Citations

Abstract Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at < 50%, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We have generated novel humanized models for G3MB by transducing neuroepithelial stem cells (NESC) derived from human induced pluripotent stem (iPSC) cells with TGFβ effectors alone and/or in combination with MYC, prioritizing combinations observed in patients. We determined that both MYC and TGFβ effectors drove tumor formation in vivo with the combination driving more aggressive tumors and higher frequency of metastasis. NESC-derived tumors clustered with human G3/G4MB, indicating our models recapitulated human disease. To decipher mechanisms of resistance, we integrated CUT&RUN for MYC genomic localization and histone PTMs with RNA-sequencing and discovered MYC-bound neural developmental genes repressed in MYC and TGFβR1-driven lines. Further interrogation identified JARID1B, a MYC binding partner, as a regulator of many of these repressed neural genes. We postulate that deregulation of MYC and context-specific targeting to the chromatin template culminates in transcriptional alterations that promote aggressive G3MB. To further investigating therapeutic vulnerabilities, we have performed a in vivo whole genome CRISPRi screen to reveal important drivers of malignancy, one of the first of it’s kind in brain tumors. We are functionally validating key candidate sgRNAs that were differentially significant in primary tumors and may also have key roles in driving metastasis. Excitingly, many sgRNAs identified from the screen were chromatin modifiers and may be important co-factors of MYC-mediated regulation on the epigenome. Collectively, our studies provide a critical framework for understanding mechanisms of resistance and the epigenetic landscape of MYC- and TGFβ-driven MB.

Abstract Background NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT‐Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR). Methods Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease‐free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6–8 weeks post‐CRT; one‐sided α = 0.05, using a χ 2 test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5‐, 2‐, and 2‐point increases, respectively, from baseline to 6–8 weeks post‐CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS. Results From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6–8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6–8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different ( p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non‐pCR patients, respectively, having improved 1‐year ECS scores. Conclusions The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.

Moderate hyperoxia (30%–60% O 2 ) in premature infants promotes bronchial airway hyperresponsiveness (AHR) via airway smooth muscle (ASM), a key regulator of bronchoconstriction, bronchodilation, and remodeling. Understanding how O 2 exposure drives long-term bronchial changes in prematurity is critical for developing therapies for airway disease across the lifespan. Premature lungs have immature antioxidant defenses, potentially due to disrupted mitochondrial dynamics, increasing susceptibility to O 2 -induced oxidative stress. Thus, mitochondrial homeostasis is highly relevant to ASM dysfunction and airway disease. We propose that hyperoxia in prematurity promotes mitochondrial dysfunction, and that the gasotransmitter hydrogen sulfide (H 2 S) mitigates O 2 -induced mitochondrial damage in developing ASM. Human fetal ASM (fASM) cells were exposed to moderate hyperoxia to investigate the effects of exogenous H 2 S donors (GYY4137, AP39) and stabilization of cystathionine β-synthase (CBS), an H 2 S biosynthetic enzyme, on mitochondrial structure and function. Hyperoxia impaired fASM cell mitochondrial integrity, while H 2 S donors in particular, or CBS stabilization attenuated adverse O 2 effects on mitochondrial morphology, ROS, respiration, calcium regulation, and contractility. These findings highlight the therapeutic potential of H 2 S in the premature lung exposed to moderate hyperoxia.

