bluuebunny/crossref_metadata_2025 huggingface dataset:
NCOG-09. PREDICTIVE GERIATRIC FACTORS IN ELDERLY PATIENTS TREATED FOR IDH-MUTANT HIGH-GRADE GLIOMAS: A FRENCH POLA NETWORK STUDY
Authors: Montégut Coline , Guillamo Jean-Sébastien , Ducray François , Dehais Caroline , Elisabeth Cohen-Jonathan Moyal , Desenclos Christine , Petit Antoine , Seizeur Romuald , Bekaert Lien , Gaultier Claude , Fotso Marie Jeannette Motuo , Blonsky Marie , Frenel Jean Sébastien , Vauléon Elodie , Langlois Olivier , Noël Georges , Carpentier Antoine , Stefano Anna Luisa Di , Bronnimann Charlotte , Figarella-Branger Dominique , Chinot Olivier , Tabouret Emeline
Published: November 2021

We aimed to describe the characteristics, patterns of care and predictive geriatric factors of elderly patients with IDH-mutant (IDHm) high-grade gliomas (HGG) included in the French POLA network, dedicated to HGG (including 68% of IDHm HGG). For IDHm HGG patients over the age of 70 years, geriatric features were collected: G8 score items (appetite, weight loss, mobility, neuropsychological disorders, body mass index, medications, self-rated health, age), Activities and Instrumental Activities of Daily Living (ADL, IADL) scores, Charlson’s comorbidity Index (CCI) and biological markers. Out of the 1433 HGG patients included in the POLA Network, 119 (8.3%) occurred in patients ≥ 70 years. Among them, 39 presented with IDHm HGG. Of these 39 patients, estimated G8 score was ≤ 14/17 for 16 patients (64%), ADL score was < 6 for 33.3%, IADL score was < 4 for 47% and CCI was ≥ 5 for 72%. Regarding treatment feasibility, 6 of the 19 patients treated by temozolomide prematurely discontinued chemotherapy including 2 for toxicity and 4 for progression. Five of the 10 patients treated by PCV prematurely discontinued chemotherapy, all for toxicity. In multivariate analysis, loss of mobility (p=0.018; p=0.008), severe neuropsychological disorders (p=0.005; p=0.047), body mass index < 21 kg/m2 (p=0.002; p=0.006) and ADL score < 6 (p=0.002; p=0.01) were significantly predictive of poor PFS and OS. Then we generated a specific brain geriatric score including these four items with a sensibility, specificity and AUC for long term survivor (≥ 48 months) of 100%, 83% and 0.948 respectively. Using a cutoff of < 10/13, this score was significantly correlated to PFS and OS (p< 0.001 both). In conclusion, geriatric predictive factors may contribute to the elderly management improvement: the brain geriatric score must now be validated in a prospective independent cohort including IDHm and IDHwt elderly patients.
NCOG-12. COGNITIVE FUNCTION (CF) & QUALITY OF LIFE (QOL) IN PATIENTS TREATED WITH PROCARBAZINE, CCNU, & VINCRISTINE (PCV) + RADIOTHERAPY (RT) VS. RT FOR ANAPLASTIC OLIGODENDROGLIOMA (AO) ON NRG RTOG TRIAL 9402
Authors: Donovan Laura , Won Minhee , Cairncross J Gregory , Iwamoto Fabio , Buckner Jan , Fink Karen , Bahary Jean-Paul , Hartford Alan , Souhami Luis , Nguyen Timothy , Cescon Terrence , Mishra Mark , Barani Igor , Pu Anthony , Roa Wilson , Huang Jiayi , Polley Mei , Mehta Minesh
Published: November 2021

BACKGROUND

PCV+RT substantially prolongs survival in AO patients, but long-term CF and QOL implications are unclear. We compared CF and QOL by treatment arm in RTOG 9402 participants and evaluated the impact that baseline characteristics had on CF, QOL, and survival.

METHODS

CF and QOL were evaluated using the Mini Mental State Exam (MMSE) and Brain-Quality of Life (B-QOL) scale at baseline and annually. Scores were analyzed between treatment arms at each time point for patients with ≥ 10 years of follow-up data. Shared parameter models evaluated MMSE and B-QOL scores and survival for all patients.

RESULTS

42/148 (28.4%) participants in PCV+RT and 20/143 (14%) in RT alone arms survived ≥ 10 years. 35/42 and 39/42 (PCV+RT) and 18/20 and 17/20 (RT) participants completed baseline B-QOL and MMSE assessments, respectively. B-QOL scores did not differ between treatment groups at any time-point. Among 16 patients (10 PCV+RT, 6 RT) who completed year 10 MMSE evaluations, mean MMSE score at 10 years was higher in the RT arm (29.83 [95% CI 22.1, 30.0] vs. 26.50 [95% CI 29.4, 30.0], P= 0.04). Change in MMSE and B-QOL scores from baseline did not differ significantly between treatment groups at any time. In shared parameter models including all patients with baseline assessments, MMSE and B-QOL scores decreased over time (MMSE P= 0.0189, B-QOL P= 0.0005), but this did not differ by treatment group (MMSE P= 0.5727, B-QOL P= 0.3592). Younger age and higher KPS predicted better scores (MMSE P < 0.0001, P = 0.0002; B-QOL P = 0.0043, P = 0.0007). PCV+RT predicted better survival in both models.

CONCLUSIONS

PCV+RT improves survival in AO. Shared parameter models show decrease in MMSE and B-QOL over time. However, relative to RT alone, the addition of PCV did not impact change in CF and QOL over time.
NCOG-16. RELEVANCE OF GERIATRIC ASSESSMENT FOR PRIMARY BRAIN TUMOR PATIENTS: IMPLICATIONS FOR RESEARCH AND CARE
Authors: Leeper Heather , Choi Anna , Vera Elizabeth , Acquaye Alvina , Briceno Nicole , Christ Alexa , Grajkowska Ewa , Jammula Varna , Levine Jason , Lindsley Matthew , Reyes Jennifer , Roche Kayla , Rogers James , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Penas-Prado Marta , Pillai Valentina , Polskin Lily , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri
Published: November 2021

BACKGROUND

The utility of geriatric assessment (GA) has been evaluated in older adults diagnosed with solid tumors other than primary brain tumors (PBT). We assessed several key GA domains in adults with PBT receiving tumor-directed treatment.

