Citations

Background: Catheter ablation for ventricular tachycardia (VT) has been increasingly performed. While it is estimated that 42% of adults in the United States are obese, the impact of obesity on VT ablation procedures remains unclear. Objective: This study aimed to evaluate the procedural outcomes and 30-day readmission among non-obese and obese patients who underwent catheter ablation of VT. Method: Using the Nationwide Readmissions Database, our study included patients aged 18 years or older who underwent catheter ablation for VT between 2017 and 2020. The study cohort was stratified into non-obese (BMI < 30kg/m 2 ) and obese (BMI ≥ 30kg/m 2 ). The in-hospital procedural outcome and 30-day readmission were analyzed between these groups. Results: Our study included a total of 835 obese patients (19.7%) and 3393 non-obese patients (80.3%). Obese group had a higher rate of prolonged length of stay (>7 days) (37.6% vs 31.2%, p<0.01) and a higher cost of hospitalization ($39 983 vs $37 015, p<0.01). Overall, there were no significant differences in early mortality (4.5% vs 3.8%, p=0.45). Apart from increased vascular complications in the obese group (1.8% vs 0.9%, p=0.03), there were no significant differences in other procedural complications between both groups. There were no significant differences in 30-day readmission rates between obese and non-obese groups (15.5% vs 14.1%, p=0.38). Additional analysis performed in the obese group revealed a non-significant decreasing trend in early mortality rate post-procedurally (5.4% to 4.8%, P trend = 0.66). On multivariable analysis, heart failure was associated with a higher risk of 30-day readmission in obese patients (OR: 2.00; 95% CI: 1.01-3.99; p=0.05). Conclusion: Our study suggests that catheter ablation for VT can be performed relatively safely in obese patients without significant differences in 30-day mortality and readmission outcomes. Patients should not be excluded from VT ablation on the basis of obesity.

Abstract Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. The prognosis of GBM is grim, with a median overall survival of 14.6 months and only 6.9% of patients surviving 5 years after the initial diagnosis. Despite poor outcomes, standard therapy of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields has remained largely unchanged. The introduction of immune checkpoint inhibitors (ICI) has been a paradigm shift in oncology, with efficacy across a broad spectrum of cancer types. Nonetheless, investigations of ICIs in both newly diagnosed and recurrent GBM have thus far been disappointing. This lack of clinical benefit has been largely attributed to the highly immunosuppressive nature of GBM. However, immunotherapy still holds promise for the treatment of GBM, with combinatorial strategies offering hope for potentially overcoming these current limitations. In this review, we discuss the outcomes of clinical trials employing ICIs in patients with GBM. Afterward, we review ICI combination strategies and how these combinations may overcome the immunosuppressive microenvironment of GBM in the context of preclinical/clinical evidence and ongoing clinical trials.

PURPOSE There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2–enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Background: Although recently available immune-based approaches in multiple myeloma produce high response rates, curative outcomes have not yet been achieved, which highlights the need for new agents that further activate the immune system without increasing toxicity. ORIC-533 is a highly potent and selective, orally bioavailable, small molecule inhibitor of CD73, an enzyme expressed by various cell types, including immune cells and which catalyzes the generation of adenosine from adenosine monophosphate (AMP) (Allard 2019). Adenosine itself is highly immunosuppressive, diminishing activity of a range of immune cell types, including T, NK, and dendritic cells (Young 2014). By blocking adenosine production from AMP via inhibition of CD73, ORIC-533 has demonstrated the ability to restore and enhance immune function. Multiple myeloma (MM) patient bone marrow (BM) contains multiple cell types that also express CD73, including immune cells, cancer-associated fibroblasts, mesenchymal stem cells, and endothelial cells (Allard 2019). Moreover, elevated adenosine levels in the MM BM niche correlate with disease progression (Horenstein 2016; Yang 2020). We have previously observed that CD73-mediated adenosine activity suppresses the cytolytic antitumor immune function in the MM BM milieu (Ray 2022). ORIC-533 treatment reduced adenosine production, overcame this immune suppression with evidence of restored DC-mediated priming and activated cytotoxic CD8 + T-cell function, and significantly enhanced immune cell cytolytic behavior against RRMM tumor cells in autologous patient ex vivo experiments (Junttila 2022), making ORIC-533 a potential immunotherapy for patients with MM. Methods: ORIC-533-01 (NCT05227144) is an ongoing i3+3 Phase 1b dose escalation study in patients with RRMM. The primary objectives are to determine single agent safety/tolerability and pharmacokinetics (PK) of ORIC-533 to select the RP2D. Pharmacodynamic assessments include measurement of CD73 functional activity in serum and BM, as well as enumeration of immune cell subsets and activation state in blood and BM. Patients are also evaluated for clinical efficacy using IMWG criteria. Results: As of 23 June 2023, 17 patients received ORIC-533 once daily across 4 dose levels (400 mg to 1600 mg). All patients were triple-class refractory, 88% were penta-refractory, and 59% also received prior anti-BCMA/CD3 bispecific therapy or anti-BCMA CAR-T therapy. Overall, ORIC-533 was very well tolerated, with 5 patients experiencing a total of 10 treatment-related adverse events (TRAEs). Fatigue was the only G3 AE and the only TRAE seen in more than 1 patient (1 event each of G3 and G2); all other events seen in 1 patient each, were G1 or G2 in severity, and of no specific system organ class. No dose limiting toxicities, no Grade ≥4 TRAEs, and no treatment-related serious adverse events have been observed. PK showed increased exposure with dose with a plasma half-life of ~24 hrs. Soluble CD73 enzymatic activity was nearly completely inhibited by C1D15 in serum of all patients across all dose levels, while the largest relative suppression in surface CD73 activity in BM cells was observed at the highest dose level. There was also evidence for increases in the abundance of circulating NK and CD8+ T cells after 1 treatment cycle, with preliminary evidence of enhanced CD8+ T-cell activation at the highest dose levels tested in both peripheral blood and BM. In addition, early evidence of single agent clinical activity was observed. Conclusions: ORIC-533 has demonstrated an acceptable safety profile and preliminary evidence of immune activation in a heavily pretreated RRMM patient population. Enrollment is ongoing and updated data will be presented.

