Citations

OBJECTIVE Ruptured, large pediatric arteriovenous malformations (AVMs) pose a significant management challenge due to high rerupture risk and the morbidity of conventional treatments. Volume-staged stereotactic radiosurgery (VS-SRS) has emerged as an alternative; however, evidence for its use in this specific population is limited. This study aimed to evaluate the long-term efficacy and safety of VS-SRS for ruptured, large AVMs in a dedicated pediatric cohort. METHODS This international, multicenter, retrospective cohort study from 21 centers analyzed outcomes for 42 pediatric patients (age < 18 years) with previously ruptured, large AVMs treated with VS-SRS. The primary outcome was complete AVM obliteration, and secondary outcomes included post-SRS hemorrhage, radiation-induced changes (RICs), and favorable outcome. Favorable outcome in this study was defined as obliteration without post-SRS hemorrhage or permanent RIC. RESULTS At the initial SRS, the median patient age was 14.5 years, and the median AVM volume was 15.0 cm 3 ; most AVMs were high grade (Spetzler-Martin grades IV and V). With a median follow-up of 41.5 months, complete AVM obliteration was achieved in 21 patients (50.0%). The cumulative obliteration rate was 37% at 5 years and 56% at 10 years. Patients with a nidus volume of ≤ 10 cm 3 had significantly higher cumulative obliteration rates than those with a nidus volume > 10 cm 3 (log-rank test, p = 0.021). Similarly, patients treated with a prescription dose > 17 Gy showed significantly higher cumulative obliteration rates compared to those treated with a dose ≤ 17 Gy (log-rank test, p = 0.012). The cumulative 5-year incidences of hemorrhage and RICs following VS-SRS were 19% and 7%, respectively. In multivariable analysis, only larger total AVM volume was an independent predictor of a lower likelihood of favorable outcome (hazard ratio 0.89, 95% CI 0.80–0.99; p = 0.036). CONCLUSIONS In this multicenter pediatric cohort, VS-SRS for ruptured, large AVMs provides a reasonable chance of long-term obliteration, but generally acceptable risks of post-SRS hemorrhage and RICs exist. VS-SRS should be considered as an option for pediatric patients with large, ruptured AVMs.

Abstract Foreign body response is a common yet serious challenge for biomedical implants. It can trigger inflammation and eventually lead to the formation of a fibrotic capsule, which compromises device function. Although significant efforts have been made to develop antifibrotic surface coatings for implantable materials, developing broadly applicable solutions remains challenging due to the diversity of materials used in biomedical implants. Here, we propose a simple and versatile strategy to develop antifibrotic coatings for biomedical implants. Photoreactive benzophenone groups are incorporated into designer polymers to enable covalent attachment to various substrates. The effect of benzophenone group density within polymer chains on surface coating efficiency was investigated, and an optimal BP incorporation ratio was identified. Polymers incorporating varying ratios of an anti-fibrotic small molecule and anti-fouling zwitterionic moieties were synthesized and successfully attached to silicone implants. In vivo evaluation of these implants in C57BL/6 mice identified an optimized polymer composition that reduced fibrotic capsule thickness by around 60%. Coating of commercial medical catheters with this optimized polymer reduced collagen deposition by over 3.5-fold following 4 weeks of implantation in the peritoneal space of C57BL/6 mice. Finally, we demonstrated that the optimized polymer coating can be readily applied to a variety of commonly used biomedical materials using this straightforward method, highlighting the versatility of the approach. This work provides a facile and broadly applicable strategy for developing antifibrotic coatings, which has the potential to expand the design of surface modifications aimed at improving the performance of biomedical implants.

ABSTRACT Germline variation shapes cancer risk, yet its influence on the evolutionary dynamics of established tumors remains poorly understood. In multiple myeloma, subclonal diversification drives disease progression and treatment failure, but the heritable factors that modulate this process are unknown. Here, we show that germline variation is associated with tumor evolutionary features, implicating inherited regulation in subclonal expansion. Integrating germline variation with tumor evolutionary parameters identifies variants associated with evolutionary features, with signals enriched in regulatory regions, consistent with a transcriptional basis. We further identify TBKBP1 as a key locus linking germline variation to tumor evolution and clinical outcome. Germline variation at this locus is associated with TBKBP1 expression and subclonal expansion, and TBKBP1 expression correlates with adverse prognosis, consistent across independent cohorts. Functional analyses demonstrate that TBKBP1 promotes proliferation and activates MYC, mTORC1 and non-canonical NF-κB signaling pathway. Together, these findings establish germline regulatory variation as a determinant of tumor evolutionary dynamics and identify TBKBP1 as a mediator linking inherited variation to subclonal expansion and disease progression in multiple myeloma.

