Citations

ABSTRACTA total of 142 patients with myeloproliferative neoplasms (MPNs) or acute myeloid leukemia (AML) associated with multihit TP53 mutations (mTP53 MUT) were accessed from the Mayo Clinic database and included (i) chronic phase MPN (MPN‐CP; N = 19), (ii) accelerated phase MPN (MPN‐AP; N = 14), (iii) blast phase MPN (MPN‐BP; N = 28), and (iv) AML (N = 81). Concurrent ASXL1 MUT, EZH2 MUT, IDH1,MUT and IDH2 MUT were more common in MPN‐MUTBP‐mTP53 compared to AML‐mTP53 MUT. At median of 11.6 months follow‐up, 124 (87%) deaths and 19 (13%) allogeneic stem cell transplantations (ASCT) were documented. Overall survival (OS), calculated from the time of mTP53 MUT detection, was similar between MPN‐BP‐mTP53 MUT (median 4.6 months) and MPN‐AP‐mTP53 MUT (5.6 months; p = 0.5) but both were inferior to MPN‐CP‐mTP53 MUT (11.6 months, p < 0.01). OS in MPN‐CP‐mTP53 MUT was similar to that of AML‐mTP53 MUT (median 7.4 months, p = 0.07). In multivariable analysis, OS was favorably affected by ASCT (HR 0.4, p = 0.03) and disease stage (i.e., chronic phase disease) or achieving response to pre‐transplant chemotherapy (HR 0.2, p < 0.01) and unfavorably by the presence of concurrent TET2 MUT or DNMT3A MUT (HR 2.7, p < 0.01). Based on these risk factors, a 3‐tiered risk model was constructed: low (no risk factors; N = 18; median OS 23.8 months); intermediate (one risk factor; N = 44; 11.1 months); and high (two or more risk factors; N = 80; 4 months; p < 0.01). The current study highlights the equally detrimental impact of mTP53 MUT on long‐term survival in MPN and AML and identifies predictors of short‐term survival.

Study Design Narrative Review. Objectives To summarize the work of the AO Spine Knowledge Forum Tumor, specifically studies from the Epidemiology, Process and Outcomes in Spine Oncology (EPOSO) study. Methods A narrative review of all published manuscripts from the EPOSO study was undertaken. EPOSO represents a multicenter, prospective registry effort across 10 North American and European sites to enroll patients with metastatic disease of the spine. Results The current review summarized all studies from the EPOSO network, divided into the following five sections: (1) quality of life and satisfaction, (2) overall survival, (3) spinal instability, (4) neurologic outcome in patients with metastatic epidural spinal cord compression or radicular pain, and (5) patient and tumor-specific factors. Several important findings were elucidated. Patient evaluation should include SINS, nutritional status, severity and duration of neurologic deficit, extent of metastatic tumor burden, and differentiation of axial from radicular pain. Moreover, SOSGOQ2.0 serves as a useful and validated instrument for patient-reported outcome instrument. Despite the palliative nature of metastatic spine surgery, clear improvement in quality-of-life is seen. Even in patients with short-survival, the remaining weeks and months of life result in improved quality-of-life. Metastatic spine surgery often improves neurologic function, potentially enhancing survival through increased performance status. Conclusions Several noteworthy results have come from the EPOSO network, highlighting important trends in metastatic spine care. The AO Spine Knowledge Forum Tumor has helped advancing metastatic spine tumor research as well as ensure these new findings reach and benefit clinicians and their patients.

Abstract The development of targeted therapy for patients with multiple myeloma (MM) is hampered by the low frequency of actionable genetic abnormalities. Gain or amplification of chromosome 1q (1q+) is the most frequent arm-level copy number gain in patients with MM and is associated with higher risk of progression and death despite recent therapeutic advances. Thus, developing targeted therapy for patients with MM with 1q+ stands to benefit a large portion of patients in need of more effective management. Here, we used large-scale dependency screens and drug screens to systematically characterize the therapeutic vulnerabilities of MM with 1q+ and displayed increased sensitivity to myeloid cell leukemia-1 (MCL1) and phosphatidyl inositol 3-kinase (PI3K) inhibitors. Using single-cell RNA sequencing, we compared subclones with and without 1q+ within the same patient tumors and demonstrated that 1q+ is associated with higher levels of MCL1 and the PI3K pathway. Furthermore, by isolating isogenic clones with different copy number profiles for part of the chromosome 1q arm, we observed increased sensitivity to MCL1 and PI3K inhibitors with arm-level gain. Lastly, we demonstrated synergy between MCL1 and PI3K inhibitors and dissected their mechanism of action in MM with 1q+, uncovering a cytostatic effect. In conclusion, this study highlights that MM with 1q+ may present enhanced sensitivity to MCL1 and PI3K inhibitors, enabling their use at lower doses without sacrificing efficacy, and may thus accelerate the development of targeted therapy for patients with MM and 1q+.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Central Nervous System Cancers provide multidisciplinary diagnostic workup, staging, and treatment recommendations for diffuse high-grade gliomas and medulloblastomas in children and adolescents. This article summarizes the studies and panel discussion that serve as the rationale for comprehensive care recommendations included in the NCCN Guidelines for Pediatric Central Nervous System Cancers.

