bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-44. CIRCULATING CELL-FREE DNA DIRECTLY INHIBITS T CELL FUNCTION AND CONTRIBUTES TO PERIPHERAL IMMUNOSUPPRESSION IN EXPERIMENTAL GBM
Authors: Ayasoufi Katayoun , Wolf Delaney , Reesman Rachael , Rangel Frances , Gulbicki Lauren , Tritz Zachariah , Jin Fang , Hansen Michael , Fain Cori , Pfaller Christian , Johnson Aaron
Published: November 2023

Glioblastoma (GBM) is aggressive form of brain cancer that is associated with severe peripheral immunosuppression. This immunosuppression is a critical barrier to patient survival and the success of immunotherapies. Immunocompetent mice harboring intracranial gliomas present with the hallmark features of peripheral immunosuppression observed in GBM patients, including T cell lymphopenia. Using parabiosis, we determined that T cell lymphopenia can be transferred from glioma-bearing to healthy mice via circulation This led to the identification of a high molecular weight immunosuppressive factor in sera of glioma-bearing mice that inhibits T cell proliferation ex vivo. Proteomics analysis identified 119 proteins uniquely upregulated in the sera of glioma-bearing mice compared to controls. These proteins are associated with pathways involved in DNA response elements, cell death, and DNA-histone complexes which imply DNA release. Additional analysis revealed serum isolated from glioma-bearing mice harbor significantly higher concentrations of double stranded cell free DNA (cfDNA) compared to controls. Reducing DNA content using DNase partially reverses the proliferation defects observed in T cells when exposed to serum of glioma-bearing mice. This is while, addition of cfDNA purified from serum of glioma-bearing mice, but not genomic DNA, potently inhibited T cell function. These results were AIM2 independent implicating a novel pathway of cfDNA sensing in T cells. We contend that cfDNA induces immunosuppressive effects in experimental GBM. Devising strategies to reduce circulating cfDNA is therefore a therapeutic approach that could improve outcomes in GBM patients.
IMMU-47. IMMUNOGENIC AND IMMUNOSUPPRESSIVE ASPECTS OF HSV-TK/GCV-MEDIATED SUICIDE GENE THERAPY IN GLIOMA CELLS
Authors: Hossain Jubayer , Latif Abdul , Chaudhuri Romi , Solel Ege , Ystaas Lars , Bjerkvig Rolf , Miletic Hrvoje
Published: November 2023

Suicide Gene therapy (SGT) has been regarded as a promising experimental treatment modality for high-grade gliomas for several decades. However, large-scale clinical trials have failed so far. One hypothesis behind this failure is that, even though SGT directly kills the bulk of the tumor cells, it fails to activate an efficient anti-tumor immune response. Indeed, despite extensive research on SGT, the mechanism of cell death caused by SGT and its immunogenic significance are largely unknown. The most prominent form of SGT— HSV-TK/GCV— for example, is known to kill tumor cells mostly by apoptosis. The immunogenicity of apoptosis in general is controversial and not yet fully explored, especially in the context of SGT. We studied the immunogenic nature of cell death caused by HSV-TK/GCV with two widely used mouse glioma models. To exclude the potential influence of viral vectors on the immune system, we used genetically engineered tumor cells that expresses HSV-TK gene. After orthotopic tumor modelling and SGT with HSV-TK/VGCV, we analyzed the change in immune landscape by using ELISPOT, IHC, FACS and Hyperion in both models. Firstly, we observed that the efficacy of SGT is entirely different in the two glioma models. While in one model tumor growth is only decreased, SGT is curative in the second model. In the non-responding model, an immunosuppressive tumor microenvironment after SGT is observed. Further investigation of the responding model shows that the successful cure is dependent on the availability of an active immune system. We have also identified that the resultant anti-tumor immunity following SGT in this model is mounted by T cells. In conclusion, our data suggest that the immunogenic nature of SGT shows intertumoral heterogeneity and warrants more research to identify the inherent determining factors and mechanisms thereof.
IMMU-51. THE LANDSCAPE OF TUMOR INFILTRATING T CELLS (TILS) OF CHILDHOOD BRAIN TUMORS
Authors: Raphael Itay , Nisnboym Michal , Sneiderman Chaim , Xiong Zujian , Pollack Ian , Chikina Maria , Rajasundaram Dhivyaa , Kohanbash Gary
Published: November 2023

T lymphocytes have a unique ability to recognize a vast array of antigens prompt by an enormous T cell receptor (TCR) repertoire. Characterization of tumor-infiltrating T cells (TILs) and their TCRs is key to understand MHC-restricted anti-tumor immunity and for developing T cell centered immunotherapies such as adoptive cell therapy and tumor vaccines. In the current work, we investigated RNAseq data from nearly 1,000 pediatric brain tumor patients and performed the first large-scale comprehensive examination of the immunogenomic and TCR landscape of TILs across the spectrum of pediatric brain tumors. We show that the relative ratio between T cell diversity (clonality) and T cell abundance within each sample, represented by the clonal expansion index (CEI), is a strong predictor of prognosis across tumor types and molecular subtypes. Interestingly, we found that CEI was strongly associated with molecular subgroups of medulloblastoma but not with known genomic features of these subgroups. Analysis of single-cell (sc)RNAseq and scTCRseq data of TILs across several tumor types, validated clonal expansion of TILs which were frequently associated with effector-cytotoxic T cell phenotypes, whereas non-expanded TILs were associated mostly with CD4 T cell phenotypes. Investigation of T cell clones recognizing a common recurrent tumor-antigen across patients based on CDR3 homology and characteristics, reveals several T cell specificity groups which are tumor type restricted with defined HLA dominance. Using machine learning investigations of genomic profiles of the patients which contain these T cell specificity groups identified novel putative HLA-restricted tumor antigens shared across patients. Importantly, our framework grounded the foundations for developing a precision medicine approach of T cell centered immunotherapies. In all, our findings have major implications for understanding the interplay between T cell and tumor genomic, and for improving immunotherapy strategies for childhood brain tumors.
IMMU-58. CHARACTERIZATION OF MYELOID CELL POPULATIONS IN PEDIATRIC HIGH-GRADE BRAIN TUMORS: THE MIMIC PROGRAM
Authors: Carvalheiro Tiago , Meesters-Ensing Joyce , Hoogendijk Raoull , Kranendonk Mariëtte , Van Baarsen Kirsten , Hoving Eelco , Calkoen Friso , van der Lugt Jasper , Nierkens Stefan
Published: November 2023

