bluuebunny/crossref_metadata_2025 huggingface dataset:
EXTH-54. COMBINATORIAL DRUG SCREENING IDENTIFIES CARFILZOMIB AND ENZALUTAMIDE FOR TREATING AGGRESSIVE MENINGIOMAS
Authors: Jungwirth Gerhard , Braun Viktor , Nalcakan Derin , Pan Yimin , Warta Rolf , Abdollahi Amir , Unterberg Andreas , Krieg Sandro , Herold-Mende Christel
Published: November 2024

The goal of combinatorial therapy is to improve the effectiveness of treatment by targeting multiple aspects of cancer cells or overcoming resistance to single drugs. Therefore, we performed an automated combinatorial drug screening in meningioma cell lines and patient-derived tumor organoids (TOs). Three grade 3 meningioma cell lines (NCH93, IOMM-Lee, and KT21-MG1) were stably transduced with blue, green, and red fluorescence proteins. The cell lines were multiplexed into 384-well plates and treated in 5x5 dose-response (0-1000 nmol/l) matrices for 48h by the automated liquid handler Hamilton MicroLAB STAR®. The drug library consisted of 166 FDA-approved anticancer drugs. The viability of each cell line was demultiplexed by using fluorescence signals and CellTiterGlo. TOs were established from single cell suspensions of freshly resected meningioma tissue (n=20). The ZIP model was used to determine synergism. This drug screening effort generated 13,695 unique drug-drug combinations per cell line. Most synergistic combinations were observed in IOMM-Lee (1.14%), followed by KT21-MG1 (0.88%), and NCH93 (0.54%). The 110 most effective drug combinations were validated in wild-type meningioma cells. 75 drug combinations demonstrated a positive most synergistic area (MSA) score, indicating synergistic effects. Based on synergy scores and literature evidence, the 16 most promising combinations were selected for screening in TOs. The proteasome inhibitor carfilzomib in combination with the androgen receptor inhibitor enzalutamide exhibited the highest synergy in TOs. In 40% (n=8/20) of the cases, the combination showed strong synergism (MSA>10) resulting in an overall average MSA of 7.36, followed by carfilzomib and neratinib, and romidepsin and gemcitabine with average MSAs of 5.49, and 4.32, respectively. Furthermore, carfilzomib and enzalutamide induced apoptosis in TOs assessed by Caspase-3/7. This comprehensive combinatorial drug screening identified the synergistic combination of the proteasome inhibitor carfilzomib and androgen receptor inhibitor enzalutamide that can be an effective treatment option for selected meningioma patients.
EXTH-69. DEVELOPMENT OF A NOVEL, HUMAN ANTIBODY TO IMPROVE ONCOLYTIC VIRUS THERAPY FOR GLIOBLASTOMA
Authors: Murphy Sara , Sivaccumar Jwala , Li Leike , Swanner Jessica , Lewis Cole , Li Jiaqi , Lee Tae Jin , Sahu Upasana , Rivera-Caraballo Kimberly , Vazquez-Arreguin Karina , Zhang Ningyan , Sharma Ashok , An Zhiqiang , Kaur Balveen
Published: November 2024

Glioblastoma (GBM) is the most aggressive, malignant, primary brain tumor with abysmal overall survival. GBM is regarded as an “immune cold” tumor due to poor immune cell infiltration and immunosuppressive signaling in the tumor microenvironment (TME). Oncolytic herpes virus (oHSV) therapy has emerged as a possible therapeutic avenue for solid tumors such as GBM. We have observed that oHSV-treated tumor cells release extracellular ATP (eATP) which functions as immunostimulatory signaling molecule. In the TME, eATP is rapidly hydrolyzed into immunosuppressive adenosine by ectoenzymes CD39 and CD73. Using global CD73 knock out (CD73KO) mice or a function-blocking murine antibody, we found that blocking CD73 activity improves oHSV therapy in vivo. Intracranial tumor-bearing CD73KO mice respond significantly better to oHSV therapy than wild type (WT). These long-term survivors also rejected a subsequent tumor challenge, demonstrating development of a memory response. scRNA-seq revealed significantly increased immune cell infiltration in CD73KO mice compared to WT. We evaluated cellular crosstalk using CellChat and uncovered a major CCL-directed signaling pathway in the CD73KO mice. Furthermore, we identified a novel, human CD73 antibody from panning an scFv phage display library derived from human tonsils. This antibody, Ab6, demonstrated functional inhibition of purified CD73 and very high binding affinity for CD73. Co-culture of human GBM cells treated with OV and Ab6 and donor PBMCs resulted in increased tumor cell death. Additionally, human DCs exposed to Ab6 and OV-treated conditioned media were better able to activate T cells. To evaluate in vivo efficacy of this novel antibody, we have generated custom humanized CD73 knock-in mice wherein human CD73 has replaced murine CD73. We are currently evaluating the efficacy of Ab6 and oHSV in these mice against intracranial glioma. These results will support the translation of Ab6 as a potential immune therapeutic to add to the arsenal against brain tumors.
EXTH-70. PRECLINICAL TRIALS OF THE ANTIBODY-DRUG CONJUGATE TISOTUMAB VEDOTIN IN ADULT-TYPE DIFFUSE GLIOMAS
Authors: Sears Thomas , Wang Wenxia , Unruh Dusten , Steffens Alicia , McCord Matthew , Horbinski Craig
Published: November 2024