BACKGROUND: Left ventricular (LV) dysfunction is a potential cardioembolic source of ischemic stroke, but its role in recurrent stroke risk and treatment response remains unclear. We explore whether LV injury associates with the risk of recurrent stroke and modifies the association between anticoagulation and stroke recurrence using real-world data. METHODS: We performed a multicenter, retrospective study of Cardiac Abnormalities in Stroke Prevention and Recurrence cohort across 27 US sites. Patients with LV ejection fraction ≥20% were included. LV injury, defined as LV ejection fraction 20% to 40% and wall motion abnormality, was the primary exposure and treatment effect modifier. The treatment of interest was anticoagulant versus antiplatelet therapy. The composite outcome included recurrent stroke, major bleeding, or death. Outcomes were evaluated using unadjusted and inverse probability weighting adjusted Cox proportional hazards models, with treatment effect modification tested by LV injury status. RESULTS: Among 2685 patients enrolled, 2328 with complete data were analyzed (median age, 65 years; 49.8% female; median follow-up, 1.6 years). LV injury was present in 310 patients (13.3%). Overall, 535 events occurred: 258 recurrent ischemic strokes, 28 hemorrhagic strokes, 67 major hemorrhages, and 256 deaths. LV injury was associated with a higher unadjusted risk of the primary outcome (hazard ratio [HR], 1.51 [95% CI, 1.21–1.87]), though nonsignificant after inverse probability weighting adjustment (adjusted HR, 1.29 [95% CI, 0.97–1.70]). In the LV injury subgroup, anticoagulation versus antiplatelet therapy was associated with a lower risk of the primary outcome (adjusted HR, 0.24 [95% CI, 0.10–0.59]), relative to the non-LV injury subgroup (adjusted HR, 1.28 [95% CI, 0.83–1.95]; p[LV-interaction], 0.001). Similar interactions were seen for EF 20% to 40% (versus >40%; adjusted HR, 0.19 [95% CI, 0.04–0.86]; p[LV-interaction], 0.001) and wall motion abnormality (versus no wall motion abnormality; adjusted HR, 0.33 [95% CI, 0.15–0.73]). CONCLUSIONS: After cryptogenic stroke, anticoagulation in those with LV injury was associated with lower rates of recurrent stroke, major bleeding, and death. These findings warrant confirmation in a dedicated randomized controlled trial. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06398366.

IgA vasculitis (IgAV) and IgA nephropathy (IgAN) are closely related disorders that usually present in childhood. Pulmonary involvement is rare and histopathologic features thereof in adults are poorly understood. Institutional archives were searched for adults with IgAV or IgAN and diffuse parenchymal lung disease. Ten patients (6 men, median age 59 years) with lung tissue sampling were enrolled. Clinical history and pathology slides were reviewed. All patients were diagnosed with IgAV or IgAN before or concurrently with lung disease. Symptoms were nonspecific but hemoptysis was common. Radiologically, bilateral ground-glass opacities, consolidation, and reticulonodular densities were typical. Histologically, 6 cases (60%) featured acute or subacute diffuse alveolar hemorrhage (DAH) accompanied by definite (40%) or probable (20%) capillaritis. Two cases (20%) featured resolved DAH only, manifesting as alveolar hemosiderosis without other changes. And 2 cases featured organizing pneumonia without DAH. Five patients had a chronic interstitial pneumonia in the background, including 3 with nonspecific interstitial pneumonia (NSIP) and 2 with unclassifiable fibrosis. Findings were similar in IgAV versus IgAN. Of 4 patients with follow-up information, 2 died during hospitalization, one died 9 weeks later of secondary complications, and one was treated with rituximab and nintedanib and is alive 2 years later. To our knowledge, this is the largest series detailing pulmonary histopathologic findings in adults with IgAV or IgAN. Most cases show acute DAH with capillaritis; less commonly, old DAH, organizing pneumonia, NSIP, or unclassifiable fibrosis may be observed. Some patients do well with treatment but fatal cases also occur.