METHODS

Patient and disease characteristics and key GA domains within patient-reported outcomes (PROs) including symptom burden (MDASI-BT), Anxiety/ Depression (PROMIS-short forms) and general health status (EQ-5D-3L) were systematically and prospectively collected between 9/2016–8/2019 from adults diagnosed with PBT. Descriptive statistics and regression analyses were used to assess PROs.

RESULTS

Of 581 participants, 92 were 65 – 85 years old (median age = 70 years; “older”) and 489 were ≤ 64 years (median age = 46 years; “younger”). Tumor grade distribution in the older group was 74% WHO grade III/IV, 26% WHO grade I/II; tumor types included gliomas and meningiomas with no tissue diagnosis in 3 patients. Older patients were 49% less likely to receive chemotherapy and twice as likely to have KPS ≤ 80 (p=0.003, OR=0.51, OR=1.98). More older patients reported problems with mobility (57% vs 44%), self-care (38% vs 26%), and usual activities (64% vs 51%) than younger patients. Charlson Comorbidity Index mean scores were significantly higher in older patients (3.5 vs 0.6, p< 0.001). The top 3 most frequently reported moderate-to-severe symptoms were similar in older vs younger groups: fatigue (44% vs 41%), feeling drowsy (29% vs 30%) and difficulty remembering (28% vs 29%). Feeling distressed was the only symptom whose frequency differed between the age groups (11% older vs 27% younger, p=0.001).

CONCLUSION

Older PBT patients had lower performance status, more co-morbidities and increased functional impairments, affirming that GA is relevant. Symptom burden was similarly high in both age groups. These findings support conducting GA concurrently in future symptom intervention and therapeutic clinical trials for adults with PBT receiving tumor-directed treatment.
NCOG-21. PREDICTORS OF SURVIVAL IN ELDERLY PATIENTS UNDERGOING SURGERY FOR GBM
Authors: Voisin Mathew , Sasikumar Sanskriti , Zadeh Gelareh
Published: November 2021

BACKGROUND

An increasing number of elderly patients are being diagnosed with GBM and undergoing surgery. These patients often present with multiple medical comorbidities and have significantly worse outcomes compared to adult patients. The goal of this study was to determine clinical predictors of survival in elderly patients undergoing surgery for GBM.

METHODS

A retrospective chart review of all consecutive patients 65 years of age and older that underwent surgery for newly diagnosed GBM from 2005-2018 was performed. A total of 150 patients were included, and subdivided into two age categories; 65-74 and 75 or older.

RESULTS

Advanced age and medical comorbidities were not associated with decreased survival (p = 0.07 and p = 0.09, respectively). Postoperative complication was associated with worse survival for all patients (HR = 2.34, p = 0.01) and occurred in patients with longer lengths of stay (p < 0.0001) and discharge destination other than home (p = 0.001).

CONCLUSIONS

The presence of medical comorbidities and advanced age are not reasons to exclude patients with GBM from surgical consideration. Postoperative complication is the most significant predictor of survival in elderly patients and can be avoided by a short length of stay and discharge home.
NCOG-23. PATIENT-REPORTED SYMPTOM BURDEN AND INTERFERENCE: A COMPARISON BETWEEN COVID-19 PANDEMIC YEAR AND NORMATIVE DATA IN PATIENTS WITH CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Pillai Valentina , Polskin Lily , Vera Elizabeth , Acquaye Alvina , Briceno Nicole , Choi Anna , Christ Alexa , Grajkowska Ewa , Jammula Varna , Leeper Heather , Levine Jason , Lindsley Matthew , Reyes Jennifer , Roche Kayla , Rogers James , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Penas-Prado Marta , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri , King Amanda
Published: November 2021

CNS tumor patients are highly symptomatic causing interference with activity and worse quality of life. Social distancing due to the COVID-19 pandemic increased demands on the patient, caregivers, clinicians, and the health care system. The NCI’s Neuro-Oncology Branch Natural History Study (NHS) systematically collected patient-reported outcomes (PROs) provide insight into how these challenges influenced symptom burden and interference during the COVID year. METHODS: Patient and disease characteristic as well as patient-reported symptoms and interference (MDASI-BT/-SP) and general health status (EQ-5D-3L) from 3/2020-2/2021) were compared to NHS normative sample collected prior to 3/2020. RESULTS: The sample (n = 178) was primarily White (82%), male (55%), median age of 45 (range 18 – 79) and KPS ³ 90 (51%). The majority had high-grade (70%) brain (83%) tumors (BT) with ≥ 1 prior recurrence (60%) and 25% were on active treatment. Clinical visits were primarily conducted via telehealth (64%) and 20% of all patients were diagnosed with progression at the time of assessment. Most commonly reported moderate-severe symptoms among BT patients were fatigue (30%), difficulty remembering (28%), feeling drowsy (22%). Among spinal cord tumor patients, fatigue (39%), pain (35%) and numbness/tingling in arms/legs/trunk (35%) were most frequently reported. These symptoms were reported in similar frequencies by the normative sample. Nearly half of the COVID year sample (48%) reported moderate-severe activity-related interference. Reported problems with mobility (38%), self-care (19%), pain/discomfort (40%), and usual activities (50%) were similar in both groups except for increased mood disturbance (53%) was reported during the COVID year. CONCLUSION: These findings support CNS tumor patients remained highly symptomatic with significant impact on health-related quality of life during the COVID year. Clinicians should develop timely individual care plans to help BT patients navigate their disease course. Evaluation of risk associated with more severe symptoms and functional limitations are ongoing.
NCOG-24. REAL-WORLD ANALYSIS OF OUTCOMES OF PATIENTS RECEIVING BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA IN BRITISH COLUMBIA
Authors: Chahal Manik , Thiessen Brian
Published: November 2021

BACKGROUND

Bevacizumab (Bev) has been publicly funded in British Columbia (BC) since 2011 for treatment of recurrent glioblastoma (rGBM). We performed a retrospective outcomes assessment of patients with rGBM treated with Bev.