The gene F3, encoding Tissue Factor (TF), is expressed in many cancers and contributes to their malignancy. Our previous work showed that, among adult-type diffuse gliomas, IDH wild-type (IDHwt) glioblastomas (GBM) express more TF than IDH mutant (IDHmut) gliomas (PMID: 27664011, 30266764, 31222125). Tisotumab vedotin (TisVed), an anti-TF antibody conjugated to monomethyl auristatin E, is a therapeutic designed to target cells expressing TF. We therefore sought to determine the therapeutic potential of TisVed in IDHwt vs. IDHmut gliomas. TisVed was more active against cultured IDHwt GBM cells than IDHmut glioma cells (P<0.0001). This activity was increased by 55% with daily washout of the soluble TF secreted by IDHwt GBM cells. TisVed extended the survival of mice intracranially engrafted with IDHwt GBM by 34% (37.5 days vs. 28 days for IgG control, P=0.006), but not mice with IDHmut glioma (30.5 days, P=0.88). TisVed also reduced the growth of IDHwt GBM flank xenografts by 58% (P=0.045). Unconjugated Tis had no antitumor effect intracranially or in the flank. All 12 flank-engrafted mice treated with Tis, and 9/12 mice treated with TisVed, developed large hematomas in and around the flank xenografts, compared to 0/12 IgG-treated mice (P<0.001). Similarly, a semiquantitative analysis showed that intracerebral hemorrhage was more extensive in Tis/TisVed- treated GBM12 mice than in IgG-treated GBM12 mice (P=0.046). These data indicate that TisVed targets high TF-expressing IDHwt GBM, but not low TF-expressing IDHmut glioma, that its activity is predominately through the vedotin conjugate rather than inhibition of TF signaling, and that it may have some effect against TF-expressing IDHwt GBM, but intracerebral hemorrhage may be a concern.
EXTH-74. COOLING GLIOBLASTOMA WITH A NEURAL IMPLANT
Authors: Enam Syed Faaiz , Barwari Mahabad , Chen Reed , Dobariya Aksharkumar , Patnaik Sourav , Evers Bret , Bellamkonda Ravi , Patel Toral , Patel Ankur
Published: November 2024

Survival rates for glioblastoma (GBM) patients are low due to the difficulty in eradicating all tumor cells, leading to frequent recurrence. This recurrence is frequently within 2-cm from the original site. Studies indicate that supra-total resection improves survival, and non-destructive local therapies show promise in preventing GBM recurrence. Our research demonstrates that non-freezing, ‘cytostatic’ hypothermia is effective against GBM in rats and can be scaled to pig models. This method, unlike ablative cryogenic hypothermia, safely inhibits GBM growth without damaging healthy tissue. Using in vitro culture models and in vivo rat models via a Peltier device, we tested cytostatic hypothermia. This was followed by finite-element modeling (FEM) to simulate bioheat transfer in human and pig brains. The system consists of a neural implant with a multiprobe array, a Peltier chip, a water block, and an artificial internal circulation system with a piezoelectric pump. In vitro tests identified a cytostatic window of 20–25°C. Miniature Peltier devices were fabricated to achieve this in rats to inhibit GBM growth and extend survival. Rats whose tumors received cytostatic levels of hypothermia survived their full study period. FEM simulations confirmed that multiprobe arrays could cool brain tissue to 25°C without significantly raising skin temperature. Portable systems were successfully fabricated and tested in pigs, achieving safe target temperatures with minimal EEG and OCTA changes. Our findings suggest that cytostatic hypothermia can be scaled to larger animals and made implantable and portable, offering a promising non-destructive approach to halting GBM growth and prolonging survival, moving closer to becoming a viable treatment option for patients with GBM.
EXTH-76. REDIRECTING STROMAL CELLS TO IGNITE ANTI-TUMOR IMMUNITY AGAINST GLIOBLASTOMA
Authors: DeVries Anna , von Roemeling Christina , Moor Rachel , Wummer Brandon , Weidert Frances , Chardon-Robles Jonathan , Ligon John , Castillo Paul , Mendez-Gomez Hector , Sayour Elias
Published: November 2024

BACKGROUND

The dismal prognosis of high-grade gliomas demands novel treatment approaches. Through the development of a novel mRNA lipid particle aggregate (RNA-LPA) vaccine, our lab has shown anti-tumor efficacy in preclinical murine studies and promising immunological responses in canine glioma models and human studies (Cell. 2024 May 9;187(10):2521-2535.e21). The translational potential necessitates further investigating the immune activation mechanism to allow greater applicability of this therapy in the future.

OBJECTIVE

We sought to unravel mechanistic cross-talk for immune initiation following intravenous administration of RNA-LPAs.

METHODS

We used Ai14 reporter mice to determine RNA-LPA transfected cellular subsets and dual reporter mice to assess cellular infiltration into murine glioma models. Murine gliomas were generated via implantation of K2 or KR158b-luc cell lines.

RESULTS

Following intravenous administration, we found fibroblastic reticular cells in secondary lymphoid organs take up RNA-LPAs. We show that FRCs have direct contact with antigen presenting cells and mediate release of full-length proteins following RNA-LPA transfection. Similar to the periphery, there is transfection of stromal cells in the brain tumor microenvironment (TME) and recruitment of infiltrating leukocytes. In response to RNA-LPAs, transfected stromal cells release type I interferon (IFN-I), which is requisite for anti-tumor efficacy. IFN-I mediates upregulation of CD69 on lymphocytes leading to sequestration following co-localization with RNA-LPAs. IFN-I is necessary for LFA-I expression on T cells, which is important for T cell trafficking across the blood-brain barrier. In preclinical models to track antigen specific immunity, we find systemic RNA administration elicits an increase in tumor reactive T cells with decreased S1P1 expression suggestive of a ‘locked-in’ response within the TME.

