bluuebunny/crossref_metadata_2025 huggingface dataset:
EXTH-63. FOCUSED ULTRASOUND HYPERTHERMIA MEDIATED CONTROL OF THERMAL RESPONSIVE CAR T CELL ACTIVITY IN BREAST CANCER BRAIN METASTASIS
Authors: Kim Chulyong , Zamat Ali , Zha Zizhen , Sridhar Shwetha , Kwong Gabe , Arvanitis Costas
Published: November 2024

HER2-targeted therapies are promising treatment options for metastatic breast cancer and have improved the median overall survival. However, breast cancer brain metastasis (BCBM), observed in up to 50% of HER2-positive breast cancer patients, remains a clinical challenge. While Chimeric Antigen Receptor (CAR) T cell therapy is promising therapeutic strategy to address the unmet need in treating BCBM, improving its effectiveness and safety is critical for clinical translation. We hypothesized that spatially and temporally controlled activity of CAR-T cells with a thermal gene switch (TS) under MRI-guided focused ultrasound (MRgFUS) would potentiate anti-tumor responses in difficult-to-treat BCBM. To test our hypothesis, we developed a closed-loop controlled MR-thermometry (MRTI) based FUS system (MRgFUS) and αHER2 CAR-T cells engineered with TS expressing the reporter gene firefly luciferase (TS.Fluc) or bi-specific engager on NKG2D ligands (TS.BTE) upon MRgFUS-hyperthermia (41.5°C). In vivo quantification of TS activity from intratumorally delivered TS.Fluc αHER2 CAR-T cells in HER2+ BCBM mice model (HER2+ MDA-MB-468 in NSG mice with primary human CAR-T cells) followed by pulsed MRgFUS-hyperthermia resulted in a ~10-fold increase in luminescent activity compared to unheated mice. To assess longitudinal activation, we quantified TS activity with a second sonication 4 days post the initial FUS treatment. Prior to the second sonication, TS.Fluc expression had returned to baseline levels, while following it robust TS.Fluc expression was observed again, demonstrating that MRgFUS can activate engineered T cells with TS in brain tumors with high spatiotemporal control. Subsequently we investigated the therapeutic efficacy of intratumorally delivered TS.BTE αHER2 CAR T cells in mixed tumor model of heterogeneous HER2 MDA-MB-468 (75% HER2+) and observed significant tumor regression of HER2- tumor cells in the treated group compared to controls, demonstrating the potential of the proposed strategy to noninvasively drive the local production of key transgenes and potentiate anti-tumor responses in difficult-to-treat BCBM.
EXTH-78. A NOVEL BISPECIFIC S100A4/TFR ANTIBODY TO REPROGRAM THE GLIOMA TUMOR MICROENVIRONMENT AND TARGET GLIOMA STEM CELLS
Authors: Wong Thomas , Leu Jia-Shiun , Fan Xuejun , Kang Reece , Abdelfattah Nourhan , Leonard Fransisca , Zhang Ningyan , Yun Kyuson
Published: November 2024

GBM (glioblastoma) is the most common and aggressive primary brain tumor in adults. While immunotherapy is a promising treatment modality for GBM, most clinical trials have thus far only provided a modest benefit to GBM patients. We propose that enhancing the efficacy of immunotherapy for GBM requires approaches that increase T cell infiltration and reprogram the myeloid cells to a more pro-inflammatory state. S100A4 is a major regulator of stemness, epithelial-mesenchymal transition, and a critical regulator of immune suppressive myeloid and T cell phenotypes in GBM. Targeting S100A4 in either glioma or stromal cells is sufficient to reprogram the tumor immune landscape and extend survival of glioma bearing mice, indicating that S100A4 is a promising immunotherapy target. We recently developed a S100A4 blocking monoclonal antibody; however, this antibody does not cross the blood brain barrier (BBB) efficiently to confer significant therapeutic benefit, limiting its efficacy in treating GBM. To overcome this challenge, we generated a bispecific S100A4-TfR antibody (BsA) that allows robust BBB penetration, and tested this in a pre-clinical syngeneic, orthotopic mouse model of GBM. Using ELISA, confocal immunofluorescent microscopy, flow cytometry, and bulk RNA sequencing, we report that systemic administration of the S100A4-TfR BsA results in increased immune cell infiltration with a preferential increase in CD4 T cell infiltration, and potent immune remodeling of the tumor microenvironment to a more pro-inflammatory state. Furthermore, the BsA is taken up by glioma cells intracellularly, which is correlated with depletion of intracellular S100A4 and decreased nuclear SOX2 localization, which would reduce stemness of glioma cells. Functionally, in vitro BsA treatment of primary glioma cell cultures shows decreased S100A4 expression, proliferation, and self-renewal. Our results suggest that S100A4-TfR BsA is a novel dual activity inhibitor to simultaneously reprogram the GBM immune landscape and reduce glioma stemness.
EXTH-85. ASSESSMENT OF ANTI-CD69 ANTIBODY THERAPY ALONE OR IN COMBINATION WITH ANTI-PD-1 IN MURINE GBM
Authors: Nisnboym Ziv Michal , Kohanbash Gary , Raphael Itay
Published: November 2024

BACKGROUND

Glioblastoma multiforme (GBM) is an aggressive central nervous system malignancy with a dismal prognosis. There is continued interest in trying multiple immunotherapy modalities for this intractable cancer. Cluster of differentiation 69 (CD69), is an early marker of T and NK cell activation. CD69 play multiple roles in T cell-mediated immunoregulation with immune inhibitory role in antitumor immunity. Previous preclinical work in non-CNS malignancies has demonstrated that targeting CD69 can improve clinical outcome and anti-tumor immunity. We aimed to assess anti-CD69 Ab therapy alone or in combination with anti-PD-1 in murine GBM.