Abstract Exposure to asbestos is the primary cause of mesothelioma, however the processes underpinning its initiation and evolutionary trajectory remain elusive. To address this knowledge gap, we conducted whole exome sequencing and phylogenetic analysis of 277 mesotheliomas. Using multidimensional Dirichlet process clustering we inferred phylogenies, uncovering mutation order dominated by early 13q,1p, 8p, 6q and 22q somatic copy number alterations. Mesotheliomas exhibit a spectrum of genomic intra-tumor heterogeneity spanning linear (L) to highly branched (B) tree topologies, quantifiable by the Weighted Shannon Entropy (WSE). Somatic copy number alterations emerge earlier than single nucleotide variants (SNVs), and at a much faster relative rate in L-mesotheliomas. BAP1 is the only positively selected driver in L-mesotheliomas, whereas, B-mesotheliomas harbor multiple positively selected drivers and an aggressive phenotype, including a bias of loss of RPL5, and MTAP deletion linked to breakpoint enriched with long interspersed nuclear elements. L-trees had lower WSE, but greater T-cell inflammation and tertiary lymphoid structures, despite having a lower neoantigen burden. WSE is higher in larger volume, immunologically cold mesotheliomas, and is associated with shorter survival. In summary, progressive genomic heterogeneity is a defining feature of more aggressive mesothelioma yet illuminates opportunities for precision therapeutic intervention.

Background Invasive micropapillary carcinoma (IMPC) of the breast is associated with a high propensity for lymphovascular invasion and lymph node metastasis. However, whether chemotherapy is associated with improved survival outcomes in these patients remains unclear. Methods This retrospective study analyzed IMPC patients from the SEER database (2010–2018) (n=1,150) and an external validation cohort from Nanjing Drum Tower Hospital (n=199). Propensity score matching assessed chemotherapy’s impact on overall survival (OS) and breast cancer-specific survival (BCSS) in the SEER cohort. A risk stratification model was developed and validated using the external cohort. Results In the SEER cohort, chemotherapy was associated with significantly improved OS (HR = 0.517, 95% CI 0.293-0.910, P = 0.020) but not BCSS. A risk model incorporating marital status, tumor size, subtype, and radiotherapy history identified high- and low-risk groups. Chemotherapy was associated with significantly better OS only for high-risk patients (internal training cohort: HR = 0.577, 95% CI 0.349-0.952, P = 0.029; internal validation cohort: HR = 0.213, 95% CI 0.070-0.647, P = 0.003). External validation consistently confirmed poorer prognosis for high-risk patients (HR = 2.969, 95% CI 1.028-8.571, P = 0.035) and verified the model’s ability to identify patients with differential OS associations with chemotherapy: chemotherapy was associated with better OS in high-risk patients (HR = 0.163, 95% CI 0.031-0.868, P = 0.016), but not in low-risk patients (HR = 0.793, 95% CI 0.153-4.103, P = 0.782). Conclusions Chemotherapy was associated with improved prognosis particularly in high-risk patients with IMPC. However, chemotherapy decisions should be made cautiously for low-risk patients, taking into account a comprehensive assessment of clinical and pathological factors.

TAR DNA binding protein 43 (TDP-43) pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43–dependent cryptic splicing on neuronal function remains unclear. Here, we report previously unidentified TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN , RAP1GAP , SYT7 , and KCNQ2 . Using human stem cell–derived neurons, we showed that TDP-43 reduction induces cryptic splicing and down-regulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occurred selectively in neurons with TDP-43 pathology. Suppressing individual cryptic splicing events using antisense oligonucleotides partially restored neuronal function, and combined targeting almost fully rescued the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.