CONCLUSION

While stromal cells are regulatory niches in glioblastoma ecosystems, we show they can be leveraged for immunologic cross-talk that facilitates T cell recruitment, trafficking and sequestration in the TME critical for immunologic reprogramming and long-lasting immunotherapy.
EXTH-77. INFANT-TYPE HEMISPHERIC GLIOMAS WITH INITIAL RESPONSE FOLLOWED BY RESISTANCE ON TARGETED AGENTS
Authors: Wilson David , Ocal Eylem , Tanaka Tomoko , Parker Lora , Jayappa Sateesh , Gokden Murat , Bielamowicz Kevin
Published: November 2024

Pediatric-type Diffuse High Grade Gliomas (pHGG) are a rare brain tumor with high mortality and need for more effective treatment options. pHGG’s make up only about 10% of CNS tumors but are responsible for a majority of the deaths. Infant-type Hemispheric Gliomas are a subtype of pHGG with tyrosine kinase alterations in genes such as ROS1, ALK, MET, and NTRK1-3. Despite advances in categorization and targeted therapies, the natural history of patients with infant HGG treated with targeted therapy over time needs to be better characterized, including the durability of objective responses. We present a retrospective case series involving two patients diagnosed with Infant-type Hemispheric Gliomas at Arkansas Children’s Hospital from 2022-2024. Each diagnosis was determined based on histology, targeted tumor sequencing, and methylation profiling. Both patients were initially treated with primary surgical resection and systemic chemotherapy. Each patient experienced disease progression. Actionable pathogenic mutations were identified in both patients (a MET alteration in patient 1 who was then started on Cabozantinib, an ALK fusion in patient 2 subsequently treated with Lorlatinib) with an objective disease response in both patients. In both cases, further relapse occurred while on targeted inhibition. Relapse specimen was not available for patient 1, but for patient 2, recurrent tumor sequencing revealed similar genetics from the diagnostic specimen except for a MET copy number gain suggesting the mechanism of resistance in this patient. Infant-type Hemispheric Gliomas with targetable alterations can show meaningful responses to pathway inhibition. Relapse after initial response may warrant additional surgical sample to identify new alterations which can lead to changes in therapy. Larger prospective cohorts are needed to study targeted agents in this population, and early integration during radiation or after initial diagnosis may be needed.
EXTH-79. BREAKING THE BARRIER: ADOPTIVE CELLULAR THERAPY HALTS GLIOMA IMMUNOSUPPRESSION BY TARGETING MYELOID-DERIVED SUPPRESSOR CELL MIGRATION AND CELL CYCLE MECHANISMS
Authors: Figg John , Francis Connor , Jin Dan , Reid Alexandra , Font Laura Falceto , Dean Bayli DiVita , Love Caitland , Hilferty David , McDonald Brianna , Flores Catherine
Published: November 2024

INTRODUCTION

Our group previously demonstrated that adoptive cellular therapy (ACT) significantly increased overall survival in mice across several brain cancer models. ACT remodels the tumor microenvironment (TME) in a pleiotropic manner, and specifically depletes immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) which are a significant barrier to efficacious immunotherapy responses. This led us to hypothesize that ACT depletes MDSCs from the glioma microenvironment by inhibiting MDSC proliferation and migration, thereby overcoming glioma immunosuppression.

METHODS

We quantified MDSC cell cycle, apoptosis, and localization in the TME and peripheral lymphoid tissues using flow cytometry as well as chemokines in the TME from glioma-bearing mice treated with ACT. C57BL/6J mice intracranially received KR158b-luciferase glioma and were treated with ACT. After treatment, MDSC cell cycle was quantified using bromodeoxyuridine and 7-aminoactinomycin to define cell cycle phases. MDSC apoptosis and cell death states were quantified by measuring annexin-V and propidium iodide. Anatomic localization of MDSCs was measured by comparing host (CD45.2) and transferred HSC-derived cell markers (CD45.1) in the TME and spleen. A multiplex array was performed using tumor lysates to quantify cytokine and chemokine levels within the TME.

RESULTS

We observed that MDSCs in the TME were significantly less proliferative and exhibited significantly increased levels of apoptosis and cell death after ACT. HSC-derived MDSCs were significantly enriched in the spleen of ACT-treated mice, but both transferred HSC-derived MDSCs and host MDSCs were depleted in the TME. Finally, ACT significantly decreased several chemokines in the TME, including interleukin-16 and monocyte chemoattractant protein-5.

CONCLUSION

These results indicate that ACT shifts MDSC cell cycle states away from proliferation towards cell death, and inhibits peripheral recruitment to the TME. Our investigation revealed novel, myeloproliferative chemokines that are decreased by ACT, representing a novel mechanism underlying disrupted MDSC migration to the glioma microenvironment and ultimately to overcoming glioma-mediated immunosuppression.
EXTH-80. A NOVEL BISAMINOQUINOLINE DERIVATIVE NANOPARTICLE (BAQ13-NP) FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Bloch Orin , Min Dullei , Lin Tzu-Yin , Li Yuanpei
Published: November 2024

