs were significantly different. The most significant associations were found in p.Tyr98His (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P < 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL mutation type and location, but did not differ between the truncating mutation p.Arg161Ter and the missense mutation p.Asn78Ser. Our study demonstrates the importance of mutation-specific phenotype prediction. With appropriate validation, the data have important implications for risk assessment and decision making in tumor prevention for carriers of the respective VHL mutations.

AbstractChronic pelvic pain (CPP), a debilitating condition affecting an estimated 25% of women worldwide, represents a significant yet understudied global health crisis. Existing research is limited and likely fails to capture the true impact of CPP on global health. What is known is that CPP results in a profound health, societal, and economic burden on women. Our inability to fully understand this burden is a critical gap in women's healthcare. To address this urgent need, the International Federation of Gynecology and Obstetrics (FIGO) and the International Pelvic Pain Society (IPPS) have partnered to develop this consensus statement where we examine the key challenges to accessing CPP care and propose a framework for overcoming these barriers. We emphasize that effective global strategies for addressing the negative health consequences of living with CPP must prioritize the lived experiences of patients, empower healthcare professionals with the necessary tools and training, and drive meaningful policy change. This call to action is grounded in a comprehensive vision of women's health and rights to address the full spectrum of conditions women experience throughout their lives. Given its high prevalence, CPP must be a central focus of this expanded vision.