METHODS

We explored transcriptomic data from 163 GBM patients using the TCGA database. We then tested the therapeutic value of anti-CD69 immunotherapy in a preclinical model of GBM and assessed the ideal timing of treatment with anti-CD69 Ab by evaluating survival and immune tumor-microenvironment by flow cytometry. Two treatment-timings with anti-CD69 Ab were further evaluated either alone, or in combination with anti-PD1 Abs and compared to control and to anti-PD1 only treatment. Survival data was collected.

RESULTS

CD69 expression was significantly increased in GBM patients tissues as compared with normal brains and increased CD69 expression was associated with worse progression-free survival. Treatment-timing with single dose anti-CD69 Ab at day 1 or three doses at days 4, 8 and 12 post tumor-injection minimally improved the median survival time of animals. In addition, effective CD69 blockage and significantly elevated PD-1 expression on NK cells was found in these timings, making them good candidates to evaluate anti-CD69 Ab therapy alone or in combination with anti-PD-1 Ab. However, when assessing these treatment-timings with anti-CD69 Ab alone or in combination with anti-PD1 no survival benefit was found.

CONCLUSION

This is the first study assessing anti-CD69 Ab therapy alone or in combination with anti-PD-1 in murine GBM. While some effect was found on the cellular level, this didn’t translate to survival benefit and results are overall negative.
QLTI-02. THE ROLE OF REOPERATION IN PAEDIATRIC PILOCYTIC ASTROCYTOMA
Authors: Kameda Michelle , Green Katherine , Hutton Dana , Jeelani Noor ul Owase , Thompson Dominic , Hargrave Darren , Aquilina Kristian
Published: November 2024

INTRO

Cerebellar pilocytic astrocytomas (cPAs) in childhood have long been recognized to have a good prognosis after total resection, but the outcome after incomplete resective surgery remains largely unpredictable, with the incidence of radiological progressive disease ranging from 18-100%. It has been traditionally thought that gross-total resection was required for long-term survival, and small residuals were classically resected in a subsequent operation.

OBJECTIVE

To determine the role of reoperation in residual or recurrent cerebellar pilocytic astrocytoma.

METHODS

The authors analyzed their pediatric low-grade clioma (PLGG) database for cases treated between 1985-2020 and filtered for intracranial PAs, to determine what clinical or radiological factors precipitated revisional resective surgery in their single quaternary care center cohort.

RESULTS

Using the PLGG database, 283 patients <18 years of age were identified to have a histopathological diagnosis or intracranial PA between 1985-2020, of which, 200 were within the cerebellum (70.7%). The majority of patients with cPA were between 1 and 10 years of age (n=145, 72.5%) without gender preponderance (M/F=99:101) usually presenting with 1 lesion (n=197, 98.5%). Gross total resection was achieved in 74.5% (n=149) of initial surgeries for cPA. In patients with subtotal resection, the mean largest diameter of the postoperative residual tumor was 1.06cm (range 0-2.95cm). Seven patients with subtotal resection did not require a second resective intervention. In 31 patients the neuro-oncology multi-disciplinary team recommended a second resection at a mean time interval of 22.9 months (range 0.13-81.6 months) from the initial surgery. Proportionally, the children who underwent multiple resections were also more likely to receive adjuvant chemo/radiotherapy. Functionally, the children in the multiple operation cohort experienced more complications of therapy including ongoing endocrinopathy, treatment-associated hearing deficit, and neuro-cognitive deficits.

CONCLUSION

Residual disease in cPA should be maintained under clinico-radiological surveillance postoperatively with adoption of a more conservative approach when residual disease is not significantly changing over time.
QLTI-03. REAL-WORLD PARADIGM FOR TREATMENT OF PRIMARY CNS LYMPHOMA PATIENTS IN CLINICAL PRACTICE
Authors: Umemura Yoshie , Nayak Lakshmi , Nijland Marcel , Mohile Nimish , Batchelor Tracy , Strowd Roy
Published: November 2024

Although high-dose methotrexate (HD-MTX) is the foundation of induction therapy for primary CNS lymphoma (PCNSL), a gold-standard regimen has yet to be established. A 10-case-based survey, to assess the practice patterns at key decision-points in adult PCNSL management outside of clinical trials, was distributed through IPCG, HOVON, and AAN Neuro-Oncology Section. Eighty-five responses were collected from North American (N=42), European (N=33), Asian (N=7), and other countries (N=3) from neurologist neurooncologists (N=35), hem-onc neurooncologists (N=24), hematologist-oncologists (N=18), neurosurgeons (N=5), radiation-oncologist (N=2), and hematopathologist (N=1). The most common first-line induction regimen was R-MP+/-V: rituximab, HD-MTX, procarbazine, +/-vincristine (N=28) followed by MATRix: HD-MTX, cytarabine, thiotepa, rituximab (N=23), then R-MT: rituximab, HD-MTX, temozolomide (N=19). For elderly patients, R-MP+/-V remained most common (N=32). The majority preferred to omit intra-CSF chemotherapy (N=50). The most preferred consolidation after complete response was high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT, N=57), or high-dose cytarabine (N=17) in elderly patients. In cases of partial response, the most common approach was still HDC-ASCT (N=24). For stable disease, participants would move to various salvage chemotherapy (N=33), continue additional induction (N=39), or to move to radiotherapy (N=10). If early progression was noted, the most preferred approach was non-methotrexate chemotherapy (N=31). For recurrences after previous complete response and HDC-ASCT consolidation, the majority preferred to try chemotherapy before moving to radiotherapy in scenarios < 1 year (N=64) or > 1 year from consolidation (N=68), and even if the performance status was poor (N=57). Close to half (N=34) participants felt there is a role for stereotactic radiosurgery in various clinical settings. This survey noted clear consensus to use multi-drug MD-MTX based chemotherapy, and common induction regimens, however, highlighted a great variety of treatment preferences after first-line therapy even amongst disease experts through clinical consortiums, suggesting likely wider range of treatments and disease response in larger community settings.
QLTI-06. NEXT GENERATION SEQUENCING SIGNIFICANTLY IMPROVES THE DIAGNOSTIC ACCURACY IN GLIOBLASTOMAS
Authors: Lath Devraj , Roy Vijaylaxmi , Sreegiriraju Vijay , Goel Pallavi , Ghanekar Yashoda , Sadasivam Subhashini , Kumari Neha , Pawar Vikas , Madiraju Surya , Ray Amit
Published: November 2024

