Citations

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: Ivosidenib (IVO) is a first-in-class oral inhibitor of the IDH1 mutant (mIDH) enzyme. In the ClarIDHy phase 3 study of previously treated patients with mIDH cholangiocarcinoma (CCA), IVO treatment led to improved progression-free survival (PFS) and overall survival (OS) vs placebo (median PFS: 2.7 vs. 1.4 months and OS 10.3 vs. 5.1 months, when adjusted for the 70% crossover rate; HR, 0.49 [95% CI, 0.34-0.70]; 1-sided P<0.001. Here, we studied the dynamics of mutations emerging after 6 months of IVO treatment using ctDNA analyses. Methods: Prior to enrollment, all subjects in ClarIDHy had IDH1 R132 mutations confirmed by a central NGS panel utilizing tumor biopsy tissue. Since post-progression tissue samples were unavailable, discovery of emerging mutations was limited to plasma ctDNA assessments. To explore molecular changes associated with acquired resistance, an analysis was performed on 18 subjects treated with IVO for ≥6 months (4 partial response; 12 stable disease, 2 NA) using matched baseline and end of treatment (EOT) samples (PGDx elioTM plasma complete, 521 gene panel). A subset of the oncogenic alterations identified were selected for confirmation by ddPCR analysis in ctDNA samples collected longitudinally. Longitudinal plasma 2HG levels were also evaluated. Results: This analysis identified several EOT mutations not present at baseline. The most common mutations were in the MAPK pathway, including activating KRAS, NRAS, and MAP2K1 mutations and loss-of-function NF1 mutations (6/18 patients, 33%). In 2/6 patients, multiple MAPK pathway mutations were detected. There was a range of variant allele frequencies (VAFs) of RAS alterations, including some that had comparable levels to the truncal mIDH, suggesting that MAPK activation may have made a major contribution to the burden of resistant disease. ddPCR analyses from longitudinal plasma samples from selected cases confirmed these findings. In addition, 2 patients had mutations affecting transcription/epigenetics (WT1 and KMT2C). Finally, only 1 patient had acquired mutations in IDH genes (IDH2-R172K and IDH1-G131V). The WT1, KMT2C, and IDH variants had a low VAF. Accordingly, EOT plasma 2HG levels were reduced vs pre-treatment levels in the patient with secondary mIDH, indicating a limited role in the overall emergence of resistance. Conclusion: Analyses of paired baseline/EOT samples suggest that multiple acquired mutations could contribute to IVO resistance, with oncogenic MAPK pathway alterations being the most common. Consistent with previous clinical studies conducted in AML, IDH1 second site mutations and isotype switching to IDH2, rarely emerge during IVO treatment. The lack of detectable mutations in the majority of patients could reflect the sensitivity of the NGS assay or a role for non-genetic mechanisms of resistance. Citation Format: Hatice Duygu Saatcioglu, Haley Ellis, Jinkai Wan, Sam Lubner, Milind Javle, Ghassan K. Abou-Alfa, James M. Cleary, Robin Kate Kelley, Mitesh J. Borad, Teresa Macarulla, Do Youn Oh, Camelia Gliser, Susan Pandya, Sung Chloe, Nabeel Bardeesy, Adriana Tron. Circulating tumor DNA analysis demonstrates newly emerging alterations in previously treated IDH1 mutated cholangiocarcinoma patients enrolled in the ClarIDHy study [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 4648.

BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis. RESULTS: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02481258). CONCLUSIONS: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02481258.

Abstract Introduction Vacuum erectile device (VED) is 1 of the main approved therapies for erectile dysfunction (ED). The introduction of phosphodiesterase type 5 inhibitor (PDE5i) for ED significantly changed the roles of VED in contemporary sexual medicine. Objective To provide updated clinical evidence to inform health care providers on best practices with VED. Methods A consensus panel was held with leading sexual medicine experts during the 5th International Consultation on Sexual Medicine (ICSM). Relevant peer-reviewed literature was reviewed with focus on research from the last 10 years, but not limited to the last 10 years. The expert panel generated consensus statements based on the quality of evidence and criteria of Grading of Recommendations Assessment, Development and Evaluation. Results As a primary or combination therapy for ED, VED has been shown to be successful in all populations studied, including difficult to treat cohorts, such as diabetes mellitus, spinal cord injury, and post-radical prostatectomy (RP), but long-term attrition rates are high. Available evidence has shown that VED can preserve or restore penile size for patients after RP, after incision and grafting surgery for Peyronie’s disease, before and after penile prosthesis, and after other post pelvic surgeries. However, it has not demonstrated a more rapid recovery of spontaneous erectile function after RP. VED does not increase penile length for subjective short penis. Studies with female specific VED for female sexual dysfunction are very limited. Conclusions Since the prior 4th ICSM, more evidence is available to support the new roles of VED in contemporary sexual medicine. Research into the penile pathophysiologic changes with VED therapy and clinical outcomes for various conditions are ongoing. We encourage sexual medicine clinicians to follow the 5th ICSM recommendations, but providers should also use their own judgement and adopt shared decision making with their patients/partners when considering VED for a specific disorder.

