bluuebunny/crossref_metadata_2025 huggingface dataset:
QOL-04. CHANGES IN FUNCTIONAL CONNECTIVITY AFTER SURGERY ARE ASSOCIATED WITH DECLINE IN FUNCTIONAL INDEPENDENCE IN PATIENTS WITH ELOQUENT GLIOMA
Authors: Noll Kyle , Bradshaw Mariana , Chen Henry , Wefel Jeffrey , Sullaway Catherine , Thomas Ashley , Kumar Vinodh , Prabhu Sujit , Liu Ho-Ling
Published: November 2023

It is unknown whether patient independence following resection of eloquent glioma is associated with postoperative functional connectomic changes. Fifteen patients with left perisylvian glioma underwent resting-state fMRI and neuropsychological evaluation before and about 1 month after resection. Functional independence was measured with the Physical Self-Maintenance Scale (PSMS) and the Instrumental Activities of Daily Living scale (IADL). Manual dexterity testing (Grooved Pegboard; N = 13), neurologic motor exam (N = 12), and performance status (KPS; N = 14) were also obtained. Graph theoretical analysis was used to calculate functional brain network properties. Postoperative need for assistance in at least 1 activity on the IADL increased from baseline in 80% of patients, most commonly in Transportation (67%), followed by Shopping (60%), Financial Management (47%), Cooking (47%), Medication Management (33%), and Phone Use (33%). Overall need for assistance (Total IADL score) significantly increased postoperatively (Mdn change = 4, p = .006). Need for assistance on the PSMS only increased in 27% of patients, with rates less than 15% across all functions. Total PSMS scores did not differ pre- and postoperatively (Mdn change = 0). KPS scores worsened in 40% of patients. None had gross motor worsening, though fine manual dexterity declined in 7% for the left and 23% for the right hand. Increased connectomic properties were significantly associated (Spearman ρ) with greater need for assistance on the IADL [Local Efficiency: Total (.72), Shopping (.71), Cooking (.64), Financial Management (.64); Clustering Coefficient: Phone Use (.63); Betweenness Centrality: Phone Use (.63); all p < .01]. PSMS and IADL ratings were not associated with KPS, manual dexterity, pre/postoperative FLAIR volume, or extent of resection. This study demonstrated that increases in certain functional connectomic properties after surgery are associated with greater need for assistance in instrumental activities in the postoperative period. Connectivity increases have also been associated with poorer cognitive outcome in this population, though specific properties involved may differ.
QOL-05. EXPLORATORY ANALYSIS OF COGNITIVE BEHAVIORAL THERAPY FOR INSOMNIA (CBT-I) AMONG PATIENTS WITH PRIMARY BRAIN TUMOR: EFFECTS ON DEPRESSION, ANXIETY, AND LIFE QUALITY
Authors: Lanoye Autumn , Fox Amber , Willis Kelcie , Zukas Alicia M , Loughan Ashlee
Published: November 2023

BACKGROUND

Sleep disturbance is among the most common complaints endorsed by patients with a brain tumor diagnosis, yet the delivery of behavioral insomnia treatment is not standard practice in neuro-oncology. Our pilot trial of a 6-session group-based telehealth CBT-I program among primary brain tumor patients demonstrated clinically significant improvements in self-reported insomnia, fatigue, and sleep quality. In other cancer patient samples, CBT-I is also associated with improvements in psychosocial outcomes beyond sleep; thus, the aim of this exploratory analysis was to examine change in depression, anxiety, and life quality among primary brain tumor patients enrolled in CBT-I.

METHODS

This was a single-arm ORBIT Model Phase IIa proof-of-concept trial. N = 40 cognitively-intact participants (Mage = 52.4 + 12 years; 50.0% female) with a primary brain tumor and insomnia enrolled in a 6-week group-based telehealth CBT-I intervention with weekly 90-minute sessions led by graduate students in clinical psychology. Questionnaires (PHQ-9, GAD-7, EORTC-QLQ-30) were completed at baseline and 6 weeks. Within-person clinically significant improvement was calculated for intervention completers (n = 34) based on established cutoffs.

RESULTS

Approximately one-third of participants experienced clinically significant improvements in symptoms of depression (n = 12, 35.3%) and generalized anxiety (n = 11, 32.3%) following CBT-I, with 0 participants experiencing a clinically significant worsening of symptoms. Thirty-two of thirty-four participants (94.1%) reported clinically significant improvement in at least 1 domain of life quality spanning physical, role, emotional, and/or social functioning.

CONCLUSIONS

Findings suggest that a brief behavioral intervention for insomnia, CBT-I, may improve depression, anxiety, and life quality in addition to sleep among primary brain tumor patients.

RESULTS

from this proof-of-concept trial suggest proceeding to a test of CBT-I in comparison to a control group in order to bolster internal validity. In addition, future studies will examine sleep and related psychosocial outcomes over a longer follow-up period to assess maintenance of intervention effects.
QOL-13. MEASURING FEAR OF CANCER RECURRENCE IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: Braun Sarah , Mladen Samantha , Langbein Jenna , Verter Jacob , Lanoye Autumn , Loughan Ashlee , Simard Sébastien
Published: November 2023

BACKGROUND

Fear of cancer recurrence (FCR) differs for those living with primary brain tumor compared to other cancers due to poorer prognosis, neurologic symptoms, and often lifelong treatment. The gold-standard instrument used to assess FCR–the FCR Inventory (FCRI)–has not been validated in patients with PBT. The present study explored the psychometric properties of the FCRI in patients with brain tumors, with items added assessing brain tumor-specific distress.

