Citations

Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.

Abstract Background: Ovarian cancer ranks fifth in cancer deaths among women. The gold standard of care for advanced disease includes cytoreductive surgery along with adjuvant or neoadjuvant platinum/taxane-based chemotherapy. Although response to this treatment is high, chemotherapy-induced nausea and vomiting due to platinum agents and allergic reactions due to both agents are common. For nearly half a century, the glucocorticoid (GC) dexamethasone (DEX) has been administered as part of supportive care. However, there have periodically been questions about the possible deleterious effects of DEX on chemotherapy response, especially in solid tumors. Methods: Platinum-sensitive, glucocorticoid receptor (GRa) expressing ovarian cancer cells were exposed to DEX prior to chemotherapy and clonogenic survival was assessed. The effects of DEX on cell cycle and apoptosis were assessed by flow cytometry. Changes in the tumor cell transcriptome after acute DEX treatment were determined by RNA sequencing. Mice bearing orthotopic ovarian cancer patient-derived xenografts (PDXs) were treated with chemotherapy ± DEX to assess changes in chemotherapy response in vivo. Findings: DEX pre-treatment decreased platinum cytotoxicity in ovarian cancer cell lines in vitro and diminished platinum response in some PDXs analyzed for chemotherapy response ex vivo. RNA-seq analysis revealed changes in transcripts encoding proteins involved in platinum detoxification and TNFa pro-survival signaling. In ovarian cancer PDXs, DEX decreased platinum response in one model and had limited impact on both platinum and platinum/taxane chemotherapy in three distinct studies. Interpretation: DEX appears to modulate chemotherapy response in some settings in vitro and ex-vivo. The impact of DEX on chemotherapy response in vivo appears to be limited. However, further investigation of this question in vivo in non-immunosuppressed murine models appears warranted. Citation Format: Annapoorna Venkatachalam, Cristina Correia, Cordelia Mcgehee, Sarah Finstuen-Magro, Paula A. Schneider, Rachel Hurley, Kevin L. Peterson, Ethan Heinzen, Melissa C. Larson, Xiaonon Hou, Ann L. Oberg, Saravut Weroha, Scott H. Kaufmann. Impact of dexamethasone on chemotherapy response in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B098.

OBJECTIVE Borden-Shucart type I dural arteriovenous fistulas (dAVFs) lack cortical venous drainage and occasionally necessitate intervention depending on patient symptoms. Conversion is the rare transformation of a low-grade dAVF to a higher grade. Factors associated with increased risk of dAVF conversion to a higher grade are poorly understood. The authors hypothesized that partial treatment of type I dAVFs is an independent risk factor for conversion. METHODS The multicenter Consortium for Dural Arteriovenous Fistula Outcomes Research database was used to perform a retrospective analysis of all patients with type I dAVFs. RESULTS Three hundred fifty-eight (33.2%) of 1077 patients had type I dAVFs. Of those 358 patients, 206 received endovascular treatment and 131 were not treated. Two (2.2%) of 91 patients receiving partial endovascular treatment for a low-grade dAVF experienced conversion to a higher grade, 2 (1.5%) of 131 who were not treated experienced conversion, and none (0%) of 115 patients who received complete endovascular treatment experienced dAVF conversion. The majority of converted dAVFs localized to the transverse-sigmoid sinus and all received embolization as part of their treatment. CONCLUSIONS Partial treatment of type I dAVFs does not appear to be significantly associated with conversion to a higher grade.