The 2021 WHO Classification of CNS Tumours recognizes the presence of TERT promoter (pTERT) mutations, combined +7/-10 chromosome copy-number alterations, or EGFR amplification as a defining molecular feature(s) of glioblastoma, independent of histology. We evaluated these biomarkers in a cohort of Indian patients using a single-run next-generation sequencing (NGS) platform at a relatively low depth of 100. Seventy-four adult diffuse gliomas were selected from the Exsegen Genomics Research Pvt Ltd Biobank established during the trial CTRI/2021/09/036861 after reviewing their clinical and pathological data. Paired surgical tissue and blood samples underwent whole-exome sequencing on an Illumina NovaSeq-6000 (Illumina, San Diego, USA). Single-nucleotide variations (SNVs) were processed using the DRAGEN pipeline to generate Mutation Annotation Format (MAF) files. Copy number variations (CNVs) analysis was performed using GATK and GISTIC2.0. Thirty-nine glioma samples with IDH1R132H mutations were excluded. A total of 32/35 (91.4%) IDH-wildtype tumours met the 2021 WHO criteria for glioblastoma, IDH-wildtype and were included. Twenty-four glioblastomas also underwent whole-transcriptome analysis. Microvascular proliferation (n=24, 75%) and necrosis (n=30, 93.9%) were present in the majority. pTERT mutations were identified in 23 (71.9%) samples, with C228T mutations (n=15/23, 65.2%) being more common than C250T mutations (n=8/23, 34.8%). EGFR amplification, defined as ≥5 copies by NGS CNV, was seen in 15 (46.9%) samples, with a strong correlation between EGFR CNV and logEGFR expression (r=0.79; p=0.017). Whole-arm +7/-10 genotype was evident in 17 (53.1%) tumours, and another 5 (15.6%) showed partial copy-number alterations. Notably, two gliomas without necrosis and proliferation initially diagnosed as oligodendrogliomas due to misinterpretation of the IDH immunostain, were reclassified as glioblastoma, IDH-wildtype. The data was validated using Sanger Sequencing and targeted panel sequencing to a depth of 500. Even low depth NGS sequencing, that is cost effective and time efficient offers significant improvements in diagnostic molecular neuropathology.
QLTI-07. COLLABORATIVE RESEARCH SUITE FOR GENOMIC ANALYSIS, DATA REPORTING AND WORKFLOW CUSTOMISATION
Authors: Sreegiriraju Vijay , Roy Vijaylaxmi , Lath Devraj , Mishra Pankaj , Ghanekar Yashoda , Sadashivam Subhashini , Goel Pallavi , Pawar Vikas , Madiraju Surya , Ray Amit
Published: November 2024

The genomic analysis pipeline involves multiple stages, including data extraction, transformation, and loading (ETL), exploratory data analysis (EDA), machine learning (ML) modeling, and reporting. The ETL stage involves data profiling and quality control measures to ensure data integrity and consistency. The EDA stage employs statistical and visualization methods to understand data distribution, identify patterns, and detect anomalies. Machine learning modelling involves supervised classification techniques, such as logistic regression and support vector machines (SVMs), to predict tumour classification and develop gene signatures. Unsupervised classification techniques, such as K-means clustering and Hierarchical clustering, identify patterns and relationships in genomic data. Quality metrics evaluate data completeness, accuracy, and consistency, ensuring data reliability and validity. The integration of data science techniques into a comprehensive framework can be achieved with the development of Application Dashboards that provide real-time insights into genomic data across every stage of the analysis pipeline. This enables clinical researchers and bioinformaticians to make informed decisions quickly, improving turn-around time and accelerating the discovery of new insights. In contrast to conventional methods of using stand-alone scripts, these dashboards offer a reusable and scalable solution, allowing for easy modification and adaptation to new datasets and analysis pipelines, thereby reducing development effort and increasing productivity. The dashboards constitute a centralized platform for data visualization, exploration, and analysis, facilitating collaboration and communication among research team members. With customizable and interactive visualizations, users can explore genomic data from multiple dimensions and the integration of multiple sources, including genomic and transcriptomic data. The technologies used to power this Research suite include Streamlit for Web App development, Python for data analysis, Opensearch for data storage and other utility libraries for reporting.
QLTI-13. A REVIEW OF THE BEST TREATMENT STRATEGY FOR NEUROFIBROMATOSIS TYPE 2 PATIENTS THROUGH A SINGLE-CENTER RETROSPECTIVE STUDY: HOW TO ORCHESTRATE MULTIMODAL TREATMENT OPTIONS
Authors: Hee Chang Jong , Choi Seonah
Published: November 2024

PURPOSE

Neurofibromatosis type 2(NF2) is an autosomal-dominant tumor predisposition syndrome that affects the whole neuro-axis and causes various neurological symptoms decreasing the quality of life throughout the patient’s lifespan. However, due to the diversity of related diseases and the complexity of treatment, there are many cases in which only partial treatments are performed, the timing of the treatment is missed, and inappropriate treatment modality selection is made despite the intervention of many clinicians. Therefore, to increase the overall understanding of the disease, the single-institution experience was analyzed.