Light chain amyloidosis (AL) is a rare, progressive, and often fatal protein misfolding disease. AL is caused by aberrant clonal plasma cell proliferation, where excess amounts of amyloidogenic monoclonal Free Light Chain (FLC) are produced, secreted into the circulation, misfolded and deposted as amyloid fibrils in various vital organs, such as the heart, kidney, liver, and nerves. The involed lambda (λ) FLC accounts for ~75% of all AL cases. Amyloidogenic FLCs (aFLCs) are believed to be the toxic species contributing to AL disease pathology. Specific quantification of aFLCs can provide critical guidance in clinical practice but has been hampered by the LCs sequence diversity as well as the lack of tests that are able to differentiate between circulating normal polyclonal FLCs and aFLCs. Contrary to non-amyloidogenic, aFLCs are kinetically and oftentimes thermodynamically unstable. aFLCs are prone to misfolding and formation of pathogenic conformations such as non-native structures, proteolytic fragments, soluble aggregates, and amyloid fibrils. We exploited such characteristics of aFLCs by applying limited proteolysis using Proteinase K, where less stable λ aFLC proteins readily yield a 23KDa fragment composed of the homodimeric LC constant domain (dLCCD) linked by a disulfide bond. Formation of the dLCCD fragment reveals a highly conserved, novel, cryptic epitope at the N-terminus of the fragment. We have generated monoclonal antibodies (mAbs) that explicitly bind to such novel epitope and developed immunoassays for the specific detection and sensitive quantification of λ aFLCs in biological samples. Western blot or Meso Scale Discovery (MSD) analyses were employed to detect and quantify dLCCD signal using the dLCCD mAbs on plasma samples from randomly selected, treatment naïve and λ-restricted cases with biopsy-proven AL amyloidosis before and after exposure to optimized proteolytic conditions. Tissue amyloid deposits of λ-type were confirmed in most AL cases. Informed consent for data and plasma sample collections were obtained from the Institutional Review Boards and in accordance with the Declaration of Helsinki. Multiple myeloma (MM) plasma samples of unknown LC restriction type, treatment or amyloid deposits status and normal volunteer control samples were purchased from BioIVT (USA). A set of representative results based on three runs are shown in Fig. 1. As little as 2 µL of biofluid was used for each assay. Upon limited proteolysis, dLCCD signal was detected in 32 of 35 AL plasmas, including two samples from patients with AL-associated IgM lymphoplasmacytic lymphoma (LPL). Of the three dLCCD negative AL samples, one presented with monoclonal IgAλ, and two cases were bi-clonal on serum immunofixation electrophoresis. dLCCD signal was not detected in 18 of 19 MM plasma samples. Similarly, dLCCD signal was undetectable in 23 normal plasmas. Overall, the dLCCD signals detected in AL plasmas were 10x-200x above that of normal control and most MM samples (Fig. 1). The low limit of quantification of the MSD assay was ~0.4 ng/dL (1.4 pM), with &gt;500x dynamic range, enabling sensitive and robust quantification of λ aFLCs in biosamples. Analysis of Proteinase K recognition potential of the cleavage site of 389 λ LC sequences from the AL-Base, a database of amyloidogenic LC sequences (https://wwwapp.bumc.bu.edu/BEDAC_ALBase/) predicted that the dLCCD assay can detect λ aFLCs in up to 99% of λ AL patients, irrespective of the FLC sequences. This was confirmed with the 100% detection rate of the dLCCD signal in a validation cohort of 35 additional monoclonal λ-restricted AL samples. In summary, we have developed a quantitative blood-based immunoassay that is sensitive and highly specific for λ aFLC irrespective of the protein sequences. The preliminary data demonstrates the potential of our assay for AL diagnostics. Additional clinical applications for future exploration will include (i) monitoring and early detection of AL amyloidosis in plasma cell dyscrasias (monoclonal gammopathy of unknown significance, MM, and smoldering MM) and lymphoproliferative disorders, including LPL; and (ii) clinical management of patients with AL amyloidosis via the assessment and monitoring of minimal residual disease and therapeutic responses. The utility of the dLCCD assay in the quantification of λ aFLCs in bi-clonal AL cases warrants further investigation.