BACKGROUND

Pediatric high-grade brain tumors (pHGBT) pose treatment challenges with limited options. Myeloid cells, particularly tumor-associated macrophages (TAMs) in the tumor-microenvironment (TME), exhibit potent immunosuppressive features inhibiting effective anti-tumor T-cell responses. Targeting these cells holds promise to improve outcomes, however the underlying mechanisms of myeloid cell dysfunction remain poorly understood. This study aimed to comprehensively characterize myeloid cell populations in pHGBT and investigate their functional phenotype.

METHODS

Spectral flow cytometry was performed on tumor tissue (biopsies or resections) and tumor fragments obtained by cavitron ultrasonic surgical aspiration (CUSA) in pHGBT patients (High-grade glioma n=2, Ependymoma n=1, Medulloblastoma n=6, Pilocytic Astrocytoma n=2) enrolled in the MIMIC program. This allowed quantification and comprehensive characterization of myeloid cell populations within the TME.

RESULTS

The pHGBT TME showed a low abundance of immune cells across different entities, with myeloid cells comprising the predominant proportion. CD49d was used to identify invading cells derived from bone marrow (CD49+) and resident microglia (CD49-). The total TAMs/microglia population was detected in both tumor tissue and CUSA tumor fragments in similar proportions, however resident CD49d- microglia were notably increased in CUSA tumor fragments. Additionally, invading TAMs displayed a mixed "M1" and "M2" polarization phenotype and exhibited higher expression of the chemokine receptor CCR2 and HLA-DR, and of the immune-checkpoint receptors SIRP1A/B, CD33, and TIM3, compared to resident microglia.

CONCLUSIONS

TAMs play a multifaceted role in pHGBT. The high expression of immune-checkpoint receptors by invading TAMs suggests an immunosuppressive phenotype, potentially facilitating tumor growth, infiltration and (immune)therapy escape. Although, differences between disease entities could not yet be analyzed, disparities were observed in the TME between tumor and CUSA samples, likely related to spatial cellular organization. Understanding TAM dynamics and functional differences between invading and resident subsets, as well as their underlying mechanisms, is crucial for advancing therapeutic efficacy in pHGBT.
INNV-02. USAGE TRENDS OF COLLAGEN TILE BRACHYTHERAPY FOR THE FIRST 1000 ORDERS
Authors: Garcia Michael , Turner Adam , Campbell Lisa , Brachman David
Published: November 2023

INTRODUCTION

Collagen tile brachytherapy (CTBT) was cleared by the FDA in 2018 for all recurrent intracranial neoplasms and in 2020 for newly diagnosed intracranial neoplasms. We sought to describe usage trends of CTBT by evaluating the first 1000 consecutive orders since CTBT became commercially available in 2019 with respect to tumor type (glioma, brain metastasis, meningioma) and CTBT treatment setting (newly diagnosed, recurrence with prior radiation, recurrence without prior radiation).

METHODS

Commercial data was accessed using Salesforce, Inc. Coefficient of correlation (r2) was estimated as a measure of orders over time. 1000 orders were divided into 4 time cohorts (Cohort 1 for 1st 250 orders, Cohort 2 for 2nd 250 orders, Cohort 3 for 3rd for 250 orders and Cohort 4 for 4th 250 orders). Order proportions were compared among time cohorts using X2 tests.

RESULTS

Time period for 1000 orders among 93 centers was 1/23/19–5/11/23. Over these 17 completed yearly quarters there was a positive trend in ordering frequency (r2=0.97). Tumor type was known for 917 orders, of which 52.2% were glioma, 37.4% metastases, and 10.4% meningioma. Proportions of orders for tumor type did not change over time cohorts (p=0.26). Treatment setting was known for 816 orders, of which 80.3% were in recurrence with previous radiation, 14.3% newly diagnosed, and 5.4% recurrence without previous radiation. For glioma and meningioma, treatment setting did not change over time cohorts (p=0.5, p=0.3, respectively). However, for metastases, the proportion of orders for use in the newly diagnosed setting increased over time: 6.4% in Cohort 1, 19.2% in Cohort 2, 21.6% in Cohort 3, 34.7% in Cohort 4 (p< 0.001).

CONCLUSION

CTBT usage is increasing over time. Proportions of orders among tumor types (glioma, meningioma, metastases) has not changed. However, use of CTBT is increasing in the newly diagnosed setting for brain metastases.
INNV-05. OUTCOMES OF RECURRENT GLIOBLASTOMA PATIENTS WITH RADIATION NECROSIS FOLLOWING GAMMATILE BRACHYTHERAPY IMPLANTATION
Authors: McCracken D Jay , McCracken Courtney , Kenning Tyler , Nowlan Adam , Dunbar Erin
Published: November 2023