MATERIALS AND METHODS

Between 1998 and 2022, a total of 80 patients who clinically suspected NF2 visited our Brain Tumor Center. After excluding the patients with follow-up loss, the remaining 48 patients were finally analyzed. The patient’s symptoms, diagnosis process, treatment process, and outcomes were analyzed.

RESULTS

The average age at the time of symptom onset was 31.0(2-63) year-old. Hearing impairment was the major primary symptom(46.8%) among the patients. Five patients(10.9%) had family history of NF2. Thirty-five patients(76.1%) was clinically diagnosed as a NF2 for the bilateral vestibular schwannomas, and 34 patients(73.9%) had intracranial meningiomas, and 37 patients(80.4%) had spinal lesions at the time of diagnosis. Eleven patients were genetically confirmed as NF2. For vestibular schwannomas, 16 patients had surgical resection and 20 patients took gamma-knife surgery as a primary or secondary treatment. For intracranial meningiomas, 16 patients had surgical resection, 13 patients took gamma-knife surgery, and 15 patients took conventional radiation therapy as a primary or secondary treatment. Ventriculo-peritoneal shunt due to increased intracranial pressure was performed in 4 patients(8.7%). For spinal lesions, 16 patients had surgical resection.

CONCLUSION

NF2 is a disease group requiring a multidisciplinary team approach. The key to treatment is to set and implement a treatment sequence and method tailored to each patient. For this, an overall understanding of the disease and the treatment options is essential.
QOL-13. FROM SURVIVING TO THRIVING WITH A BRAIN TUMOR: THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO NEUROONCOLOGY MODEL FOR AN EMPOWERED AND ENGAGED PEER VOLUNTEER SUPPORT COMMUNITY
Authors: Hoffer Naomi , Rodriguez-Almaraz Eduardo , Fetting Mary Lacy , Choi Elizabeth , Destri Mary , Taylor Jennie , Chang Susan
Published: November 2024

BACKGROUND

Brain tumor patients often experience feelings of isolation, identity loss, and existential distress, and peer support can have a positive impact in these areas. Providing peer support, however, can be emotionally demanding and presents unique challenges for neuro-oncology patient volunteers, with little guidance available to address these issues. We describe an innovative program that supports volunteers and provides a roadmap for implementing peer volunteer programs in clinical neuro-oncology practices.

METHODS

In 2020, the UCSF Sheri Sobrato Brain Cancer Survivorship Program established an initiative to match brain tumor patients seeking support with trained patient volunteers. To address potential challenges, an optional, ongoing support community for volunteers was created by a health coach educator, with co-facilitation from a rehabilitation neuropsychologist and a social worker. The weekly meetings included supplemental training, personal check-ins, and group discussions. Volunteer feedback was collected through direct volunteer communication with the facilitator and an annual online survey.

RESULTS

From August 2020 through October 2023, 46 peer volunteers were trained in six cohorts. There were 116 patients requesting peer support. In total 132 volunteer-patient matches were made for an average of 2.87 matches per volunteer. Seventy percent of volunteers attended 11 or more meetings/year. Average attendance was 12 volunteers per meeting. All respondents to the annual online survey (n=31) reported a high level of satisfaction with the program. Volunteers highlighted benefits such as mutual support, impactful contributions, and personal growth and empowerment. Volunteers who reported higher levels of preparedness attended >11 meetings per year.

DISCUSSION

In our experience, patient peer volunteer programs show promise in reducing isolation and restoring purpose. This unique 3-year pilot suggests that ongoing group support and training is a plausible and effective way to enhance a peer volunteer program. Future efforts will focus on developing a structured curriculum for neuro-oncology patient peer volunteers.
QOL-17. REFLECTIONS ON A PSYCHOEDUCATION INTERVENTION FOR PATIENTS WITH NEWLY DIAGNOSED BRAIN TUMORS (NEUROPATHWAYS): A QUALITATIVE STUDY
Authors: Whitman Jessica , Strander Sumita , Podgurski Alyx , Willis Kelcie , Chiu Daniel , Parsons Michael , Maguire Amy , Steele Sarah , Curtis Christopher , Warner Kara , McCone Joelle , Temel Jennifer , Traeger Lara , Forst Deborah
Published: November 2024

BACKGROUND

Patients with newly diagnosed primary malignant brain tumors (PMBT) face unique challenges processing and absorbing information regarding their diagnosis, often while contending with cognitive and communication deficits. Limited research exists regarding optimal information provision and support for this highly distressed population. We used input from clinician, patient, and caregiver stakeholders to design a population-specific, psychoeducation intervention (“NeuroPathways”) to address these needs.

METHODS

We conducted a single-arm study (N=12) to pilot and refine NeuroPathways in English-speaking patients within six-weeks of a PMBT diagnosis. Neuropathways comprises 1) a comprehensive (105 pages) handbook covering information about PMBT diagnosis, treatment, coping, self-care, and vetted resources, and 2) four brief, individual telehealth sessions with a trained interventionist (e.g., psychologist, physician) over 4-8 weeks to assist and empower patients to obtain information, support, and coping guidance at their preferred depth and pace, using the handbook as a resource. Ten participants completed all four sessions and participated in semi-structured exit interviews. We used rapid qualitative analysis to explore participants’ perceptions of intervention delivery, content, and benefit.

RESULTS

Participants (83% male, median age=52 years) uniformly described NeuroPathways as accessible, citing the telehealth format as particularly important for facilitating participation given logistical challenges related to cancer treatment. Perceived benefits of participation included: a) access to well-organized information targeting both current and future disease- and treatment-related concerns; b) increased skill in problem solving and communication with loved ones and/or medical providers; c) personalized emotional support from interventionists. While most felt the timing was appropriate, several who enrolled later in the eligibility window stated a desire for earlier intervention.

