Search

Purpose:Despite standard of care (SOC) established by Stupp, glioblastoma remains a uniformly poor prognosis. We evaluated IGV-001, which combines autologous glioblastoma tumor cells and an antisense oligonucleotide against IGF type 1 receptor (IMV-001), in newly diagnosed glioblastoma.Patients and Methods:This open-label protocol was approved by the Institutional Review Board at Thomas Jefferson University. Tumor cells collected during resection were treated ex vivo with IMV-001, encapsulated in biodiffusion chambers with additional IMV-001, irradiated, then implanted in abdominal acceptor sites. Patients were randomized to four exposure levels, and SOC was initiated 4–6 weeks later. On the basis of clinical improvements, randomization was halted after patient 23, and subsequent patients received only the highest exposure. Safety and tumor progression were primary and secondary objectives, respectively. Time-to-event outcomes were compared with the SOC arms of published studies.Results:Thirty-three patients were enrolled, and median follow-up was 3.1 years. Six patients had adverse events (grade ≤3) possibly related to IGV-001. Median progression-free survival (PFS) was 9.8 months in the intent-to-treat population (vs. SOC, 6.5 months; P = 0.0003). In IGV-001–treated patients who met Stupp-eligible criteria, PFS was 11.6 months overall (n = 22; P = 0.001) and 17.1 months at the highest exposure (n = 10; P = 0.0025). The greatest overall survival was observed in Stupp-eligible patients receiving the highest exposure (median, 38.2 months; P = 0.044). Stupp-eligible patients with methylated O6-methylguanine–DNA methyltransferase promoter (n = 10) demonstrated median PFS of 38.4 months (P = 0.0008). Evidence of immune activation was noted.Conclusions:IGV-001 was well tolerated, PFS compared favorably with SOC, and evidence suggested an immune-mediated mechanism (ClinicalTrials.gov: NCT02507583).

Determination of severity for adverse events

Pan-Cancer Immunity Panel for advanced analysis of T cell activation scores

Objective To develop and implement a customized toolkit within the electronic medical record (EMR) to standardize care of patients with brain tumors. Patients and Methods We built a customized structured clinical documentation support toolkit to capture standardized data at office visits. We detail the process by which this toolkit was conceptualized and developed. Toolkit development was a physician-led process to determine a work flow and necessary elements to support best practices as defined by the neuro-oncology clinical team. Results We have developed in our EMR system a customized work flow for clinical encounters with neuro-oncology patients. In addition to providing a road map for clinical care by our neuro-oncology team, the toolkit is designed to maximize discrete data capture. Several hundred fields of discrete data are captured through the toolkit in the context of our routine office visits. We describe the characteristics of patients seen at our clinic, the adoption of the toolkit, current initiatives supported by the toolkit, and future applications. Conclusion The EMR can be effectively structured to standardize office visits and improve discrete data capture. This toolkit can be leveraged to support quality improvement and practice-based research initiatives at the point of care in a neuro-oncology practice.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic adverse drug reaction occurring in

PDGFRA has been shown to be commonly altered in high-grade gliomas (HGGs), including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a disease with almost no long-term survivors. Here, we performed comprehensive genomic and transcriptomic analysis of 260 high-grade glioma cases, which revealed PDGFRA genomic alterations (mutations and/or amplifications) in 13% of patients. H3K27M DMGs had significantly higher PDGFRA expression compared to H3 wild-type tumors, and PDGFRA gene amplification resulted in even higher expression levels in H3K27M DMGs as well as H3 wild-type HGGs. We tested a panel of patient- derived pHGG/H3K27M DMG models against a range of PDGFRA inhibitors, including avapritinib, a potent small molecule inhibitor with relatively selective activity against both wild-type and mutant PDGFRA. Avapritinib showed supra-micromolar blood-brain barrier penetration in our pre-clinical models and demonstrated significant survival impact in an aggressive patient-derived H3K27M DMG mouse xenograft model. Finally, building on this preclinical activity, we report here the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib has thus far been well tolerated with no significant acute toxicities. Most importantly, our preliminary data reveal radiographic response evaluated by RAPNO criteria in 50% of patients, a striking outcome rarely seen in this patient population. In summary, we report that avapritinib is a selective, CNS-penetrant small molecule inhibitor of PDGFRA that shows potent activity in preclinical models and produces promising clinical responses with good tolerability in patients with high-grade glioma. This suggests a promising role for avapritinib therapy in this population with previously dismal outcomes. Citation Format: Lisa Mayr, Maria Trissal, Kallen Schwark, Jenna Labelle, Andrew Groves, Julia Furtner-Srajer, Jeffrey Supko, Liesa Weiler-Wichtl, Olivia Hack, Jacob Rozowsky, Joana G. Marques, Eshini Pandatharatna, Ulrike Leiss, Verena Rosenmayr, Frank Dubois, Noah F. Greenwald, Sibylle Madlener, Armin S. Guntner, Hana Pálová, Natalia Stepien, Daniela Lötsch-Gojo, Christian Dorfer, Karin Dieckmann, Andreas Peyrl, Amedeo A. Azizi, Alicia Baumgartner, Ondřej Slabý, Petra Pokorná, Pratiti Bandopadhayay, Rameen Beroukhim, Keith Ligon, Christof Kramm, Annika Bronsema, Simon Bailey, Ana Guerreiro Stücklin, Sabine Mueller, David T. Jones, Natalie Jäger, Jaroslav Štěrba, Leonhard Müllauer, Christine Haberler, Chandan Kumar-Sinha, Arul Chinnaiyan, Rajen Mody, Mary Skrypek, Nina Martinez, Daniel C. Bowers, Carl Koschmann, Johannes Gojo, Mariella Filbin. Clinical response to the PDGFRα inhibitor avapritinib in high-grade glioma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5719.