Abstract Glioblastoma multiforme (GBM) is a highly lethal human cancer thought to originate from a self-renewing and therapeutically-resistant population of glioblastoma stem cells (GSCs). The intrinsic mechanisms enacted by GSCs during 3D tumor formation, however, remain unclear, especially in the stages prior to angiogenic/immunological infiltration. In this study, we performed a deep characterization of the genetic, immune, and metabolic profiles of GBM organoids from several patient-derived GSCs (GBMO). Despite being devoid of immune cells, transcriptomic analysis across GBMO revealed a surprising immune-like molecular program, enriched in cytokine, antigen presentation and processing, T-cell receptor inhibitors, and interferon genes. We find two important cell populations thought to drive GBM progression, Special AT-rich sequence-binding protein 2 (SATB2+) and homeodomain-only protein homeobox (HOPX+) progenitors, contribute to this immune landscape in GBMO and GBM in vivo. These progenitors, but not other cell types in GBMO, are resistant to conventional GBM therapies, temozolomide and irradiation. Our work defines a novel intrinsic immune-like landscape in GBMO driven, in part, by SATB2+ and HOPX+ progenitors and deepens our understanding of the intrinsic mechanisms utilized by GSCs in early GBM formation.

Background: Anecdotal cases of rapidly progressing dementia in patients with dural arteriovenous fistulas (dAVFs) and cortical venous drainage have been reported in small series. However, a comprehensive description of the angiographic features of this dAVFs is lacking. We conducted an analysis of the largest cohort of dAVFs presenting with cognitive impairment (dAVFs-CI), aiming to provide a better characterization of this subset of dAVFs. Methods: The CONDOR Consortium, a multicenter repository comprising 1077 dAVFs, served as the study population. Among the dAVFs, patients with dAVFs-CI were analyzed. A propensity scores matching analysis was conducted to compare dAVFs-CI with Borden type II and type III dAVFs without cognitive impairment (controls). Logistic regression was employed to identify angiographic characteristics specific to dAVFs-CI. Post-treatment outcomes were analyzed. Results: A total of 60 patients with dAVFs-CI and 60 control dAVFs were included. Outflow obstruction leading to venous hypertension was observed in all dAVFs-CI. Sinus stenosis was significantly associated with dAVFs-CI (OR 2.85, 95% CI: 1.16-7.55, p = 0.027). dAVFs-CI were more likely to have a higher number of arterial feeders (OR 1.56, 95% CI 1.22-2.05, p < 0.001) and draining veins (OR 2.05, 95% CI 1.05-4.46, p = 0.004). Venous ectasia increased the risk of dAVFs-CI (OR 2.38, 95% CI 1.13-5.11, p = 0.024). A trend toward achieving asymptomatic status at follow-up was observed in patients with successful closure of dAVFs (OR 2.86, 95% CI 0.85-9.56, p = 0.09). Discussion: Venous hypertension is a key angiographic feature dAVFs-CI. dAVFs-CI exhibit a complex angioarchitecture characterized by an increased number of arteriovenous connections and stenosed sinuses. The presence of venous ectasia further exacerbates the impaired drainage and contributes to the development of dAVFs-CI. Notably, closure of the dAVF has the potential to reverse symptoms in certain cases (Figure).