CONCLUSION

Participant feedback highlights the accessibility and potential benefits of this psychoeducation intervention for patients with newly diagnosed PMBT. These data will inform refinement of NeuroPathways in preparation for a pilot randomized controlled trial to formally assess feasibility and acceptability.
QOL-18. MANAGING CANCER AND LIVING MEANINGFULLY (CALM) IN PRIMARY AND SECONDARY MALIGNANT BRAIN TUMOR PATIENTS: INTERIM ANALYSIS OF A PHASE IIC RANDOMIZED CONTROL PILOT TRIAL
Authors: Loughan Ashlee , Lanoye Autumn , Davies Alexandria , Kleva Chris , Zarrella Giuliana , Fox Amber , Rodin Gary
Published: November 2024

BACKGROUND

Patients with both primary and secondary brain tumors demonstrate substantial psychological distress but have been historically excluded from psychological research. Managing Cancer and Living Meaningfully (CALM), a supportive- expressive- psychotherapy, has proven to reduce depression and death-anxiety in advanced cancer patients but trials in neuro-oncology have been limited. Interim analyses (50% accrual) of the first randomized control pilot trial (RCT) of CALM in neuro-oncology are presented here.

METHODS

In this ongoing NIH ORBIT model Phase IIc pilot RCT, 60 adults with primary or secondary malignant brain tumors and heightened distress (PHQ/DADDS) are randomized (2:1) to a six-session CALM intervention or usual care. Data collection includes established feasibility and acceptability metrics, intervention satisfaction surveys and interviews, and clinically meaningful changes in distress severity scores across three timepoints (pre-, post-CALM, follow-up).

RESULTS

Of 64 patients screened, 36 were eligible and 32 enrolled (n=20 CALM, n=12 Control; 65% female; 90% White; Mage=46yrs). A multimodal recruitment model was used. Currently, assessment completion rates are: post-CALM (80%) and follow-up (67%). Reasons for withdrawal include disinterest in intervention topics (n=1) and lost to follow-up (n=1). Intervention retention is currently at 90%, with 8 participants still in active treatment. No adverse events have been documented. Perceived benefit appears high (4.1/5) and all participants report they would recommend CALM to others. Pre- to post-CALM, depression severity reductions appear equal across arms (CALM PHQ-9=30%; Control=33%) but death anxiety severity reductions appear more prevalent in the treatment group (CALM DADDS=70%; Control=50%).

CONCLUSIONS

Interim data suggests promising feasibility and acceptability results in this pilot RCT. Enrollment, retention, and assessment completion rates appear adequate. Participants are reporting high benefit and recommendation of CALM. Improvement in death anxiety appears greater in those treated with CALM compared to controls. These interim RCT findings are promising and suggest completion of the current phase.
QOL-21. PSYCHOMETRIC VALIDATION OF THE FEAR OF CANCER RECURRENCE INVENTORY FOR PRIMARY BRAIN TUMOR PATIENTS
Authors: Cheng Emilie , Mladen Samantha , Cook Sarah , Lanoye Autumn , Loughan Ashlee , Simard Sebastian , Braun Sarah
Published: November 2024

BACKGROUND

Fear of cancer recurrence and progression (FCR) is a significant concern among those living with primary brain tumor and may be distinct compared to FCR in other cancer populations due to poorer prognosis, neurologic symptoms, and often lifelong treatment. The gold-standard comprehensive assessment tool for FCR–the FCR Inventory (FCRI)–includes 42 items with seven subscales. Validation of the FCRI scale excluded those with primary brain tumors. The present study is the first examination of the psychometric properties of the full FCRI in a heterogeneous sample of patients with primary brain tumors.

METHODS

Adult patients with primary brain tumors (n=334) completed the FCRI, with six additional brain tumor-specific items, and psychological, medical, and demographic questionnaires. In accordance with best practices of measure development, exploratory factor analysis (EFA) was conducted on the FCRI at the subscale level. Correlations investigated construct validity.

RESULTS

EFA largely supported the overall psychometric properties of the original FCRI. Several subscales were unchanged: Psychological Distress, Functioning Impairments, Insight, and Reassurance. One brain tumor-specific item (researching treatments) exhibited good fit on the Coping Skills subscale. On the Severity subscale, one item (belief that the tumor will not return) did not fit with an otherwise strong one-factor model. Additionally, five new brain tumor-specific items demonstrated good fit with the Triggers subscale. The resultant FCRI-Brain includes 41 original FCRI items plus six new brain tumor-specific items. FCRI-Brain demonstrated good convergent validity with measures of depression (r=.72), anxiety (r=.75), and death anxiety (r=.80; ps<.05).

CONCLUSIONS

This is the first validation of the comprehensive FCRI in patients with primary brain tumors. Factor analysis identified a theoretically similar and brain-tumor specific seven-factor model for the FCRI-Brain. Item-level and subscale statistics will be presented, including factor iteration and construction. Future work will use the FCRI to investigate FCR intervention efficacy in neuro-oncology.
QOL-23. MEASURING BODY FUNCTIONALITY APPRECIATION IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Cook Sarah , Davies Alexandria , Cheng Emilie , Lanoye Autumn , Loughan Ashlee , Braun Sarah
Published: November 2024

BACKGROUND

Body image is a multifaceted construct consisting of thoughts, feelings, and perceptions about one’s body and its functioning. Perception of one’s own physical functioning and capabilities may be an important consideration in neuro-oncology given the sequalae of brain tumors and associated treatment; however, it is understudied in this population. One brief measure of body image, the Functionality Appreciation Scale (FAS) is a comprehensive tool, focused on one’s perceived physical functioning and capabilities, rather than perceived appearance. We aimed to examine the psychometric properties of the recently developed Functionality Appreciation Scale (FAS) among patients with primary brain tumors.