Aminoquinolines, such as hydroxycholoquine, are known to inhibit autophagy and slow cancer cell growth, improving survival in preclinical models of glioblastoma. Unfortunately, they failed to demonstrate benefit in clinical trials due to a lack of sufficient potency and BBB penetration. We have developed a novel bisaminoquinoline derivative packaged in a nanoparticle (BAQ13-NP) with improved potency and intratumoral accumulation after systemic administration, confirmed by distribution and toxicity studies in animals. In this study, we evaluated the impact of BAQ13-NP on tumor cell autophagy and survival using patient-derived glioma cell lines and murine models. GBM patient-derived cell lines (n=4) and murine glioma cells (GL261, CT-2A) were treated with BAQ13-NP (1-4 µM) in culture, demonstrating growth restriction to less than 50% of control at 5-7 days (p<0.01) by MTT assay. Cells treated with BAQ13-NP also demonstrated reduced autophagy with significant increases in accumulation of LC3B and p62 (p<0.01) and reduced IL-6 dependent STAT3 phosphorylation in tumor cells, T cells, and myeloid cells (p<0.01). In addition, treatment of tumor cells with BAQ13-NP reduced IL-6 production over 50% (p<0.01). Mice with orthotopic GL261 or CT2A tumors were treated with BAQ13-NP by tail vein injection (25 mg/kg q2 days) starting 7 days post implantation. Significantly increased survival was observed in BAQ13-NP treated GL261 (HR 0.75, p=0.030) and CT2A (HR 0.78, p=0.033) bearing mice compared to vehicle control treated animals. Reduced tumor size at specific intervals was also observed with BAQ13-NP treatment, corelating with improved survival. BAQ13-NP can inhibit autophagy and slow glioma tumor growth, improving survival in preclinical models. Given the excellent distribution and low toxicity of this novel agent when delivered intravenously, we believe it has great potential to improve outcomes for GBM patients. Our drug has recently received IND approval and will soon be tested in a phase I clinical trial.
EXTH-84. A DURABLE RECURRENT INTRACEREBROVENTRICULAR INFUSION METHOD IN MICE FOR PRECLINICAL ASSESSMENT OF CELLULAR THERAPEUTICS
Authors: Chen Chao-Hsien , Curran Michael
Published: November 2024

BACKGROUND

Significant advancement in cellular treatments for glioblastoma has been made in recent years. The administration route has shifted from intravenous access to local delivery, namely intracerebroventricular (ICV) delivery, in order to prevent the injected cellular products from becoming trapped in peripheral organs such as liver and spleen. There is currently no reliable preclinical system available to accurately examine new cellular treatments that involve long-term recurrent infusion into the cerebral ventricles.

METHOD

We optimized the surgical device and technique by modifying a commercially available ICV device with a predetermined needle length, eliminating the requirement for spacers hence relieving the tension of the surgical wounds. To avoid skin puncture, we substituted the tunneled catheter with a silicon catheter. The surgical incisions were secured with autoclips in replacement of sutures. We administered periodic infusions of engineered monocytes on a weekly basis using the tunneled catheter for a duration of 8 weeks. The rate of wound dehiscence was monitored.

RESULTS

The delivery of the engineered monocytes to the cerebral ventricle via the ICV device has been confirmed using a bioluminescence-based imaging. The device and the tunneled catheter demonstrate a long-lasting durability for a minimum of 8 weeks. The optimized device and method effectively reduce the occurrence of post-operative wound dehiscence. Using a silicon catheter minimizes skin punctures.

CONCLUSION

Our optimized ICV device, material, and surgical approach offer a dependable preclinical instrument for the long-term and recurrent delivery of cellular therapies that reflect patients’ clinical treatment schedules and provide a more accurate evaluation of their translational potential.
QLTI-04. UPDATE ON HIGH-GRADE GLIOMA PATIENTS TREATED WITH TTFIELDS FROM NANFANG HOSPITAL IN CHINA
Authors: Zheng Haojie , Que Tianshi , Yi Guozhong , Li Zhiyong , Qu Shanqiang , Zhang Peidong , Yuan Xi , Wang Yajuan , Liu Junlu , Nan Jing , Liu Ting , Xu Haiyan , Qi Songtao , Huang Guanglong
Published: November 2024

OBJECTIVE

Tumour-treating fields (TTFields) have changed the first-line clinical practice of glioblastoma worldwide due to their promising therapeutic efficacy. The aim of this study was to investigate the clinical efficacy of TTFields therapy for HGG in Nanfang Hospital, China. In 2023 ASNO we reported PFS.Now we reporte update about OS from our single center study.

METHODS

From January 2019 to December 2022, a total of 25 patients with newly diagnosed HGG (ndHGG) treated with TTFields were retrospectively included in our study. Among these patients, 9 patients received concurrent radiochemotherapy in combination with TTFields and 16 patients received non-concurrent chemoradiotherapy in combination with TTFields. The primary endpoint of the study was mPFS and mOS (Kaplan-Meier method used to estimate PFS and OS survival curves). Secondary endpoint was the influences about KPS score in PFS and OS.

RESULTS

The 25 ndHGG patients treated with TTFields included nine males and sixteen females with a mean age of 47.1 years (12-68). Gross total resection (GTR) was performed in eighteen patients. Twenty-one patients were IDH wild type, eleven patients showed methylation of the MGMT promoter. Followed up until January 2024, the median PFS was 13.3 months [95% CI: 11.33-15.2] with TTFields combined and 4.0 months (95% CI, 3.8-4.4) without TTFields treatment in EF-14.Median OS was 26.53 months [95% CI:19.47-33.57] with TTFields and 16.0 months (95% CI, 3.8-4.4) control in EF-14. In the KPS stratification, OS was 27.5 months (95% CI: 22.95-32.1) vs 4.3 months (95% CI: 0-11.2), p=0.0001. The OS of patients with concurrent chemoradiotherapy combined with TTFields vs. without concurrent chemoradiotherapy combined with TTFields was 26.5 months (95% CI: 24.33-28.7) vs 21.2 (95% CI: 3.1-39.3) months, p=0.59.