AbstractMetabolic pathways are known to generate byproducts—some of which have no clear metabolic function and some of which are toxic. Nicotinamide adenine dinucleotide phosphate hydrate (NAD(P)HX) is a toxic metabolite that is produced by stressors such as a fever, infection, or physical stress. Nicotinamide adenine dinucleotide phosphate hydrate dehydratase (NAXD) and nicotinamide adenine dinucleotide phosphate hydrate epimerase (NAXE) are part of the nicotinamide repair system that function to break down this toxic metabolite. Deficiency of NAXD and NAXE interrupts the critical intracellular repair of NAD(P)HX and allows for its accumulation. Clinically, deficiency of NAXE manifests as progressive, early onset encephalopathy with brain edema and/or leukoencephalopathy (PEBEL) 1, while deficiency of NAXD manifests as PEBEL2. In this report, we describe a case of probable PEBEL2 in a patient with a variant of unknown significance (c.362C>T, p.121L) in the NAXD gene who presented after routine immunizations with significant skin findings and in the absence of fevers.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been demonstrated to improve outcomes in congestive heart failure (HF). However, their effect in hypertrophic cardiomyopathy (HCM) is unknown. Research Question: Can SGLT2i improve clinical outcomes in HCM patients? Methods: Using TriNetX Global Research Network from March 2013 to February 2021, patients diagnosed with HCM (ICD-10 codes I42.1, I42.2) were identified and categorized into 2 groups: those on SGLT2i vs. those who are not. To avoid inclusion of other causes of left ventricular hypertrophy, patients with aortic stenosis or systemic hypertension were excluded. Propensity score matching (PSM) was used to limit confounders. Primary outcome was all-cause mortality and secondary outcomes were HF exacerbation, all-cause hospitalization, and documented cardiovascular symptoms (chest pain, dyspnea, palpitations, or leg edema) over a 2-year follow-up period. Results: A total of 27,561 HCM patients were identified; 408 (1.5%) on SGLT2i and 27,153 (98.5%) were not. Patients on SGLT2i were older (55 ± 15 vs. 48 ± 19, p<0.01) and had more comorbidities, including a nearly 6-fold higher prevalence of diabetes mellitus (44% vs. 7%, p<0.01) and congestive HF (65% vs. 10%, p<0.01). After PSM, each group consisted of 355 patients. HCM patients on SGLT2i had lower rates of all-cause mortality (OR 0.22 [95% CI: 0.12, 0.39]; p<0.01), hospitalizations (OR 0.72 [95% CI: 0.53, 0.98]; p=0.04), and cardiovascular symptoms (OR 0.71 [95% CI: 0.52, 0.97]; p=0.029) when compared to patients not on SGLT2i. There was no statistical difference in the rate of HF exacerbation (OR 0.82 [95% CI: 0.54, 1.24]; p=0.3). Conclusion: In this large dataset, SGLT2i use in a select subset of HCM patients was associated with improved survival, less hospitalizations, and fewer cardiovascular symptoms. These data support future randomized trials to evaluate the efficacy and safety of SGLT2i in more diverse HCM patient populations.

BACKGROUND AND OBJECTIVES: Anecdotal cases of rapidly progressing dementia in patients with dural arteriovenous fistulas (dAVFs) have been reported in small series. However, large series have not characterized these dAVFs. We conducted an analysis of the largest cohort of dAVFs presenting with cognitive impairment (dAVFs-CI), aiming to provide a detailed characterization of this subset of dAVFs. METHODS: Patients with dAVFs-CI were analyzed from the CONDOR Consortium, a multicenter repository comprising 1077 dAVFs. A propensity score matching analysis was conducted to compare dAVFs-CI with Borden type II and type III dAVFs without cognitive impairment (controls). Logistic regression was used to identify angiographic characteristics specific to dAVFs-CI. Furthermore, post-treatment outcomes were analyzed. RESULTS: A total of 60 patients with dAVFs-CI and 60 control dAVFs were included. Outflow obstruction leading to venous hypertension was observed in all dAVFs-CI. Sinus stenosis was significantly associated with dAVFs-CI (OR 2.85, 95% CI: 1.16-7.55, P = .027). dAVFs-CI were more likely to have a higher number of arterial feeders (OR 1.56, 95% CI 1.22-2.05, P < .001) and draining veins (OR 2.05, 95% CI 1.05-4.46, P = .004). Venous ectasia increased the risk of dAVFs-CI (OR 2.38, 95% CI 1.13-5.11, P = .024). A trend toward achieving asymptomatic status at follow-up was observed in patients with successful closure of dAVFs (OR 2.86, 95% CI 0.85-9.56, P = .09) CONCLUSION: Venous hypertension is a key angiographic feature of dAVFs-CI. Moreover, these fistulas present at a mean age of 58 years-old, and exhibit a complex angioarchitecture characterized by an increased number of arteriovenous connections and stenosed sinuses. The presence of venous ectasia further exacerbates the impaired drainage and contributes to the development of dAVFs-CI. Notably, in certain cases, closure of the dAVF has the potential to reverse symptoms.