Abstract Background PARP-1 has a well-established role in DNA repair. PARP-1 selective inhibitors are a new subclass of PARPi that offer potential for improved tolerability. NMS-03305293 (NMS-293) is an oral, brain-penetrant PARP-1 selective inhibitor with strong antitumor activity in BRCA mutated preclinical models. Furthermore, NMS-293 is synergistic with temozolomide (TMZ) in glioblastoma mouse models. Methods Two phase I/I-II dose-escalation/expansion studies assessed safety, tolerability, and preliminary antitumor activity of NMS-293. Both are actively recruiting. In PARPA-293-001 (NCT04182516), NMS-293 was administered orally, ranging from 20 mg (QD) to 160 mg (BID) for 21 or 28 days on 28-day cycle in adult patients with advanced/metastatic, relapsed/refractory solid tumors who have exhausted standard treatment options. In PARPA-293-002 (NCT04910022), NMS-293 was administered in a range of doses orally, QD or BID on days 1-7 plus TMZ 150mg/m2 QD on days 1-5 in repeated 28-day cycle in adult patients with recurrent diffuse gliomas. Tumor responses were measured by investigator-assessed RANO criteria. Results The unpooled safety database at the data-cut-off (02-AUG-23), includes 45 patients in PARPA-001 and 21 patients in PARPA-002. PARPA-001 showed an MTD of 100 mg BID for 28 days on a 28-day cycle, a dose with meaningful PK relative to preclinical activity. PARPA-002 dose finding is ongoing with no DLTs as of cutoff date. The most frequent (≥10%) any-grade treatment related adverse events (TRAEs) in PARPA-001 were reversible QTcF prolongation, nausea, asthenia, decreased appetite and vomiting, mainly mild/moderate. In PARPA-002, with discontinuous NMS-293 plus TMZ, no G≥3 TRAEs were reported. The most frequent (≥10%) any-grade TRAEs were: nausea, fatigue, vomiting, decreased appetite, and platelet count decreased, mainly G1 adverse events. Overall, no dose-dependent trends of myelosuppression have been observed. 14 recurrent glioma patients across dose levels in PARPA-002 were evaluable for tumor response. A patient with glioblastoma had confirmed partial response (PR) with duration 7.6+ weeks, remaining on treatment at cutoff date. A patient with grade 3 IDH-mutant astrocytoma had unconfirmed PR with ongoing tumor shrinkage at 16.1+ weeks. A patient with glioblastoma had complete radiological disappearance of enhancing non-target lesions, remaining on treatment at cutoff date. NMS-293 PK profiles showed an increase in exposure with the dose with approximately 5 to 13 hours half-life. Conclusion NMS-293, a PARP-1 selective, brain penetrant inhibitor was well tolerated in phase I clinical trials with no dose dependent trends of myelosuppression. Furthermore, NMS-293 showed encouraging clinical activity in combination with TMZ in difficult-to-treat recurrent glioma patients. Citation Format: Marjolein Geurts, Dorothee Gramatzki, Sara Merler, Matteo Duca, Fabio Girardi, Ugur T. Sener, Domenico Roberti, Grazia Saturno, Patrizia Crivori, Alessia Montagnoli, Lisa Mahnke, Siqing Fu, Paola Gaviani, Kurt A. Jaeckle, Jian Zhang, Yehui Shi, Valentina Guarneri, Michael Weller, Sani H. Kizilbash, Martin J. van den Bent, Michele Milella, Silvia Damian. Initial results from 2 Phase I studies of NMS-03305293, a selective PARP1 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A12.