METHODS

Patients with rGBM treated at BC Cancer centers with Bev between January 2011 and December 2016 were reviewed. Patient demographics, tumor characteristics, treatment regimens, and dates of radiographic progression and death were collected. Kaplan-Meier method was used to assess survival, and comparisons were made using the log-rank test.

RESULTS

138 patients were reviewed. There were 136 reported deaths with median PFS 3 months (CI95 = 2.5 - 3.5) and OS 7 months (CI95 = 6.1-8.0) from Bev initiation. 64% of patients on corticosteroids prior to Bev reduced their dose shortly after initiation. The majority of patients (72%) were treated with multiple lines of therapy prior to Bev, with a median time from chemoradiation to Bev initiation of 8 months (range 1-67). Patients started on Bev < 6 months from chemoradiation (prior to completion of adjuvant temozolomide) had improved OS compared to those who started Bev later (p = 0.05), but there was no association between extent of treatment prior to Bev and outcomes (p = 0.182). Addition of chemotherapy to Bev did not improve survival over Bev monotherapy (p = 0.175).

CONCLUSIONS

Despite limited benefits to overall survival, Bev is associated with reduction in corticosteroid use and likely improvement in quality of life. Bev combinations with chemotherapy did not confer survival advantage over Bev monotherapy. Furthermore, our results show that patients receiving Bev before completion of adjuvant chemotherapy have better outcomes, suggesting pseudoprogression may have prompted the therapeutic switch. Further research is required to optimize patient selection for and administration of Bev. Additional analysis of rGBM patients prescribed Bev until 2020 in BC is currently underway.
NCOG-25. REVISITING THE PIGNATTI RISK SCORE IN LOW-GRADE GLIOMA PATIENTS IN THE MOLECULAR ERA
Authors: Jungk Christine , Gluszak Mara , Trong Philip Dao , von Deimling Andreas , Herold-Mende Christel , Unterberg Andreas
Published: November 2021

Until now, the Pignatti risk score has been used to guide treatment decisions after histological diagnosis of diffuse glioma WHO grade 2. However, its prognostic value was derived from a historic cohort that has been diagnosed by morphologic rather than molecular criteria. We re-challenged the Pignatti score in a contemporary, molecularly characterized cohort. From our institutional cohort of 422 diffuse gliomas WHO grade 2, 202 patients were identified for whom IDH mutation status was known and 1p/19q co-deletion or loss of ATRX expression unambiguously classified tumors into astrocytoma or oligodendroglioma. Patients with IDH wildtype astrocytoma (n=9), multifocal lesions or brainstem involvement were excluded. Potential prognostic factors including the individual items of the Pignatti score (astrocytoma; age ≥40 years; neurologic deficit; maximum tumor diameter ≥6cm; tumor crossing midline) were correlated with progression-free survival (PFS) by univariate log-rank und multivariate Cox regression analysis. 165 patients with astrocytoma or oligodendroglioma were analysed of whom 109 (66%) did not receive adjuvant radio- or chemotherapy. 94 untreated patients with a minimum follow-up of 24 months entered survival analysis. These patients were classified as “high-risk” (Pignatti 3-5) and “low-risk” (Pignatti 0-2) in 15% and 85% and did not differ with regard to potential prognostic factors (gender; resection vs. biopsy; tumor recurrence) other than the individual Pignatti score items. Diameter ≥6 cm (p=0.006; HR=2.18) and midline crossing (p=0.003; HR=3.54) were identified as independent prognostic factors of PFS. Noteworthy, prognostic factors coincided when all patients (n=144) with a minimum follow-up of 24 months, regardless of adjuvant treatment, were analysed. In IDH mutant, molecularly characterized diffuse gliomas WHO grade 2, the Pignatti risk score as a whole no longer seems to be of prognostic relevance. Instead, outcome seems to be determined by tumor burden.
NCOG-28. THE IMPACT OF MULTIPLE MENINGIOMAS ON PROGRESSION-FREE SURVIVAL: A 10-YEAR MULTI-CENTER STUDY
Authors: Ramos-Fresnedo Andres , Domingo Ricardo , Sanchez-Garavito Jesus , Perez-Vega Carlos , Akinduro Oluwaseun , Jentoft Mark , Brown Paul , Porter Alyx , Bendok Bernard , Link Michael , Middlebrooks Erik , Trifiletti Daniel , Chaichana Kaisorn , Quinones-Hinojosa Alfredo , Sherman Wendy
Published: November 2021

INTRODUCTION

Multiple meningiomas (MM) occurs in up to 18% of meningioma patients and progression data are scarce. The objective of this study is to explore the influence of number of lesions and clinical characteristics on progression-free survival (PFS) and time to a second intervention (TTSI) in patients with WHO grade 1 meningiomas.

METHODS

We retrospectively reviewed records of all adults diagnosed with a meningioma at our three main sites from January 2009 to May 2020. Progression was considered as time from diagnosis until radiographic progression of the originally resected meningioma. A secondary analysis was carried to evaluate the time from diagnosis to time of a second intervention. Univariable and multivariable analyses were conducted to assess whether number of lesions or any associated variables (age, sex, race, radiation, location, and extent of resection) had a significant impact on PFS and TTSI.