METHODS

Adult patients with primary brain tumors (N=237) completed the FAS and other measures of psychological distress as well as medical and demographic characteristics. An exploratory variance factor analysis (EFA) using principal axis factoring and a Promax rotation was conducted. Convergent validity was examined via correlations to measures of psychological distress.

RESULTS

The EFA supported the single-factor structure, which accounted for 62.71% of the variance with all items loading significantly onto this factor. The FAS had good internal consistency (Cronbach’s a=.90). Convergent validity was demonstrated by negative associations (ps<.05) with symptoms of depression (r=-.30), generalized anxiety (r=-.21), and death anxiety (r=-.17).

CONCLUSION

Results confirmed the single factor structure of the FAS in primary brain tumor patients. Furthermore, the expected negative relationships with measures of psychological distress provide evidence of convergent validity. The FAS is valid and reliable in patients with primary brain tumors. Our findings suggest that body functionality and appreciation may be important to target in psychosocial interventions for those with primary brain tumors.
RBIO-02. DEVELOPMENT OF FLASH-CAR RADIOIMMUNOTHERAPY FOR PEDIATRIC BRAIN TUMORS
Authors: Ni Haiwei , Reitman Zachary , Kirsch David , Gong Yanqing , Fan Yi
Published: November 2024

Pediatric brain tumors including medulloblastoma and high-grade glioma are generally refractory to T cell-based immunotherapy, largely due to an immune-hostile microenvironment infiltrated extensively with immunosuppressive macrophages. Ultra-high dose rate (FLASH) radiotherapy holds promise for treating solid tumors, given the potential lower toxicity in normal tissues and possible favorable impact on tumor immunity. Using a genetically engineered mouse model of medulloblastoma and glioma, we show that FLASH radiation stimulates pro-inflammatory polarization in tumor macrophages. Single-cell transcriptome analysis shows that FLASH proton beam radiation skews macrophages towards proinflammatory phenotypes and increases T cell infiltration in the medulloblastoma model. Further bulk transcriptome analyses reveal that FLASH radiation reduces peroxisome proliferator-activated receptor (PPAR)-γ and arginase-1 expression and inhibits immunosuppressive macrophage polarization under stimulus-inducible conditions. Mechanistically, FLASH radiation abrogates lipid oxidase expression and oxidized low-density lipid (oxLDL) generation to reduce PPARγ activity, while standard radiation induces reactive oxygen species (ROS)-dependent PPARγ activation in macrophages. Notably, FLASH radiotherapy improves infiltration and activation of chimeric antigen receptor (CAR) T cells and sensitizes tumors to GD2 CAR T immunotherapy in the autochthonous medulloblastoma and syngeneic glioma models. These findings suggest that FLASH radiotherapy may reprogram macrophage lipid metabolism to reverse tumor immunosuppression and that combination FLASH-CAR radioimmunotherapy may offer exciting opportunities for treatment of pediatric brain tumor.
RBIO-03. A SMALL ANIMAL RADIATION RESEARCH PLATFORM (FLASH-SARRP) TO MEASURE IMMUNOLOGICAL EFFECT OF ULTRA HIGH DOSE RATE (FLASH) RADIOTHERAPY
Authors: Aziz Khaled , Sforza Daniel , Tajik-Mansoury Ehsan , Rezaee Mohammad , Kleinberg Lawrence
Published: November 2024

Patients who undergo radiation therapy (RT), particularly fractionated courses, often develop lymphopenia. Clinical outcome for various cancer types, including brain tumors, identifies lymphopenia as a negative prognostic factor. The mechanism for RT induced lymphopenia is unclear. Simulated models suggest the volume of blood flowing through a radiation field could play a crucial role in death of radiosensitive lymphocytes. FLASH RT is ultrahigh dose rate administration of RT, >100 times faster dose rate than standard RT that has been observed to improve the therapeutic ratio in preclinical models by preferential normal tissue sparing. Hypothesized mechanisms include chemical reactions depleting oxygen in well oxygenated normal cells creating radioresistance, differing pro-inflammatory signaling impacting tumor and normal tissue, and less impact on circulating immune cells consequent to decreased proportion exposed during a treatment session which may enhance antineoplastic response. We designed the novel FLASH kV x-ray cabinet system for preclinical laboratory research (FLASH-SARRP) to deliver ultra-high dose rates up to 100 Gy/s as well as conventional dose rates of 1.0 Gy/s to facilitate comparative studies. A custom designed docking system was developed to reproducibly position and immobilize mouse for stereotactic radiation of the brain. Dose and dose rate measurements were performed with calibrated Gafchromic EBT3 film in solid water with 0.025 mm additional copper filter. FLASH-SARRP system delivered kV x-rays at an average dose-rate of 79.2±2.1Gy/s corresponding to 10 mm depth in the immobilized mouse brain. For the delivery of 15 Gy, treatment duration was 0.2 seconds for FLASH RT administration whereas it was 244 seconds for conventional dose rate. We successfully designed a high-precision platform to study partial brain x-ray FLASH effects in mice and studies are ongoing to assess differential impact on normal brain tissue, circulating cytokines, and immune cell populations for single dose and fractionated administration of FLASH and standard radiotherapy.
RTID-01. ACCELERATOR-BASED BORON NEUTRON CAPTURE THERAPY, RANDOMIZED CONTROLLED TRIAL FOR RECURRENT AND REFRACTORY HIGH-GRADE MENINGIOMAS
Authors: Miyatake Shin-Ichi , Wanibuchi Masahiko , Furuse Motomasa , Nonoguchi Naosuke , Kawabata Shinji , Nihei Keiji , Ono Koji , Takeno Satoshi , Fu Naonori
Published: November 2024

INTRODUCTION

High-grade meningiomas (HGMs) recurred after X-ray treatment showed pessimistic prognosis. We started “A phase II investigator-lead RCT using accelerator-based BNCT system for refractory recurrent high-grade meningioma”.