METHODS

Adult patients with brain tumors (n = 87) completed the FCRI and other psychological medical, and demographic questionnaires. Exploratory factor analysis (EFA) was conducted on the FCRI with five additional items informed by neuro-oncology patients and professionals assessing brain tumor-specific hypervigilance (e.g., interpreting headache or cognitive difficulties as possible tumor growth) and one item assessing tendency to research treatments—for a total of 48 items. Correlations investigated convergent/discriminant validity and relationships with relevant medical and demographic variables.

RESULTS

After iteration, EFA revealed a seven-factor model with 24 retained items, accounting for 68.19% of variance, with factor correlations between .12 and .65. The seven-factor model echoed but did not fully replicate the original FCRI. FCRI-Brain factors were: Triggers, Psychological Distress, Functional Impairments, Insight, Reassurance, Emotion-Focused Coping, and Problem-Focused Coping (Total: Cronbach’s a = .92). The resultant FCRI-Brain demonstrated good convergent validity with measures of depression (r = .57), anxiety (r = .71), and death anxiety (r = .81; ps< .05). Lack of correlation with education (p > .05) supported discriminant validity. There was no relationship with time since diagnosis (p > .05).

CONCLUSIONS

These data represent the initial validation of an FCR measure in patients with brain tumors. Factor analysis identified a theoretically similar; yet unique seven-factor model for the FCRI-Brain. Item-level exploration will be presented, including further discussion of factor iteration and construction. Future work will build on this data in larger samples and inform intervention development.
QOL-14. INTEGRATING A TECHNOLOGY-ENABLED PLATFORM FOR PATIENT REPORTED OUTCOMES INTO A NEURO-ONCOLOGY PRACTICE
Authors: Mahotz Mariah , Nguyen Minhdan , George Renee , Swisher Christine , Weinreb Jason , Tang Yiqing , Mauritson Emmaline , Wagle Naveed , Carrillo Jose , Martin Neil , Kesari Santosh , Sharma Akanksha
Published: November 2023

BACKGROUND

Neuro-oncology (NOC) patients experience various symptoms from disease and treatment which are deleterious to function and quality of life (QOL). Evidence demonstrates the use of electronic patient-reported outcomes (ePROs) improves health-related QOL, mental functioning, patient-provider communication, and overall survival. Despite this knowledge, uptake across cancer services has been slow. In this pilot study, we sought to understand the utility of an electronic symptom monitoring platform (ESMP) in this population.

METHODS

We implemented an ESMP at a NOC practice and conducted a preliminary analysis of ePROs over 7-month period. Patients were prompted to report their symptoms at least 3 times/week through multiple-choice questions targeting 19 distinct symptoms and their severity (tiered 1-4). The care team was automatically notified through the electronic medical record predefined symptom severities.

RESULTS

During a 7-month period, 28 neuro-oncology patients were enrolled and monitored for a total of 660.7 patient-weeks or an average of 23.6 weeks per patient. In total, 314 questionnaires were completed; each patient completed 0.6 per week on average. We found questionnaire compliance to be the highest initially, declining in subsequent weeks. Symptoms were reported in 42.8% of questionnaires; the most frequent of which were peripheral neuropathy (16.6%), fatigue (11.5%) and headache (10.5%). Alerts were sent to the care team for 103 (32.8%) questionnaires, 38 resulted in additional interventions for the patient.

CONCLUSION

Our results support the hypothesis that technology-enabled integration of ePROs enables monitoring followed by automated alerts and customized responses to NOC patients. We note that peak usage was at the beginning of active treatment which occurred concurrently with onboarding. Opportunities and challenges involve the continuous promotion of patient engagement and optimization of workflow to encourage discussions and utilization. Future work also includes determining if this platform can lead to improved clinician efficiency and patient outcomes in this patient population.
QOL-15. THE PIVOTAL TRIDENT STUDY OF TUMOR TREATING FIELDS (TTFIELDS) THERAPY WITH CHEMORADIATION, FOLLOWED BY MAINTENANCE TTFIELDS THERAPY/TEMOZOLOMIDE (TMZ), IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: Shi Wenyin , Glas Martin , Roberge David , Kleinberg Lawrence , Jeyapalan Suriya , Goldlust Samuel , Nagpal Seema , Lustgarten Leonardo , Combs Stephanie , Nishikawa Ryo , Reardon David , Grossman Rachel
Published: November 2023

INTRODUCTION: TTFields are electric fields which act to disrupt processes necessary for cancer cell division and tumor progression. TTFields therapy is a noninvasive, locoregional treatment with US FDA approval for ndGBM and recurrent GBM, as well as pleural mesothelioma. TTFields therapy concomitant with maintenance TMZ is standard of care in ndGBM after chemoradiation based on the pivotal EF-14 study (NCT00916409) reporting significant improvements in progression-free survival (PFS) and overall survival (OS) vs TMZ alone. Preclinical and pilot clinical studies subsequently demonstrated that concomitant TTFields therapy also enhanced the therapeutic effect of radiotherapy (RT). TRIAL DESIGN: TRIDENT (EF-32, NCT04471844) is a pivotal multicenter study investigating TTFields therapy (200 kHz) concomitant with RT/TMZ in adult patients with histologically confirmed ndGBM. Eligibility criteria include life expectancy (≥ 3 months) and Karnofsky performance status (≥ 70). Patients (n≈950) stratified by MGMT promoter methylation status and extent of resection are randomly assigned 1:1 to receive TTFields therapy from the first day of chemoradiation (experimental arm), or approximately 4 weeks after completion of chemoradiation (control arm). All patients will receive TTFields therapy uninterrupted for 24 months, or until second disease progression (PFS2). The primary endpoint is median OS and other endpoints include survival rates at 1 and 2 years, PFS (overall, PFS2, and rates at 6 and 12 months), overall radiological response, safety, quality of life and dependence of OS on TTFields dose. The sample size is powered for a hazard ratio of < 0.8 (5% type I error). A stratified log-rank test will be used to test the hypothesis that OS is significantly improved with first line TTFields therapy/RT/TMZ vs RT/TMZ. This global study is open at sites in 11 countries.
QOL-19. TUMOR TREATING FIELDS (TTFIELDS) THERAPY IN GLIOBLASTOMA (GBM): RELATIONSHIP BETWEEN PATIENT EXPERIENCE, GLOBAL REGION, AND AGE
Authors: Shockley Shermona , Gage Gwyn P , Adams Renae , Batzianouli Eleni , Johnson Heather , Abdullah Huda Ismail
Published: November 2023

BACKGROUND

TTFields therapy is a noninvasive, locoregional anticancer treatment approved for newly diagnosed and recurrent GBM based on efficacy and safety results in 2 global, randomized pivotal studies, supported by real-world evidence.