RESULTS

838 patients were included. Log-rank test evaluating PFS and TTSI between single and multiple lesions showed significantly shorter progression for MM (p< 0.001 and p< 0.001, respectively). Multivariable Cox regression showed significantly inferior PFS on MM vs. single lesion (HR 2.262 [CI 95%, 1.392-3.677], p=0.001) and a significantly inferior TTSI for patients with MM vs. single meningioma (HR 2.377 [CI 95%, 1.617 – 3.494], p=0.001). When input as a continuous variable, PFS was significantly inferior for each additional meningioma (HR 1.350 [CI 95% 1.074-1.698], p=0.010) and TTSI is significantly inferior as well (HR 1.428 [CI 95% 1.189 – 1.716], p< 0.001). African-Americans had an inferior PFS when compared to Non-Hispanic White patients (HR 3.472 [CI 95% 1.083-11.129], p=0.036).

CONCLUSION

The PFS of meningiomas is influenced by the number of lesions present. Patients with MM are more prone to undergo a second intervention for progressive disease. Hence, a closer follow-up may be warranted in patients who present with multiple lesions.
NCOG-31. GIANT PITUITARY ADENOMA (GPA) SCORE: A NOVEL SCORING SYSTEM TO PREDICT POSTOPERATIVE OUTCOMES OF GIANT PITUITARY ADENOMAS
Authors: Enam Syed Ather , Hashmi Fauzan Alam , Ghazi Sanam Mir , Khan Ahsan Ali , Tariq Muhammad Bilal , Shamim Muhammad Shahzad , Raghib Muhammad Faraz
Published: November 2021

BACKGROUND

Giant pituitary adenomas (GPA) are uncommon and highly variable in morphology and extension. There is no scoring system that considers all the dimensions of adenoma invasion. We developed a new Giant Pituitary Adenoma score and report our surgical experience and evaluate outcomes after resection of these tumors in accordance with the preoperative score.

METHODS

We developed a novel scoring system for classifying giant pituitary adenomas, and 11-year data of GPA surgery at our center was collected retrospectively, based on this scoring system. GPA Score considered tumor’s parasellar extension, encasement of cavernous internal carotid artery (ICA), suprasellar extension > 2 cm, suprasellar extension > 4cm and retrosellar extension. Maximum possible score was 9. The scoring system was applied to 53 patients of GPA who underwent surgical resection between January 1, 2006, and December 2017. The Lundin-Pederson (ABC/2) method was used to calculate the tumor volume both pre- and post-resection and linear regression was used to assess the relationship between extent of tumor resection and GPA score.

RESULTS

The median age of the study population was 42.08 ± 16.49 years. The mean maximum diameter of the pituitary adenomas was 5.0 cm (range 4.0 cm-8.5cm) while the mean volume of the adenomas was 27.3 cm3 (range 10 cm3-149 cm3). There were 3 cases of score 2, 5 cases of score 3, 13 cases of score 4, 20 cases of score 5, 9 cases of score 6 and 3 cases of score 7. The range of tumor volumes of tumors for scores from 2-7 was 17.3 cm3 to 65.8 cm3 and GPA score was correlated with the percent residual tumor using linear regression that was statistically significant (p= 0.001).

CONCLUSION

GPA Score is a reliable scoring system to predict the extent and subsequent difficulty in tumor resection in GPA.
NCOG-34. A DESCRIPTIVE ANALYSIS OF GLIOMATOSIS CEREBRI CASES, COMPARED ACCORDING TO IDH STATUS
Authors: Boris Lisa , Vera Elizabeth , Acquaye Alvina , Briceno Nicole , Choi Anna , Christ Alexa , Grajkowska Ewa , Jammula Varna , Leeper Heather , Levine Jason , Lindsley Matthew , Reyes Jennifer , Roche Kayla , Rogers James , Timmer Michael , Burton Eric , Lollo Nicole , Panzer Marissa , Polskin Lily , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Wu Jing , Abdullaev Zied , Aldape Kenneth , Quezado Martha , Gilbert Mark , Armstrong Terri
Published: November 2021

Gliomatosis cerebri (GC) is a controversial entity no longer recognized as a histopathologic-defined diagnosis, characterized by diffuse, commonly bilateral infiltration of cerebral hemispheres. The purpose of this report is to describe clinical, imaging, patient-reported outcomes (PRO’s) and pathologic characteristics of clinically-defined cases from a large natural history study cohort (N=769). Of 19 patients, 10 male, 16 white, mean age at diagnosis 43 (19-70), seventeen presented as primary GC, while 2 developed GC after treatment. Ten patients were IDH-WT, 7 IDH-M, and 2 IDH undetermined. The majority (7/10) IDH-WT patients presented acutely (5 with seizures), whereas, 3 had a protracted presentation of 2 weeks-3months with 6/10 having enhancing tumors and 8/10 undergoing biopsy only. On histopathologic review, 4 were anaplastic astrocytoma (AA), 3 GBMs, 2 grade II astrocytoma, and 1 histone-mutated glioma. Nearly all (9/10) IDH-WT patients received radiation with concurrent and adjuvant temozolomide. 7/10 IDH-WT patients had a survival of only 1.5yrs or less from diagnosis. Of the 7 IDH-M patients, 4 had protracted presentations of 1 month-5 years. 6/7 had non-enhancing tumors at presentation. 4 had biopsy only and 3 underwent partial resection. 3 were AA, 2 grade II astrocytoma, 1 grade II oligodendroglioma, and 1 grade IV astrocytoma. 3/7 received radiation with concurrent and adjuvant temozolomide, 3/7 chemotherapy alone, and 1 RT alone. All 7 IDH-M patients survived 3+ years from diagnosis (range 3-10+ yrs). Both patients who developed GC later, were IDH-M, with prolonged survival (3.5yrs and the other still alive 10+yrs). PRO's at time of last clinical assessment revealed GC patients to be highly symptomatic with mean overall symptom burden, depression, and anxiety higher than our overall glioma population. GC patients have a varied clinical course mandating further investigation to enable better prognostic definition to refine treatments based on the varying clinical and molecular characteristics.
NCOG-35. THE LATE INTRACRANIAL ADVERSE EVENTS OCCUR MORE FREQUENTLY IN INTRACRANIAL GERMINOMAS TREATED WITH HIGH DOSE RADIOTHERAPY
Authors: Arakawa Yoshiki , Yamamoto Etsuko , Umeda Katsutsugu , Mineharu Yohei , Uto Megumi , Takita Junko , Mizowaki Takashi , Miyamoto Susumu
Published: November 2021

OBJECTIVE

The standard treatment for intracranial germinoma has been radiotherapy covering the whole ventricle together with chemotherapy. Radiotherapy is important, but it is a cause of the late brain damages. Therefore, the recent clinical trials have been planned to evaluate the reduced radiation dose. The aim of this study was to evaluate the intracranial adverse events in the patients with intracranial germinomas treated in our hospital.

