Citations

Abstract NF-κB signaling can be subdivided into canonical and noncanonical pathways, culminating in the transcriptional activity of RELA and RELB, respectively. However, the upstream signals that activate these transcription factors and their specific regulatory roles in pancreatic ductal adenocarcinoma (PDAC) remain incompletely understood. Here, we demonstrate that TNFα is the primary activator of canonical NF-κB signaling via RELA, while TWEAK engages noncanonical signaling through RELB in PDAC. Using transcriptome-wide gene expression, genome-wide occupancy profiling, and epigenome mapping, we delineate distinct temporal dynamics and regulatory activities of each pathway. Single-cell RNA-seq analysis and multiplex immunofluorescence staining in primary PDAC samples further reveal extensive and distinct interactions with components of the tumor microenvironment. Motif analysis of RELA- and RELB-bound regions uncovers a particularly strong association of RELB with AP1 elements. Notably, while RELA binds to both open and closed chromatin, RELB exclusively occupies regions with pre-existing chromatin accessibility and AP1 co-binding. Collectively, these findings underscore the distinct and complementary roles of TNFα and TWEAK in PDAC, with TNFα engaging a broader transcriptional program via RELA and TWEAK selectively targeting genes marked by accessible chromatin and epigenetic activity. This study provides critical insights into the regulatory dynamics of NF-κB signaling in PDAC, highlighting unique and complementary functions of RELA and RELB in modulating downstream gene expression. Significance TNFα and TWEAK selectively activate RELA and RELB in pancreatic cancer, revealing that RELB-driven noncanonical signaling depends on chromatin accessibility and AP-1, uncovering distinct, targetable epigenetic dependencies from canonical signaling. Graphical abstract

Abstract We conducted this systematic review to evaluate outcomes of thrombolysis followed by anticoagulation vs anticoagulation alone in pediatric patients with venous thromboembolism (VTE). This systematic review addresses mortality, VTE resolution, recurrence, bleeding, and organ-specific outcomes in 5 PICO (population, intervention, comparison, outcomes) questions on thrombolysis across pulmonary embolism (PE), extremity deep vein thrombosis (DVT), right atrial thrombosis (RAT), cerebral sinus venous thrombosis (CSVT), and renal vein thrombosis (RVT). Meta-analysis reported risk ratios or differences (95% confidence intervals [CIs]), and absolute effects per 1000 patients. Certainty of evidence was assessed using GRADE (Grading of recommendation, assessment, Development, and Evaluation) guidelines. Thirteen nonrandomized studies were included and no randomized clinical trials addressed these questions. Thrombolysis might be associated with a higher risk of major bleeding, clinically relevant nonmajor bleeding, or unspecified bleeding with risk differences of 0.09 (95% CI, −0.06 to 0.23), 0.06 (95% CI, −0.11 to 0.22), and 0.09 (95% CI, −0.04 to 0.23), respectively. In PE with hemodynamic compromise, thrombolysis might be associated with a lower risk of mortality but conclusions on PE progression were uncertain in submassive PE. In DVT, thrombolysis may have little to no effect on mortality or thrombus resolution but might be associated with lower risk of postthrombotic syndrome. In RAT, thrombolysis might have little to no effect on thrombus resolution but a higher risk of major bleeding and mortality. For CSVT and RVT, the evidence was very limited. These findings were based on very-low-certainty evidence because of confounding and imprecision from small sample sizes. This systematic review highlights key challenges in developing recommendations for thrombolysis in children with VTE.