OBJECTIVE Stereotactic radiosurgery (SRS) is an effective treatment for refractory tremor. However, the lack of reliable patient-specific targeting biomarkers leads to varying outcomes. Although connectomic-based targeting is commonly used in deep brain stimulation, its application in SRS is limited. This study aimed to develop a new targeting approach by using patient-specific structural connectivity to improve outcomes after SRS. METHODS The authors performed a retrospective study of patients in a prospective trial for frameless virtual-cone SRS on a linear accelerator for essential tremor or tremor-dominant Parkinson disease. The primary endpoint was percentage improvement in Fahn-Tolosa-Marin tremor rating scale scores contralateral to the treatment side. Probabilistic tractography assessed connectivity from each thalamic voxel to the primary motor cortex (M1), primary sensory cortex (S1), and supplemental motor area/premotor cortex (SMA/PMC). Group-level comparisons were conducted to evaluate the relationship between the sweet spot for maximum contralateral tremor improvement and areas maximally connected to M1, S1, and SMA/PMC. Multiple regression analysis assessed the relationship between the lesion centerpoint coordinates and the maximally connected voxel to M1, S1, and SMA/PMC at the individual level. RESULTS The analysis included 27 patients with a mean follow-up of 17.9 ± 11.1 months. The sweet spot for maximal contralateral tremor improvement at the group level was in the region most connected to M1 cortex. Smaller y-distances (anterior-posterior) from the lesion center to the M1 maximally connected voxel significantly correlated with tremor improvement at the single-subject level (p < 0.001). However, the authors found no significant correlation between the lesion y-coordinate and the maximally connected voxel to SMA/PMC and S1, nor between the x-distances from the lesions to the SMA/PMC, M1, and S1 voxels (p > 0.07). CONCLUSIONS This study demonstrates that patient-specific connectivity between the treatment target and M1 correlates with treatment outcomes. The authors’ approach provides a practical targeting method for SRS thalamotomy for tremor.

AbstractCases of myelin oligodendrocyte glycoprotein (MOG) antibody‐associated disease (MOGAD) co‐occurring with neoplasms have been reported. In this international, retrospective cohort study in South Korea and the USA, 16 of 445 (3.6%) patients with MOGAD had concurrent neoplasm within 2 years of MOGAD onset, resulting in a standardized incidence ratio for neoplasm of 3.10 (95% confidence interval [CI], 1.77–4.81; P < 0.001) when compared to the age‐ and country‐adjusted incidence of neoplasm in the general population. However, none of the nine tumor tissues obtained demonstrated MOG immunostaining. The slightly increased frequency without immunohistopathological evidence suggest with true paraneoplastic MOGAD is extremely rare.

Abstract Introduction Penile prosthesis (PP) is one of the main approved therapies for erectile dysfunction (ED). Greater than 50 years of clinical use has led to considerable innovation in PP surgery and patient care. Objectives To summarize the current literature and provide updated clinical evidence to inform healthcare providers on best practices with PP. Methods A consensus panel was held with leading sexual medicine experts during the 5th International Consultation on Sexual Medicine (ICSM). Relevant peer-reviewed literature was reviewed with focus on research from but not limited to the last 10 years. The quality of each individual study was judged with Oxford levels of evidence (LOE) criteria, but overall LOE were not used as systematic review was not performed. The expert panel generated consensus statements based on the quality of evidence and criteria of GRADE (Grading of Recommendations Assessment, Development and Evaluation). Results PP provides excellent outcomes for the treatment of ED. The panel developed 35 recommendations building upon previous recommendations. Nine recommendations (4, 5, 11,13,17, 25, 26, 31, and 32) are retained without change from 2015. Twelve recommendations (1, 2, 3, 7, 9,14,16,19,21, 28, 33, and 34) change syntax to make statements more active or change details. Fourteen recommendations (6, 8, 10, 12, 15, 18, 20, 22, 23, 24, 27, 29, 30, and 35) are novel in this update. Conclusion Since the 4th ICSM, new evidence has emerged to guide PP use in modern sexual medicine. While multi-institutional studies are needed to improve outcomes, key challenges remain: reducing infections, enhancing devices, and improving awareness and accessibility. We recommend following 5th ICSM guidelines while emphasizing the importance of clinical judgment and shared decision-making for optimal PP outcomes.

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261