Citations

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.

Abstract Introduction: Hormone receptor positive (HR+), HER2- breast cancer (BC) is the most common subtype of BC. Despite advances in chemotherapy and endocrine therapy optimization, local and systemic recurrences frequently occur, especially for patients with node-positive disease. Recent data suggest a subset of patients with this tumor phenotype may benefit from the addition of anti-Programmed Death-1(aPD1) to neoadjuvant chemotherapy. However, T-cell infiltration (TCI), a biomarker of response to aPD1 and chemotherapy, is typically low in this BC subtype. Preclinical models show that combining preoperative radiation therapy (preop RT) with immune checkpoint inhibitors can enhance TCI and anti-tumor immunity. We conducted the first randomized trial to test whether no-, low- or high-dose RT combined with aPD1 increases TCI and improves responses in non-irradiated, metastatic lymph nodes in HR+/HER2- BC (NCT04443348). Materials & Methods: Eligible patients had ER and/or PR≥10%, HER2 negative invasive BC with clipped and biopsy-proven positive axillary node(s), cT1c-T4c, cN1-3, and at least one of the following criteria: grade 3 or grade 1-2 with cN2-N3, Ki67 >20%, or high genomic assay score. Between 2022-2024, 51 patients from 10 centers were randomized to no (0Gy; control arm), low (9Gy) or high (24Gy) doses of preop RT to the primary tumor with concurrent pembrolizumab followed by a 2-week tumor biopsy. Stratification factors were T1c vs. T2-4 and N1 vs. N2-3. Patients subsequently received pembrolizumab with 12 weeks of paclitaxel, followed by 4 cycles of adriamycin-cyclophosphamide (q2wk or q3wk) with pembrolizumab (200 mg q3 wks or 400 mg q6 wks). Surgery and adjuvant therapy followed standard-of-care. Dual co-primary endpoints were 2wk tumor TCI and nodal pathologic complete response (ypN0) at time of definitive surgery. TCI was assessed by multiplex immunofluorescence (pan-cytokeratin, CD3, CD8), using a rank-based Immunoscore (range 0-1), compared to baseline reference biopsies via two-tailed Mann-Whitney test. ypN0 was evaluated non-comparatively. Secondary endpoints included pCR and Residual Cancer Burden (RCB) 0/1. Results: Among 51 patients enrolled, 49 were evaluable for TCI and 48 for the ypN0 endpoint. Median age was 49.5 years (range 23-78). The cohort had a high-risk clinical profile: 92% had cT2-4, 50% N2-3, and 62% grade 3 tumors. Median ER and PR positivity were 90% (20-100) and 68% (1-98), respectively. Multifocal or multicentric tumors were present in 32%. TCI was assessed at 2 weeks post-treatment. The proportion of tumors with TCI in the upper quartile increased with RT dose escalation: 31% (0Gy), 40% (9Gy), and 53% (24Gy). Median TCI scores at 2 weeks were 0.60 (0Gy), 0.56 (9Gy), and 0.82 (24Gy), compared to a median baseline value of 0.50 from untreated reference samples. A statistically significant increase in TCI was observed only in the 24Gy cohort relative to the untreated group (p=0.027). 70.8% underwent mastectomy, with 39.6% receiving immediate reconstruction. 8% experienced G2/3 wound complications, balanced across arms. Median number of lymph nodes removed was 6.5 (1-42). The overall ypN0 rate was 29%, and 24%(0Gy), 29%(9Gy) and 33%(24Gy) per arm. pCR/RCB 0-1 rates were 18%/27% in the entire cohort and 6%/18%(0Gy), 29%/29%(9Gy), and 19%/33%(24Gy), respectively. Conclusion: The addition of 24Gy preop RT to aPD1 significantly increased tumor TCI in HR+/HER2- early-stage BC. Non-irradiated nodal response rates were promising despite over one-third of the study population with grade 1/2 tumors and high disease burden, laying the foundation for a future randomized trial comparing the efficacy of this novel approach against standard of care for node-positive HR+/HER2- BC. Citation Format: G. Gupta, A. Y. Ho, F. Gharibpoor, Y. Abdou, J. D. Anampa, R. C. Blitzblau, B. C. Calhoun, D. L. Casey, S. F. Dent, L. A. Carey, J. R. Bellon, L. E. Warren, J. Lu, T. J. Hieken, A. G. Taghian, A. Bardia, T. Traina, G. Plitas, K. Gallagher, K. Daugherty, A. Thompson, I. Krop, A. Wolff, E. Mittendorf, J. Fox, H. Garber, E. Hwang, A. J. Khan, J. P. Loene, R. Mutter, S. Patil, C. Santa-Maria, B. V. Vincent, J. L. Wright, L. Spring.Primary Results from the HR+/HER2- Cohort of TBCRC-053 (P-RAD): A Randomized Trial of No, Low, or High Dose Preoperative RADiation with Pembrolizumab and Chemotherapy in Node-Positive, HER2-Negative Breast Cancer [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 GS2-05.