CONCLUSIONS

TTFields therapy is an effective treatment for HGG. In this study the addition of TTFields resulted in a statistically significant improvement in PFS and OS.
QLTI-10. IMPACT OF A NEURO-ONCOLOGY HOSPITALIST MODEL ON INPATIENT CANCER CARE DELIVERY AT A SINGLE INSTITUTION
Authors: Barden Mary
Published: November 2024

Patients with brain tumors are often admitted to the hospital at critical stages of their disease course: initial diagnosis, relapse, end-of-life, and for management of serious complications. Patients who develop neurologic complications from systemic cancers and their treatments also frequently require management in the hospital setting. Most neuro-oncologists have busy outpatient practices and limited inpatient responsibilities. Their experience with hospital workflows, bandwidth to see inpatients, and comfort level managing certain diagnoses such as immunotherapy neurotoxicities may be variable, even within a single institution. Recent literature supports the beneficial role of the Oncology Hospitalist, a physician who specializes in the care of hospitalized patients with cancer. Oncology Hospitalist care improves length of stay, cost effectiveness, and the patient and oncologist experience. To our knowledge, the role of a hospitalist who specializes in the care of patients with neuro-oncologic issues has not yet been investigated. Here we describe the responsibilities and examine the impact of a Neuro-Oncology Hospitalist at a single institution over a 2-year period, with a focus on metrics of quality and efficiency of care. Patients and cancer care systems benefit from the dedicated inpatient presence of a neuro-oncologist, supporting the development of a Neuro-Oncology Hospitalist model.
QLTI-11. PREDICTORS OF PROLONGED LENGTH OF STAY IN LASER INTERSTITIAL THERMAL THERAPY FOR INTRACRANIAL PATHOLOGIES: A SINGLE CENTER EXPERIENCE
Authors: Berke Chandler , Knott Maxon , Khalafallah Adham , Shah Ashish , Ivan Michael , Komotar Ricardo
Published: November 2024

INTRODUCTION

Laser interstitial thermal therapy (LITT) offers a minimally invasive approach for treating intracranial pathologies, often with shorter hospital stays than traditional craniotomies. Yet, some patients still face prolonged length of stay (PLOS), highlighting the need to identify contributing factors and improve post-LITT outcomes.

OBJECTIVE

To evaluate factors contributing to PLOS following LITT for intracranial pathologies.

METHODS

A retrospective review was conducted between 2013-2023 for patients undergoing LITT for intracranial pathology at a tertiary care center. PLOS was defined as discharge >2 days. Multivariate logistic regression analyzed variables as contributors to PLOS including ICU LOS (hours), preoperative maximum tumor diameter (cm), lesion location, lesion pathology (high grade glioma (HGG)/glioblastoma (GBM) vs. other), and mFI-11 score (binary ≥ or < 75th percentile).

RESULTS

The cohort consisted of 288 patients, with 29% (83/288) and 71% (205/288) having PLOS and non-PLOS, respectively. Mean age was similar between the PLOS (63-years) and non-PLOS (60-years) groups (p=0.09). The PLOS group had a 55% male predominance compared to 57% female in the non-PLOS group. Greater mFI-11 scores showed increased risk of PLOS [4.01, (2.11, 7.60), p<0.000]. Lesions having a subcortical location [3.43 (1.70, 6.95), p=0.001] or diagnosis of HGG or GBM [2.87 (1.54, 5.34), p=0.001] had increased risk of PLOS. Importantly, maximum pre-operative diameter did not significantly alter risk of PLOS [1.05 (0.98, 1.13), p=0.151].

CONCLUSION

For the first time, we show that patient comorbidities, subcortical lesion location, HGG/GBM pathology, and greater time spent in the ICU portend increased risk of PLOS following LITT. Future work should validate our model with the goal of optimizing post-operative patient management and resource allocation.
QLTI-15. MEDICAL MALPRACTICE AND GLIOMA
Authors: Fluss Rose , Crisman Celina
Published: November 2024

BACKGROUND

Medical malpractice affects the practice of medicine in every field and specialty. It is a particular concern in high risk specialties including neurological surgery, which has the greatest risk of malpractice litigation. Treatment of glioma patients is complex and requires diagnosis based on presentation and imaging, followed by the decision of resection versus biopsy to confirm diagnosis and potentially improve prognosis. The possibility of a complication accompanies every procedure and patients generally also go on to receive chemotherapy and radiation. Interdisciplinary care is a hallmark. We explored medical malpractice litigation pertaining to gliomas with a focus on outcomes and the role of the defendants as well as the liabilities prompting litigation.

METHODS

WestLaw Precision, an established legal database, was queried for all cases relevant to “glioma” occurring since 2000. Cases and settlements, in particular, were considered. Keywords included “glioma” and “medical malpractice” with the date range including all cases after January 1, 2000. Cases were identified and analyzed for variables of interest.

RESULTS

Fourteen relevant cases were identified and reviewed. There were three plaintiff verdicts, one settlement and ten defense verdicts in favor of the defense. Two cases involved minors, while all others concerned adults. Both cases pertaining to the care of minors with gliomas resulted in findings for the defense. The majority of cases centered on failure to diagnose occurring before surgery or treatment. Defendants included neurosurgeons, pathologists, radiologists, nurses and hospital systems. Although the number of cases considered here is small, jury verdicts in favor of plaintiffs resulted in far higher payouts compared with settlements.

CONCLUSIONS

Medical malpractice allegations relating to glioma treatment are shown to be rare and infrequent. The majority of cases alleged a failure to appropriately diagnose, before surgery or treatment took place. The great majority of cases reported within WestLaw Precision resulted in jury verdicts for the defense.
QLTI-16. QUALITY IMPROVEMENT PROJECT (QIPR) FOR IMPLEMENTATION OF PSYCHOSOCIAL ASSESSMENTS FOR ONCOLOGY CLINICAL CARE
Authors: Body Anjelica , Johnson Hannah , Patel Drashti , Pereira Deidre , Ghiaseddin Ashley
Published: November 2024

BACKGROUND

Patient-reported outcomes (PROs) have been used to assess individuals’ quality of life (QoL) throughout cancer treatment. Individuals with cancer often experience physical, psychological, and social challenges. It is crucial to evaluate their QoL to provide supportive care services to improve survival and treatment outcomes in real-world cancer clinical settings. Patients’ ability to engage with completing PROs is critical to ensuring PRO implementation efficacy. This QIPR (UF: 2216) examined these completion rates in coordinated medical-behavioral cancer care.

