Citations

PURPOSE Recent studies reveal that 5%-18% of children with cancer harbor pathogenic variants in known cancer-predisposing genes. However, DNA damage repair (DDR) genes, which are frequently somatically altered in pediatric tumors, have not been systematically examined as a source of novel cancer-predisposing signals. METHODS To address this gap, we interrogated 189 DDR genes for presence of germline predisposing variants (PV) among 5,993 childhood cancer cases and 14,477 adult noncancer controls (discovery cohort). PV were determined using a tiered approach incorporating ClinVar annotations, InterVar classification, and in silico tools (REVEL, CADD, and MetaSVM). Using logistic and firth regression, we identified genes with PV statistically enriched in the germline of children with tumors and replicated findings among 1,497 additional childhood cancer cases across three independent cohorts. RESULTS Analysis across all cases with cancer revealed enrichment of TP53 PV. Cancer-specific analyses confirmed known associations including germline TP53 PV in adrenocortical carcinoma, high-grade glioma (HGG), and medulloblastoma (MB), PMS2 in HGG and non-Hodgkin lymphoma (NHL), MLH1 in HGG, BRCA2 in NHL, and BARD1 in neuroblastoma. In addition, four novel associations were uncovered, including BRCA1 in ependymoma, SPIDR in HGG, SMC5 in MB, and SMARCAL1 in osteosarcoma (OS). Importantly, the SMARCAL1 :OS association was significant in the discovery (6/230, 2.6%, false discovery rate [FDR] logistic = 0.0189) as well as all three replication cohorts (Childhood Cancer Survivor Study: 8/275, 2.9%; P Fisher < .0001; Cancer Predisposition Syndrome-German Childhood Cancer Registry: 4/135, 3%, P Fisher = .002; Individualized Therapy for Relapsed Malignancies in Childhood: 4/217, 1.8%, P Fisher = .012). The remaining wild-type SMARCAL1 allele was deleted in three of four OS tumors with available data. CONCLUSION Our study confirms the relevance DDR genetic variation in pediatric cancer risk and establishes SMARCAL1 as a novel OS predisposing gene, providing insights into tumor biology and creating opportunities to optimize care for patients with this challenging tumor.

Syndrome of the Trephined (SoT), also known as sunken or sinking skin flap syndrome (SSFS), is a rare sequela of decompressive craniectomy caused by an atmospheric pressure gradient over the underlying brain parenchyma following bone flap removal. Cranioplasty is the definitive treatment of SoT, although some patients are not surgical candidates or require bridging to definitive treatment. This systematic review identified 7 articles describing nonsurgical interventions for patients with SoT. Three treatment modalities emerged: external orthotics, scalp traction, and Trendelenburg positioning. These approaches demonstrated rapid improvements in neurological symptoms, including restored motor function, improved cognition, resolution of midline shifts, and, in some cases, re-expanded brain parenchyma. While these results are limited to case reports and small case series, they demonstrate promising early outcomes for the noninvasive management of Syndrome of the Trephined.