Introduction Patients (pts) with multiple myeloma (MM) have a higher risk of progression/death following an inadequate response to frontline ASCT (van de Velde Eur J Haematol 2017). Therapies (Tx) with novel mechanisms of action may further improve response outcomes. Ide-cel previously demonstrated frequent, deep, and durable responses in KarMMa (Munshi N Engl J Med 2021) and significantly improved median progression-free survival (PFS) and overall response rate (ORR) versus standard regimens in KarMMa-3 (Rodríguez-Otero N Engl J Med 2023) in pts with triple-class-exposed relapsed and refractory MM. KarMMa-2 (NCT03601078) is a multicohort, phase 2, multicenter trial evaluating the efficacy and safety of ide-cel in pts with MM; cohort 2c included pts with NDMM who had an inadequate response to frontline Tx with ASCT. In cohort 2c, with a median follow-up of 27.9 months, ide-cel demonstrated deep and durable responses; complete response (CR) rate was 74.2% (ORR, 87.1%), with a 24-month PFS rate of 83.1% (Dhodapkar Blood 2022). Here, we report results with an additional 11.5 months of median follow-up for updated efficacy and safety data, and health-related quality of life (HRQoL) outcomes in cohort 2c. Methods Eligible pts had NDMM, received ≥ 3 cycles of induction Tx (including a proteasome inhibitor, an immunomodulatory agent, and dexamethasone), had &lt; very good partial response (VGPR) 70-110 days after ASCT (single/tandem), and had Eastern Cooperative Oncology Group performance status ≤ 1. Pts received a single infusion of ide-cel (dose range: 150-450 × 10 6 CAR+ T cells) after lymphodepletion and could receive maintenance Tx post-infusion at investigator's discretion. The primary endpoint CR rate and secondary endpoints ORR, duration of response (DOR), PFS, overall survival (OS), safety, and patient-reported outcomes on HRQoL, assessed via European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) and EORTC Quality of Life Multiple Myeloma Module 20 Questionnaire (QLQ-MY20), are reported. The exploratory endpoint of minimal residual disease (MRD) negativity (sensitivity, 10 -5) is also reported. Results At data cutoff (May 3, 2023), with a median follow-up of 39.4 (range, 31.6-44.7) months, all 31 pts who were infused with ide-cel were alive; 28 (90.3%) remained in follow-up, with 3 (9.7%) having discontinued due to disease progression. The ORR and CR rates were 87.1% and 77.4%, respectively ( Table); best overall response in 1 pt improved from VGPR to stringent CR. The median DOR was not reached (NR; 95% CI, NR-NR), neither was median PFS (95% CI, 38.0-NR) or median OS (95% CI, NR-NR); the 36-month event-free rates were 80.9%, 76.8%, and 100.0%, respectively. In pts who did not receive lenalidomide (LEN) maintenance, 9 (29.0%) had disease progression; of the 8 pts who received LEN maintenance post ide-cel infusion, none experienced disease progression. At 36 months, MRD negativity was confirmed in 9/14 (64.3%) evaluable pts; all 9 achieved ≥ CR. In this extended follow-up, safety results were generally consistent with the previous data cutoff. All pts experienced ≥ 1 any-grade adverse event (AE), most commonly hematologic, including neutropenia (80.6%), anemia (38.7%), leukopenia (32.3%), and thrombocytopenia (29.0%); infection and infestation AEs occurred in 74.2% of pts. No grade 5 AEs were reported. Incidence of any-grade cytokine release syndrome (58.1%; no grade ≥ 3) was unchanged and there were no additional reports of parkinsonism since the previous report. Overall, HRQoL improved ( Figure) and MM disease symptoms were stable over time based on the EORTC QLQ-C30 and QLQ-MY20, respectively, following ide-cel treatment; by month 3, &gt; 75% of pts had improved or stable global health status/QoL. Conclusions Ide-cel continued to demonstrate deep, durable responses in pts with an inadequate response to frontline ASCT, no new safety signals were observed with extended follow-up, and no deaths were reported. No pts who received LEN maintenance post ide-cel experienced disease progression. Ide-cel treatment resulted in stable or improved HRQoL. Overall, ide-cel continued to demonstrate a favorable clinical benefit-risk profile in NDMM after ASCT. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.