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Abstract Background: Polycythemia vera (PV) is characterized by excessive erythrocytosis and elevated hematocrit (Hct), which is associated with increased risk of thrombotic events. Controlling Hct levels (<45%) is a key therapeutic goal to reduce thrombotic events. Sapablursen (ISIS 702843) is a liver-directed, ligand-conjugated antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6) to enhance hepcidin production thereby restricting iron availability and reduced erythrocytosis. We are reporting the topline results of the IMPRSSION study (NCT05143957), an ongoing global, open-label phase 2 trial evaluating the safety and efficacy of sapablursen for Hct control and reducing phlebotomy rate in patients with PV. Methods: Eligible patients met 2016 WHO diagnostic criteria for PV, were required to have >3 phlebotomies within six months prior to screening, including >1 phlebotomy in the last 12 weeks. There were no exclusions for HCT prior to randomization. Patients received monthly subcutaneous doses of sapablursen in Cohort A (high dose) or Cohort B (low dose), during a 37-week treatment period. The primary efficacy endpoint was the reduction in the frequency of phlebotomy during the last 20 weeks of the treatment period (Week 17-37) compared to baseline (defined as the mean weekly phlebotomy rate during the six months prior to screening through the first dose of sapablursen). Phlebotomy was performed when Hct levels were ≥45% or at the investigator's discretion, confirmation of Hct was not required for phlebotomy. Serial assessments of serum hepcidin, TSAT and ferritin were conducted. The 10-item Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) assessed the change in symptoms from baseline to Week 37. Results: Forty-nine (49) patients received at least one dose of sapablursen (full analysis set) in either Cohort A (n=32) or Cohort B (n=17). The median age was 61 years, 40 (82%) were male, and 29 (59%) classified as high risk. The primary endpoint was met at both dose levels. The weekly phlebotomy rate (mean±SD) decreased from baseline of 0.15±0.07 (~7.8/yr) to 0.05±0.09 (~2.6/yr) during the primary endpoint window (Week 17-37) in Cohort A (n=32, p<0.0001; 95%CI, -0.13, -0.07), and from 0.17±0.07 (~8.9/yr) to 0.07±0.07 (~3.6/yr) in Cohort B (n=17, p=0.0001; 95%CI, -0.14, -0.06). The mean MPN-SAF-TSS was reduced at Week 37 by 32% in Cohort A (change from baseline LSM -6.2, p=0.005) and 11% in Cohort B (change from baseline LSM -2.7, p=0.344). The proportion of patients with Hct control (<45%) without phlebotomy from week 17 to 37 in Cohort A and B was 53% (17/32) and 35% (6/17), respectively. Serum hepcidin was increased from baseline values of 0.25±0.6 to 5.05±4.7 nM at Week 13 in Cohort A (p<0.0001) and from 0.68±1.7 to 2.06±3.6 nM in Cohort B (p=0.0142). A sustained low TSAT was observed between Weeks 17-37 (6.0±2.1% and 5.5±2.0% in Cohort A and 8.9±5.0% and 7.0±3.4% in Cohort B). Serum ferritin increased over time from 18±22 ng/mL and 28±58 ng/mL at baseline in Cohort A and B, respectively, to 44±47 ng/mL and 41±85 ng/mL at Week 37, respectively. Sapablursen was generally safe and well-tolerated. The incidence of injection site reactions was 12.2% (6/49). Injection site reactions did not recur following multiple injections, were not progressive and resolved spontaneously. There was one death on study due to transformation to AML which was deemed as not related to the study drug. Conclusions: Treatment of PV patients with sapablursen increased serum hepcidin, controlled Hct, reduced phlebotomy need and improved quality of life in a dose-dependent manner. These findings highlight the potential of sapablursen as a therapeutic approach in PV and support further development.

Abstract Background and Objectives Lucid episodes (LEs) in advanced dementia are characterized by spontaneous, transient recovery of functional abilities. Despite recent increases in research on this previously understudied phenomenon, standard definitional criteria are lacking, presenting challenges for research. Researchers have proposed a preliminary framework to guide uniform labeling and operationalization of salient data elements for investigating LEs and developing definitional criteria. This study leverages this framework to characterize reports of LEs from caregivers and advance their definition and measurement. Research Design and Methods Family caregivers (N = 259) completed an electronic survey with quantitative and open-ended questions about LEs they witnessed (N = 479 episodes). Respondents were purposively sampled for qualitative interviews. Open-ended question responses (n = 208) and in-depth interviews (n = 24) were analyzed using content analysis. Results Caregiver descriptions suggest that the content and context of LEs are heterogeneous. Descriptions included observable changes from baseline, with behavior or communication that was distinguishable from routine cognitive fluctuations. LEs were sometimes, but not always specified by logically organized actions; recognition or awareness of people, emotions, and surroundings; and insight of their cognitive limitations. Many LEs required deep personal knowledge to attribute it as a meaningful shift. Discussion and Implications Findings suggest that definitional features may universally specify a significant return of ability with more flexible criteria for how this return manifests in observed actions and domains of recovery (i.e., insight, function, and communication). The impact of LEs on observers may be better measured separately, although further research should explore this.