Implantation of collagen tile brachytherapy GammaTile (GT Medical Technologies Tempe, AZ) allows for targeting of radiation to residual malignancy following surgical resection of gross disease. Radiation necrosis (RN) can develop after radiotherapy or brachytherapy. We sought to determine outcomes in recurrent glioblastoma patients with RN after treatment with Gammatile. All patients were previously treated with surgical resection followed Stupp protocol chemoradiation. At recurrence, patients underwent repeat surgical resection and implantation of GammaTile. Subsequent MRIs were assessed for stability, presumed RN or progression. Symptomatic RN patients were treated with corticosteroids or bevacizumab. From December 2020 to February 2023, 19 patients were treated. Median time from initial radiation to GammaTile therapy was 270 days. A total of 8 patients (42%) developed RN at a median time of 81 days from GammaTile. In RN patients vs those that did not develop RN, pathological tumor viability was lower (20% vs 50%, p=0.3), age was lower (54 vs 63, p=0.06), tumor volume was lower (10.8 cc vs 51.9 cc, p=0.02), time from initial surgery was longer (470 days vs 299 days, p=0.46), number of GammaTiles placed was lower (5 vs 8, p=0.045), rate of gross total resection (GTR) was higher (100% vs 64%, p=0.04), and MGMT methylation rate was higher (63% vs 11%, p=0.03). No patients in the RN group experienced radiographic progression (0% vs 45%, p=0.009) and 3 (38%) required bevacizumab therapy. Median overall survival from GammaTile surgery in the RN group was 325 days vs 188 days (p=0.03). Our series demonstrates a significant survival benefit in patients who develop RN following GammaTile implantation after glioblastoma recurrence. RN developed in younger patients with smaller tumor volumes, lower pathological tumor viability, and higher rates of GTR and MGMT methylation status.
INNV-06. SIGNIFICANCE OF MOLECULAR DIAGNOSTICS FOR THERAPEUTIC DECISION-MAKING IN RECURRENT GLIOMA
Authors: Blobner Jens , Dengler Laura , Blobner Sven , Eberle Constantin , Weller Jonathan , Teske Nico , Karschnia Philipp , Ruehlmann Katharina , Heinrich Kathrin , Ziemann Frank , Greif Philipp , Jeremias Irmela , Wuerstlein Rachel , Hasselmann Korbinian , Dorostkar Mario , Harter Patrick , Quach Stefanie , Stoecklein Veit , Albert Nathalie , Niyazi Maximilian , Tonn Joerg-Christian , Thon Niklas , Westphalen Benedikt , von Baumgarten Louisa
Published: November 2023

BACKGROUND

Targeted therapies have substantially improved survival in cancer patients with malignancies outside the brain. Whether in-depth analysis for molecular alterations may also offer therapeutic avenues in primary brain tumors remains unclear. We herein present our institutional experience for glioma patients discussed in our interdisciplinary Molecular Tumor Board (MTB) implemented at the Comprehensive Cancer Center Munich (LMU).

METHODS

We retrospectively searched the database of the MTB for all recurrent glioma patients after previous therapy. Recommendations were based upon next-generation sequencing results of individual patient’s tumor tissue. Clinical and molecular information, previous therapy regimens and outcome parameters were collected.

RESULTS

Overall, 73 consecutive recurrent glioma patients were identified. In the median, advanced molecular testing was initiated with the third tumor recurrence. The median turnaround time between initiation of molecular profiling and MTB case discussion was 48 ± 75 days (range: 32 - 536 days). Targetable mutations were found for 50 recurrent glioma patients (68.5%). IDH1 mutation (27/73; 37%), EGFR amplification (19/73; 26%) and NF1 mutation (8/73; 11%) were the most detected alterations and a molecular-based treatment recommendation could be made for all of them. Therapeutic recommendations were implemented in 12 cases (24%) and one third of these heavily pretreated patients experienced clinical benefit with at least disease stabilization.

CONCLUSION

In-depth molecular analysis of tumor tissue may guide targeted therapy also in brain tumor patients and considerable anti-tumor effects might be observed in selected cases. However, future studies to corroborate our results are needed.
INNV-07. ADJUVANT POST-SURGERY TREATMENT OF RECURRENT IDH2 MUTANT ANAPLASTIC OLIGODENTROGLIOMA (AO) WITH IDH2 INHIBITOR, ENASIDENIB: A CASE REPORT
Authors: Kong Xiao-Tang , Fu Beverly Dan , Myung Joon , Bota Daniela
Published: November 2023

INTRODUCTION

Recent phase III trial presented by Mellinghoff at 2023 ASCO demonstrated successful treatment of Isocitrate dehydrogenase (IDH)–mutant grade 2 gliomas with Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes. Ivosidenib and enasidenib are separate inhibitors of mutant IDH1 and IDH2, which have shown single-agent activity for the treatment of IDH1- or IDH2-mutant acute myeloid leukemia but the effect in the treatment of glioma is uncertain. Here we report a case of IDH2 mutant AO, who was treated with enasidenib for about two years with fair tolerance and was postponed the next intervention.

CASE REPORT

A 36 yo female was diagnosed anaplastic ogligodentroglioma in 2006, 17 yrs ago. The patient underwent surgery resection, radiation and Temozolomide (TMZ), and 4 cycles of adjuvant TMZ. In 2021, fifteen years later, she was found tumor recurrence. She had a second surgery with near gross total resection. Pathology confirmed anaplastic oligodentraglioma with negative IDH1 mutation but positive IDH2 R172K mutation. To avoid re-radiation nor re-challenge with TMZ, the patient opted IDH2 inhibitor therapy after surgery. The patient tolerated the treatment, and her brain MRI demonstrated no tumor recurrence until one year later when her brain MRI showed vague sub-centimeter nodular non-enhancing lesion at surgical area. Enasidenib was continued for additional 6 months until recent MRI showed small and slow growth. Total therapy is 20 months. Clinically, the patient has no symptoms from tumor.