METHODS

In 2022, 2 questionnaires (mail or online) surveyed the real-world experiences of patients with GBM receiving TTFields therapy (NovoTTF-200A; Novocure®, GmBH) and their caregivers in Germany, Austria, and Switzerland (DACH), and the USA.

RESULTS

545/1197 surveys were returned in DACH (46%); 1332/5031 in the USA (26%). Most respondents indicated satisfaction/high satisfaction with TTFields (in patients starting therapy, 82% [DACH] and 58% [USA]; in patients with >6 months use, 67% [DACH] and 72% [USA]). The following data pertain to patients with >6 months of TTFields use (n = 114 DACH; n = 375 USA). 63% in DACH reported that daily life was changed “much”/“very much”, and 35% “hardly at all”; in the USA, 17% indicated they were able to live as they did before therapy, 61% had to make adjustments but had returned to a normal routine, and 23% said therapy had markedly impacted daily life. 74% (DACH) and 73% (USA) would recommend to other patients. Common reasons for low satisfaction included skin irritation and device handling. To assess any impact of age, responses from patients aged ≥70 years ( >6 months use) from the USA (n = 82 [22%]) were analyzed (there were not enough elderly patients with >6 months use in DACH [n = 8] to analyze). As with the overall population, elderly patients in the USA reported they were satisfied/very satisfied (67%). 66% of elderly patients (USA) were very likely to recommend TTFields to someone else.

CONCLUSIONS

Surveys of patient/caregivers in DACH and the USA who used TTFields for GBM identified a high degree of satisfaction, including elderly patients. Most respondents would recommend TTFields to others.
QOL-22. USE OF TUMOR TREATING FIELDS THERAPY WITH ADJUVANT TEMOZOLOMIDE AND IMMUNOTHERAPY FOR NEW DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: Cheng Samantha , Hormigo Adilia
Published: November 2023

BACKGROUND

Treatment options for GBM remain limited, and novel approaches are required. One of them, Tumor Treating Fields (TTFields) therapy, is a non-invasive treatment modality that delivers low intensity, intermediate frequency, alternating electrical fields and increases survival through multiple mechanisms, including disrupting cell mitosis, triggering tumor cell death, and expanding CD8+ cytotoxic lymphocytes.

METHODS

In this prospective study, adult patients with ndGBM underwent standard-of-care treatment with maximal resection, followed by radiotherapy and temozolomide. Use of TTFields therapy, with a recommended daily use of ≥ 18 hours/day, throughout adjuvant temozolomide treatment and with immunotherapy, was investigated.

RESULTS

Eight patients received TTFields therapy. Use of TTFields was 2, 5, 6, 6, 8, 8, 10, and 16 months with an average of 10.2 months. The patient with the lowest use developed a grade 1 papulopustular scalp rash and discontinued use. Monthly average daily use ranged from 0% to 87%. Average daily use over treatment was 39%, 47%, 48%, 53%, 67%, 69%, 78%, and 83%. None of the patients achieved the goal for daily use every month. Four patients had a daily use ≥ 80% for at least one month of treatment. Except for one patient, whose daily use increased from 72% in the first month to 79% in the last month, all other patients down-trended in TTFields use. Six patients completed EORTC-QLQ-C30 surveys throughout the study. 3/8 had an overall increase in their global quality of life scale, 3 patients had a decrease, and 2 patients did not complete the survey.

DISCUSSION

In this study, the use of TTFields was suboptimal. We presume that with multiple treatments in the adjuvant phase including 6 cycles of temozolomide and optional TTFields use, patients did not recognize the potential therapeutic benefit of continued TTField therapy use and opted to remain only in the immunotherapy treatment.
QOL-27. EXPLORING DYADIC CHANGES IN ANXIETY AND DEPRESSION SYMPTOMS FOR PRIMARY BRAIN TUMOR PATIENTS AND THEIR FAMILY CAREGIVERS
Authors: Bacharz Kelsey , Body Anjelica , Ernster Alayna , Hanvey Grace Ann , Rahman Maryam , Mitchell Duane , Wilborn Adaixa , Pereira Deidre , Ghiaseddin Ashley
Published: November 2023

A primary brain tumor (PBT) diagnosis impacts not only the diagnosed person but their family caregivers. Prior research has established that the psychosocial outcomes (i.e., fear of cancer recurrence, quality of life) of individuals with a PBT and their caregivers are interrelated. Actor-partner interdependence modeling (APIM) can account for this interdependence and be used to assess for dyadic changes over time or different variables. The purpose of the present study was to assess longitudinal dyadic changes in anxiety and depressive symptoms for PBT patients and their caregivers. 38 PBT patient/caregiver dyads completed assessments of anxiety and depressive symptoms during routine oncology clinic visits. All dyads completed at least two assessments, at least 8-weeks apart utilizing the PROMIS anxiety and depression short forms. APIM analyses via mixed linear modeling revealed significant actor effects for both depression and anxiety symptoms (i.e., how the same person’s scores are related from baseline to follow-up) but non-significant partner effects (i.e., how one person’s score at the first timepoint is related to the other person’s score at the second timepoint). Specifically, a one-point increase in T-score at the first timepoint was associated with the same person having a 0.58 increase in their PROMIS depression T-score and 0.50 increase in their PROMIS anxiety T-score, respectively, at the second timepoint (p < .001). There were no significant partner effects detected for depression (p = .168) or anxiety (p = .998). Despite the lack of significant relationship between patient and caregiver outcomes in these results (possibly influenced by small sample size), it is notable that, overall, there was an increase in psychological distress over time for both depression and anxiety symptoms for both patients and caregivers. Thus, future research should continue to focus on how to reduce distress and ensure that both patients and caregivers are supported throughout the disease trajectory.
RBIO-04. INHIBITING THE SHH PATHWAY AND PARP1 IN COMBINATION ENHANCES THE RADIATION SENSITIVITY OF PEDIATRIC SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Price Laura , Lau Bonnie
Published: November 2023