Abstract Glioblastoma, IDH-wildtype (GBM), and primary central nervous system lymphoma (PCNSL) are two aggressive brain tumors with distinct treatment strategies but overlapping imaging features on MRI. Accurate preoperative differentiation remains a clinical challenge, due to their overlapping imaging features, even when advanced MRI techniques are employed. This study explored deep learning approaches leveraging multi-sequence MRI to distinguish GBM from PCNSL. Models were developed utilizing 146 PCNSL cases, which were matched to146 GBM by age, sex and year of diagnosis. A 3D-DenseNet121 convolutional neural network was trained using two analytical strategies: (i) loss-based model selection and (ii) ensemble prediction using five-fold cross-validation. Model performance was evaluated on an independent validation set of 256 GBM and 37 PCNSL from the same institution as well as 36 PCNSL cases from an external institution. All MRIs were preprocessed using the FeTS pipeline. Using the independent validation cohort, area under the receiver operating characteristic curve (AUC) and 95% confidence intervals (CI) were computed overall and stratified by demographic characteristics. Using both T1 post-contrast (T1Gd) and T2-weighted images, the loss-based model achieved AUC=0.83 (95% CI: 0.77-0.88) and the ensemble model yielded an AUC=0.82 (95% CI: 0.76-0.89). Model performance was similar across males and females; however, model performance was better for subjects older than 50 years of age versus younger than 50. When using only T1Gd images, the loss-based model dropped to AUC=0.55 (95% CI: 0.48-0.63), whereas the ensemble model had AUC=0.79 (95% CI: 0.72-0.85). Models trained with only T2 images achieved AUCs of 0.67 (95% CI: 0.60-0.73) (loss-based) and 0.75 (95% CI: 0.69-0.82) (ensemble). These results highlight the added value of the multi-sequence input. Our results confirm the feasibility of using automated deep learning models to differentiate GBM from PCNSL. Notably, the model generalized well to external MRI data, emphasizing its potential utility as a diagnostic aid in real-world clinical workflows.

Abstract Polyamines are small molecules that play a critical role in tumor progression and in the regulation of immune responses within the tumor microenvironment. Elevated levels of polyamines in cerebrospinal fluid and tumor tissue have been reported in multiple studies and are shown to correlate with glioma grade. These findings suggest that the polyamine metabolic pathway may represent a therapeutic target in gliomas. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, expected to exert antitumor effects through polyamine depletion. Although the impact of DFMO against glioblastoma as a monotherapy appears limited, opportunities for synergy with other therapies remain understudied. In this study, we evaluated the therapeutic efficacy of DFMO using both in vitro and in vivo experiments with a murine glioma model (CT-2A) and patient-derived xenograft (PDX) cell lines. Among the models tested, CT-2A cells exhibited the highest expression of ODC1 and demonstrated strong sensitivity to DFMO in vitro. We compared two CT-2A variants: a commercially available line responsive to immunotherapy, and a widely used subline resistant to PD-1 blockade. While DFMO did not improve survival in mice implanted with the immunotherapy-sensitive commercial CT-2A line, it extended median survival by 8 days in mice bearing tumors derived from the immunotherapy-resistant subline. Transcriptomic analysis revealed that the DFMO-responsive, immunotherapy-resistant tumors exhibited lower baseline expression of immune-related genes, including those involved in interferon-β, interferon-γ, and IL-12 signaling pathways, compared to the immunotherapy-sensitive tumors. The latter showed markedly higher expression of STAT1 and interferon-γ and were enriched for immune-related Gene Ontology terms. These findings suggest that polyamine-targeted therapy may be appropriate for gliomas with an immunosuppressive, “cold” phenotype. Ongoing RNA sequencing analyses aim to further elucidate the immunomodulatory mechanisms of DFMO, and other agents comprising an adaptive toolkit to optimize and sustain anti-tumoral immunity.