Despite advances in drug and device technology, health care delivery, and research infrastructure, cardiogenic shock (CS) continues to have nearly 50% in‐hospital mortality. In patients with CS, both the initial severity of Society for Cardiovascular Angiography and Intervention CS and its subsequent trajectory predicts the clinical outcomes. Accordingly, delayed initial recognition and failure to escalate or deescalate treatment can significantly affect the outcomes of CS. Traditional assessment methods, with the exception of blood pressure measurement, require a high index of suspicion and frequent reassessment by the clinical team. Electronic medical record‐based detection has been successfully implemented in acute and critical care patients with septic shock and acute kidney injury. In CS, electronic medical record‐based studies have largely focused on using models to predict outcomes in patients with CS, with limited data on electronic medical record‐based tools to assist with either predicting CS or providing real time alerts when escalation or de‐escalation might be indicated. Early detection of CS may be associated with detection of earlier Society for Cardiovascular Angiography and Intervention stages of CS and potentially prevent deterioration to higher stages. In this review, we seek to highlight a blueprint for electronic medical record‐based detection of CS that focuses on reproducibility, convenience, clinical decision support, and research aspects.

Background: A critical component of conducting systematic reviews or meta-analyses is assessing the methodological quality and bias of included studies. Several methodological quality assessment tools have been developed; however, these tools may not be relevant to observational sports medicine research, which carries numerous unique nuances and biases. Purpose: To develop the Sport Publication Observational Research Tool (SPORT), which evaluates and scores the methodological quality of observational sports medicine research. Study Design: Consensus statement. Methods: SPORT was developed through a modified Delphi approach involving members from the Herodicus Society and The FORUM. All active members were invited to participate in the process aimed at building consensus on SPORT content and scoring. After finalizing SPORT, a power analysis led to the independent selection of 55 observational clinical sports medicine studies, which were scored twice by 4 reviewers of varying training levels. Interrater and intrarater reliability for SPORT was assessed using intraclass correlation coefficients (ICCs). The distribution and percentiles for total SPORT score across the 55 studies were calculated. SPORT was also compared with the methodological index for non-randomized studies (MINORS), a commonly utilized quality assessment tool. Results: A total of 51 members participated and achieved 100%, 100%, 98.0%, and 98.0% completion rates for rounds 1 through 4, respectively. The final SPORT included 19 subscores related to methodological quality and bias and achieved 94% consensus approval. Mean SPORT completion time was 6 minutes and 19 seconds per study, which varied significantly by reviewer training level. The subscore "peer review" demonstrated unacceptable reliability and was removed. The remaining 18 subscores exhibited ICC ranges of 0.599 to 0.955 for interrater reliability and 0.530 to 0.936 for intrarater reliability. Total SPORT score demonstrated excellent agreement, for interrater (ICC, 0.967) and intrarater reliability (ICC, 0.966). Median SPORT score across the 55 studies was 20.0 and skewed toward lower scores. There was a moderate significant correlation between SPORT and MINORS ( r [53] = 0.575; P < .001). Conclusion: An objective tool to assess the methodologic quality of observational sports medicine research (SPORT) was successfully developed through a modified Delphi approach with numerous content experts in the field. This tool may be useful in assessing the methodological quality of primary observational sports medicine studies included in systematic reviews and meta-analyses.