Background: Tumor-associated macrophages (TAMs) are essential regulators of the glioblastoma (GBM) microenvironment; their functional heterogeneity and interaction networks are not fully elucidated. We identify RNF135 as a novel TAM-enriched gene associated with immune activation and adverse prognosis in GBM. Methods: To evaluate RNF135’s expression profile, prognostic significance, and functional pathways, extensive transcriptome analyses from TCGA and CGGA cohorts were conducted. The immunological landscape and cellular origin of RNF135 were outlined using single-cell RNA-seq analyses and bulk RNA-seq immune deconvolution (MCP-counter, xCell and ssGSEA). Cell–cell communication networks between tumor cells and RNF135-positive and -negative tumor-associated macrophage subsets were mapped using CellChat. Results: RNF135 predicted a poor overall survival and was markedly upregulated in GBM tissues. Functional enrichment analyses showed that increased cytokine signaling, interferon response, and innate immune activation were characteristics of RNF135-high samples. Immune infiltration profiling showed a strong correlation between the abundance of T cells and macrophages and RNF135 expression. According to the single-cell analyses, RNF135 was primarily expressed in TAMs, specifically in proliferation, phagocytic, and transitional subtypes. RNF135-positive TAMs demonstrated significantly improved intercellular communication with aggressive tumor subtypes in comparison to RNF135-negative TAMs. This was facilitated by upregulated signaling pathways such as MHC-II, CD39, ApoE, and most notably, the CCL signaling axis. The CCL3/CCL3L3–CCR1 ligand–receptor pair was identified as a major mechanistic driver of TAM–TAM crosstalk. High RNF135 expression was also linked to greater sensitivity to Selumetinib, a selective MEK1/2 inhibitor that targets the MAPK/ERK pathway, according to drug sensitivity analysis. Conclusions: RNF135 defines a TAM phenotype in GBM that is both immunologically active and immunosuppressive. This phenotype promotes inflammatory signaling and communication between cells in the tumor microenvironment. Targeting the CCL–CCR1 axis or combining RNF135-guided immunomodulation with certain inhibitors could be a promising therapeutic strategies for GBM.

IDH1/2 mutations (IDH mut ) increase methylation of DNA and histones in gliomas. IDH mut inhibitors are effective against low-grade IDH mut gliomas, but new strategies against high-grade IDH mut gliomas are needed. Although histone deacetylase inhibitors (HDACi) are ineffective against IDH wt glioblastoma (GBM), their potential in IDH mut gliomas has not been extensively studied. We previously established that IDH mut gliomas are more sensitive to HDACi than IDH wt GBM. Here we show that IDH mut is associated with greater sensitivity to HDACi only in glioma, not in IDH mut chondrosarcoma or cholangiocarcinoma. While HDACi induced more histone acetylation and gene regulation in IDH mut glioma than in IDH wt GBM, such acetylation was mostly within gene deserts, whereas IDH mut glioma promoters paradoxically lost histone acetylation. Two mediators of HDACi resistance, YAP and TAZ, were methylated and suppressed in IDH mut gliomas but not in other IDH mut cancers. Inducing YAP or TAZ expression in IDH mut gliomas conferred resistance to HDACi. Finally, belinostat extended in vivo survival only in IDH mut glioma models, not in IDH mut GBM models. Our findings provide a mechanistic rationale for further studies of HDACi in patients with IDH mut glioma, as well as the potential use of YAP/TAZ as a biomarker of HDACi sensitivity in cancers.

Abstract Clinical and translational research is important for health care and the growth of medical specialties. Physical medicine and rehabilitation offers many opportunities for research, but research growth in physical medicine and rehabilitation is lacking, and research resources and productivity vary across academic physical medicine and rehabilitation departments across North America. The Physiatric Research Consulting Program was developed by the Association of Academic Physiatrists to provide customized recommendations to enhance research capacity and productivity in physical medicine and rehabilitation departments. This report outlines the three components of the Physiatric Research Consulting Program, including a previsit needs assessment, an in-person visit, and a postvisit follow-up final report. The report also provides a qualitative assessment of the impact of the Physiatric Research Consulting Program, with general themes of feedback, site visit evaluations, and final report evaluations. The Physiatric Research Consulting Program was found to be valuable in identifying gaps and needs for physical medicine and rehabilitation departments, providing outside perspectives, and energizing faculty toward research growth in their departments.