PATIENTS AND METHODS

65 patients were diagnosed as intracranial germinoma. Patients with hCG > 100 IU/l and/or AFP > 10 ng/ml were excluded. Patients, who were diagnosed as germinoma by imaging without histology, were included.

RESULTS

Follow-up time was from 2 to 467 months (median 136 months). Until 2005, 37 patients were treated with radiotherapy >30 Gy alone or with chemotherapy. After then, 23 patients received whole-ventricle radiotherapy 24-30 Gy with chemotherapy. 2 patients were treated with chemotherapy alone, 3 were unknown. 10-year PFS was 82.05% in radiotherapy >30 Gy alone, 86.36% in radiotherapy >30 Gy with chemotherapy and 100% in radiotherapy 24-30 Gy with chemotherapy. The intracranial adverse events after the initial treatment were identified, such as pituitary dysfunction: 6 (9.2%), hearing disturbance: 2 (3.1%), neurocognitive dysfunction 6 (9.2%), microbleeds 10 (15.4%), cavernous angioma 6 (9.2%), brain tumor 1 (1.5%), cerebral artery stenosis 1 (1.5%). The frequency of late adverse brain events is higher in radiotherapy >30 Gy with/without chemotherapy than 24-30 Gy (total events, 25 vs. 9, P< 0.03).

CONCLUSION

Patients with intracranial germinoma obtain long-term survival but suffer from the late intracranial adverse events. The late intracranial adverse events occur more frequently in intracranial germinomas treated with radiotherapy >30 Gy than 24-30 Gy. Long-term follow-up is important to promptly identify and deal with the late brain damages.
NCOG-39. EXPLORING PATIENT REPORTED OUTCOMES (PROS) ACROSS ETHNORACIAL GROUPS IN PRIMARY BRAIN TUMOR (PBT) PATIENTS: DIFFERENCES IN THE ILLNESS EXPERIENCE
Authors: King Amanda , Minyety Julianie De La Cruz , Acquaye Alvina , Briceno Nicole , Choi Anna , Christ Alexa , Grajkowska Ewa , Jammula Varna , Leeper Heather , Levine Jason , Lindsley Matthew , Reyes Jennifer , Roche Kayla , Rogers James , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Polskin Lily , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri , Vera Elizabeth
Published: November 2021

SIGNIFICANCE AND AIMS

Past research in PBT patients has demonstrated that minorities may have a survival advantage compared to Whites for high-grade tumors, though little is known about their illness experience given their underrepresentation in clinical trials. This study explored differences in PROs across race-ethnicity within a large PBT cohort describing associated burden and risk for minority populations where data is scarce.

METHODS

Demographic, clinical characteristics, MDASI-Brain Tumor, PROMIS Depression and Anxiety Short-Forms, and Neuro-QoL Cognitive Function were collected from the most recent timepoint for PBT patients enrolled on the Natural History Study. Descriptive statistics, one-way ANOVA, and linear regression were used to report results.

RESULTS

The sample included 562 PBT patients (58% male, median age = 50 [18-85]) comprised of 79% White, 6% African American (AA), 10% Hispanic, and 5% Asian patients per self-report. Most patients had a high-grade glioma (60%), with 28% on active treatment and 44% with good KPS (90-100). Among the most commonly reported moderate-severe symptoms were fatigue ( > 40% in all groups), difficulty remembering (30-40% of Asians, AAs, and Whites), and disturbed sleep (44% in Asians, 29% in Hispanics), while hemiparesis was common only for AA patients (37%). There were no differences between groups with respect to symptom burden and interference, mood disturbance, or cognitive function. Race/ethnicity group was not predictive of overall symptom burden or interference, but for all groups, higher KPS predicted lower symptom and interference scores (p < .001 and p = .004, respectively).

CONCLUSION

While some symptoms were common across ethnoracial groups, there were differences in symptom patterns, suggesting there may be other factors driving their illness experience. Future exploration of socioeconomic and cultural factors that might contribute to the symptom burden of minorities is warranted, which may allow development of targeted interventions to improve clinical outcomes in these groups.
NCOG-40. AWAKE CRANIOTOMY FOR EXCISION OF BRAIN TUMORS; INITIAL 200 CONSECUTIVE CASES FROM AN LMIC
Authors: Bakhshi Saqib Kamran , Baig Erum , Laghari Altaf Ali , Khan Daniyal Aziz , Junaid Mazin , Shafiq Faraz , Shamim Muhammad Shahzad , Khan Saad Akhtar , Enam Syed Ather
Published: November 2021