Background: The economic burden associated with idiopathic pulmonary fibrosis (IPF) is not well understood, especially since the approval of antifibrotic medications to treat IPF in 2014. Objective: This study assessed healthcare resource utilization (HCRU) and costs for patients with and without IPF among insured patients in the United States. Methods: This retrospective study used claims data from the Optum Research Database from 01 January 2016 through 31 December 2023. The IPF cohort included patients with at least 2 claims for IPF within 365 days. A comparator cohort was exact matched to the IPF cohort in a 4:1 ratio on demographic characteristics. Follow-up all-cause and respiratory-related HCRU and costs were collected. Outcomes were presented as weighted per-patient per-month (wPPPM) to account for variable follow-up. Descriptive results were reported by cohort, overall, and stratified by insurance type. All-cause and respiratory-related wPPPM costs were modeled using generalized linear models and time to all-cause and respiratory-related inpatient visits were modeled using Cox proportional hazards regression models, adjusted for baseline comorbidities. Results: A total of 7582 patients were included in the IPF cohort; 10.4% were commercially insured and 89.6% insured by Medicare Advantage Prescription Drug (MAPD) plans. The comparator cohort included 30 328 demographically matched controls. Overall, mean all-cause wPPPM counts of HCRU during follow-up were significantly higher in the IPF cohort than the comparator cohort for all categories (all P < .001). Similarly, mean (SD) follow-up all-cause wPPPM total healthcare costs were higher for the IPF cohort than the comparator cohort ($4667 [$8252] vs $1196 [$2114], P < .001). After adjustment, the cost ratio for all-cause total healthcare costs between the IPF and comparator cohorts was 3.4 (95% confidence interval [CI], 3.10-3.64), and patients in the IPF cohort were 2.1 times (95% CI, 1.97-2.15) more likely to be hospitalized for all causes than the comparator cohort. For both HCRU and costs, similar patterns were observed in both the commercial and MAPD populations. Conclusion: Patients with IPF incurred substantially higher HCRU and costs than the demographically matched comparator cohort. Study results suggest the need for treatment options to improve management of IPF and reduce costly HCRU.

ABSTRACT Truncating mutations in the tumor suppressor STAG2 , which encodes a component of the cohesin complex, are prevalent across diverse human cancers. Here, we report that acute reconstitution of physiological STAG2 levels in STAG2 -mutant human glioblastoma multiforme cancer cells triggers a rapid reduction in the size of chromatin loops genome-wide. Despite this global change in chromatin loop size, early transcriptional responses to STAG2 restoration are limited to a small number of genes, most of which are induced by STAG2 reconstitution. Notably, the growth-suppressor EFEMP1 (Fibulin-3), a secreted glycoprotein that functions as an extracellular matrix-associated inhibitor of glioblastoma growth and invasion, was the only gene consistently induced across all experimental models. The most robust and conserved STAG2-induced genes all reside within intense chromatin loops whose anchors and overall intensity did not appear to change in response to STAG2 reconstitution. These findings suggest that inactivating mutations of STAG2 promote neoplastic transformation by alleviating a restriction on chromatin loop size, allowing for an expanded range of chromatin interactions that disrupts the maintenance of a tumor-suppressive transcriptome.

TPS7101 Background: Patients with high-risk CLL/SLL not achieving a complete response (CR) after ≥ 12 months of BTK inhibitor (BTKi) monotherapy remain at risk for early progression due to residual disease and BTKi resistance. A BCL-2 inhibitor (BCL-2i) introduces a complementary, BCR-independent apoptotic mechanism that may deepen responses and prolong progression-free survival (PFS). Lisaftoclax, a selective oral BCL-2i with a short half-life (4-6 h), enables once-daily dosing and is approved in China as second-line CLL therapy. Lisaftoclax monotherapy has demonstrated overall response rates (ORRs) of 67% in relapsed/refractory CLL and 62.5% in BTKi-refractory disease, including del(17p)/ TP53 -mutated cases. Lisaftoclax combined with acalabrutinib achieved ORRs >97% with favorable tolerability. This study evaluates whether lisaftoclax plus BTKi (acalabrutinib, zanubrutinib, or ibrutinib) improves PFS and/or overall survival (OS) (vs continued BTKi monotherapy) in patients with CLL/SLL and residual disease after prolonged BTKi treatment. Methods: This study will enroll approximately 440 patients randomly allocated to receive lisaftoclax plus BTKi or BTKi alone. Eligible patients have CLL/SLL and, after ≥12 months of BTKi monotherapy (lines 1-3), have achieved neither CR nor progressive disease (PD). Randomization is stratified by del(17p)/ TP53 status. Key inclusion criteria include age ≥18 years, ECOG PS 0-2, and residual disease with either high-risk features (del(17p)/ TP53 mutation, unmutated IGHV , or complex karyotype [≥5 abnormalities]), or measurable residual disease with lymph nodes ≥2.5 cm in the absence of high-risk features. Exclusion criteria include prior BCL-2i therapy or Richter transformation. Patients in the investigational arm will undergo a 5-day oral lisaftoclax ramp-up to 400 mg once daily plus physician's choice of BTKi in 28-day cycles until progression or toxicity. Control patients continue their current BTKi monotherapy. Safety and disease assessments (CT/MRI) will occur regularly. The primary endpoint is PFS by independent review committee (iwCLL 2018); key secondary endpoint OS; and other secondary endpoints, PFS by investigator, ORR, duration of response, MRD negativity, and safety. Enrollment is ongoing across 126 sites in 18 countries (ClinicalTrials.gov ID: NCT06104566). Clinical trial information: NCT06104566 .