METHODS

Questionnaires delivered to neuro-oncology and psycho-oncology patients through the electronic health record (EHR) prior to scheduled office visits were: PROMIS – Anxiety, Depression, Pain Interference, Ability to Participate in Social Roles, and Cognitive and Physical Function. Data collection occurred from July 2023-January 2024. Descriptive statistics were calculated to assess battery completion rates. Information from the first 3 encounters following initiation of the battery into clinical practice were analyzed.

RESULTS

Of 906 scheduled encounters, 491 (54.2%) were attended by 280 unique patients. The battery was completed at least once by 106 (37.9%) patients. 72.6% (N=77) of these patients completed the battery at the first scheduled visit at which it was assigned. Of patients with 2 scheduled visits (N=25, 23.6%); 24.0% (N=6) completed the battery at both visits. Of patients that had 3 scheduled visits (N=12, 11.3%); 16.7% (N=2) completed it at all 3 visits.

CONCLUSION

Only approximately 38% of patients completed the battery at least once across 3 consecutive visits. The highest battery completion rate was at the first visit at which it was assigned. Completion rates were lower across additional visits. Future work will seek to understand barriers and facilitators of these completion rates to optimize implementation of PROs in coordinated medical-behavioral oncology care.
QLTI-21. STREAMLINING THE STUDY INTAKE PROCESS AT THE CANCER CLINICAL AND TRANSLATIONAL RESEARCH OFFICE (CCTRO)
Authors: Faddah Raid , Walbert Tobias , Snyder James , Gadgeel Shirish , Philip Philip , Lange Lisa
Published: November 2024

Challenges in the Protocol Intake/Activation process at the Henry Ford Cancer Center, particularly during the budget negotiation and coverage analysis (CA) phases, hamper operational efficiency and financial prospects. This study aimed to improve budget time and process efficiency. Process flow mapping, Value Stream Mapping (VSM), and cause-effect analysis using a fishbone diagram were used to identify and analyze key bottlenecks, focusing on the budget negotiation and CA phases. Budget negotiation took an average of 121.5 days in 2023 due to multiple procedures and a lack of standardized practices. Delays ranged from 127.75 days in August to a low of 69.84 days in November of 2023. The budget build process averaged 13.31 days, with an additional 7.57 days for approval, totaling 20.89 days. The CA phase had an average cycle time of 10.82 days (range 2-10 days). To improve approval times, it was recommended to implement an Electronic Document Management System to automate routing, signing, and tracking of budget and CA-related documents, standardized budget templates to streamline negotiations, a detailed electronic checklist to streamline task lists for document collection and budget negotiation, automated reminders for internal and external stakeholders to ensure timely submission of necessary documents, and timely submission policies enforced by a dedicated finance member on committees. Newly developed Key Performance Indicators (KPIs) such as ‘time to collect documents,’ ‘time between committees,’ and ‘time for budget negotiation process,’ along with a dual tracking system in Excel, were proposed to monitor and improve these metrics. The recommendations are expected to significantly enhance the efficiency of the Protocol Intake/Activation process. By reducing the budget negotiation phase to less than 60 days and optimizing the CA process, faster study initiation, better resource utilization, and improved responsiveness to research opportunities will be achieved. This study underscores the critical need to address operational challenges in clinical trial management to enhance CCTRO’s capability to conduct timely and effective research.
QLTI-22. TEMOZOLOMIDE CHEMOTHERAPY EFFECTS ON GLIOMA PATIENT FERTILITY AND THEIR OFFSPRING: A RETROSPECTIVE REVIEW
Authors: Lu Austin , Vu Mia , Schuman Eva , Ware Cornelius , Hsu Sigmund , Zhu Jay-Jiguang
Published: November 2024

Gliomas represent ~30% of primary brain tumors. Temozolomide (TMZ) chemotherapy with concurrent radiation or following radiation is the main course of treatment. Avoidance of pregnancy in female patients and partner of male patients is strongly encouraged due to unknown teratogenic and long-term effects to the health and development of fetus. Patients of childbearing age must wrestle with receiving TMZ treatment, potentially impacting fertility, and the desire for biological children in the future. Gamete preservation prior to TMZ induction is the current solution, which is often financially prohibitive, leaving patients to consider natural conception after completion of TMZ. We intend to identify potential difficulties in conception, pregnancy complications, birth abnormalities, and childhood developmental deficiencies that may be correlated to TMZ exposure prior to conception. Included patients conceived and delivered one or two children after completing treatment with TMZ. All patients received antiepileptic drugs (range = 1-4) which have variable known teratogenic effects during pregnancy. We identified 13 patients (7 male, 6 female; median age of 29) with diagnoses of astrocytoma (n=5), oligodendroglioma (n=5), oligoastrocytoma (n=2; diagnosed prior to 2021 WHO classification), and glioblastoma (n=1). Two reported issues with conceiving (1 male and 1 female) and 17 children were born. One child had developmental abnormalities (6%), and all other 16 children were healthy per parental assessment. Complete results of pregnancy complication and childhood development data will be updated at the meeting. Information on teratogenic and developmental effects of TMZ in humans is largely unknown. Animal studies have shown an increase in fetal malformations when exposed to TMZ during pregnancy. Despite the limitations of a retrospective study, our findings suggest that natural conception after the conclusion of TMZ treatment may be safer than suspected. Given the limited sample size, future comprehensive studies are warranted to corroborate these observations.
QOL-05. COMPARING DISEASE-SPECIFIC QUALITY-OF-LIFE OUTCOMES OF MICROSURGERY, RADIOTHERAPY, AND OBSERVATION IN VESTIBULAR SCHWANNOMA PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Salman Afia , Ghazanfar Shamas , Naeem Unaiza , Kumar Kanwal Ashok , Javaid Aaisha , Rafi Hania Mansoor , Naeem Komal , Lucky Hassan , Farhan Rida
Published: November 2024

BACKGROUND

Vestibular schwannoma (VS), also known as acoustic neuromas, are common tumors arising from the vestibulocochlear nerve and are located in the cerebellopontine angle. The benign tumor has a substantial impact on the patient-perceived quality of life (QoL) outcomes, which contribute to the decision regarding the ideal management plan. In this systematic review and meta-analysis, we aimed to compare the impact of microsurgery, radiotherapy, and observation on the QoL outcomes of VS patients.