Abstract Introduction: Metaplastic breast cancer (MpBC) is a rare, aggressive subtype of breast cancer that has limited evidence-based data to guide treatment. Historically, MpBC has had limited response to chemotherapy; however, the response of MpBC to antibody-drug conjugates (ADCs) remains poorly characterized. Methods: We performed a retrospective cohort study of patients (pts) with pathologic diagnosis of MpBC who received ADC therapy as part of standard of care in the metastatic setting across 4 NCI-designated cancer centers. The primary endpoints were objective response rate (ORR) at time of best response to ADC & real world PFS (rwPFS) of ADC compared to non-ADC therapy, defined as time from treatment start to time of progression or death. Results: We identified 48 pts with MpBC who received at least one ADC between 3/2016 and 10/2025. Median age was 54 years (range 31-77); all pts were biological females. Most pts had triple negative disease (n=39, 81%), 5 (10%) had HER2+ disease, 3 (6%) had hormone receptor positive disease & 17 (35%) were confirmed HER2-low (IHC 1+ or 2+, ISH nonamplified). The most common MpBC subtypes were with squamous differentiation (n=17, 35%), chondroid (n=11, 23%), matrix-producing (n=11, 23%) & spindle cell differentiation (n=10, 21%). Ten pts (21%) had de novo metastatic disease & 38 (79%) had recurrent disease. Most common metastatic sites were lung (n=33, 69%) & liver (21, 44%). 37/38 (97%) patients had curative intent anthracycline & taxane, with median disease-free interval of 16 months (range 2-241). 18 pts (38%) received curative intent immune checkpoint inhibitor. Most pts received ADC in the first (n=19, 40%) or second line (n=18, 38%) with Sacituzumab govitecan being the most common (n=38, 79%) ADC, followed by Trastuzumab deruxtecan (n=9, 19%). 7 pts (15%) received a second ADC. ORR at time of best response was 38% (n=18), with 4 pts experiencing complete response (1 patient who received ADC in 1L, 3 in the 2L) & 14 experiencing partial response. 3 pts (6%) experienced stable disease, & 27 pts (56%) experienced progressive disease as best response. Median rwPFS of pts receiving ADC in the first line was 2.3 months, compared to 4.3 months in those receiving non-ADC/chemotherapy (HR 1.34; 95% CI 0.72-2.49, p=0.89). Median rwPFS of pts receiving ADC in the second line was 2.6 months, compared to 2.3 months in those receiving non-ADC/chemotherapy (HR 0.56; 0.28-1.11; p=0.10). Toxicity resulted in dose reductions in 17 pts (35%), dose delays in 14 (29%), & ADC discontinuation in 2 (4%). Conclusion: In this multi-institutional cohort of pts with metastatic MpBC, ADC treatment yielded a 38% ORR, including four complete responses. However, rwPFS was poor overall & similar between ADC & non-ADC therapy. These findings highlight the need to develop new treatment strategies for MpBC, though a subset of pts may experience meaningful response to ADC. Citation Format: S. Jacob, S. Premji, S. Fisch, A. LeVee, S. Marion, D. Schmolze, J. Mortimer, L. Huppert, D. Idossa, A. Nayak, P. Wileyto, A. DeMichele, P. D. Shah. Efficacy of antibody drug conjugates in patients with advanced metaplastic breast cancer: a multi-institutional retrospective cohort study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-09-18.

