Citations

Abstract Pancreatic ductal adenocarcinoma (PDAC) is unresponsive to immune checkpoint therapies largely due to immunosuppression mediated by myeloid and lymphoid cells. Effective treatment strategies require, in addition to immune stimulation, the depletion of these immunosuppressive cells and their interactions. Here, we demonstrate for the first time, that a single verteporfin-based photodynamic therapy (PDT) treatment triples median survival in a KPC-PDAC model when combined with anti-PD1 therapy. Mechanistically, apart from reducing CK19 + tumor cells, PDT depletes immunosuppressive myeloid (CD11c+) and lymphoid (FOXP3+) cell populations, by ~ 4- and ~ 18.4-folds, respectively. PDT further disrupts interactions between these immunosuppressive cells, attenuating a key immune-tolerance axis. At the systemic level, PDT reduces splenic immunosuppression through modulation of tumor-derived cytokines. Within this reprogrammed immune-landscape, anti–PD-1 therapy elicits robust CD8 + T-cell responses, reflected by an ~ 6.7-fold increase in the intratumoral CD8+/Treg ratio. Collectively, these findings establish verteporfin-PDT as an immune-priming strategy that complements anti–PD-1 therapy by alleviating immunosuppression in PDAC.

Abstract Patients with multiple myeloma have an elevated risk of severe complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) infection. To demonstrate proof of concept for a pandemic preparedness and response network, the American Society of Hematology Research Collaborative Multiple Myeloma Program developed a prospective, decentralized study within a site-based provider network. In the COVID-19 outcomes in myeloma and the impact of vaccines (COSMIC) study, patients provided consent, permitted electronic health record data collection, completed patient-reported outcomes at baseline, day 30, and day 180 through an electronic study portal, and were compensated for participation. Clinicians at participating sites facilitated study recruitment and shared best practices monthly to accelerate study execution. The COSMIC study rapidly consented 201 patients from 8 participating sites over 4 months (22 January 2024 through 17 May 2024). Consented participants were 30 to 93 years old, with a median age of 67; 46% were female, 69% were non-Hispanic White, 17% were non-Hispanic Black, and 8% were Hispanic/Latino. Patient-reported data completion was 97% at baseline, 81% at 1 month, and 79% at 6 months. At baseline, 55% of patients reported a history of COVID-19 infection and had received a median of 4 SARS-CoV-2 vaccines. For all patients, there were an additional 18 COVID-19 infections and 57 vaccines received during the 6-month observation period. There were no significant differences in health-related quality of life over time or by history of COVID-19 infection. COSMIC demonstrates the feasibility of an innovative evidence generation strategy to drive rapid accrual of patients to address an evolving area of need. This trial was registered at www.clinicaltrials.gov as #NCT05831787.

Background Bileaflet aortic valve prevalence in transcatheter aortic valve replacement (TAVR) patients is poorly defined. We evaluated a TAVR cohort to determine the bileaflet aortic valve prevalence and understand features which may improve detection. In addition, we related valvar morphology to the occurrence of permanent pacemaker implantation (PPI) following TAVR. Methods Aortic valvar morphology diagnosis was recorded from the pre-procedural cardiac CTA reports prior to TAVR. Commissural angles, comparison of commissural heights, and dynamic visual inspection of the aortic valve were subsequently evaluated on pre-procedural cardiac CTA by an expert cardiac anatomist and imager, methods previously validated in a surgical cohort, to determine aortic valvar morphology and compared to the historical diagnosis. Relationships between valvar morphological characteristics with the need for PPM within 30-days post-TAVR were determined. Results Four-hundred and thirty-three (mean age 81.3 ± 6.6 years, 53.8% female) underwent TAVR [corrected diagnosis: 393 (90.8%) trileaflet vs. 40 (9.2%) bileaflet valves]. Bileaflet valves were historically misdiagnosed in 80% of pre-procedural cardiac CTA reports. Thirty-four (85.0%) had intercoronary leaflet fusion [mean commissural angle = 148.1 (18.3) degrees]. A commissural angle threshold of 141.1 degrees had a sensitivity of 0.73 and specificity of 0.86 for identifying a bileaflet valve. PPI post-TAVR occurred in 38% bileaflet vs. 19% trileaflet patients ( p = 0.0114 ) [unadjusted OR for bileaflet valve requiring PPI = 2.54, 95% CI (1.25–5.01)]. Conclusions Bileaflet aortic valves are commonly misdiagnosed. Assessment of the commissural angle and comparison of commissural heights may improve CTA-based diagnostic accuracy prior to TAVR. Improved detection may guide improved outcomes in this higher risk population.

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

Background/Objectives: We performed a systematic review of preclinical literature on the use of high-LET particle therapy, DDRi, and/or immunotherapy specifically in pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, and carbon) or X-ray radiation either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICIs) in pMMR colorectal cancer models. Results: In total, 131 studies met the inclusion criteria, including 70 preclinical studies. These studies consistently demonstrate that high-LET radiation amplifies immunogenic cell death, increases cGAS-STING pathway activation, and enhances tumor antigen presentation, thereby fostering greater immune infiltration and systemic antitumor responses. Concurrent irradiation with DDRi enhances persistent DNA damage and cytosolic DNA accumulation. In murine models, high-LET therapies show excellent local control, with manageable toxicity profiles. Combination regimens with ICIs exhibit improved local control and elicit systemic antitumor immune responses. Conclusions: High-LET particle radiation and/or the use of concurrent DDRi with ICI have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increased response rates to immunotherapy. The clinical evidence will be reviewed in the companion manuscript.