AbstractBreast cancer affects millions globally, necessitating precise biomarker testing for effective treatment. HER2 testing is crucial for guiding therapy, particularly with novel antibody‐drug conjugates (ADCs) like trastuzumab deruxtecan, which shows promise for breast cancers with low HER2 expression. Current HER2 testing methods, including immunohistochemistry (IHC) and in situ hybridization (ISH), have limitations. IHC, a semi‐quantitative assay, is prone to interobserver variability. While ISH provides higher precision than IHC, it remains more resource‐intensive in terms of cost and workflow. However, turnaround time is typically faster than that of other advanced molecular methods such as next‐generation sequencing. We adapted the clustering‐constrained‐attention multiple‐instance deep learning model to improve IHC testing and reduce dependence on reflex fluorescence ISH (FISH) tests. Using 5,731 HER2 IHC images, including 592 cases with FISH testing, we trained two models: one for predicting HER2 scores from IHC images and another for predicting FISH scores from equivocal cases. The HER2 IHC score prediction model achieved 91% ± 0.01 overall accuracy and a receiver operating characteristic (ROC) area under the curve (AUC) of 0.98 ± 0.01. The FISH score prediction model had an ROC AUC of 0.84 ± 0.07, with sensitivity at 0.37 ± 0.13 and specificity at 0.96 ± 0.03. External validation on cases from 203 institutions showed similar performance. The HER2 IHC model maintained a 91% ± 0.01 accuracy and an ROC AUC of 0.98 ± 0.01, while the FISH model had an ROC AUC of 0.75 ± 0.03, with sensitivity at 0.28 ± 0.04 and specificity at 0.93 ± 0.01. Our model advances HER2 scoring by reducing subjectivity and variability in current scoring methods. Despite lower accuracy and sensitivity in the FISH prediction model, it may be a beneficial option for settings where reflex FISH testing is unavailable or prohibitive. With high specificity, our model can serve as an effective screening tool, enhancing breast cancer diagnosis and treatment selection.

ABSTRACT Background Cardiac implantable electronic device (CIED) infections are a serious complication associated with significant morbidity, mortality, and healthcare costs. Despite guideline recommendations for complete device removal, disparities in healthcare access and resource availability between urban and rural settings may influence patient outcomes. This study aims to evaluate rural–urban disparities in the management and outcomes of patients hospitalized with CIED infections. Methods A retrospective cohort analysis was conducted using the National Readmissions Database (NRD) from 2016 to 2021. Patients aged ≥ 18 years hospitalized with CIED infections were identified using ICD‐10 codes. Hospital location was categorized as urban or rural based on the Urban Influence Codes. Baseline characteristics, complications, and outcomes were compared using chi‐square and t ‐tests, and a multivariable logistic regression model was employed to assess the independent association of hospital settings with transvenous lead removal (TLR) utilization. Results A total of 288,402 patients were hospitalized for CIED infections, with 94.9% treated in urban hospitals and 5.1% in rural hospitals. Urban hospital patients had a higher prevalence of key comorbidities, including heart failure, valvular heart disease, atrial fibrillation and peripheral vascular disorders. In‐hospital mortality was significantly higher in urban hospitals (6.2% vs. 4.8%, p < 0.01) likely due to higher burden of comorbidities and higher rates of acute complications such as stroke (3.1% vs. 1.8%, p < 0.01) and systemic embolism (1.4% vs. 0.7%, p < 0.01). TLR was more frequently performed in urban hospitals (20.1% vs. 9.6%, p < 0.01), with rural hospitals exhibiting 59% lower odds of receiving TLR (OR: 0.41, 95% CI: 0.36–0.47, p < 0.01). TLR was associated with reduced in‐hospital mortality, 30‐day mortality, and 30‐day readmission rates across both hospital settings. Conclusion Our study highlights significant rural–urban disparities in CIED infection management. Despite rural hospitals admitting patients with a lower comorbidity burden, TLR utilization was significantly lower, potentially due to limited access to specialized expertise and procedural resources. Given TLR's association with improved survival and reduced readmissions, regardless of the hospital setting, targeted interventions are needed to enhance access to specialized care in rural settings. Further research is warranted to explore strategies for bridging these disparities and optimizing CIED infection outcomes nationwide.

AbstractBackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Bipolar disorder (BD) is characterized by disrupted circadian rhythms and neuronal loss. Lithium amplifies circadian rhythms and is neuroprotective, indicating mechanistic overlap across cellular systems. We examined the role of neuroprotection in determining lithium response and how circadian clock genes regulate apoptosis. In stem‐cell‐derived neuronal progenitor cells (NPCs) from BD patients, and in immortalized mouse hippocampal neurons, lithium was neuroprotective against staurosporine (STS)‐induced apoptosis. However, neuroprotection did not distinguish lithium‐responders (Li‐Rs) from nonresponders (Li‐NRs). Disruption of selected clock genes—period circadian regulator 1 ( PER1 ), basic helix–loop–helix ARNT like 1 ( ARNTL , also known as BMAL1 ), and nuclear receptor subfamily 1 group D member 1 ( NR1D1 ; also known as REV‐ERBα )—with small interfering RNA (siRNA) had distinct effects on apoptosis in mouse neurons and human NPCs. In BD patient NPCs, reduced expression of PER1 and BMAL1 increased apoptosis more in Li‐NR NPCs vs. Li‐R NPCs. Reduced expression of REV‐ERBα caused more extensive apoptosis in BD vs. control NPCs, but did not distinguish Li‐Rs vs. Li‐NRs. The REV‐ERB agonist GSK4112 was neuroprotective in mouse neurons and control NPCs, but did not reduce apoptosis in BD NPCs. Simultaneous treatment of NPCs with STS and GSK4112 revealed BD‐ and Li‐R‐associated differences in apoptosis‐related gene expression. In summary, the pharmacological effects of lithium in promoting neuroprotection are not sufficient to distinguish between Li‐Rs and Li‐NRs. However, genetic and pharmacological manipulations of the circadian clock reveal distinct roles in apoptosis in BD patient NPCs, some of which do distinguish Li‐Rs and Li‐NRs. We conclude that genetic disruption of cellular circadian clocks may predispose neurons to apoptosis preferentially in BD and/or Li‐NR. These findings imply that differences in BD between Li‐Rs/Li‐NRs primarily arise from defining biological characteristics of patient subgroups, not from distinct pharmacodynamic factors following lithium treatment.

Abstract Determining the balance between DNA double strand break repair (DSBR) pathways is essential for understanding treatment response in cancer. We report a method for simultaneously measuring non-homologous end joining (NHEJ), homologous recombination (HR), and microhomology-mediated end joining (MMEJ) and show that HR and MMEJ are therapeutically-targetable treatment resistance mechanisms in glioblastoma. Using a targeted screen of clinically relevant small molecules, we identify the ATM kinase inhibitor, AZD1390, as a potent dual HR/MMEJ inhibitor. Mechanistic studies in GBM cell lines show that AZD1390 suppresses DSB end resection and blocks radiation-induced phosphorylation of DSBR proteins including nibrin, Rad50, and Mettl16. Interestingly, AZD1390 enhances the cytotoxic effects of TMZ and radiation in both treatment-naïve and treatment-resistant GBM samples harboring mutations in the TP53 gene. We show that TP53 mutation is associated with upregulation of ATM pathway genes in GBM patient samples along with heightened ATM-dependent HR and MMEJ in GBM cell lines. Finally, we show that TP53-mutant GBMs fail to arrest in G2 phase after radiation/AZD1390 or TMZ/AZD1390 combinations and instead attempt mitosis, leading to mitotic cell death. Expression of the mitotic DSBR factor, RHINO1, is associated with poor prognosis in patients with TP53-mutant GBMs, suggesting that factors that promote efficient mitotic DSBR protect TP53-mutant GBMs from treatment-induced cell death. This report identifies ATM-dependent HR and MMEJ as targetable resistance mechanisms in TP53-mutant GBM and establishes ATM inhibition as a potential strategy for overcoming intrinsic and acquired treatment resistance in TP53-mutant GBMs. Citation Format: Daniel J Laverty, Shiv Gupta, Gary Bradshaw, Jiajia Chen, Brett L Carlson, Nery Matias Calmo, Shulan Tian, Jann N Sarkaria, Zachary D Nagel. ATM inhibitors exploit checkpoint defects and ATM-dependent double strand break repair to induce mitotic cell death in TP53-mutant glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A011.

Background. Liver transplantation (LT) is the standard treatment for liver failure secondary to alcohol-associated liver disease, but limited literature and best practices exist for post-LT treatment of alcohol use disorder (AUD). This study explores current AUD management practices and providers’ perceived barriers to effective post-LT AUD management. Methods. A 45-item survey on post-LT AUD treatment practices was distributed to members of the American Society of Transplant Surgeons, the Association of Consult/Liaison Psychiatry Transplant Special Interest Group, and both the American Society of Transplantation’s Liver and Intestine Community of Practice and Psychosocial and Ethics Community of Practice discussion boards, between December 2021 and April 2022. Univariate analysis of categorical variables was performed using the chi-square test. Data were analyzed using center volume tertiles, country region, and provider professional activity. Results. Two hundred thirty-two respondents from 70 LT centers across all 11 United Network for Organ Sharing regions completed the survey. Half of the them were attending physicians and 16.4% were nurse coordinators. Most centers (84%) aimed for alcohol abstinence for all post-LT patients. Perceived barriers to AUD treatment efficacy included ongoing desire to drink (18%), denial about alcohol misuse (14.9%), and lack of posttransplant support (14%). Additionally, 62.1% of centers had no policy for prescribing medication-assisted therapy to treat AUD, and 32.7% of centers reported no center-level changes in AUD care. Providers identified primary needs as hiring additional mental health professionals (30.8%), dedicating specific staff to AUD care (24.7%), and standardizing psychiatric/psychological care in transplant clinics (17.2%). Conclusions. Despite the increasing volume of LT for alcohol-associated liver disease, significant perceived barriers to effective AUD treatment remain.