DISCUSSION

Our case review found post-surgery therapy with IDH2 inhibitor Enasidenib for IDH2 mutant recurrent AO is tolerated and could postpone next intervention such as re-radiation or re-challenge with TMZ.
INNV-14. INTERIM REPORT OF A PHASE 1/2 STUDY OF SONODYNAMIC THERAPY (SDT) USING AMINOLEVULINIC ACID (ALA) AND LOW-INTENSITY FOCUSED ULTRASOUND IN PEDIATRIC PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: Syed Hasan , Kilburn Lindsay , Packer Roger , Keating Robert , Mueller Sabine , Patel Nirali , Fenn Peter , Clanton Ryan , Andresen Corina , Marcus Stuart , Benaim Ely
Published: November 2023

BACKGROUND

DIPGs are devastating pediatric brain tumors with limited treatment options, poor prognosis, and survival of 9-11 months. Preclinical studies demonstrate that performing SDT through MR-guided focused ultrasound (MRgFUS) activates ALA metabolite, protoporphyrin IX (PpIX), leading to tumor cell death and prolonging survival in rodent glioma models through generation of reactive oxygen species and lipoperoxidation, without affecting normal tissue. MEDTHODS: Herein we report preliminary data from an ongoing first-in-child dose-escalation trial of ALA-SDT post-radiation therapy in children ≥ 5 years with DIPG. The trial aims to evaluate the safety and tolerability of ALA-SDT, determine the recommended-phase-2-dose and assess preliminary efficacy and pharmacokinetics (PK) of ALA administered intravenously.

RESULTS

The first study cohort completed enrollment of 3 subjects. Six hours prior to SDT, patients received an infusion of ALA (SONALA-001) at a dose of 5 mg/kg, followed by sonication with 200J. The first subject was treated in 2 sessions: each to half of the pons 30 days apart. Two subsequent subjects had the entire pons treated in a single session. No dose-limiting toxicity (DLT) or related adverse event grade ≥ 3 were observed. For SONALA-001, the Cmax occurred at the end of infusion, followed by rapid clearance (15.7 mL/min/kg), with a plasma half-life of < 1 hour, indicating rapid distribution (5530 ml/kg). For PpIX, the Cmax occurred 6 hours post-dose and declined with a longer mean half-life of 3.8 hours. Both Cmax and AUCall demonstrate circulating PpIX and systemic exposure were significantly lower than for ALA.

CONCLUSION

SDT signals an innovative and well-tolerated approach for patients with DIPG in our first study cohort. As expected, the PK for SONALA-001 demonstrate rapid infusion and clearance, whereas for PpIX, the PK are consistent with formation of a metabolite. Clinical trial enrollment is ongoing and dose-escalation cohorts will provide additional PK and safety data.
INNV-17. TREATMENT DECISION AND QUALITY OF LIFE OF PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA RECEIVING TUMOR TREATING FIELDS (TTFIELDS) THERAPY IN ROUTINE CLINICAL CARE: RESULTS FROM THE TIGER STUDY
Authors: Bähr Oliver , Tabatabai Ghazaleh , Fietkau Rainer , Goldbrunner Roland , Glas Martin
Published: November 2023

BACKGROUND

TTFields therapy, concurrent with temozolomide, is approved for treatment of newly diagnosed glioblastoma (ndGBM), following results from the pivotal EF-14 study. The multicenter, prospective TIGER study (NCT03258021) investigated real-world use of TTFields therapy in patients with ndGBM during routine clinical care in Germany. Data on patient treatment decisions and health-related quality of life (HRQoL) are reported.

METHODS

Reasons for patient decision to receive TTFields therapy were evaluated via questionnaire (scoring scale: 1 [not at all] to 5 [strongly]) at baseline. In patients who decided to receive TTFields therapy, HRQoL was assessed via the EORTCQLQC30/BN20 questionnaire at baseline, and 2 and 4 months after initiating therapy. HRQoL parameters included: global health status and functioning, insomnia, headaches, fatigue, nausea/vomiting, pain, itchy skin, hair loss, seizures, dyspnea, appetite loss, constipation, diarrhea, visual disorder, leg weakness, drowsiness, bladder control, motor dysfunction, communication deficit, future uncertainty, and financial difficulties.

RESULTS

Overall, 710 patients (259 female; 451 male) were enrolled (Aug 2017–Nov 2019). Mean age was 59 years (range: 19–85). In total, 582 (82%) patients decided to start TTFields therapy, while 128 (18%) declined; the proportion of women was similar in each group (36% and 38%, respectively). Predominant reasons for deciding to start TTFields therapy were the prospect of treatment success (mean score: 4.5) and doing something to fight their disease (4.2). Predominant reason for deciding against TTFields therapy was carrying the device (4.4). During 4-month study follow-up, there was no decline or improvement in any HRQoL parameter, except for more itchy skin, consistent with EF-14 data.

CONCLUSION

TIGER is the largest non-interventional study to date on TTFields therapy use in routine clinical care. Most patients opted to receive TTFields therapy, with fighting their disease and hope for treatment success as major motivators. HRQoL was not impaired during follow-up, except for skin itchiness.
INNV-18. MULTIPHASE COMBINED TREATMENT, INCLUDING INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY FOR ADULTS WITH GBM: SINGLE INSTITUTE REAL WORLD MEDICAL DATA IN THE LIGHT OF CLINICAL TRIAL RESEARCH DATA
Authors: Van Gool Stefaan , Van de Vliet Peter , Kampers Linde , Makalowski Jennifer , Sprenger Tobias , Schirrmacher Volker , Stuecker Wilfried
Published: November 2023