Abstract Response Assessment in Pediatric Neuro-Oncology (RAPNO) is an international working group dedicated to developing standardized recommendations for response assessment in children with central nervous system tumors enrolled on clinical trials. This standardization facilitates easier and more reliable comparison of responses across trials. Since the first RAPNO publication in 2013, response guidelines have been issued for medulloblastoma (MB), low-grade glioma (LGG), high-grade glioma (HGG), diffuse intrinsic pontine glioma, ependymoma, and craniopharyngioma. Many of these guidelines have already been incorporated into clinical trials to evaluate their effectiveness and accuracy. RAPNO has always been predicated on the idea that these consensus recommendations will require updates over time as they are applied in practice given technological advancements, evolving treatment approaches, and growing knowledge of disease pathology. A half-day RAPNO symposium sponsored by the Society of Neuro-Oncology was held in San Diego, California, United States, on May 15, 2025. This event coincided with the 8th Biennial Pediatric Society of Neuro-Oncology meeting. The main objectives were to identify ongoing RAPNO challenges, discuss potential updates, and plan future initiatives across 3 specific groups: (1) LGG/Craniopharyngioma, (2) HGG/diffuse midline glioma (DMG)/Ependymoma, and (3) MB and other seeding tumors. This manuscript reviews the symposium proceedings and highlights key topics and challenges discussed, as well as outlining future RAPNO initiatives.

Background/Objectives: We performed a systematic review of the current clinical and preclinical literature on the use of particle therapy, DDRi, and/or immunotherapy, specifically for pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, carbon) either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICI), or X-ray radiotherapy (XRT) in combination with DDRi/ICI. Results: In total, 133 studies met the inclusion criteria, including 62 clinical studies. Clinically, particle therapies show excellent local control and normal tissue sparing, with manageable toxicity profiles. Trials with any form of radiation and DDRi are few, potentially owing to toxicity concerns. ICI combinations showed promising efficacy with XRT, with no randomized trials comparing them to particle radiation. Conclusions: Particle radiation and/or DDRi have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increase response rates to immunotherapy (presented in the companion manuscript). Despite strong preclinical evidence and rationale, clinical trials including all three modalities are scarce. Existing evidence suggests a potential benefit based on extrapolation from photon-based studies and supports prospective evaluation with careful attention to treatment-related toxicity, which remains a concern.

OBJECTIVE: To evaluate the effect of joint preparation and patient factors on outcomes and complications in patients treated acutely with hindfoot fusion nails for ankle and pilon fractures. METHODS: Design: Retrospective chart review. Setting: Thirteen US trauma centers and 2 UK trauma centers. Patient Selection Criteria: Ankle and pilon fractures (AO-OTA types A-C) from 2010 to 2020 acutely treated definitively with hindfoot fusion nail were reviewed. Patients at least 18 years old and with minimum 6 months follow-up or earlier diagnosis of complication were included. Exclusion criteria included nonambulatory at baseline, prior internal fixation that failed and underwent revision, and prior tibiotalar or subtalar arthrodesis. Outcome Measurements and Comparisons: The primary outcome was final postoperative ambulatory status. Secondary outcomes were infectious and fracture-related complications. RESULTS: One hundred forty-nine patients (75 men; 74 women; age 20–99; median 63 years) were treated for ankle (104) or pilon (45; 8A, 13B, 24C) fractures. Eighty-five patients (44%) had open fractures and 55 (37%) had diabetes. Thirty-six patients (24%) had joint preparation at the time of surgery. Forty-five (30%) were made weight bearing as tolerated postoperatively; the median time to mobilize was 1.5 days (0–210) and to full weight bearing was 35 days (0–1462). Fifty-seven patients (85%) returned to their preinjury ambulatory status, which was not affected by joint preparation (50% vs. 59%, P = 0.327). Joint preparation led to higher articular fusion rates (94% vs. 24%; P = 0.001) and fewer hardware removals (19% vs. 42%, P = 0.013), but trended toward a higher fracture nonunion rate (19% vs. 8%, P = 0.053). Forty-five patients (30%) had infectious complications, 60 (40%) had a fracture-related complication, and 67 (45%) had additional procedures. Open fractures did not lead to any differences in superficial or deep infection. Insulin-dependent diabetes was associated with higher rates of infectious complications (31% vs. 15%, P = 0.028) and amputation (17% vs. 4%, P = 0.029). CONCLUSIONS: Hindfoot fusion nails for acute ankle and pilon injuries had high complication rates. More complications occurred in patients with insulin-dependent diabetes. While 95% regained ambulation, only 57% returned to preoperative status. Joint preparation led to higher rates of articular fusion (94% vs. 24%, P < 0.001) but not fracture union (81% vs. 66%, P = 0.106). LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate are intended to serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; help guide decisions related to genetic testing; and facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary breast, ovarian, pancreatic, and prostate cancer. The current guidelines focus primarily on assessment of pathogenic and likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants associated with increased risk of these cancers. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding screening for prostate cancer and pancreas cancer, as well as testing criteria for nonepithelial ovarian cancer.