Medulloblastoma accounts for 20-25% of all pediatric brain tumors. These patients undergo craniospinal and focal radiation therapy during their treatment, resulting in negative long-term consequences such as bone and tissue hypoplasia and decreased neurocognitive functioning. One of the most concerning effects is the significantly increased risk for secondary radiation induced cancers later in life. Thus, there is a critical need for novel approaches to radiation therapy that can effectively target and kill tumor cells while minimizing long lasting toxic effects. Here, we investigate a novel approach to radiation therapy that relies on the combination of two classes of therapeutic agents, Sonic Hedgehog (SHH) inhibitors and Poly (ADP-ribose) Polymerase (PARP) inhibitors. The SHH pathway plays a key role in medulloblastoma tumorigenesis and affects the radiation sensitivity of various cancer types such as basal cell carcinoma. The PARP family, specifically PARP1, plays a key role in DNA damage repair and affects the radiation sensitivity of pediatric brain cancers such as high-grade glioma and medulloblastoma. We hypothesize that combining these approaches by inhibiting Smo and Gli1 in the SHH pathway, and PARP1 simultaneously, will enhance medulloblastoma tumor cell killing following radiation therapy. We found that in vitro treatment with Sonidegib, GANT61, and Veliparib alone and in combination with was sufficient to significantly decrease tumor cell viability and self-renewal as measured by clonogenic survival assays (p < 0.01). 24 hours following these targeted treatments, 2 Gy of radiation was administered which resulted in a greater degree of decreased cell viability and self-renewal (p < 0.01), as well as in increased cell death. Together, this data suggests that inhibition of Smo, Gli1, and PARP1 either alone as single agents, or in combination is a promising therapeutic strategy for increasing the radiation sensitivity of pediatric SHH medulloblastoma.
RBIO-08. GTP SIGNALING LINKS ALTERED METABOLISM, DNA REPAIR AND TREATMENT RESISTANCE IN GLIOBLASTOMA
Authors: Zhou Weihua , Zhao Zitong , Lin Angelica , Yang John , Xu Jie , Wilder-Romans Kari , Yang Annabel , Li Jing , Solanki Sumeet , Speth Jennifer , Walker Natalie , Scott Andrew J , Kothari Ayesha , Yao Yangyang , Peterson Erik , Korimerla Navyateja , Werner Christian , Liang Jessica , Jacobson Janna , Palavalasa Sravya , Obrien Alexandra , Elaimy Ameer , Ferris Sean , Zhao Shuang , Sarkaria Jann , Győrffy Balázs , Zhang Shuqun , Al-Holou Wajd , Umemura Yoshie , Morgan Meredith , Lawrence Theodore , Lyssiotis Costas , Peters-Golden Marc , Shah Yatrik , Wahl Daniel
Published: November 2023

OBJECTIVE

We sought to define the mechanisms by which purines regulate DNA repair and therapy response.

METHODS

Phosphoproteomics was used to identify GTP-dependent (de)phosphorylation events after radiation (RT) and antibodies generated against novel sites. Animal models of glioblastoma (GBM) and normal tissues were used to assess DNA repair and treatment responses in vivo.

RESULTS

Pharmacogenomic inhibition of GTP (but not ATP) synthesis sensitized GBM cells to RT by inhibiting the activity of non-homologous end joining, but not homologous recombination. We found a GTP-dependent RT-induced dephosphorylation event on Abl interactor 1 (Abi-1) serine 323 (S323) using phosphoproteomics. We generated a new antibody for p-Abi-1 (S323), validated its specificity, and confirmed that RT causes a GTP-dependent dephosphorylation of Abi-1 (S323). Knockout of Abi-1 slowed RT-induced double-strand break (DSB) repair, and this was rescued by re-expression of dephosphomimetic Abi-1 (S323A) but not phosphomimetic Abi-1 (S323D). Abi-1 canonically binds to G protein Rac1. Expression of constitutively active Rac1 promoted but dominant negative Rac1 blocked the dephosphorylation of Abi-1 (S323) and DSB repair. Knock-down or inhibition of protein phosphatase 5 reversed the GTP- and Rac1-mediated dephosphorylation of Abi-1 and DSB repair. In GBM PDX samples, p-Abi-1 (S323) levels negatively correlated with Rac1 activity and predicted favorable efficacy of genotoxic treatments. In orthotopic GBM mouse models, inhibiting Rac1 enhanced RT responses and suppressed Abi-1 (S323) dephosphorylation. Abi-1 knockout enhanced efficacy of genotoxic treatments and could be rescued by Abi-1 S323A (but not Abi-1 S323D) re-expression. This regulation is generalizable beyond brain cancer, as GTP supplementation promoted DNA repair and p-Abi1 (S323) dephosphorylation in non-malignant cells and protected mice from RT-mediated gastrointestinal injury and bleomycin-induced pulmonary fibrosis.