METHODS

This study was conducted in accordance with the PRISMA guidelines and a total of four research databases were searched for eligible studies from inception to May 2024. The primary outcome of the study was the Penn Acoustic Neuroma Scale (PANQOL) total score and the secondary outcomes included the PANQOL subdomain scores. Data was pooled using the random-effects model and analyzed as OR (odds ratio) with 95% CI (confidence interval).

RESULTS

Compared to observation, radiotherapy was associated with superior QoL outcomes only in the face domain [MD (mean difference) = -4.59 [-7.29,-1.88]; I2= 85%; p = 0.0001], with observation being associated with superior outcomes across all others [PANQOL - total: MD = 4.94 [2.51,7.38]; I2= 85%; p = 0.0001]. Microsurgery, compared to radiotherapy, was associated with better outcomes only in the general domain [MD = -4.38 [-6.60,-2.16]; I2= 0%; p = 0.0001], with RT being associated with superior outcomes across all other domains [PANQOL - total: MD = 3.61 [1.29,5.93]; I2= 63%; p = 0.002]. Compared to microsurgery, observation was associated with superior QoL outcomes across all domains [PANQOL - total: MD = 9.22 [7.30,11.13]; I2= 64%; p = 0.0001].

CONCLUSION

The findings indicate that, broadly, observation is associated with better QoL outcomes relative to both radiotherapy and microsurgery; with radiotherapy superseding microsurgery. However, the association with QoL improvement was not uniform across all domains.
QOL-07. LONG-TERM FOLLOW-UP OF PHYSICAL FUNCTION AND SOCIAL CONDITIONS IN CENTRAL NERVOUS SYSTEM GERM CELL TUMORS
Authors: Takami Hirokazu , Nishikawa Ryo , Matsutani Masao
Published: November 2024

BACKGROUND

This paper presents an analysis of iving and social conditions from a long-term follow-up of Phase II clinical trial for central nervous system germ cell tumors conducted between 1995 and 2003.

METHODS

A retrospective analysis was performed on 228 cases, including 161 germinomas, 66 non-germinomas, and 1 mature teratoma, over a median follow-up of 222 months. There were 56 recurrences and 39 deaths recorded. The analysis at the final follow-up included final educational level, employment status, activities of daily living (ADLs), marital and parental status, and hormone replacement therapy. The study targeted 157 cases with more than 10 years of follow-up data.

RESULTS

At 20 years post-treatment, survival rates were 91% for germinomas and 65% for non-germinomas. At the last follow-up, ages ranged from 19 to 58 years (median 36 years). The Karnofsky Performance Status (KPS) was 80 or higher in 118 cases, 70 in 7 cases, and 60 or lower in 32 cases. Educational achievements were: elementary school in 1 case, middle school in 8, high school in 52, university in 45, and graduate school in 2. Employment status showed 37 unemployed, 4 in school, 23 part-time, 80 full-time, and 2 homemakers. Childbirth was reported in 16 men (18%) and 4 women (16%). The frequency of a KPS≧80 at the final follow-up was higher in initial germinoma cases than in non-germinoma cases (80 vs 62%, p=0.04), and was also higher in cases without recurrence (83 vs 47%, p<0.0001). Only the proportion of growth hormone supplementation showed a significant correlation with KPS (≧80: 19% vs <80: 3%, p=0.03).

CONCLUSION

Long-term social outcomes are favorable for germinoma patients without recurrence, while non-germinoma patients who have recurred and survived face tougher conditions, indicating significant treatment impacts. Managing treatment intensity and ensuring comprehensive long-term follow-up are crucial.
QOL-08. HEALTH-RELATED QUALITY-OF-LIFE (HRQOL) IN ADULTS AND CHILDREN WITH NEUROFIBROMATOSIS TYPE 1-ASSOCIATED PLEXIFORM NEUROFIBROMA (NF1-PN) TREATED WITH MIRDAMETINIB: PIVOTAL, PHASE 2B RENEU TRIAL
Authors: Babovic-Vuksanovic Dusica , Hirbe Angela , Moertel Christopher , Shuhaiber Hans , Sidhu Alpa , Bielamowicz Kevin , Viskochil David , Bell Timothy , Weber Michael , Langseth Abraham , Lokku Armend , Weintraub Lauren , Hajjar Fouad , Foreman Nick , Gershon Timothy , McNall-Knapp Rene
Published: November 2024