Importance Inherited pathogenic variants (PVs) in known predisposition genes can greatly increase breast cancer risk, but the combined impact of PV status, family history, and other factors on breast cancer risk in the general US population has not been well described. Objective To evaluate population-based breast cancer risk estimates for those with established PVs overall and stratified by first-degree family history of breast cancer and other factors. Design, Setting, and Participants This study used pooled data from 13 US-based breast cancer case-control studies participating in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Enrollment for individual studies occurred between 1976 and 2013, and results are based on data released March 2023, with analyses conducted from June 2022 to July 2025. Exposures PVs, breast cancer family history, self-reported race and ethnicity, and established risk factors. Main Outcomes and Measures Breast cancer rate ratios for PVs in 7 genes were estimated from the CARRIERS consortium. PV status and incidence and mortality statistics were combined using the Individualized Coherent Absolute Risk Estimation (iCARE) model to estimate conditional cumulative breast cancer risks and 95% CIs, stratified by family history and standardized to the US population. Models that incorporated population-based data and published estimates for established epidemiologic risk factors were also evaluated. Results A total of 67 692 women were studied, including 33 841 who were diagnosed with breast cancer. PVs in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 were strongly associated with breast cancer risk, with BRCA1 and PALB2 PVs showing evidence of heterogeneity by family history. In models considering PVs, family history, and established risk factors, the estimated cumulative risks of breast cancer by age 50 years ranged from 2.4% (95% CI, 2.4-2.4) in women with no PVs and no family history to 35.5% (95% CI, 21.6-55.1) in PALB2 PV carriers with a family history. Among women who have not been diagnosed with breast cancer by age 50 years, the cumulative risk of breast cancer by age 80 years ranged from 11.1% (95% CI, 11.0-11.2) in noncarriers with no family history to 70.5% (95% CI, 52.8-83.5) for PALB2 carriers with a family history. PV-specific cumulative risk estimates varied across subgroups defined by race and ethnicity and potentially modifiable epidemiologic risk factors. Conclusions and Relevance In this study, population-based estimates of cumulative breast cancer risk for established PVs, as informed by the CARRIERS case-control sample, varied by family history and potentially modifiable risk factors. These estimates provide guidance for identifying individuals who will most benefit from enhanced screening and prevention strategies.

Study Design: Retrospective cohort analysis. Objective: To determine the effect of long-segment posterior cervical decompression and fusion (PCDF) on perioperative changes in vertebral Hounsfield Units (HUs) and the impact of these changes on radiographic outcomes and fusion status. Summary of Background Data: Low preoperative CT HUs have been associated with adverse outcomes after spinal fusion, including hardware complications and reoperation. No existing studies have investigated the preoperative to postoperative change in HUs after cervical spinal fusion. Stress shielding may decrease bone quality within the fusion construct. Whereas, altered junctional loading and increased segmental mobility may precipitate bony hypertrophy in the terminal and adjacent levels. Methods: All adult patients who underwent C2-T2 PCDF for myelopathy/ myeloradiculopathy at an academic center between 2013 and 2020 were retrospectively identified. Preoperative and postoperative HUs were assessed on axial CT images in the cranial, middle, and caudal C2, C6, T2, and T3 vertebral bodies, outside of the region of instrumentation and artifact by 2 independent reviewers. Paired t test compared preoperative to postoperative changes in HUs. Preoperative and long-term postoperative cervical alignment, fusion, and revision rates were assessed. Univariate and regression analysis compared patient factors and outcomes between groups with perioperative increase versus decrease in vertebral HUs. Results: One hundred patients were included. The average preoperative to postoperative change in HUs in the C2, C6, T2, and T3 vertebral bodies were −19.80 (P=0.008), −52.63 (P<0.001), 15.15 (P=0.014), and 9.41 (P=0.346), respectively. Perioperative increase in C2 HUs was predictive of increased postoperative distal junctional angle (β=3.41, P=0.048) and increased T1–T4 kyphosis (β=6.50, P=0.003). Perioperative increase in C6 HU predicted pseudoarthrosis (fusion odds ratio: 0.19, P=0.007). Conclusions: Significant perioperative decreases in C6 HUs within a long-fused construct may demonstrate stress shielding. The significant association between greater distal kyphosis and an increase in C2 HUs may be attributed to a stress riser effect. Level of Evidence: Level III.