BACKGROUND: Cervical artery dissection (CeAD) may result in dissecting aneurysm (DA) formation. We aimed to characterize risk factors and clinical outcomes associated with DA in a large, international CeAD cohort. METHODS: We performed a secondary analysis of STOP-CAD (Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection), an international, multicenter, retrospective cohort. Patients with spontaneous CeAD were assessed for DA at baseline and de novo DA formation. Significant covariates in univariable analysis were included in multivariable regression models aiming to identify factors associated with DA formation. Logistic regression and Cox proportional hazards models evaluated the association of DA with ischemic and hemorrhagic outcomes. RESULTS: Among 4008 patients with CeAD, 546 (13.6%) had a DA at baseline, and 221/2938 (7.5%) patients developed a de novo DA during follow-up, of which 172/221 (78.2%) were detected in the first 180 days. Patients with DA had a mean age of 47 years, and 383 (49.9%) were women. Baseline or de novo DA was associated with a history of connective tissue disorder (adjusted odds ratio [aOR], 2.02 [95% CI, 1.22–3.36]), fibromuscular dysplasia (aOR, 1.69 [95% CI, 1.28–2.25]), and multiple vessel dissection (aOR, 1.53 [95% CI, 1.19–1.98]). Lower odds of DA were seen in Hispanic ethnicity (aOR, 0.64 [95% CI, 0.43–0.97]) and ischemic stroke presentation (aOR, 0.41 [95% CI, 0.34–0.49]). Fibromuscular dysplasia was associated with de novo DA formation (aOR, 2.30 [95% CI, 1.52–3.49]). DA was not associated with ischemic stroke (hazard ratio, 0.71 [95% CI, 0.44–1.16]; P =0.173) or intracranial hemorrhage (HR, 1.09 [95% CI, 0.42–2.84]; P =0.86) by day 180. CONCLUSIONS: DAs are relatively common manifestations of CeAD, typically occurring within 6 months of CeAD diagnosis. DA was not associated with an increased risk of subsequent ischemic stroke or intracranial hemorrhage.

The mammalian lung operates under a biological paradox, requiring architectural fragility for gas exchange while maintaining robust regenerative plasticity to withstand injury. The Hippo signaling pathway has emerged as a central “rheostat” in orchestrating these opposing needs, yet the distinct roles of its downstream effectors remain underappreciated. This review synthesizes recent genetic and mechanobiological advances to propose a “Tale of Two Effectors” model, arguing for the functional non-redundancy of YAP and TAZ. We posit that YAP functions to drive airway progenitor expansion, mechanical force generation, and maladaptive remodeling. Conversely, TAZ—regulated uniquely via transcriptional mechanisms and mechanotransduction—acts as an obligate driver of alveolar differentiation and adaptive repair through an NKX2-1 feed-forward loop. Furthermore, we introduce the “See-Saw” model of tissue fitness, where mesenchymal niche collapse releases the mechanical brake on the epithelium, triggering the bronchiolization characteristic of pulmonary fibrosis. Finally, we extend this framework to malignancy, illustrating how Small Cell Lung Cancer (SCLC) subtypes mirror these developmental and regenerative states. This integrated framework offers new therapeutic distinct targets for modulating tissue fitness and resolving fibrosis.