In recent years, reports from developed countries have shown that awake craniotomy has been shown to improve outcomes of surgical resection of brain tumors. However, no such data is available from low- and middle-income countries. We retrospectively reviewed 200 cases of awake craniotomy performed at our center for excision of brain tumors during last 5 years, and assessed clinical outcomes. Data was collected from patients’ medical records, and included demographics, tumor location/histology, clinical complains, and functional status. We used Karnofsky performance scale (KPS) to assess function. Extent of resection was determined on post-operative MRI. Statistical analysis was done using SPSS version 22. Seven attending surgeons performed these cases; however, 168 (84%) surgeries were performed by a single surgeon who is the senior author (SA Enam). Mean age was 39.3 ± 11.9 years and 79% (158) were male. Left frontal lobe was the most common location for tumors (50; 25%). Although 52% (104) patients had malignant neoplasms, seizures were the most common presenting symptom in 63% (126) cases followed by motor deficits in 29% (58). The most common tumors were low grade oligodendroglioma (58; 29%%) followed by glioblastoma (42; 21%). Mean length of hospital stay was 3.15 days ± 1.7 days. Gross total resection was achieved in 82 (41%) patients. New intraoperative neurological complains were seen in 31 (15.5%) patients, however, 22 (11%) of these had recovered by median follow-up of 1.4 months. KPS at last follow-up improved in 92 (46%), remained stable in 94 (47%) and deteriorated in 14 (7%) patients. Although absence of a control group decreases the strength of this, with our large sample size we can safely conclude that AC allows maximum safe excision of brain tumors, and offers a good chance of preserving patients’ functional status, along with adequate extent of resection.
NCOG-43. RELATIONSHIPS BETWEEN MOOD DISTURBANCE, SYMPTOM INTERFERENCE, AND DISEASE PROGRESSION IN GLIOMA PATIENTS
Authors: Roche Kayla , Vera Elizabeth , Acquaye Alvina , Briceno Nicole , Choi Anna , Christ Alexa , Grajkowska Ewa , Jammula Varna , Leeper Heather , Levine Jason , Lindsley Matthew , Reyes Jennifer , Rogers James , Timmer Michael , Boris Lisa , Burton Eric , Lollo Nicole , Panzer Marissa , Polskin Lily , Penas-Prado Marta , Pillai Valentina , Theeler Brett , Wu Jing , Gilbert Mark , Armstrong Terri , King Amanda
Published: November 2021

Cross-sectional studies indicate that patients with gliomas report significant depressive/anxiety symptoms and symptom-related interference with daily activities at diagnosis and throughout the illness trajectory. Our study aimed to explore relationships between these mood disturbances and symptom interference with respect to progressive disease (PD) in glioma patients. Demographic, clinical characteristics, MDASI-Brain Tumor (interference items), and PROMIS Anxiety and Depression Short-Forms were collected at the time of imaging surveillance, before discussing imaging results. Comparisons between patients with/without PD and respective change scores were calculated at study entry and at subsequent assessments. Independent t-tests, Chi-square tests, and paired sample t-tests were used to report results. The sample included 438 glioma patients (62% male, 84% Caucasian, 82% high-grade) with median age of 51 years (range 18-82); 42% had PD with 60% reporting past recurrence(s); 45% had poor Karnofsky Performance Status (KPS); and median time from diagnosis was 2 years (range: 0-30). On average, patients with PD on imaging at time of assessment reported significantly greater anxiety (p = 0.008), depression (p < 0.001), and symptom interference (p < 0.001) than those with stable disease. Additionally, more patients with PD reported moderate-severe anxiety (25%) and depression (22%) than patients with stable disease (15% and 12%, respectively). When evaluating change scores, patients with PD reported worse symptom interference (p < 0.001) but stable mood disturbance, while patients with stable disease reported improved depression (p = 0.018) and unchanged anxiety symptoms compared to baseline. Although mood disturbance is higher for patients with PD, some of these patients do not experience worsening, but rather a continuation of ongoing psychological symptoms, which may portend a worse illness trajectory. Identifying these patients early in this trajectory to evaluate potential biologic correlates between mood and prognosis is warranted to validate these findings.
EXTH-07. TEMPORAL ASSESSMENT OF ALTERED PERI-ABLATION BLOOD-BRAIN BARRIER PERMEABILITY FOLLOWING TUMOR CYTOREDUCTION BY THERMAL THERAPY IN A RAT ORTHOTOPIC GLIOBLASTOMA MODEL
Authors: Nagaraja Tavarekere , Bartlett Seamus , Cabral Glauber , Farmer Katelynn , Knight Robert , Valadie Olivia Grahm , Brown Stephen , Ewing James , Lee Ian
Published: November 2021

Laser interstitial thermal therapy (LITT) is a minimally invasive tumor cytoreductive treatment for recurrent gliomas, brain tumors in eloquent regions and/or otherwise inaccessible. Following reports of persistent peri-ablation blood-brain barrier (BBB) opening in humans, we examined this phenomenon using a rat glioblastoma model. Athymic female rats were implanted with U251 tumor cells in one brain hemisphere. Tumor growth was monitored using magnetic resonance imaging (MRI) and dynamic contrast enhanced (DCE)-MRI. When tumors reached about 4 mm in diameter, they were ablated under supervision of diffusion-weighted MRI using Visualase®, a clinical LITT system. Four rats were used as controls. Longitudinal MRI data were obtained before LITT, and at post-LITT 2 (n=9), 3 (n=3) and 4 (n=9) weeks. After the terminal MRI at each time point, rats were injected intravenously with fluorescent isothiocyanate dextran (FITC-dextran; 2000 kDa) and Evans Blue (68 kDa after binding to plasma albumin) and the brains immersion fixed in 10% paraformaldehyde. The brains were cut into 100 μM thick slices in a vibratome and examined for the distribution of the two fluorophores. All rats survived the LITT procedure. The sham controls showed increased tumor burden by 2 weeks and were sacrificed. DCE-MRI data and fluorescent data showed elevated BBB permeability in peri-ablation regions, with leakage of a gadolinium contrast on DCE-MRI and of Evans Blue, but not of FITC-dextran. Histology showed little tumor tissue at 2 weeks, but evidence of recurrence at ablation margins at later times. These data demonstrate that LITT is adaptable to rat glioma models and can be performed under MRI monitoring. Peri-ablation regions showed selective increase in BBB permeability acutely due to sublethal heating, but later increases in permeability may be due to tumor recurrence. We suggest this model is useful for examining the temporal and spatial development of peri-ablation BBB opening following LITT.
EXTH-08. STAT3 AT THE CROSSROADS OF INNATE IMMUNE ACTIVATION IN GLIOBLASTOMA
Authors: von Roemeling Christina , Hoang-Minh Lan , Doonan Bently , Li Chenglong , Mitchell Duane
Published: November 2021