Abstract Introduction: Metaplastic breast cancer (MpBC) represents a rare subtype, constituting <1% of all breast cancer cases. It is pathologically characterized by epithelial and mesenchymal cellular components exhibiting a basal molecular pattern, hormone receptor and HER2-negativity, and high grade. Clinically, MpBC exhibits an aggressive course with early disease progression and poor survival. Antibody-drug conjugates (ADCs) have been shown to penetrate the central nervous system (CNS); however, little is known about the response of ADCs in MpBC, particularly in patients with CNS disease. Here we aimed to describe features of CNS disease in a subset of patients (pts) who received an ADC for MpBC . Methods: We conducted a multi-institutional retrospective observational study of pts with advanced MpBC treated with ADCs at 4 NCI-designated cancer centers (abstract #A-345). This analysis includes a subset of this cohort with CNS metastases, with the aim of examining the incidence, characteristics, and treatment patterns. Clinical outcomes were evaluated for pts with information available, including CNS median progression-free survival (mPFS; defined from initiation of systemic therapy to time of further documented CNS progression or death) and median real world PFS (rwPFS; defined from time of treatment initiation to documented disease progression or death). Results: We identified 48 pts with MpBC who received an ADC. Among them, we identified 15 (31%) who developed CNS metastases. Of these, the majority (n=11, 73%) had triple-negative breast cancer, and 4 (27%) had HER2-positive breast cancer. The median age was 50 years (32-75 years). The median interval from the initial MpBC diagnosis to CNS metastasis was 13 months (0-54 months). Excluding those with de novo CNS disease, the median interval from time of metastatic diagnosis to development of CNS metastasis [mets] was 3 months (0-22 months). 4 (27%) pts had de-novo metastatic disease, of which 2 (50%) presented with CNS disease. 4 (27%) pts had screening CNS imaging prior to their diagnosis of CNS metastatic disease. At the time of CNS disease diagnosis, 9 (60%) pts had oligometastatic intraparenchymal CNS disease (defined as <5 CNS mets), 5 (33%) had diffuse (>5 CNS mets) CNS disease, and 1 (6%) had leptomeningeal and intraparenchymal disease. Most pts 14(93%) with CNS disease were symptomatic at time of diagnosis. One pt underwent resection, 9 (60%) underwent stereotactic radiosurgery (SRS), 6 (40%) underwent whole brain radiation therapy (WBRT), and 1 pt received intrathecal chemotherapy with methotrexate. The median number of lines in the metastatic setting prior to documented CNS disease was 1 (range 0-3). The majority 13 (87%) underwent a change in systemic therapy at time of CNS disease diagnosis, with 60% changing to an ADC at the time of CNS diagnosis or progression. Among pts with progression of CNS disease warranting change in systemic therapy, the median time from first CNS event to further CNS progression was 6.5 months. Median CNS PFS was 3.5 months (range 1 -74 months) and median rwPFS was 4.4 months. For those patients who used ADCs after diagnosis of metastatic CNS diagnosis (12/15), median rwPFS was 4 months. Conclusions: Within this CNS sub-cohort study, we found that 31% of pts with MpBC developed CNS metastasis. The majority of pts had neurological symptoms at diagnosis, but most pts did not undergo routing screening for CNS disease. Given the high rate of CNS mets within a short timeframe from diagnosis with poor outcomes, CNS screening should be considered. The extremely short median CNS PFS and low median rwPFS of this cohort highlight the guarded prognosis associated with MpBC. Given the small sample size of this cohort, larger studies are warranted to validate these findings. Citation Format: S. Premji, S. Jacob, A. LeVee, S. Marion, S. Fisch, L. Huppert, J. Mortimer, D. Schmolze, A. Nayak, A. DeMichele, P. Shah, R. Leon-Ferre, D. Idossa. Central nervous system disease in patients with metaplastic breast cancer receiving antibody drug conjugates: a multi-institutional study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-09-07.