MATERIALS AND METHODS

We prepared 2 study arms, BNCT test treatment arm (12 subjects) and control best supportive care arm (6 subjects) in randomized controlled trial (RCT) fashion. PFS judged by the third-party committee was primary endpoint and PFS judged by investigators themselves and OS of BNCT arm were secondary endpoints. Rescue BNCT was permitted for control group patients, if they showed progress disease (PD).

RESULTS

Three and two grade 3 subjects were included in BNCT and control arm, respectively. Others were grade 2 subjects. As of March 31, 2024, 10 out of 12 in BNCT arm and all 6 cases in control arm were judged as PD. mPFS judged by investigators showed 65 and 8 weeks for BNCT and control arm, respectively (P=0.0002, Wilcoxon). Six out of 12 in BNCT and 4 out of 6 cases in the control arm were dead. OS-2 year rates of BNCT and control arms are 91.7% and 33.3%, respectively (p=0.045, Wilcoxon). Five out of 6 cases in control arm received rescue BNCT after PD assessments. With regard to best response on MRI, PR, SD were 5 and 7 cases in treatment arms (ORR was 41.7%).

CONCLUSION

mPFS judged by third party committee is still being closed and unknown, so far. With regard to secondary endpoints, there are marked differences in both arms in mPFS judged by investigators. Recently, the results of RCT of “Trabectedine” organized by EORTC was reported. Unfortunately there was no effect of Trabectedine not only in PFS but in OS. In our current RCT results BNCT arm is extremely excellent in comparison with EORTC RCT of “Trabectedine” both in OS and PFS.
RTID-04. A MULTICENTER, RANDOMIZED, CONTROLLED PHASE 2B TRIAL OF SURVIVIN VACCINE SURVAXM PLUS ADJUVANT TEMOZOLOMIDE FOR NEWLY-DIAGNOSED GLIOBLASTOMA (SURVIVE)
Authors: Ahluwalia Manmeet , Ciesielski Michael , Abad Ajay , Reardon David , Ozair Ahmad , Khosla Atulya , Aiken Robert , Barbaro Marissa , Sinicrope Kaylyn , Peereboom David , Odia Yazmin , Brenner Andrew , Venur Vyshak , Belal Ahmed , Qiu Jingxin , Schilero Cathy , Casucci Danielle , Mechtler Laszlo , Fenstermaker Robert
Published: November 2024

BACKGROUND

Glioblastoma cells express high levels of survivin protein, whose presentation by MHC class I gets recognized by antibodies and cytotoxic T-lymphocytes (CTLs). A phase 2a trial (NCT02455557) demonstrated a median overall survival (OS) of 25.9 months in newly-diagnosed glioblastoma (nGBM) patients with 15-amino-acid-peptide-conjugate survivin vaccine (SurVaxM), which also stimulated production of survivin-directed antibodies and anti-tumor CTL. This phase 2b trial aims to further investigate efficacy and safety of SurVaxM plus adjuvant temozolomide (TMZ) for nGBM.

METHODS

SURVIVE is an ongoing, multicenter, randomized, placebo-controlled, investigator- and patient-blinded, phase 2b trial that randomizes nGBM patients receiving standard-of-care therapies to either SurVaxM (SurVaxM arm) or saline (control arm) in 3:2 ratio at 15 sites. Included patients have age ≥18 years, normal organ function, KPS≥70, and receive surgical resection with ≤1cm3 residual MRI contrast enhancement within 72 hours post-resection plus TMZ. Patients with recurrent, multicentric, brainstem- or cerebellar-origin GBM are excluded as well as patients on TTFields or other immunotherapies. All patients undergo 3 phases: (1) vaccine priming (VP) phase, starting ≤4 weeks after completing chemoradiation – 4 doses of SurVaxM or placebo administered q2weeks; (2) TMZ phase, started after ≥1 VP dose; and (3) vaccine maintenance phase, started 8 weeks after VP, with SurVaxM or placebo given q8weeks. TMZ phase overlaps with VP and VM phases. Primary endpoint is median OS. Assuming 1-year-OS of 75% in SurVaxM arm, based on prior trials, and 60% for control, the required sample size is N=228; 137 in SurVaxM and 91 in control arm. Accounting for dropouts, we aimed to enroll 239 patients. A log-rank test stratified by KPS (70-80 vs 90-100), MGMT methylation status, and IDH mutation status will be used for analysis. Secondary endpoints are OS and PFS at 15, 18, and 24 months, median PFS, and toxicity. A single sequential OS-driven interim analysis is planned when 50% of deaths occur. Trial is fully enrolled (NCT05163080).
SURG-08. A PHASE III RANDOMIZED TRIAL OF GROSS TOTAL RESECTION VERSUS POSSIBLE RESECTION OF FLAIR HYPERINTENSITY LESION ON MR IMAGE FOR NEWLY DIAGNOSED SUPRATENTORIAL GLIOBLASTOMA (JCOG2209)
Authors: Sonoda Yukihiko , Sekino Yuta , Mizusawa Junki , Shibahara Ichiyo , Sasaki Keita , Sekita Tetsuya , Ichikawa Mayumi , Igaki Hiroshi , Kinoshita Manabu , Shibahara Junji , Ichimura Koichi , Arakawa Yoshiki , Narita Yoshitaka
Published: November 2024

BACKGROUND

Complete resection of contrast-enhanced lesion (gross total resection: GTR) without severe neurological deficits has been generally accepted as the goal of surgery. However, it remains unclear if additional resection of surrounding FLAIR hyper-intense lesion combined with GTR (FLAIRectomy) has survival advantage of primary glioblastoma patients. Purpose: Multicenter, open-label, randomized phase III trial was commenced to confirm the superiority of FLAIRectomy to GTR alone followed by radiotherapy with concomitant and adjuvant temozolomide in terms of overall survival (OS) for primary glioblastoma IDH-wildtype patients. This trial investigates not only survival but also postoperative neurological and neurocognitive deficits in detail.