BACKGROUND Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and METHODS Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results. RESULTS 331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine. CONCLUSION Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.

Pediatric high-grade glioma (pHGG) is an incurable disease with a median survival of less than 6 months post-progression and no effective targeted therapy. PDGFRA is commonly altered in pHGG, but targeting PDGFRA in this disease has been unsuccessful, likely due to poor central nervous system (CNS) penetrance. Avapritinib is a novel and CNS-penetrant PDGFRA/KIT inhibitor that is FDA-approved for adults with unresectable or metastatic PDGFRA exon 18-mutant gastrointestinal stromal tumor (GIST) and is being studied in CNS tumors. We performed a pre-clinical and clinical assessment to determine the potential suitability of avapritinib therapy in PDGFRA-driven glioma. A multi-institutional cohort genetic analysis revealed PDGFRA amplification and mutation in 10.2% and 6.1% of pHGG, respectively. Additionally, PDGFRA expression in the absence of genetic events was significantly increased in H3K27-altered diffuse midline glioma (DMG) compared to H3-wildtype pHGG. Avapritinib performed well in: (i) mutant PDGFRA enzyme inhibition and wildtype inhibition at high dose, (ii) minimal off-target kinase inhibition, (iii) brain penetration (peak 10 µM), and (iv) proliferation/pPDGFRA reduction in PDGFRA-amplified and mutant pHGG cell lines. Avapritinib treatment in an aggressive PDX model of pHGG resulted in significant survival benefit. We pursued treatment of eight pediatric and young adult HGG patients with avapritinib across seven institutions. Patients were a mixture of local (N = 4) and metastatic disease (N = 4); all patients were post-initial radiation, with 7/8 having progressed on prior treatment. 7/8 patients had PDGFRA amplifications or mutations, and 7/8 had H3K27M mutations. Therapy was generally well-tolerated. 4/8 patients showed radiographic response to avapritinib, with one patient demonstrating complete response of target lesion and remains on therapy. Avapritinib levels in patients’ CSF and brain tumor tissue reached micromolar levels. These results demonstrate that avapritinib is a potent, selective, and CNS-penetrant PDGFRA/KIT inhibitor that is promising for further study in pHGG with relevant alterations.

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment. Wang et al. perform integrated proteogenomic analysis of adult glioblastoma (GBM), including metabolomics, lipidomics, and single nuclei RNA-Seq, revealing insights into the immune landscape of GBM, cell-specific nature of EMT signatures, histone acetylation in classical GBM, and the existence of signaling hubs which could provide therapeutic vulnerabilities.

Through this article the authors examine data collected from 126 women seeking services at a transitional housing facility, primarily for women leaving street-based prostitution. Descriptive statistics on the women's ethno-racial identity, numbers of children, and experiences with violence are presented and analyzed to determine correlations and implications for social service providers working with this unique population of women. Nearly half of respondents are women of color, a majority have given birth to at least one child, and more than half are in a non-commercial intimate partnership, with a significant number reporting extensive experiences with violent trauma and abuse. Results indicate statistically significant differences in women's ethno-racial self-identification and their experiences of sex work and violence, as well as their marital status. Most notably, African-American and Hispanic women face the greatest and most diverse forms of intimate partner violence and negative sex industry experiences, with African-Americans more likely to engage in sex work as minors, be sexually abused as children, work for a pimp, and face physical assault and instances of sex trafficking. Results also support existing research showing correlations between traumatic childhood events and adult substance abuse, sexual assault, and other negative outcomes.

Women who decide to leave street-based sex work often struggle with addiction, trauma-related mental health consequences, and exclusion from employment and housing. To offer recommendations for social service providers, this article draws upon primary data from interviews and surveys with 87 residents at a transitional housing facility for women leave sex work to elucidate: 1) a demographic profile of the women, 2) life history patterns and circumstances that encourage women to leave street-based sex work and 3) recommendations for service providers. Results indicate the need for service providers to assist women with basic needs, strengthen referral networks, and extend trauma-informed services.

We examined expedited partner therapy for chlamydia and gonorrhea in college and university health centers by institutional and policy characteristics. Expedited partner therapy awareness and use was low (44.1% used), did not differ by institutional characteristics, and differed by policy environment. Our findings suggest missed opportunities for sexually transmitted disease prevention in college and university health centers.

Hip pain in dancers is typically attributed to musculoskeletal etiologies due to local “wear-and-tear”; however, one must be aware of neurologic etiologies that may present with additional clinical findings and require specialized treatment. This article explores the presentation, potential causes, suggested work-up, and treatment options for femoral neuropathy, lateral femoral cutaneous syndrome, and piriformis syndrome.

The HIV/AIDS pandemic continues to challenge the African American community with disproportionate rates of infection, particularly among young women ages 25 to 34 years. Development of a preventive HIV vaccine may bring a substantial turning point in this health crisis. Engagement of the African American community is necessary to improve awareness of the effort and favorably influence attitudes and referent norms. The Theory of Reasoned Action (TRA) may be a useful framework for exploration of community engagement outcomes including future attendance, community mobilization, and study participation. Within the context of HIV vaccine outreach, we conducted a cross-sectional survey in early 2007 with 175 African-American adults (/= 18 years). Confirmatory factor analysis and structural equation modeling were performed and the findings support the potential of the model in understanding behavioral intentions toward HIV vaccine research.