707 Background: Due to insufficient data, therapy for unresectable, locally advanced pancreatic adenocarcinoma (LAPAC) is based on trials in metastatic disease, and outcomes remain poor. TTFields disrupt cancer cell division using alternating low-frequency electric fields delivered externally by a portable device. In the phase 3 PANOVA-3 trial (NCT03377491), TTFields with gemcitabine/nab-paclitaxel (GnP) significantly improved overall survival (OS; HR 0.82) and pain-free survival (HR 0.74) vs GnP in patients with unresectable LAPAC. Methods: In PANOVA-3, patients with newly diagnosed LAPAC were randomized 1:1 to receive GnP with or without concomitant TTFields. Kaplan-Meier methodology was used for time-to-event analyses. Response evaluations were based on RECIST V1.1. OS, pain-free survival, and safety were analyzed post-hoc in subgroups based on sex (male, female), age ( < 65, ≥65 years), and BMI (<25, ≥25 kg/m 2 for efficacy; ≤20, 20–25, 25–30, ≥30 kg/m 2 for safety). Differences between treatment arms were compared using the log-rank test. Results: Efficacy outcomes are shown in the table. TTFields significantly extended pain-free survival in females and patients ≥65 years. Device-related adverse events (AEs) were comparable between sexes, older and younger patients, and across BMI ranges. Some device-related skin adverse events occurred more frequently in females (e.g. dermatitis, 33.1% vs 22.7%; rash 21.8% vs 13.5%, females vs males, respectively); others occurred more often in males (e.g. maculo-papular rash, 9.8% vs 14.2%; erythema, 9% vs 12.1%, females vs males, respectively). Dermatitis and pruritus had a higher incidence in the BMI ≥30 kg/m 2 subgroup (38.5%), whereas patients with BMI <30 kg/m 2 did not show noticeable differences in device-related AEs. Skin irritation (11.5% vs 5.5%) and skin reactions (8.5% vs 2.8%) were more common in patients ≥65 years than patients <65 years. Conclusions: Median OS and pain-free survival in these post-hoc subgroup analyses are generally consistent with the overall analysis, supporting use of TTFields with GnP in unresectable LAPAC. No new safety concerns were noted; observations were consistent with the general PANOVA-3 population. Clinical trial information: NCT03377491 . Survival outcomes for the subgroup analyses. Median OS, months TTFields + GnP GnP P value Age<65 years≥65 years 18.6 (n=113)15.4 (n=172) 16.0 (n=114)12.9 (n=172) 0.2060.061 SexFemaleMale 16.8 (n=138)15.7 (n=147) 14.5 (n=161)13.4 (n=125) 0.1140.145 BMI<25≥25 16.7 (n=166)16.2 (n=117) 14.2 (n=174)14.5 (n=108) 0.1550.105 Median pain-free survival, months Age<65 years≥65 years 16.5 (n=113)13.1 (n=172) 9.2 (n=114)8.3 (n=172) 0.4070.035 SexFemaleMale 16.5 (n=138)15.2 (n=147) 8.3 (n=161)9.3 (n=125) 0.0260.478 BMI<25≥25 16.6 (n=166)14.7 (n=117) 9.1 (n=174)8.3 (n=108) 0.1170.088

Study Design Narrative Review. Objectives To summarize the scientific contributions generated from the AO Spine Knowledge Forum Tumor (AOSKFT) databases, focusing on primary spine tumors, and highlight key findings, research trends, and future directions. Methods Data from the Primary Tumor Retrospective (PT-Retro) and Primary Tumor Research Outcome Network (PTRON) registries were analyzed. The nineteen studies included were peer-reviewed manuscripts focused on primary spine tumors, excluding abstracts, book chapters, systematic reviews, and metastatic studies. Results The PT-Retro registry compiled data from 1495 patients across 18 primary tumor histologies, offering insights into recurrence, survival, and treatment paradigms. Key findings emphasize the importance of Enneking-appropriate (EA) resection in improving survival and reducing recurrence in tumors such as chordoma, chondrosarcoma, and osteosarcoma. Genetic markers, including hTERT promoter mutations and rs2305089 SNP, were linked to prognosis in specific histologies. Benign tumors, such as giant cell tumors and aneurysmal bone cysts, demonstrated variable outcomes with different surgical approaches and selective arterial embolization. Conclusions The AOSKFT registries have significantly advanced knowledge in primary spine tumor management, emphasizing preoperative staging, surgical margins, and multidisciplinary approaches. International, multicentric registries are essential for studying rare diseases like primary spine tumors, enabling robust data collection, improved statistical power, and broader applicability of findings across diverse clinical settings. Ongoing prospective data collection through PTRON will further refine evidence-based care for these rare and challenging conditions.