Abstract BACKGROUND Many cancers demonstrate upregulated amino acid transport. In glioblastoma (GBM), evidence for upregulated amino acid flux includes high signal on amino acid PET imaging, increased expression of LAT1 (L-type amino acid transporter 1), and elevated extracellular amino acid levels via microdialysis. LAT1-targeted therapies have shown antitumor effects in certain cancer models by restricting essential amino acid supply and inhibiting the mTOR pathway, but their utility for GBM remains unknown. In this study, we evaluated impacts of a competitive LAT1 inhibitor, nanvuranlat, and a non-competitive inhibitor, JPH034 against glioblastoma. METHODS Murine (CT-2A, GL261) and human (GBM6, GBM39) GBM cell lines were tested under varying concentrations of nanvuranlat or JPH034. The competitive impacts of added essential amino acids, serum, and albumin were evaluated in vitro. Survival impacts were evaluated in an intracranial CT-2A glioma model. RESULTS Supplementing essential amino acids in vitro significantly decreased tumor cell sensitivity to nanvuranlat but did not change the IC50 of JPH034. Conversely, supplementing serum or albumin significantly reduced tumor cell sensitivity to JPH034 but did not change the IC50 of nanvuranlat. These findings were reproducible in all human and murine cell lines tested. In the intracranial mouse model, JPH034 treatment prolonged median overall survival from 16 days in the control group to 18.5 days, representing a 2.5-day extension (p = 0.060). CONCLUSION The antitumor effects of nanvuranlat and JPH034 on glioma cells in vitro, are influenced by concentrations of essential amino acids and albumin. Specifically, amino acids decreased impact of the competitive inhibitor (nanvuranlat) while albumin decreased impact of the non-competitive inhibitor (JPH034). These results suggest that the composition of the tumor microenvironment, which is impacted by BBB-disruption within GBM may differentially attenuate the therapeutic efficacy of certain drugs including LAT1 inhibitors.

Abstract Glioblastoma (GBM) diagnosis integrates morphology and tumor molecular alterations. Patients with classic morphology are designated as histologic GBM (hGBM). Patients without classic morphology harboring TERT promoter mutation (TERTp), or epidermal growth factor receptor amplification (EGFRamp), or combined gain of chromosome 7 and loss of 10 (+7/-10) designate molecular GBM (mGBM). We compared radiographic features, genomic alterations, and clinical outcome between hGBM and mGBM. 109 mGBM Mayo Clinic cases diagnosed between 1993-2021 were matched to 101 cGBM by age, sex, year of diagnosis, and TERT promoter (TERTp) status. Clinical and radiographic data abstraction was blinded. Progression-free and overall survival were compared across groups in the subset of patients who received standard of care. Contrast enhancement was present on index MRI (MRI at diagnosis) for 98% (96/98) hGBM and 50% (54/107) mGBM (p<0.0001) patients. mGBM tumors harbored fewer total copy number alterations (median of 16.5 vs 20, p=0.029) and were less likely to have CDKN2A/B homozygous deletion (56% vs 77%, p=0.005). Among the 87 mGBM and 82 hGBM receiving standard of care, median overall survival was longer for mGBM versus hGBM (2.24 vs 1.62 years, p=0.016). mGBM patients with +7/-10 (HR=2.60, p=0.035) or CDKN2A/B (HR=3.61, p=0.002) had poorer overall survival compared to mGBM patients without the corresponding alteration. On index MRI mGBM patients without contrast enhancement had better overall survival compared to hGBM (HR=0.50; p=0.003) whereas there was no survival difference between mGBM with enhancement and hGBM. mGBM with enhancement on index MRI likely represent undersampled, or early / evolving hGBM. mGBM patients with non-enhancing MRI, younger than 60, with long symptom profile including seizures, and some combination of non-anaplastic morphology, TERTp only, no homozygous deletion of CDKN2A/B, and low copy number complexity may represent other IDHwt glioma entities. Caution is advised in counseling, management, discussing prognosis, and inclusion in clinical trials.

Abstract BACKGROUND CNS ependymal tumors rarely demonstrate mixed subependymal and ependymal pathology. The clinical course of these tumors is difficult to predict, but prior studies have identified TERT mutations and loss of chromosome 6 as poor prognostic factors in these tumors when located in the posterior fossa. METHODS In this retrospective single-institution study, patients with a diagnosis of mixed subependymoma/ependymoma were identified and chart reviewed to describe demographics, pathological findings, treatment courses and clinical outcomes. RESULTS Eleven patients (median age 57, 2 female, 9 male) were identified. Ten tumors were in the posterior fossa and 1 in the cervical spine. At diagnosis, 2 underwent gross total resection, 8 underwent subtotal resection, and 1 was only biopsied. Radiotherapy was administered to 5 patients at initial diagnosis (54Gy in 30 fractions). Systemic therapy (temozolomide and bevacizumab) was administered at recurrence to 2 patients. Loss of chromosome 6 was present in 5 /11 patients and TERT mutations were present in 4/11 patients, with both present in 3/11 patients. Median progression-free survival (mPFS) was 90.1 months (95% CI: 90.1–NA), with 3 progression events observed at 22, 90, and 107 months. Median follow-up duration was 27.9 months. Receiving radiotherapy had a longer mPFS (98 vs 22 months, p=0.15), although non-significant. At the time of data cut-off none of the patients were deceased. CONCLUSIONS Mixed subependymoma/ependymoma is a rare diagnosis with varying clinical outcomes. Our case series demonstrated that the majority of patients did not exhibit the previously identified poor prognostic factors. Although non-significant due to limited case numbers, radiotherapy was suggestive of longer mPFS.