CONCLUSION

The GTP-Rac1-PP5-Abi-1 signaling axis links metabolism and DNA repair. Disrupting this pathway can overcome GBM resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues.
RBIO-09. HMGB2 INHIBITION RADIO-SENSITIZES GLIOBLASTOMA CELLS INDEPENDENTLY OF THEIR TP53-MUTATION STATUS
Authors: Becker Aline , Becker Valesio , Sebastian Ebin , Showalter Christian , McElroy Joseph , Jaharul Haque S , Chakravarti Arnab
Published: November 2023

Alterations in TP53 are major drivers of radiation resistance in gliomas. High Mobility Group Box 2 (HMGB2) has been implicated in resistance to temozolomide through p53-phosphorylation during DNA double-strand break repair and in silico analysis suggests its involvement in the p53-p21-RB signaling pathway. Nevertheless, the role of HMGB2 in radiation response has not been fully explored in gliomas. While HMGB2 is virtually not expressed in the normal adult brain, increasing expression with histopathological glioma grade correlates with poor patient survival. We confirmed increased HMGB2 expression in grade 3 compared to grade 2 gliomas using ClariomD and observed spatial heterogeneous HMGB2 expression in glioblastomas (GBMs) in histopathology-targeted supervised proteomic analysis employing liquid chromatography tandem mass spectroscopy (LC-MS-MS). Here, we aimed to study HMGB2 effects in cell proliferation and response to radiation in a set of molecularly distinct genetically engineered GBM cell lines (IDHwt). Using an established U87 GBM cell line and isogenic primary GBM cell lines GBM3359 TP53wt and CRISPR/Cas9-engineered mutant TP53 (R248W) generated in our laboratory, we successfully produced clones with either HMGB2 shRNA knockdown (KD – over 70% reduction) or HMGB2 lentiviral-mediated overexpression (OE – 3-76x higher expression). HMGB2-KD reduced cell proliferation (10% in U87; 20-25% in isogenic GBM3359 cell lines) and colony formation (more than 50% reduction), which was further rescued with HMGB2 OE in all cell lines. Half maximal inhibitory concentration (IC50) for radiation was determined by methylene blue cell proliferation and clonogenic assays, which showed that HMGB2-KD decreased the IC50 while rescued HMGB2 OE increased RT resistance of all clones. Taken together, our data suggest that HMGB2 inhibition may improve radiation response independently of TP53 status in gliomas. Further mechanistic studies to elucidate the relationship between HMGB2 and TP53 are underway to unfold the contribution of heightened HMGB2 expression to radiation resistance mechanisms in gliomas.
RTID-01. A RANDOMIZED STUDY OF LOW-INTENSITY FOCUSED ULTRASOUND FOR BLOOD-BRAIN BARRIER DISRUPTION FOR BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER (LIMITLESS)
Authors: Ahluwalia Manmeet , McDermott Michael , Ozair Ahmad , Khosla Atulya , Sahgal Arjun , Mishra Mark V , Achrol Achal , Sahni K Singh , Sanai Nader , Lipsman Nir , Woodworth Graeme F
Published: November 2023

BACKGROUND

Blood-brain barrier disruption (BBBD) has been demonstrated, in preclinical models, to improve systemic drug delivery for BM. Low-intensity focused ultrasound (LIFU) with intravenously (IV) administered microbubble oscillators results in non-invasive BBBD, potentially permitting drug delivery. This randomized controlled trial (RCT) aims to determine the safety and efficacy of LIFU-mediated BBBD for NSCLC BM with immunotherapy.

METHODS

LIMITLESS is an ongoing prospective, multicenter, parallel-arm, open-label RCT that randomizes patients with NSCLC-BM on pembrolizumab monotherapy prescribed as per standard-of-care to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM, with ≥1 BM meeting measurable disease RANO-BM criteria. Patients on both arms receive standard-of-care therapy, while those on arm 1 also undergo LIFU before each dose of pembrolizumab (200 mg IV every 3 weeks). These patients undergo pre-treatment MRI brain, followed by IV administration of oscillating microbubbles for enhanced sonication. MR-guided BBBD is then performed using 220 kHz LIFU device with real-time acoustic feedback. Pembrolizumab is infused immediately thereafter, and repeat MRI done confirming BBB closure each cycle. Primary study endpoint is overall objective response rate (ORR) at 6 months as per RANO-BM criteria. Using a Bayesian design, a superior ORR of 60% is assumed for the LIFU arm versus 30% in the control arm for N = 96, 64 subjects in LIFU and 32 in control arm, for 80% power, with alpha = 0.05. For upper-bound estimate ORR of 45% in LIFU arm and 30% in control arm, the study needs N = 369 subjects; 246 in the LIFU arm and 123 in the control arm. Secondary outcomes are the best overall response rate and median time-to-response. Exploratory outcomes are median PFS, OS, intracranial PFS, extracranial PFS, and quality of life. Clinical trial information: NCT05317858.
RTID-02. SILMET TRIAL: A RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE SILIBININ IN PREVENTING INTRACRANIAL RECURRENCE AFTER COMPLETE RESECTION OF A SINGLE BRAIN METASTASIS FROM NSCLC OR BREAST CANCER
Authors: Pellerino Alessia , Pace Andrea , Angileri Filippo Flavio , Caffo Maria , Gatti Marco , Olivi Alessandro , D'Alessandris Quintino Giorgio , Fabi Alessandra , Bertero Luca , Ricci Alessia Andrea , Mangherini Luca , Garbossa Diego , Priego Neibla , Bosch-Barrera Joaquim , Valiente Manuel , Soffietti Riccardo , Rudà Roberta
Published: November 2023