A phase III prospective externally controlled cohort trial recently demonstrated beneficial effects of DCVax®-L for adults with GBM. The beneficial effect of TTF was demonstrated in a RCT. We designed a multiphase combined treatment using subsequentially 1/ modulated electrohyperthermia and Newcastle Disease Virus therapy to induce immunogenic cell death (ICD) during temozolomide maintenance chemotherapy, 2/ two autologous DC vaccinations (IO-Vac®), and 3/ ICD immunotherapy, long-peptide vaccines and one boost IO-Vac® vaccine. During phase 2 + 3, individualized modulatory immunotherapy was provided. Fifty adults with first-line IDH1wt GBM were retrospectively analysed: MGMT promoter-unmethylated (unmeth, 10 f, 18 m); -methylated (meth, 12 f, 10 m). Median age was 48y, median Karnofsky performance index was 80. More than half of the patients had less than complete resection. Dynamics in tumor biology and immune response were demonstrated during treatment (e.g. mRNA expression for PDL1 in circulating tumor cells), and required treatment adaptations (checkpoint inhibitors). The median OS of unmeth and meth patients were 22m (2y-OS: 42%) resp. 38m (2y-OS: 81%, p=0.0414). There were no considerable treatment-related adverse reactions. The (external) control arms in the DCVax®-L and TTF trials, which reflect the current standard-of-care clinical results, showed median OS and 2y-OS of 15m/21% in unmeth and 21m/42% in meth patients. TTF improved the OS in both unmeth and meth patients (17m/27% and 32m/59%), while DCvax®-L improved OS only in meth patients (15m/19% and 30m/58%). These real world data support to prospectively explore the addition of individualized multimodal immunotherapy during and after standard of care, and the role of treatment adaptations during treatment.
INNV-19. LANGUAGE ACTIVATION AREAS AND PATHWAYS INTEGRITY ASSESSMENT FOLLOWING GLIOMA RESECTION AND SUBSEQUENT RADIATION TREATMENT
Authors: Haisraely Ory , Cohen Zvi , Anton Wohl , Livny Abigial , Tsarfaty Galia , Belenky Eugenia , Kaisman-Elbaz Thila
Published: November 2023

BACKGROUND

It is a well-established practice to perform brain-mapping scans of patients diagnosed with dominant frontal/temporal lesions to evaluate their language activation areas (LAAs) and pathways prior to surgical intervention. Dependent on the pathology, brain functional regions and their associated pathways may be exposed to post-operative radiation as part of the patient's treatment protocol. The post-radiation detrimental effect on cognition is well-known, however, the effect of surgical resection and subsequent radiation on LAAs and pathways' integrity is not well studied. Here, the impact of surgical resection and radiation on LAAs and pathways integrity is examined.

METHODS

8 patients that underwent surgical resection to frontal/temporal lesion located at their dominant hemisphere followed by radiation treatment with at least two brain-mapping scans in Sheba Medical Center between the years 2012 to 2021 were collected. Location of functional LAAs (such as Broca's and Wernicke’s areas) as well as that of structural fiber tracts (such as the arcuate fasciculus) were determined. Volumetric and tumor geometry data was measured and documented. Laterality index of activation and Fractional Anisotropy (FA) quantitative values were calculated and compared from the baseline scan to the post-treatments scan for each patient.

RESULTS

Patients’ demographics analysis showed that their median age-at-diagnosis was 41 years (range, 4-64). The median overall survival was 89 months (range, 19-130) and the median follow-up duration was 80 months (range, 16-129). Radiation mean dose was 57Gy (range 40.05-60) and Planning treatment volume was 315ml (range 123.3-456.5) Notably, the mean laterality index of LAAs was also affected by intervention (p=0.044). Additionally, the arcuate fasciculus’ FA values differed in the post-interventions scan compared to the pre-interventions scan

CONCLUSION

surgical resection and radiation treatment may cause changes in the lateralization of the LAAs that may represent an attempt to compensate for a significant brain injury.
INNV-23. HEALTH AND HEALTHCARE FACTORS THAT SHAPE THE GLIOMA PATIENT EXPERIENCE THROUGHOUT THE CANCER CONTINUUM: THE VALUE OF CARE COORDINATION AND COMMUNICATION
Authors: Ernster Alayna , Canzona Mollie , Hsu Fang-Chi , Weaver Kathryn , Hutchinson Angelica , Lesser Glenn , Houston Kristin , Marshall Alexandria , DeTroye Alisha , Strowd Roy
Published: November 2023

BACKGROUND

Cognitive or communication deficits from glioma may pose challenges in patients’ ability to manage their illness and navigate the healthcare system. Disease-specific barriers must be overcome to achieve patient-centered care and shared-decision making. This study identified health and healthcare factors that enhance or complicate the patient experience throughout the glioma-cancer continuum.

METHODS

Semi-structured interviews (N=8) or focus groups (N=6) were conducted in-person or via phone call with 23 glioma patients at any point during their cancer care. The constant comparative method was used to identify themes illustrating the healthcare factors that shape the glioma patient experience.

RESULTS

Three themes that facilitate the healthcare experience and six themes that complicate the healthcare experience were identified. Facilitating themes included (1) free exchange of information with healthcare providers (HCP), (2) HCP expectation setting and efforts to support patient agency, and (3) HCP relationship building efforts. Complicating themes included (1) early attempts to address initial symptoms in healthcare settings, (2) patient perception of initial symptoms, (3) long wait times and time-intensive appointment schedules, (4) accessing and navigating procedures for appointments and multiple locations, (5) timing and delivery of information during treatment, and (6) mixed messages about prognosis and treatment recommendations.

DISCUSSION

Health and healthcare factors that influence the glioma patient experience are concentrated around patients’ relationships and communication with HCP and the logistics of cancer care delivery. Logistical barriers to care delivery negatively affect the patient experience and highlight the need for interventions that aim to streamline care delivery, help patients manage care, fulfill healthcare information needs, and enhance team-based cross-disciplinary communication.
INNV-29. THE CLEARPOINT PRISM® LASER ABLATION SYSTEM: A NEW PLATFORM FOR LASER INTERSTITIAL THERMAL THERAPY (LITT) IN NEURO-ONCOLOGY
Authors: Wilson Hannah , Chen Clark
Published: November 2023

BACKGROUND

Laser interstitial thermal therapy (LITT) has advanced the surgical treatment of brain cancer. However, technical constraints in the first-generation laser ablation systems limit the full potential of this technology. ClearPoint Prism® Laser Ablation System was developed to overcome many of these limitations, including a larger ablation window, a faster refresh rate for magnetic resonance thermometry, and integration with an MRI-compatible stereotactic system. This system was FDA cleared for neurosurgical use in 2022.

METHODS

We prospectively followed the first three patients who underwent LITT using the ClearPoint Prism® Laser Ablation System in the U.S. to establish feasibility and safety of this technology platform.