PURPOSE Neoadjuvant immunotherapy (IO) has become the standard of care for early-stage triple-negative breast cancer (TNBC), but not yet for other subtypes. We previously developed a clinical-grade mRNA-based immune classifier (ImPrint) predicting response to IO that is now being used in I-SPY2.2 as part of the response predictive subtypes. We report the performance of ImPrint in hormone receptor–positive and human epidermal growth factor receptor 2–negative (HR+HER2–) patients from five IO arms. METHODS A total of 204 HR+HER2– (MammaPrint high-risk) patients from five IO arms (anti–PD-1, anti–PD-L1/poly [ADP-ribose] polymerase inhibitor combination, anti–PD-1/toll-like receptor 9 dual-IO combination, and anti–PD-1 ± lymphocyte activation gene 3 dual-IO combination) and 191 patients from the chemotherapy-only control arm were included in this analysis. Patients were classified as ImPrint+ (likely sensitive) versus ImPrint– (likely resistant), using pretreatment mRNA. Performance of ImPrint for predicting pathologic complete response (pCR) to IO-containing arms was characterized and compared with tumor grade (III), MammaPrint (ultra) High2 risk (MP2), and estrogen receptor (ER)-low (ER ≤ 10%). RESULTS Overall, the pCR rate across the five IO arms was 33%. 26% of HR+HER2– patients were ImPrint+, and pCR rates with IO were 75% in ImPrint+ versus 17% in ImPrint–, with the highest pCR rate >90% in a dual-IO arm. In the control arm, pCR rates were 33% in ImPrint+ and 8% in ImPrint–. Tumor grade (III), MP2, and ER-low showed pCR rates in IO of 45%, 56%, and 63%, respectively, with lower pCR odds ratios (OR < 7.5) compared with ImPrint (OR = 14.5). CONCLUSION Using an accurate selection strategy, HR+HER2– patients could achieve pCR rates similar to what is seen with best neoadjuvant therapies in TNBC and HER2+ (ie, pCR rate >65%-70%). ImPrint, an Food and Drug Administration IDE-enabled assay, may represent a way to identify HR+HER2– patients for IO that best balances likely benefit versus risk of serious immune-related adverse events.

ABSTRACTOverviewBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic neoplasm that involves multiple organs, including the skin, bone marrow and blood, lymph nodes, and central nervous system. Violaceous tumors or plaques appearing in sun‐exposed areas are characteristic and present in most patients. The disease typically affects adult men aged 60–70 years, although children and younger adults may also be affected.DiagnosisDiagnosis is based on biopsy of an involved site and is typically based on the identification of blastoid cells displaying the classical immunophenotypes CD123, CD4, and CD56 in addition to specific pDC markers.PrognosisThe median overall survival is 18–24 months. Potential risk factors for shortened survival include older age, overt bone marrow involvement, and genetic abnormalities.Therapy and ManagementEither chemotherapy‐based regimens or tagraxofusp, a CD123‐directed interleukin 3 conjugated with diphtheria toxin, may be used for upfront therapy. Eligible patients are recommended to be consolidated with hematopoietic allogeneic stem cell transplantation. Assessment and treatment of the central nervous system is mandatory, and careful monitoring of skin disease in conjunction with dermatology is essential.

Background: Levetiracetam administration via intravenous push (IVP) may improve outcomes in status epilepticus (SE) by decreasing time to administration. However, there is a paucity of literature describing the safety of IVP administration of higher loading doses used for early management of SE. Objective: The purpose of this evaluation was to investigate the safety of high-dose IVP levetiracetam. Methods: This was a retrospective, single-arm cohort study conducted at an academic medical center. Patients were included if they received IVP levetiracetam ≥3000 mg. The primary outcome was a composite of clinically significant adverse events (AEs) within 1-hour post-administration of levetiracetam: hypotension, hypertension, bradycardia, tachycardia, arrhythmia, and/or injection site reaction. Results: A total of 140 patients met inclusion criteria, receiving a median levetiracetam dose of 4000 mg (interquartile range [IQR] = 3000, 4500). Seventeen (12.1%) patients experienced a clinically significant AE. The most common clinically significant AE was hypotension (9.2% [10/109]), followed by tachycardia (3.6% [4/112]), arrhythmia (1.8% [2/112]), hypertension (0.9% [1/109]), and injection site reaction (0.7% [1/140]). Eighty percent [8/10] of patients who experienced clinically significant hypotension were on at least 1 medication with potential confounding hemodynamic effects. Conclusion and Relevance: In this retrospective, single-arm analysis, high-dose (≥3000 mg) IVP levetiracetam was relatively well-tolerated but associated with a higher rate of clinically significant hypotension than has been reported in the previous literature, although several confounding factors may have contributed to this outcome. Our findings support the continued use of high-dose IVP levetiracetam with appropriate hemodynamic monitoring; hemodynamic effects should be further explored in future studies.

The NCCN Guidelines for Survivorship include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from adult-onset cancer and its treatment and provide a framework for coordination of survivorship care. They also include recommendations to help cancer survivors enhance their wellness and maintain a healthy lifestyle. These NCCN Guidelines Insights summarize the panel’s current recommendations and recent updates regarding physical activity, nutrition, and weight management for cancer survivors.