BACKGROUND: The incidence of early-onset colorectal cancer is rising, yet survivorship care guidelines rarely address concerns unique to younger adults. Although treatment for colorectal cancer can have devastating consequences related to sexual function and fertility, these issues remain underrecognized and seldom addressed. OBJECTIVE: To better understand the impact of colorectal cancer diagnosis and treatment on sexual and reproductive health. DESIGN: Qualitative study of patients with early-onset colorectal cancer. SETTINGS: Semi-structured one-to-one Zoom interviews of patients recruited through convenience sampling from 7 academic institutions. PATIENTS: Sixty-three individuals diagnosed with colorectal cancer aged 50 years or younger were interviewed between March 2021 and August 2024. MAIN OUTCOME MEASURES: Patient perspectives regarding the sexual and reproductive health impacts of colorectal cancer diagnosis and treatment. Data were analyzed iteratively using directed and conventional qualitative content analysis. RESULTS: Participants discussed sexual and reproductive health side effects resulting from surgery, chemotherapy, and radiation. These side effects ranged in severity, with some experiencing almost none and others facing significant issues. They identified several domains, including surgical and treatment side effects, psychological impacts, effects on relationships, and unmet needs. Subdomains included sexual health, reproductive health, emotional distress, body image, communication challenges, impacts on dating, informational needs, financial support, and consultations. LIMITATIONS: Participants were recruited from academic medical centers only, and as such, responses may not reflect the experiences of those cared for in nonacademic settings. CONCLUSIONS: Sexual and reproductive health are critical but often overlooked concerns among younger patients with CRC, with significant impacts on physical functioning, partner relationships, and psychological well-being. Current survivorship guidelines fail to adequately address these needs. Our findings highlight the importance of pretreatment counseling and fertility preservation as well as the need for ongoing mental health support during and after cancer treatment. See Video Abstract . «NADIE ME LO DIJO»: ESTUDIO CUALITATIVO SOBRE LAS PREOCUPACIONES SEXUALES Y REPRODUCTIVAS TRAS EL TRATAMIENTO DEL CÁNCER COLORRECTAL DE APARICIÓN TEMPRANA ANTECEDENTES: La incidencia del cáncer colorrectal de aparición temprana está aumentando, pero las directrices sobre cuidados para supervivientes rara vez abordan las preocupaciones específicas de los adultos jóvenes. Aunque el tratamiento del cáncer colorrectal puede tener consecuencias devastadoras para la función sexual y la fertilidad, estas cuestiones siguen sin reconocerse lo suficiente y rara vez se abordan. OBJETIVO: Comprender mejor el impacto del diagnóstico y el tratamiento del cáncer colorrectal en la salud sexual y reproductiva. DISEÑO: Estudio cualitativo de pacientes con cáncer colorrectal de aparición temprana. ENTORNO: Entrevistas individuales semiestructuradas por Zoom a pacientes reclutados mediante muestreo por conveniencia en siete instituciones académicas. PACIENTES: Se entrevistó a 63 personas diagnosticadas con cáncer colorrectal antes de los 50 años entre marzo de 2021 y agosto de 2024. PRINCIPALES MEDIDAS DE RESULTADOS: Perspectivas de los pacientes sobre el impacto del diagnóstico y el tratamiento del cáncer colorrectal en la salud sexual y reproductiva. Los datos se analizaron de forma iterativa mediante un análisis de contenido cualitativo dirigido y convencional. RESULTADOS: Los participantes discutieron los efectos secundarios en la salud sexual y reproductiva derivados de la cirugía, la quimioterapia y la radiación. Estos efectos secundarios variaban en gravedad, ya que algunos no experimentaban casi ninguno y otros se enfrentaban a problemas importantes. Identificaron varios ámbitos, entre ellos los efectos secundarios de la cirugía y el tratamiento, las repercusiones psicológicas, los efectos en las relaciones y las necesidades no satisfechas. Los subámbitos incluían la salud sexual, la salud reproductiva, el malestar emocional, la imagen corporal, los problemas de comunicación, las repercusiones en las relaciones sentimentales, las necesidades de información, el apoyo financiero y las consultas. LIMITACIONES: Los participantes fueron reclutados únicamente en centros médicos académicos, por lo que es posible que las respuestas no reflejen las experiencias de las personas atendidas en entornos no académicos. CONCLUSIONES: La salud sexual y reproductiva son cuestiones fundamentales, pero a menudo se pasan por alto entre los pacientes jóvenes con CCR, con repercusiones significativas en el funcionamiento físico, las relaciones de pareja y el bienestar psicológico. Las directrices actuales para la supervivencia no abordan adecuadamente estas necesidades. Nuestros hallazgos ponen de relieve la importancia del asesoramiento previo al tratamiento y la preservación de la fertilidad, así como la necesidad de un apoyo continuo a la salud mental durante y después del tratamiento del cáncer. (AI-generated translation )

Abstract Background Follow-up blood cultures (FUBCs) for streptococcal bacteremia are infrequently positive and may not provide sufficient clinical impact to justify the time and resources expended for their routine use. We aimed to evaluate the frequency of and risk factors for positive FUBCs in patients with streptococcal bacteremia and to compare clinical outcomes among patients with or without positive FUBCs. Methods We retrospectively reviewed hospitalized patients with streptococcal bacteremia from September 2023 to June 2024 within a multisite health system. Patients ≥18 years old with ≥1 positive blood culture for a Streptococcus species were included. Patients with polymicrobial bacteremia, those who died or were discharged to hospice within 48 hours of their index culture, and Minnesota residents who declined research authorization were excluded. Results We included 454 patients, with 48 (10.6%) having positive FUBCs. The rate of positivity ranged from 0% for Streptococcus pyogenes to 18.5% for Streptococcus anginosus. Endocarditis and osteomyelitis were more common in the positive than in the negative FUBC group (22.9% vs 12.1%, respectively, for endocarditis [P = .04] and 16.7% vs 5.4% [P = .005] for osteomyelitis). Positive FUBCs were associated with a higher incidence of infection relapse (8.5% vs 2.7%; P = .047) and longer duration of antibiotics (30 vs 16 days; P = .01), but no differences in mortality rate, length of stay, or infection-related readmission were observed. Conclusions Positive FUBCs were infrequent for S pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, and group C and G streptococci. It may be reasonable to forego FUBC for these streptococcal species if endocarditis or osteomyelitis are not clinically suspected.