RESULTS

Three patients underwent procedures involving MRI-guided needle biopsy followed by LITT. The radial error of stereotaxis relative to the intended target ranged 0.8-1.6 mm (with a median of 1.0 mm). Definitive diagnosis was achieved in all cases. The average time required to establish the trajectories was 98.7 + 16.6 minutes. The average time required to perform the biopsy and LITT was 110 + 19.3 minutes. These times are not statistically different from our published results for comparable procedures using other available LITT systems. The average LITT time required to achieve ablation of > 1cm radius was 49 seconds (range: 29-133 seconds). There were no procedural complications. All patients were discharged home by postoperative day three. The postoperative MRIs demonstrated expected ablation findings consistent with intraoperative thermometric assessment. With a median follow-up of 219 days (range: 185-259 days), there were no 30-day readmission, 90-day emergency visits, or wound complications.

CONCLUSION

In this study, we provide the clinical outcome of the first three patients in the U.S. who underwent LITT through the FDA cleared ClearPoint Prism® Laser Ablation System. The system has distinct advantages that warrant consideration in further investigations and clinical applications.
INNV-34. A NOVEL APPROACH TO ADDRESSING THE UNIQUE NEEDS OF ADOLESCENT AND YOUNG ADULT (AYA) BRAIN TUMOR PATIENTS: A FRAMEWORK FOR A VIRTUAL PEER-LED YOUNG ADULT SUPPORT GROUP
Authors: Hines Dace , Scotford Katie , Bryson-Cahn Phoebe , Hoffer Naomi , Destri Mary , Greenstein Alexa , Chang Susan , Schulte Jessica
Published: November 2023

INTRODUCTION

Adolescent and young adult (AYA) patients (age 15-39) constitute 14.3% of new brain tumor diagnoses annually. While navigating cognitive and physical challenges from their tumor, these patients are also pursuing social independence, education, careers, relationships, and family planning. These patients have unique, and often unmet, psychosocial needs compared to older patients, requiring a new approach for comprehensive care.

METHODS

Three YA neuro-oncology patients from UCSF volunteered to facilitate a monthly virtual support group. Facilitators were trained in peer support mentorship and support group facilitation by a licensed psychologist. A program planning committee consisted of: a social worker, nurse practitioner, program manager, communications specialist, two neuro-oncologists, and the peer facilitators. Promotion was done through flyers, the UCSF and ABTA websites, and word-of-mouth. Feedback was collected via anonymous survey and informal discussions, and the planning committee met monthly to adapt to evolving group needs. Participants used a video chat app to stay connected between meetings.

RESULTS

Over one year, 73 patients registered, and 40 total participated (average 15/session). Participant age range was 19–44, and age at diagnosis was 10–43. From 19 survey responses, 84% preferred a mix of open and topic-driven discussions. Key topics desired for peer discussion included meditation/mindfulness (68%), cognitive changes (58%), symptom management (58%), relationships/sexual health (58%), exercise (58%), and anxiety (58%). By contrast, participants wanted healthcare providers to address tumor treatment (37%), cognitive challenges (37%), symptom management (32%), seizures (26%), nutrition (26%), and integrative health (21%). Qualitative feedback highlighted community and social support from similarly-aged peers facing similar challenges amongst the most valuable aspects.

CONCLUSIONS

AYA patients have different information and support needs from peers versus providers. Peer-led support groups effectively provide social support for AYA brain tumor patients. Successful implementation involves volunteer facilitators, training, regular planning committee meetings, and participant feedback.
INNV-37. BELZUTIFAN IMPACT ON VHL-ASSOCIATED CNS HEMANGIOBLASTOMAS
Authors: Demers Abigail , Abukhdeir Amal , Gatewood Tyra , Doynova Antoniya Marinova , Chahoud Jad , Spiess Phillippe , Malafa Mokenge , Iacono David , Sahebjam Solmaz , Tran Nam , Mokhtari Sepideh
Published: November 2023

INTRODUCTION

CNS hemangioblastomas are a leading cause of morbidity and mortality among patients with Von Hippel-Lindau (VHL) disease. Belzutifan, a selective hypoxia-inducible factor (HIF-2a) inhibitor, has been approved for the treatment of hemangioblastomas in VHL patients; however, long-term efficacy and safety data are lacking.

METHODS

The authors performed a retrospective chart review of all type Ia VHL with symptomatic CNS hemangioblastomas who were treated with Belzultifan at the Moffitt Cancer Center from August 2021 to June 2023. Patient demographics, clinical characteristics, tumor characteristics, and complications were assessed. Patients were re-evaluated with repeat CNS imaging every 3-6 months.

RESULTS

Eleven patients were identified. Median age is 35 years (IQR: 24-56) and 4/11 patients (36%) are female. Eight out of 11 patients had accessible genetic testing and 87.5% had a missense mutation in the VHL gene. Two patients (18%) had pathology-proven RCC and no patients had pheochromocytomas. One patient (9%) had complete response, eight (73%) had partial response, and two patients (18%) had stable disease at 6 months. Treatment was stopped on 8 patients once they reached stable response to treatment, with 1 patient at 6 months (12.5%), 5 patients at 1 year (62.5%), and 2 patients at 16 months (25%). Five out of 8 patients (62.5%) had sustained response (≥ 3 months) during the time Belzutifan was held. Treatment was restarted on the 3 patients who had progression of disease and all 3 had positive response to treatment at 3 months. All patients had anemia (CTCAE grade 1-2), but did not require blood transfusions, and 1 patient had visual disturbances after restarting Belzutifan.