BACKGROUND: A subpopulation of reactive astrocytes (RAs) with activated signal transducer and activator of transcription 3 (STAT3) signalling in peritumoral tissue of brain metastases (BM) has been shown to favor a pro-metastatic microenvironment. High-pSTAT3 expression in RAs of BM has been correlated with a shorter intracranial progression-free survival (i-PFS) as compared with low-pSTAT3 BM. Pharmacological inhibition of the STAT3 pathway with silibinin has been suggested to be active in preliminary cohort of patients with BM. Patients and methods. A new “prevention” trial has been initiated in June 2023 to investigate the efficacy of silibinin in comparison to placebo (PCB) to prevent a secondary intracranial relapse in a multicentric cohort of patients with gross-total resected BM from NSCLC and breast cancer. Inclusion criteria are as follows: histologically confirmed BM from NSCLC or BC; single BM who underwent a complete resection; systemic disease not requiring a change of antineoplastic therapy; pSTAT3 presence in RAs of peritumoral tissue confirmed by central assessment; ≥ 18 – 70 years of age; KPS ≥ 70. The primary endpoint is to demonstrate a superiority of silibinin in prolonging time to local recurrence as compared to PCB. The secondary endpoints are time to distant recurrence of BM in the brain, i-PFS, overall PFS (intracranial and/or systemic), overall survival, tolerability, quality of life. Collection of blood and CSF samples for the analysis of STAT3 downstream pathways is an exploratory objective. The sample size (70 patients) was calculated by assuming a median time to local recurrence of BM of 7.5 months for PCB (control arm) according to Mahajan [1] and ≥15 months for silibinin arm. Clinical trial information: NCT05689619 [1] Mahajan A et al. Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017
RTID-04. GLUGLIO - A PHASE IB/II RANDOMIZED DRUG REPURPOSING TRIAL OF GLUTAMATE SIGNALING INHIBITORS IN COMBINATION WITH CHEMORADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NCT05664464)
Authors: Wirsching Hans-Georg , Roth Patrick , Fischer Angela , Hottinger Andreas , Hundsberger Thomas , Migliorini Denis , Ochsenbein Adrian , Laeubli Heinz , Seystahl Katharina , Imbach Lukas , Hortobagyi Tibor , Held Leonhard , Bink Andrea , Weller Michael
Published: November 2023

Glioblastoma synthesizes and secretes large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Several brain-penetrating drugs that have obtained clinical approval in other pathologic conditions can inhibit glutamate synthesis, secretion and signalling, respectively, including (i) the anti-seizure drug gabapentin, which inhibits the glutamate synthesis enzyme, branched chain amino acid transaminase 1, (ii) the anti-inflammatory drug sulfasalazine, which inhibits glutamate secretion by blocking the cystine-glutamate exchanger system Xc, and (iii) the cognitive enhancer memantine, which can prevent glutamate-driven, calcium-induced neuronal death and tumor cell invasion by blocking N-methyl-D-aspartate (NMDA) type glutamate receptors. The multi-centre, open-label, parallel-group, two-arm, 1:1 randomized, phase Ib/II trial GLUGLIO explores the efficacy of a triple-combination of daily oral gabapentin, sulfasalazine and memantine in combination with standard chemoradiotherapy compared to chemoradiotherapy alone. Dosing of either drug will be sought up to the maximum approved dose and will be reevaluated in an interim safety analysis after 20 patients have been randomized into the experimental arm. The primary endpoint is progression-free survival at 6 months (PFS-6). The sample size of N = 120 patients was calculated to detect an increase in PFS-6 from 50% to 70% with a power of 80% performing exploratory hypothesis testing at a one-sided significance level of 10%. Secondary endpoints include progression-free, overall and seizure-free survival, response rate, quality of life of patients and caregivers, symptom burden, cognitive functioning, tumor glutamate levels by magnetic resonance spectroscopy as well as anti-convulsant and steroid use. Surgical tissues as well as peripheral blood and electroencephalography recordings will also be sampled longitudinally for translational analyses. Recruitment is ongoing and foreseen to be completed by mid 2026. The simultaneous targeting of glutamate synthesis, secretion and signalling will clarify whether glutamate should be further explored as a clinical target in glioblastoma patients.
RTID-05. SURGICAL WINDOW OF OPPORTUNITY TRIAL REVEALS MECHANISMS OF RESPONSE AND RESISTANCE TO NAVTEMADLIN (KRT-232) IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Rendo Veronica , Lee Eudocia , Bossi Connor , Khuu Nicholas , Pal Sangita , Reynolds Abigail , Fassinou Auriole , Ligon Keith , Beroukhim Rameen , Wen Patrick , Rudek Michelle
Published: November 2023

Over half of glioblastoma multiforme (GBM) patients retain wild-type p53, resulting in potential susceptibility to MDM2 inhibitors. These molecules disrupt the interaction between p53 and its negative regulator MDM2, resulting in downstream pathway signaling and cell fate decisions such as growth inhibition and death from cellular stress. We have analyzed clinical samples from 21 patients with recurrent GBM treated with the MDM2 inhibitor KRT-232, all of which relapsed despite the biological promise of this small molecule. By analyzing on-treatment biopsy samples, we detected upregulation of p53 transcriptional targets, suggesting blood-brain barrier penetrance and drug pharmacodynamics. However, in patient-derived cell lines, treatment with KRT-232 at the clinically achieved concentration was only sufficient to stall but not reduce tumor growth. Cell death via apoptosis was achieved in these cell line models when MDM2 inhibition was combined with the chemotherapeutic agent temozolomide. These drugs have non-overlapping mechanisms of action and exhibit synergy in our cell line models. Normal human bone marrow cells underwent a reversible growth inhibition phenotype when treated with KRT-232 and TMZ, supporting the idea that a therapeutic window exists with this combination. We additionally observed that tumor progression occurred in the absence of p53 inactivating mutations, suggesting that other mechanisms of resistance to KRT-232 may modulate drug response and resistance in GBM. Indeed, drug treatment induced an adaptive response in human tumors, characterized by the upregulation of genes involved in glial cell differentiation processes. Ongoing work is focused on understanding how tumor heterogeneity and cell state modulate response and resistance of GBMs to MDM2 inhibition and other therapeutic strategies that reactivate p53 signaling. Our study highlights the utility of tissue sampling during clinical trials and represents the first clinical effort to detect adaptive changes in human tumor tissue associated with p53 reactivation.
SURG-01. DIFFERENTIATION OF GLIOBLASTOMA AND MALIGNANT MENINGIOMA FROM NORMAL BRAIN BY TISSUE STIFFNESS UTILIZING MICROSURGICAL FORCEPS EQUIPPED WITH HAPTICS TECHNOLOGY
Authors: Ezaki Taketo , Kisima Kohki , Shibao Shunsuke , Matsunaga Takuya , Pareira Eriel Sandika , Kitamura Yohei , Takahara Kento , Iwama Takashi , Sampetrean Oltea , Ohnishi Kouhei , Shimono Tomoyuki , Sasaki Hikaru
Published: November 2023