Patients with NF1-PN experience pain and other symptoms that negatively impact functioning and quality-of-life. We present patient- and parent proxy-reported HRQoL outcomes from ReNeu (NCT03962543), a pivotal, phase 2b trial of mirdametinib, an investigational MEK1/2 inhibitor, in adults and children (≥2 y) with NF1-PN causing morbidities. Fifty-eight adults and 56 children received mirdametinib (2 mg/m2 BID; 3-weeks-on/1-week-off, 28-d cycles). Change in HRQoL was assessed by Pediatric QoL Inventory (PedsQL) 4.0 Generic Core Scales from baseline across the 24-cycle treatment phase; change from baseline at Cycle 13 (C13) was a prespecified secondary endpoint. PedsQL is a HRQoL measure for adults and children with a Total Score (TS) and 4 subscales: physical, emotional, social, and school/work. Items are reported on a 0-100 scale (higher scores=better HRQoL). Clinically meaningful improvement was defined as change from baseline >9.7 points for adults, >8.5 points for child self-report, and >9.0 points for parent proxy-report. PedsQL-TS improvement (least-squares mean, LSM [SE] change) from baseline at C13 was 3.9 (1.6; P=.018; n=34) for adults, 4.0 (2.4; P=.096; n=38) for children by self-report, and 5.6 (1.9; P=.005; n=43) by parent proxy-report. PedsQL-TS improvements for adults and children by parent proxy-report (not by children self-report) were observed early (at C5 and C3, respectively) and sustained through C24. Clinically meaningful improvement in PedsQL-TS from baseline at C13 was achieved by 37% (10/27) adults, 45% (13/29) children by self-report, and 47% (15/32) children by parent proxy-report (among patients who could have achieved a clinically meaningful change from baseline). Significant (P<.05) improvement from baseline to C13 was reported for physical (adults, children, and parent proxy-report), school/work (adults), and emotional and social (parent proxy-report) subscales. Adults and children (by parent proxy-report) with NF1-PN had clinically meaningful, early, and sustained improvement in HRQoL over the course of mirdametinib treatment.
QOL-09. “I’VE DEFINITELY CHANGED WHO I AM”: A THEMATIC ANALYSIS OF CHALLENGES FACED BY PATIENTS WITH IDH-MUTANT GLIOMAS
Authors: Chiu Daniel , Whitman Jessica , Strander Sumita , Willis Kelcie , Temel Jennifer , Traeger Lara , Forst Deborah
Published: November 2024

BACKGROUND

Despite their more favorable prognosis, patients with isocitrate dehydrogenase (IDH)-mutant gliomas experience significant psychological distress across their disease trajectory. The specific drivers of distress in this population are poorly understood, and interventions to support these patients are lacking. We sought to better characterize drivers of distress and ways to enhance support for patients with IDH-mutant gliomas as they confront potentially prolonged but ultimately unpredictable survival with an incurable, progressive brain tumor.

METHODS

Eligible individuals were English-speaking adults ages 65 and younger diagnosed with an IDH-mutant glioma at a single academic medical center. We conducted semi-structured interviews (N=20) to better understand the distress patients experience as they progress along their illness trajectories. We audio-recorded and transcribed interviews and analyzed interview content using reflexive thematic analysis.

RESULTS

Distress among participating patients (female = 7/20; age <40 years = 10/20) was linked to their struggles to maintain a coherent sense of identity while adapting to 1) neurocognitive changes and 2) altered life plans amidst prognostic uncertainty. Patients described feeling self-conscious and distrustful of their cognitive capacities, frequently comparing their current performance to their premorbid functioning (e.g. by checking their symptoms and indexing perceived deficits against scan results). Patients felt overwhelmed by the need to make decisions and set priorities (e.g., regarding family planning, retirement) due to the uncertain timing of their tumor’s progression and its unclear impact on their future functioning. Patients identified the transition from treatment to surveillance as a time of heightened worry, as they shifted their focus from the logistics of cancer care to the task of planning – financially, occupationally, socially – for an uncertain future.

CONCLUSION

These findings highlight the need for tailored supportive care to help patients with IDH-mutant gliomas cope with the distress caused by significant changes to identity and ongoing uncertainties regarding their future.
QOL-22. VACILLATING EMOTIONS AND SHIFTING INFORMATION PREFERENCES: A QUALITATIVE ANALYSIS OF CAREGIVER DISTRESS IN FACING A MALIGNANT GLIOMA DIAGNOSIS
Authors: Patnaik Pooja , Chiu Daniel , Whitman Jessica , Strander Sumita , Hauswirth Anna , Willis Kelcie , Temel Jennifer , Traeger Lara , Forst Deborah
Published: November 2024

BACKGROUND

Caregivers of patients with malignant gliomas (MG) experience considerable psychological distress as they contend with the implications of their loved one’s terminal illness. However, caregivers’ specific reactions to the patient’s diagnosis/prognosis and optimal ways to support caregivers in the months following diagnosis remain poorly understood.

METHODS

At a single academic medical center, we enrolled English-speaking adults identified by patients with newly diagnosed MG as their primary caregiver. Using a semi-structured interview guide, we conducted in-depth interviews with caregivers at the conclusion of concurrent chemoradiation exploring their experiences learning about the patient’s diagnosis and their prognostic information preferences. We used rapid qualitative analysis to analyze interview data.

RESULTS

We interviewed 7 caregivers (female: 5/7; spouse/partner: 6/7, sibling: 1/7) of MG patients (glioblastoma: 5/7). Caregivers described the time following diagnosis as tumultuous and difficult as they struggled to cope with their distress related to navigating the practical burdens of cancer treatment while also managing the emotional burden (e.g. fear, sadness) of living amidst uncertainty. Caregivers vacillated between feeling devastated by the patient’s poor prognosis and wanting to remain hopeful (e.g., by seeking out inspiring survivorship stories). Caregivers also reported varying and often evolving preferences regarding the manner, timing, and context in which they received information about the patient’s MG. Many caregivers desired more prognostic information (e.g., to facilitate planning for their future and for the patient’s eventual demise) while some chose to focus on the present (e.g., to avoid “dwelling” on potential negative outcomes), in light of inherent uncertainty about the patient’s trajectory.

CONCLUSIONS

Caregivers experience significant distress in the context of vacillating emotions and shifting information needs as they adapt to life in the aftermath of a MG diagnosis. These results highlight the need for tailored prognostic information and support for caregivers during this stressful, emotionally fraught time.