BACKGROUND

Innate immune cells comprise the majority of the immune microenvironment in glioblastoma (GBM) tumors where they are chiefly thought to foster a hospitable environment for cancer cells by regulating immune suppression and driving resistance to immunotherapy. Of these, myeloid-derived suppressor cells (MDSCs) are regarded as one of the most potent contributors to immune suppression in GBM and thus have become a focus of targeted therapy. Signal transducer and activator of transcription 3 (STAT3) is a key phenotypic regulator of MDSCs. Therefore, we sought to examine if targeted STAT3 inhibition may augment the immunogenicity of these tumors. HYPOTHESIS: Targeted STAT3 inhibition reduces GBM tumor infiltration by MDSCs.

METHODS

Using syngeneic murine models of GBM, we performed pharmacological inhibition analyses using a specific small molecule inhibitor of STAT3, LLL12B. Circulating numbers of immune cells were assessed in tumor bearing animals with or without concomitant focal radiation. Treated tumors were examined for immune infiltrates, and additional phenotyping analyses were performed. Therapeutic responses to LLL12B alone and in combination with immune checkpoint blockade were evaluated.

RESULTS

STAT3 is activated in the bone marrow of tumor-bearing animals, preferentially by Gr-1 positive granulocytic myeloid cells. Increased circulating numbers of these cells were also detected. These observations were markedly enhanced in tumor-bearing animals following cranial irradiation. Therapeutic inhibition with LLL12B could mitigate these effects, indicating a dependency on STAT3. Within the tumor compartment, granulocytic myeloid cells that successfully infiltrated following treatment demonstrated a pro-inflammatory phenotype denoted by interferon-gamma expression. Improved survival was also observed following combination treatment with LLL12B and radiation or immune checkpoint blockade.

CONCLUSIONS

These findings advocate a critically important role for STAT3 in regulating granulocytic myeloid cell mobilization and trafficking to GBM tumors. It further illustrates the plasticity of these cells within these tumors, which may be useful in designing successful immunotherapeutic strategies.
EXTH-12. INHIBITION OF EPIDERMAL GROWTH FACTOR RECEPTOR AND PLATELET-DERIVED GROWTH FACTOR RECEPTOR-ALPHA EXERTS SYNERGISTIC EFFICACY IN GLIOBLASTOMA
Authors: Noch Evan , Alnahhas Iyad , Palma Laura , Cantley Lewis
Published: November 2021

Epidermal growth factor receptor (EGFR) alterations, including amplification and activating mutations, occur in more than half of GBM cases. EGFR is located on Chr. 7, and Chr. 7 gain is one of the earliest events precipitating gliomagenesis. EGFR inhibitors, monoclonal antibodies, vaccines, and CAR-T cells have failed in GBM due to intrinsic heterogeneity and receptor tyrosine kinase (RTK) bypass pathways that mediate therapeutic resistance. New targeted therapeutic approaches to leverage synergistic combinations are desperately needed to improve GBM prognosis. Using the TCGA and other GBM databases, we previously demonstrated that PDGFRA amplification in patients with EGFR-amplified GBM carries significantly worse survival. EGFR and PDGFRA co-expression occur in more than one-third of GBM patients. The PDGFRA ligand PDGFA is also located on Chr. 7, and its expression is significantly increased with Chr. 7 gain and EGFR copy number increase. Therefore, Chr. 7 gain inherently leads to co-activation of both EGFR and PDGFRA signaling. We used patient-derived glioblastoma cells with Chr. 7 gain to test combined inhibition of EGFR and PDGFRA in vitro. We found that combined inhibition of both EGFR and PDGFRA using FDA-approved EGFR-targeted agents (Erlotinib, Gefitinib, Dacomitinib, Neratinib, and Osimertinib) and Crenolanib, respectively, leads to synergistic cytotoxicity in vitro. Inhibition of either EGFR or PDGFRA led to receptor cross-activation, and EGF and PDGF-AA-induced RTK activation was blocked by Neratinib and Crenolanib. Immunoprecipitation experiments and proximity ligation assays demonstrated that combined inhibition prevents EGFR and PDGFRA heterodimerization and pathways of therapeutic resistance. This combined inhibition led to decreased activation of downstream signaling pathways, including PI3K and MAPK. We show that combined inhibition of EGFR and PDGFRA exerts synergistic cytotoxicity in GBM and prevents resistance pathways that emerge during single-agent targeted therapy. These pathways are targetable with FDA-approved agents that could be used in patients with GBM with Chr. 7 gain.
EXTH-15. MULTI-FACETED INHIBITION OF TET PATHWAY WITH CELL-PERMEABLE 2HG AND BOBCAT 339 REDUCES PROLIFERATION AND INDUCES APOPTOSIS IN DIPG
Authors: Parthasarathy Akhila , Arnold Antje , Eberhart Charles , Raabe Eric
Published: November 2021