METHODS

We assumed a 2-year OS of 50% in the GTR arm and expected a 15% improvement in the FLAIRectomy arm. A total of 130 patients is required with a one-sided alpha of 5%, power of 70%, and will be accrued from 49 Japanese institutions in 4 years and follow-up will last 2.5 years. Patients 18-75 years of age will be registered and randomly assigned to each arm with 1:1 allocation. The primary endpoint is OS, and the secondary endpoints are progression-free survival, frequency of adverse events, proportion of Karnofsky performance status preservation, proportion of National Institutes of Health stroke scale preservation, proportion of mini-mental state examination preservation and proportion of health-related quality of life preservation. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in May 2023. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in July 2023.

DISCUSSION

If FLAIRectomy is superior to GTR alone, aggressive surgery will become a standard surgical treatment for glioblastoma with resectable contrast-enhanced lesion. Trial registration: Registry number: jRCT1031230245. Date of registration: 19/July/2023. Date of first participant enrollment: 28/July/2023. Funding for this study is provided by National Cancer Center Research and Development Fund (2023-J-03).
SURG-22. BRAIN METASTASIS FROM ADVANCED GASTRIC CANCERS: HIGH INCIDENCE OF LEPTOMENINGEAL DISSEMINATION AND ITS CLINICAL IMPACT ON SURVIVAL
Authors: Kim Euihyun
Published: November 2024

OBJECTIVE

Advanced gastric cancer is one of the most common and fatal cancers worldwide, and due to its highest incidence rate in Eastern Asian, it is steadily considered important. However, brain metastasis from advanced gastric cancer is very rare, and its incidence is reported as less than 1% of patients with primary advanced gastric cancer. There have been very few studies describing on the incidence and clinical outcome of patients with brain metastasis from advanced gastric cancers.

METHOD

We retrospectively analyzed 128 patients diagnosed as brain metastasis from advanced gastric cancers, and then underwent treatment from 2005 to 2021 April in our institution. Patients’ survival and its associated prognostic factors were evaluated. Especially, subgroup analysis on patients with leptomeningeal dissemination (LMD) was performed.

RESULT

Of total 128 patients of advanced gastric cancer with brain metastasis, 74 patients (58%) were diagnosed with LMD. Overall survival of LMD group was significantly shorter than that of non-LMD group (p<0.001). Patients treated with tumor removal (TR) followed by whole brain radiotherapy (WBRT) showed superior overall survival than patients with WBRT alone (p=0.002). Among 74 LMD patients, those who underwent WBRT combined with intrathecal methotrexate (IT MTX) showed better outcome than patients with WBRT alone (p=0.025). Specifically, for the 51 pure LMD patients without parenchymal brain metastasis, the superiority of adjuvant IT TMX on survival outcome was more apparent (p=0.011).

CONCLUSION

The incidence of LMD has been underestimated as 58% of patient with brain metastasis from advanced gastric cancers presented LMD on radiological and cytological studies. If the brain tumor is surgically resectable, TR followed by WBRT can be the first choice of treatment provides survival benefit. Patients with LMD are most benefited from IT MTX combined with WBRT.
SURG-25. PREOPERATIVE EMBOLIZATION IMPROVES LOCAL CONTROL AND REPROGRAMS GENE EXPRESSION IN ATYPICAL WHO GRADE 2 MENINGIOMAS
Authors: Haddad Alexander , Ramesh Rithvik , Zakimi Naomi , Quintana Daniel , Gil Eugene , Kabir Aymen , Sibih Youssef , Morales Blanca , Bhalla Shuhbhang , Morshed Ramin , Winkler Ethan , Aghi Manish , Raleigh David
Published: November 2024

Preoperative embolization is hypothesized to reduce blood loss and surgical time for meningioma resection, but the impact of embolization on long-term clinical outcomes and molecular profiling of meningiomas is incompletely understood. To address this, we evaluated the impact of embolization on outcomes and molecular features of WHO grade 2 meningiomas. A series of patients with grade 2 meningiomas who underwent resection at our institution from 1997 to 2021 were identified and reviewed. Available DNA methylation profiling and bulk RNA sequencing data were analyzed (n=200). Univariate and multivariate analyses, Cox proportional hazards modeling, and propensity matching (sex, age at surgery, previous surgery, extent of resection, postoperative radiation) were used. A total of 357 patients with WHO grade 2 meningiomas were included, 129 (36.1%) of which underwent preoperative embolization. Mean age at diagnosis was 53.5 years and 61.4% of patients were female. There was no significant difference in time to recurrence with or without embolization for cases with gross total resection (229/357), but embolization was independently associated with improved local control for cases with subtotal resection even after accounting for postoperative radiotherapy (HR 0.49, 95% CI 0.32-2.20 p=0.028). The average time to recurrence of atypical WHO grade 2 meningioma was 3.3 years after subtotal resection and 6.7 years after embolization and subtotal resection (p<0.001, propensity matched). The distribution of Merlin-intact vs Immune-enriched vs Hypermitotic meningioma DNA methylation groups was equivalent with versus without embolization, but differential gene expression analysis of RNA sequencing data revealed enrichment of hypoxia related pathways after embolization that were unique to each DNA methylation group. In summary, these data show that preoperative embolization improves local control and reprograms gene expression in atypical WHO grade 2 meningiomas. Additional investigation into the impact of embolization on clinical outcomes and gene expression for meningiomas, especially for higher-grade tumors, is warranted.