Abstract Background Research on gender and ethnic differences in white matter tracts yields mixed results. Although men show larger global corpus callosum (CC) in absolute values, women have demonstrated larger splenium and isthmus. Additionally, men have shown greater white matter and fractional anisotropy (FA) in multiple regions than women. This study investigates sex and ethnic differences in the corpus callosum and transcallosal white matter tissue microstructure of older individuals with normal cognition and memory disorders. Method 191 participants (Female n = 120; Hispanics n = 115; Non‐Hispanics n = 76; Age mean = 71.07; SD = 7.75) were included in the sample from the 1Florida ADRC with cognitively normal ( n = 75), MCI ( n = 88), and dementia ( n = 28) diagnoses. Corpus callosum volumes were collected using a Siemens Skyra 3T MRI scanner and were divided into anterior, mid‐anterior, central, mid‐posterior, and posterior regions. Also, MRI‐based free water diffusion tensor imaging (FW‐DTI) measured FW‐corrected FA (fwcFA) to assess and compare the integrity of transcallosal tract templates (TCATT) across motor, temporal, parietal, and occipital regions across males and females and ethnic groups. Result Univariate ANCOVAs controlling for age and clinical diagnosis were performed; females had larger normalized CC volumes in the posterior, F (1, 184) = 8.92, p = .003, η p 2 = .046, mid‐anterior, F (1,184)= 5.68, p = .018, η p 2 = .030, and anterior, F (1,184)= 14.54, p < .001, η p 2 = .073, regions, which all survived FDR corrections, with no ethnic differences observed. For transcallosal tracts, females had higher fwcFA in the inferior temporal gyrus, η p 2 Hispanics had higher fwcFA in the premotor cortex, η p 2 η p 2 Conclusion Sex and ethnicity influence white matter changes during aging independently of age and cognitive diagnosis. However, the effect explained by these demographic variables was very small, suggesting the influence of additional factors.

Background Deep brain stimulation (DBS) has been investigated for patients with drug-resistant epilepsy who are not candidates for resective surgery. Because different types of epilepsy involve distinct brain networks, numerous DBS targets have been explored, yet a comprehensive synthesis is lacking. Methods To provide a comprehensive overview of this expanding literature, we conducted a systematic review of studies for DBS in epilepsy, including case series, prospective and retrospective studies. We collected data on surgical targets, individual disease characteristics, outcomes and precise electrode placements. DBS electrode coordinates were gathered into a common template space and related to clinical outcomes. Results We included 124 studies, corresponding to 1210 patients and 20 distinct surgical targets. While the anterior (ANT) and centromedian (CM) nuclei of the thalamus remain the most studied, we also review less commonly used targets that show promise for specific forms of epilepsy and may warrant further investigation. Substantial variability in targeting strategies and electrode placement was observed within each of the target regions. Importantly, significant relationships between stimulation location and outcomes were identified for ANT-DBS and CM-DBS. For ANT-DBS, shorter distance to the mammillothalamic tract junction was associated with greater seizure reduction on both study-level and patient-level analyses (r=−0.55, p<0.001 and r=−0.51, p<0.001, respectively). For CM-DBS, localisation effects may be dependent on the form of epilepsy, with stimulation of the parvocellular CM being associated with better outcomes in generalised epilepsy. Conclusions Our results emphasise the importance of accurate targeting in DBS for epilepsy. Our database and atlas of DBS targets are made publicly available, potentially serving further meta-analytical work. PROSPERO registration number CRD420250649304.