Abstract There is a large and increasing rate of incarcerated individuals that face a risk of cancer. Cancer is the leading cause of death among the incarcerated population, resulting in a significantly shortened survival rate amongst said population. Very few studies have been conducted to truly assess the knowledge gap between incarceration and cancer outcomes. But, from the few that have been done, like the population-based study done by UF Radiation Oncology assistant professor, Dr. Oladeru, it was discovered that a higher risk of cancer mortality was prevalent in those who were diagnosed with cancer during their time incarcerated as well as one year post release than the general population. My goal and intent with this literature review is to open the conversation about possible ways to bridge the knowledge gap between cancer health disparities amongst incarcerated patients and contribution factors. Citation Format: Tamia Isaacs, Oluwadamilola Oladeru, Jian Li, Yoshiko Iwai. Bridging the gap: A literature review of cancer mortality and incarcerated individuals [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C015.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42–4.96]; P <0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93–2.28]; P =0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M 1 : 0.86–0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

Abstract BACKGROUND Diffuse hemispheric glioma (DHG) is an uncommon infiltrating glioma, defined in the World Health Organization 2021 guidelines by a mutation in the H3F3A gene at codon 34 (H3.G34). DHG primarily affects children and young adults. Due to its rarity, there is paucity of knowledge regarding factors affecting overall survival (OS). We retrospectively assessed our institutional experience and present a review of the literature. METHODS We searched our institution’s pathology records to identify six cases of DHG. Demographic, clinical, diagnostic, treatment, and outcome data were recorded. We next searched for published articles regarding DHG cases via PubMed through May 2023. Four-hundred-fifty-four published individual cases of H3.G34 glioma were identified, 204 of which were hemispheric/supratentorial tumors with OS data reported, providing a combined 210 cases for analysis. 132 of these cases included MGMT promoter methylation status. 111 included extent of surgical resection. Kaplan-Meier and Cox regression survival analysis was performed. RESULTS Age range for DHG patients was 7-66 years (median 17). Median OS was 18.5 months (95% CI, 17-25). Greater extent of surgical resection and presence of MGMT promoter methylation were associated with better prognosis. Median OS for biopsy alone was 12 months (95% CI, 10-NA), subtotal resection was 16 months (95% CI, 14-23), and gross total resection was 27 months (95% CI 23-NA) – log-rank p&lt; 0.001. OS for MGMT promoter unmethylated was 14 months (95% CI 12-22), MGMT promoter methylated was 24 months (95% CI, 17-30) – log-rank p=0.028. Contrary to previous reports, patient age was not found to impact prognosis (using 18, 21, and 40 years as cutoffs or as a continuous variable with Cox regression). CONCLUSION Extent of surgical resection and MGMT promoter methylation status are important prognostic factors for DHG. Unlike many primary brain tumors, survival does not appear to be significantly impacted by age.

Abstract Glioblastoma (GBM) is the most common and aggressive form of brain tumor in adults. Despite maximal surgical resection, irradiation, and chemotherapy, median overall survival (OS) for recurrent GBM (rGBM) remains at only 30 weeks. GBM tumors have an immune-suppressive microenvironment with low numbers of tumor-infiltrating lymphocytes (TILs). Interleukin 7 (IL-7) plays a key role in T cell homeostasis and survival, with IL-7 inducing T cell expansion in lymphopenic conditions. Efineptakin alfa (NT-I7), a long-acting IL-7, has been shown to increase effector CD8 T cells and reduce suppressor T-regulatory cells in murine GBM models, with subsequently improved OS. We recently completed a Phase I study in newly diagnosed GBM patients which showed that NT-I7 is safe, well-tolerated, and increased absolute lymphocyte counts (ALCs), and determined maximum tolerated dose for Phase II. We hypothesized that NT-I7 may not only mitigate GBM treatment-associated immune suppression, but also potentiate the effect of immune checkpoint blockade, leading to an increase in TILs and improved survival. The purpose of this study is to evaluate the safety and efficacy of combining NT-I7 and pembrolizumab in rGBM patients. This is an open-label, single arm one-stage Phase II study of NT-I7 and pembrolizumab as neoadjuvant and adjuvant therapy with surgery for adult patients with rGBM. We plan to enroll 30 evaluable patients, including a 6-patient safety run-in. The primary endpoint is the 9-month OS rate. Secondary endpoints include progression-free survival, objective response rate, changes in ALC, and adverse events profile. The correlative endpoints include studies to assess the anti-glioma immune response, changes in T cell subsets and functionality, peripheral cytokine quantification, and immunohistochemical analysis of GBM tissue. Longitudinal cerebrospinal fluid proteomics is optional. This study opened in Jan 2023. Six (6) of the planned thirty (30) patients had been enrolled by time of submission.