Stiffness of human cancers strongly correlate with their pathology, and it is reported that stiffness can be used as a biomarker. Furthermore, comprehensive analysis has suggested the usefulness of cancer stiffness in diagnosis and malignancy prediction and its association with molecular expression, as well as its potential for predicting and diagnosing postoperative complications. Neurosurgeons perform tumor resection relying on the sensations that they feel with their own fingertips (tactile sensation), but it takes years of surgical experience to accurately distinguish brain tumor from the surrounding normal brain tissue.

Haptics is a new technology regarding touching sensation. Especially, our technology, real haptics, can communicate, record, and reproduce the real sensation. It is also possible to measure and analyze the physical property such as stiffness of the touching object from the obtained haptic data.

We developed a surgical forceps equipped with haptics technology to distinguish brain tumor tissue from surrounding normal brain tissue. three glioblastoma cell lines (SF126, U87, U251) and a malignant meningioma cell line (IOMM-Lee) were each transplanted intracranially into 5 nude mice. Tumor size was periodically monitored and mice were euthanized at appropriate time points. The stiffness of the tumor and normal brain tissue was measured using a master-slave integrated surgical forceps prototype. The results statistically showed that all four types of brain tumor tissues were stiffer than normal brain tissues. (p = 0.001) In addition, malignant meningioma was statistically stiffer than glioblastomas. (p = 0.025) This result is consistent with actual surgical sensations.

We have shown that our surgical forceps has the ability to distinguish pathology of brain tumors as well as to distinguish brain tumor from normal brain tissue. The forceps is also helpful for the neurosurgeons to sense minute change in tissue stiffness.
SURG-05. HYPER SMART CYBER OPERATING THEATER TO PERFORM FUTURE PREDICTIVE SURGERY
Authors: Muragaki Yoshihiro , Masamune Ken , Sasayama Takashi , Kawamata Takakazu
Published: November 2023

Gliomas are invasive tumors in which the extent of tumor resection is believed to correlate with prognosis. However, aggressive extraction risks deterioration due to functional tissue damage. One strategy for resolving this conflict is the technology of new modalities. The basis of this technology is digital transformation (DX), converting analog information called tacit knowledge on experiences into digital information for explicit knowledge. In the future, we will develop an AI system, generated by DX data, and support intraoperative decision-making with highly accurate future predictions. In order to realize this future-prediction surgery, we have developed a smart cyber operating theater (SCOT) with intraoperative MRI. More than 20 medical devices are connected by middleware (OPeLiNK®), and navigation spatial records and time-synchronized data are displayed on the strategy desk. A hyper version of SCOT has currently performed 277 surgeries, including 262 gliomas, 51 awake craniotomies, and 88 photodynamic therapies. For WHO grade 4 glioblastomas, we try to remove contrast-enhanced areas, and for grade 2/3 gliomas, to formulate an extraction strategy for each 3 genotypes, we perform preoperative AI prediction and intraoperative genetic diagnosis for genotype. Intraoperative flow cytometry is useful to predict the genotype (oligodendroglioma) and determine the extent of resection in some cases. Time-synchronized data showed points of surgical maneuvers causing speech arrest in awake surgery and decreases in MEP, and provided feedback during and after surgery. AI technology is also used for preoperative surgical simulation (GRID®), artifact reduction in iMRI, and brain shift prediction. The hyper SCOT supports the optimal removal of gliomas through intraoperative future prognosis prediction through device data and AI analysis. Furthermore, we are developing an AI robot (AIREC) that performs surgery through deep predictive learning, with the aim of commercialization after 2040. This work was partially supported by JST [Moonshot R&D] [Grant Number JPMJMS2031].
SURG-06. DEVELOPING A LASER INTERSTITIAL THERMAL THERAPY (LITT) PLATFORM FOR THE TREATMENT OF INTRACRANIAL LESIONS IN CANINES
Authors: Wachsmuth Lucas , Ruterbories Laura , Tsvankin Vadim , Bramall Alexa , Tyc Richard , Mariani Christopher , Fecci Peter
Published: November 2023