Diffuse Intrinsic Pontine Glioma (DIPG) is one of the worst forms of pediatric brain tumors, with a 100% mortality-rate. A prominent mutation observed in them is a lysine to methionine change in histone3 which causes trapping of the repressive-chromatin-complex, leading to genome-level hypomethylation, affecting global epigenetic-regulation. Ten-Eleven Translocation (TET) proteins are alpha-ketoglutarate (α-KG) dependent dioxygenases that mediate the conversion of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC), a key-step in removing DNA methylation-marks. We previously identified increased levels of 5hmC and TETs in DIPG. In IDH mutant glioma, the R132H-IDH produces an oncometabolite, 2-hydroxyglutarate (2HG), instead of α-KG. 2HG competitively inhibits TET function, resulting in a hypermethylated genome. Bobcat339, a cytosine-analog targets TETs by blocking the cytosine binding-site on TETs. We hypothesized that cell-permeable 2HG and Bobcat339 would synergize to block TET activity in DIPG, restore epigenetic-balance by increasing genomic methylation, and induce cell-death. 2HG induced apoptosis in DIPG cells at concentrations ranging from 100-300uM, as measured by cleaved-PARP western and cleaved-caspase3 immunofluorescence (2-7fold increase in CC3, depending on cell line). Cell-permeable 2HG also decreased proliferation, measured by phospho-RB western in DIPG cells (30-50% reduction in pRB band intensity, depending on cell line). Similarly, Bobcat339 suppressed proliferation at concentrations from 10-50uM, measured by BrdU incorporation (25% reduction in BrdU+ at 50uM, p= 0.02 compared to control). Bobcat339 induced apoptosis, measured by cPARP western and CC3 immunofluorescence (4-10fold more of CC3+ compared to control p< 0.0004). In combination, cell-permeable 2HG (100-200uM) and Bobcat339 (10-20uM) combined to suppress cell-viability, measured by CellTiterBlue assay, producing ZIP scores of ~20 in DIPG cells (indicating high-level synergy). In combination, 2HG and Bobcat339 increased apoptosis in DIPG (3-fold increase in cleaved-PARP band intensity in JHH-DIPG1 cells treated with 20uM Bobcat339 + 100uM 2HG, compared to single-treated cells). Our results may lead to new approaches that target TET pathway in DIPG tumors.
EXTH-18. IL-12 ARMORED CAR T CELL THERAPY FOR HETEROGENEOUS GLIOBLASTOMA
Authors: Shen Steven , Reedy Jessica , Suryadevara Carter , Hotchkiss Kelly , Snyder David , Sanchez-Perez Luis , Sampson John
Published: November 2021

INTRODUCTION

Glioblastoma (GBM) is a lethal primary malignant brain tumor with a median survival of < 20 months. Our next generation immunotherapy utilizes chimeric antigen receptor (CAR) T cells targeted to GBM-specific overexpression of epidermal growth factor receptor variant III (EGFRvIII), “armored” with IL-12, a stimulatory cytokine that enhances T cell persistence and function, to treat orthotopic heterogeneous GBM.

METHODS

C57Bl/6 mice were intracranially implanted with 5 x 105 of either CT2AvIII tumor cells or a 1:1 mixture of CT2AvIII and CT2A parental tumor cells. Seven days post-implant, mice were treated with 2 x 106 IL-12 CARvIII and monitored for survival. For endogenous T cell activity assessment, TCRα -/- mice were intracranially implanted with either CT2AvIII cells or a 1:1 mixture of CT2AvIII:CT2A parental cells and treated 7 days post implant with intracranial IL-12 CARvIII therapy.

RESULTS

IL-12 CARvIII therapy was curative in the treatment of CT2AvIII homogeneous tumors and confers a long-term survival in 50% of CT2AvIII:CT2A mice. Furthermore, IL-12 CARvIII therapy successfully eradicated the homogeneous CT2AvIII tumors in TCRα-/- mice but failed to produce any efficacy against the heterogeneous CT2AvIII:CT2A parental tumors, suggesting that endogenous T cells are required for IL-12 CARvIII therapeutic success against heterogeneous tumors.

CONCLUSIONS

Our findings suggest that IL-12 CARvIII may be an effective treatment against heterogeneous glioma. Furthermore, this data provides insight on treatment against the immunosuppressive tumor microenvironment and applications against other solid tumors. In anticipation of translating this therapy into a phase I clinical trial, we are also investigating adjuvant therapies such irradiation to improve antitumor efficacy of IL-12 CARvIII against heterogeneous glioma.
EXTH-25. ENHANCING GLIOBLASTOMA CELL STRESS RESPONSE TO IMPROVE GAMMA DELTA T-CELL IMMUNOTHERAPY
Authors: Jones Amber , Rochlin Kate , Lamb Lawrence , Hjelmeland Anita
Published: November 2021

Glioblastoma (GBM) is an aggressive cancer that has been largely intractable to novel therapies, however, enhancing the efficacy of immunotherapy could potentially overcome immunosuppression and potentially improve patient outcomes. The cellular stress induced by Temozolomide (TMZ) increases innate immune ligands, which could be exploited to promote immune recognition. TMZ-induced DNA damage can activate the stress response pathway, increasing the expression of NKG2D ligands (NKG2DL) on tumor cells. This leads to an increase in NKG2DL recognition by NKG2D receptors on both natural killer and cytotoxic T-cells to elicit a cytotoxic effect. The lymphodepleting effect of TMZ, however, can limit the ability of these cells to recognize and kill tumor cells. TMZ was shown to induce NKG2DL in gliomas both in vitro and in vivo, providing the basis for clinical trials of TMZ in combination with genetically engineered TMZ-resistant gamma delta T-cells (NCT04165941). To further promote immune recognition, we sought to augment the TMZ-induced stress response by exploring the combination of DNA alkylation with either PARP (Niraparib) or ATM Kinase inhibition (AZD1390). Combinatorial therapy significantly, but heterogeneously, increased differential subsets of NKG2DL genes in comparison to TMZ alone in GBM cells isolated from patient derived xenografts (PDX): 1) MICA and MICB were increased at least 10-fold in D456 (proneural) cells; 2) ULBP1 and ULBP2 were increased at least 2-fold in JX39 (classical) cells; and 3) minimal increases in NKG2DLs were observed in JX22 (mesenchymal) cells. Repression of NKG2DLs by hypoxia/low glucose was also heterogeneous, being observed in two of three GBM models tested. We are currently determining whether these combinatorial treatments improve gamma delta T-cell cytotoxicity against GBM cells and in vivo tumor models. Taken together, our data suggest that enhancing cell stress responses induced by chemotherapies may permit novel immunotherapy therapeutic interventions for brain tumor patients.