CONCLUSION

All patients responded positively to Belzutifan based on surveillance CNS imaging, with no major side effects. The majority of patients had sustained response after having stopped the drug for 3 months.
INNV-39. INVESTIGATING MULTI-AGENT INTRATHECAL CHEMOTHERAPY AS A TREATMENT FOR PRIMARY AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA: SAFETY AND EFFICACY RESULTS FROM AN INSTITUTIONAL COHORT STUDY
Authors: Wilding Hannah , Aastha Aastha , De Macedo Filho Leonardo Jose Monteiro , Bhanja Debarati , Heebner Madison , Khan Shahbaz , Mikolajewicz Nicholas , Ignatchenko Vladimir , Kislinger Thomas , Glantz Michael , Mansouri Alireza
Published: November 2023

INTRODUCTION

Despite exquisite responses to initial therapy for CNS lymphoma, relapse is common and overall responses are disappointing compared to non-CNS diffuse large B-cell lymphomas. Literature reports 1 and 3 year survival rates of 50% and 30-40% respectively, with standard treatment. Intravenous, high-dose-methotrexate-based therapies have become the standard of care, with many variations but no consensus. Incorporation of multi-agent intrathecal chemotherapy (MAITC) alongside systemic therapy is novel but not widely adopted. We report our institutional data on safety and efficacy of MAITC in CNS lymphoma.

METHODS

A retrospective review of patients with primary or secondary CNS lymphoma, treated with MAITC between August 2015 and December 2021, was conducted. Each cycle includes alternating combinations of 2-3 of the following drugs: methotrexate, rituximab, cytarabine, etoposide, topotecan, gemcitabine, and thiotepa, via ommaya reservoir. Log-rank tests and Cox regression were used to evaluate survival differences.

RESULTS

59 patients were reviewed (21 primary; 38 secondary CNS lymphoma). Median age at start of MAITC was 66 years (range 25-90). Only six patients received external beam radiation (EBRT). Median MAITC cycles was 8 (range 2-23). 76% of patients with primary and 66% with secondary CNS lymphoma were alive 1 year after starting MAITC. Of 37 eligible patients, 17 (46%) were alive 3 years after starting MAITC. After a median 19.2 months follow-up, median OS was not reached. No significant difference was noted in OS between primary and secondary CNS lymphoma. KPS > 80 was positively while leptomeningeal disease, secondary CNS lymphoma, and EBRT were negatively associated with OS. Ommaya-related infections occurred in 8 patients (13.5%); only 1 required removal.

CONCLUSION

Based on our institutional data, MAITC can potentially offer a significant OS advantage with minimal safety concerns. Factors associated with poor survival were identified, which are being addressed in a larger dataset along with baseline CSF biomarkers.
INNV-40. DURABLE 10-YEAR RESPONSE TO VEMURAFENIB IN A PATIENT WITH CNS HAIRY CELL LEUKEMIA
Authors: Li Yi , Drappatz Jan , Mantica Megan
Published: November 2023

Hairy cell leukemia (HCL) is an uncommon form of chronic B-cell lymphoproliferative disease, accounting for approximately 2% of all cases of leukemias. Although there have been rare instances of HCL affecting the central nervous system (CNS), these cases usually involve highly fatal leptomeningeal disease or direct leukemic infiltration into the brain. The BRAF V600E mutation, leading to the constitutive activation of the MAPK/ERK signaling pathway, is recognized as a key activating mutation in HCL and is present in almost all HCL patients. First-line treatment for HCL remains purine analogs; however, up to 20% of patients only achieve a partial response. Vemurafenib, an oral inhibitor of BRAF V600E, has demonstrated strong anti-tumor activity in patients with systemic relapsed/refractory HCL and has good CNS penetration. In this case study, we present a 67-year-old patient with HCL who initially presented with multifocal cranial neuropathies In August of 2013. His brain MRIs demonstrated multiple enhancing leptomeningeal foci. While a combination of cytarabine, methotrexate, and rituximab initially prevented disease progression, he experienced multiple relapses over the course of 2 years and eventually became refractory to treatment. Subsequently, the patient was started on vemurafenib, which resulted in the complete resolution of all lesions observed on MRIs. This response has persisted for 10 years since starting the medication. We suggest that besides its high response rate in systemic relapsed/refractory HCL, vemurafenib may offer benefits for patients with CNS involvement who are refractory to conventional chemotherapies and can achieve a durable response. Further investigation is needed to potentially establish vemurafenib as a first-line treatment option for HCL patients with CNS involvement.
PATH-01. COMPARATIVE EVALUATION OF THE DIAGNOSTIC AND PROGNOSTIC PERFORMANCE OF CNSIDE™ VERSUS STANDARD CYTOLOGY FOR LEPTOMENINGEAL DISEASE
Authors: Appel Haley , Rubens Muni , Saxena Anshul , Roy Mukesh , Mohler Alexander , Kotecha Rupesh , Hall Matthew , Ahluwalia Manmeet , Mehta Minesh , Castaneda Serguei , Odia Yazmin
Published: November 2023

OBJECTIVE

We compared the real-world performance of the cerebrospinal fluid (CSF) CNSide™ versus cytology assays in diagnosing leptomeningeal disease (LMD).

METHODS

Consecutive patients with suspected LMD from January 2020 to December 2022 who underwent lumbar punctures for CSF cytology and CNSide™ analyses were reviewed. LMD diagnosis was defined by EANO criteria. We used descriptive statistics, confusion matrix, Kaplan Meier curves, and Cox proportional regression methods to analyze outcomes.