Malignant gliomas are devastating intracranial tumors with dismal prognoses that impose unique therapeutic challenges. Treatment options include surgical resection, radiation, and chemotherapy, but efficacy is limited and carries associated morbidity. Promise persists for newer modalities, such as immune-based platforms, but obstacles include limited therapeutic access due to the blood-brain barrier (BBB) and the highly immunosuppressive tumor microenvironment. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical intervention permitting thermal ablation of intracranial tumors. During LITT, a laser probe is stereotactically placed in the lesion through a skull burr hole. Real-time MRI is used to calculate thermal dosage zones to monitor ablation progress. LITT is not only cytoreductive but also opens the BBB and induces a powerful hyperthermia-driven anti-tumor immune response; it thus may synergize with other emerging therapies. Spontaneous canine glioma offers a matchless, optimally recapitulative appropriately sized tumor model, providing a unique opportunity to investigate and optimize the LITT platform. We adapted a commercially available LITT system (Monteris Medical) for application in canines with intracranial lesions. Initially, canine cadavers were used to optimize LITT procedures; we then performed LITT in live dogs. Our approach consists of 1. obtaining volumetric MRI studies for trajectory planning, 2. fixing canine patients to the surgical bed, 3. registering anatomic landmarks (Brainlab) to a volume rendered image, 4. using an integrated instrument holder (Varioguide, Brainlab) to guide drilling of 4.5 mm skull burr holes for placement of self-tapping titanium “mini-bolts” (Monteris Medical), and 5. introducing the laser through the mini-bolts for ablation in the MRI suite. This method allows for rigid stereotaxy, successful neuronavigation, and a minimally invasive approach. We have successfully performed LITT on four canine patients with intracranial gliomas. Future studies will explore immunologic mechanisms underlying the post-LITT anti-tumor response as well as combination therapeutic platforms, including nanoparticles and stereotactic radiotherapy.
SURG-08. THE CLEARPOINT ARRAY® FRAME: A NOVEL MRI COMPATIBLE SYSTEM THAT SUPPORTS NON-CRANIOTOMY, MULTI-TRAJECTORY (NCMT) STEREOTACTIC PROCEDURES
Authors: Hamade Youssef , Chen Clark
Published: November 2023

BACKGROUND

With continued evolution in stereotactic techniques and an expanding armamentarium of therapeutic options, non-craniotomy stereotactic procedures in neuro-oncology are becoming increasingly complex, often requiring multi-trajectory approaches. Here we demonstrate that the ClearPoint SmartFrame Array®, a second-generation MRI-compatible stereotactic frame, supports such non-craniotomy, multi-trajectory (NCMT) stereotactic procedures.

METHODS

Through a case report, we previously established the feasibility of NCMT through the ClearPoint SmartFrame Array®. Here we prospectively followed the next ten consecutive patients who underwent such multi-trajectory procedures to establish procedural safety and clinical utility.

RESULTS

Ten patients underwent complex, multi-trajectory stereotactic procedures, including combinations of needle biopsy + cyst drainage and laser interstitial thermal therapy (LITT) targeting geographically distinct regions of neoplastic lesions under the same anesthetic event. For each intended target, the maximal radial error of stereotaxis ranged 0.1-2.7 mm (with a median of 1.0 mm). In all cases, definitive diagnosis was achieved, and >90% of the intended targets were ablated. The average stereotaxis time (time required to establish the trajectories) for the multi-trajectory procedure was 119 + 22.2 minutes, which is not statistically different from our published results for single-trajectory procedures (80 + 9.59 minutes, p = 0.125). There were no procedural complications. Post-procedure, the neurologic condition of one patient improved, while the remaining nine patients remained stable. All patients were discharged home, with a median hospital stay of one day (range: 1-12 days). With a median follow-up of 376 days (range: 155-1438 days), there were no 30-day readmission or wound complications. There were two 90-day readmissions (a patient with hydrocephalus and another with new spine metastasis) unrelated to the procedures performed.

CONCLUSION

Geographically distinct regions of a brain cancer can be safely and accurately accessed through the ClearPoint Array® frame in NCMT stereotactic procedures.
SURG-13. PEDIATRIC PRIMARY CENTRAL NERVOUS SYSTEM NEOPLASMS: RELATIVE UTILITY OF OPEN, MULTI-STAGE CRANIAL SURGERY
Authors: Brown Nolan , Bui Nicholas , Kuo Cathleen , Gendreau Julian
Published: November 2023

OBJECTIVE

Staged surgery for skull base lesions has been utilized to facilitate maximal safe resection and optimize outcomes in pediatric patients. Despite its extensive applications, there is a paucity of information regarding open multi-stage resection of intrinsic, intra-axial neoplasms. We reviewed the literature in order to shed light on relevant considerations including the timing between surgeries, indications for staged approaches, and clinical outcomes following staged resection of pediatric intra-axial neoplasms.

METHODS

We conducted a literature search using PubMed, Web of Science, and Cochrane databases according to PRISMA recommendations.

RESULTS

Of 115 results, 7 articles were included for final analysis and consisted of 17 pediatric patients, including 6 (35%) male, 5 (29%) female, and 6 (35%) unspecified sex patients. Age ranged from 18 months to 17 years (mean 9 years). Tumor pathologies consisted of 5 (29%) astrocytomas, 2 (12%) ependymomas, 2 (12%) teratoid rhabdoid tumors, 2 (12%) oligodendromas, 1 (6%) glioma, 1 (6%) dysembryoplastic neuroepithelial tumor, 1 (6%) meningioangiomatosis, 1 (6%) pleomorphic xanthoastrocytoma, 1 (6%) ganglioglioma, and 1 (6%) germ cell tumor. Primary sites of the tumor included 4 (24%) temporal lobe, 3 (18%) thalamic, 3 (18%) thalamopeduncular, 3 (18%) frontal lobe, 2 (12%) posterior fossa, 1 (6%) cerebral hemisphere, and 1 (6%) frontoparietal lobe. Three studies reported complications, which included subtle hemiparesis, hydrocephalus, cranial nerve (CN) VI and VII palsies, truncal ataxia, and cerebellar mutism. Timing between surgeries varied from 5 days to several weeks

CONCLUSION

Indications for performing multi-stage resections included large tumor volume requiring multiple long stages of debulking, significant tumor vascularity, multicompartmental lesions, and planned staging due to presence of large tumors requiring resection around eloquent speech and motor cortical and white matter tract lesions that enabled use of awake functional mapping after a primary debulking performed in proximity to less eloquent regions.