RESULTS

87 patients with median age of 63 years (range:23-93) were evaluated, of which 82 (94%) met EANO positive (possible, probable, or confirmed criteria) cohort. Of the EANO cohort, 33 (40%) had uncontrolled systemic disease and 25 (46%) were on systemic therapy with medium/high CNS penetrance. The median time from initial cancer diagnosis to LMD was 31 months (range:21-43). LMD was diagnosed by CSF cytology (EANO confirmed) in 23 cases, all identified by CNSide™. CNSide™ identified an additional 13 cases, increasing diagnostic yield by 56.5%. Commonest primary histologies in the EANO cohort were breast (36, 44.0%) and lung (34, 41.5%); 18 (53.0%) of lung cancers harbored actionable molecular alterations, while breast cancers expressed hormone receptors in 27 (75%) and HER2 alterations in 8 (22%). Median overall survival (OS) for the CNSide™ cohort was 19.5 weeks (95%CI:11.0-28.0) and 31 weeks (95%CI:21-43) for EANO positive cases. Median OS for breast patients in CNSide™ cohort was 42 (R: 15-65) weeks, about 7-fold that of lung (median 6.5, R: 2-20). There was no correlation between OS and cell density by CNSide™ (HR:1.000, 95%CI:0.999-1.001, p=0.909). OS was higher for cases treated with intrathecal chemotherapy (HR:0.189, 95%CI:0.053-0.672, p=0.010), but not statistically different by radiotherapy modality (HR, 0.583, 95%CI:0.264-1.287, p=0.181).

CONCLUSIONS

This retrospective, single-institution, real-world analysis of CNSide™ showed increased sensitivity versus cytology and provided clinically relevant, cell-based molecular CSF analyses.
PATH-05. PRIMARY AND SECONDARY GLIOSARCOMA: RADIOLOGICAL AND PROGNOSTIC DIFFERENCES USING COMPREHENSIVE MULTI-OMICS ANALYSIS
Authors: Chen Ko-Ting , Chang Ian Yi-Feng , Hsu Peng-Wei , Chuang Chi-Cheng , Huang Yin-Cheng , Chen Pin-Yuan , Chang Chen-Nen , Liu Hsuan , Tan Bertrand Chin-Ming , Jung Shih-Ming , Wei Kuo-Chen
Published: November 2023

Purpose Gliosarcoma (GS), a rare variant of glioblastoma (GB), is further classified into primary (de novo) gliosarcoma (PGS), and secondary gliosarcoma (SGS), which is defined as recurrence after a diagnosis of diffuse glioma. Poorer survival of SGS than PGS has been reported, however, the detailed mechanism remains unknown. METHODS: A retrospective retrieval of pathological confirmed GS was performed. All the clinical, radiological, and pathological comparisons were based on the diagnosis of GS. A multi-omics, including whole exome sequencing, transcriptome, proteome and phosphoproteome, approach was used to acquire the molecular profiles of these specimens. RESULTS: From 2003 to 2020, a total of 28 GSs were identified, including 19 PGSs and 9 SGSs. The age tended to be younger in SGS group than PGS group (52.1 ± 10.9 vs. 60.8 ± 11.5, p=0.069). SGSs tended to present with dural attachment (p=0.071) and were significantly associated with major vessel encasement (p=0.002) than PGSs. The Ki-67 index tended to be higher in SGSs than PGSs (p=0.081). The GS survival was significantly shorter in SGS group than PGS group (median: 7.9 vs. 32.4 months, p< 0.001). The multi-omics analysis demonstrated SGSs had significantly higher expression of negative regulation of megakaryocyte differentiation, telomere capping, and DNA replication nucleosome assembly pathways than PGSs. Next, using proteome / phosphoproteome nonnegative matrix factorization analysis, PGS was categorized into two clusters (PGS_C1 versus PGS_C2) with distinct multi-omics features. Of which, PGS_C1 (n=4) tended to have shorter survival than PGS_C2 (n=15, p=0.054). Notably, the survival of patients in PGS_C1, who had similar multi-omics signature to SGS, were as poor as those of SGSs. CONCLUSIONS: In summary, this study provides, for the first time, in depth evidence for understanding GS and presents multi-omics biomarkers with prognostic significance. Further therapeutic translation should based on current findings to benefit GS patients.
PATH-06. HISTOPATHOLOGICAL CHARACTERISTICS OF TREATMENT-INDUCED EFFECTS VERSUS PROGRESSION IN 180 RE-RESECTION SAMPLES FROM IRRADIATED GLIOMAS GRADE 2-4
Authors: Flies Christina , Becker Aline , van Hecke Wim , Kobalka Peter , Robe Pierre , Snijders Tom
Published: November 2023

Histopathological studies of re-resected glioma tissue are considered the gold standard to distinguish actual tumor progression (TP) and treatment-induced effects (TIE) after radiotherapy. The objectives of this mono-center, retrospective cohort study were to provide detailed histopathological characterization of re-resected glioma tissue, and to correlate pathological findings with survival (data driven). Consecutive adults with a diffuse glioma (WHO grade 2-4), previously treated with (chemo-)radiation and progressive lesion were reviewed. New histological slides from the recurrent-resected tissue were prepared and stained with routine and exploratory immunohistochemical (IHC) stains. Two neuropathologists used a scoring sheet to independently assess 33 items on standard H&E and IHC stains. We included 180 samples, from 165 patients. Of these, 159 samples (88.3%) originated from a second resection (first re-resection). TIE were diagnosed in 34 (19%), a mixed TIE and TP lesion in 91 (51%), and TP in 55 (31%). Median survival after first re-resection for the groups TIE, mixed and TP were respectively 14.4 (interquartile range (IQR)=8.7-42.4), 7.6 (IQR=4-12.9) and 11.5 months (IQR=7.2-25.4). A diagnosis of TIE was associated with histological findings of hyalinization, endothelial thickening, cortical infiltration, (radio)necrosis, thrombosis, lymphocytic infiltration (CD3, CD8 positive), and positivity for CD34. Percentage of viable tumor and PTBP1 stain correlated negatively with TIE. Survival in the group TIE was significantly longer than in the groups with any viable tumor (p-value of log-rank test 0.008). In multivariable Cox regression analysis, hemorrhage and higher PTBP1 positivity were associated with a poor overall survival after re-resection. Dystrophic calcifications, IDH mutations, and a higher KPS correlated with improved survival. In conclusion, we confirm the previously described characteristics of treatment-induced effects in a large consecutive cohort of re-resected diffuse gliomas. However, none of these characteristics correlated with survival. PTBP1 could be a promising marker to differentiate TIE from TP in treated glioma samples.