bluuebunny/crossref_metadata_2025 huggingface dataset:
CSIG-28. THE HEDGEHOG GENE EXPRESSION PROGRAM REGULATES LIPID FEEDBACK MECHANISMS UNDERLYING HEDGEHOG-ASSOCIATED MEDULLOBLASTOMA
Authors: Daggubati Vikas , Choudhury Abrar , Vykunta Akshara , Saulnier Olivier , Gardell Zachary , Reiter Jeremy , Taylor Michael , Raleigh David
Published: November 2022

Misactivation of the Hedgehog pathway can cause cancers such as medulloblastomas, the most common malignant brain tumors in children. Hedgehog signals are transmitted through primary cilia, where Hedgehog ligands bind to Patched1 and activate Smoothened through interactions with cilia-associated sterol lipids. The gene expression programs driving cellular responses to ciliary Hedgehog signals are incompletely understood. Thus, to define Hedgehog target genes and elucidate mechanisms underlying Hedgehog-associated medulloblastomas, we performed RNA sequencing of cells after treatment with Hedgehog ligands (Shh, Dhh, Ihh), cilia-associated lipids (7b,27-dihydroxycholesterol, 24(S),25-epoxycholesterol), or synthetic lipids or small molecules that activate Smoothened (20(S)-hydroxycholesterol, SAG). Nonspecific gene expression changes were identified by performing RNA sequencing (1) after treatment of CRISPR mediated Smo-/- cells with the same Hedgehog pathway agonists, (2) after treatment with vehicle controls, or (3) after treatment with sterol lipids that are unable to activate Smoothened (7a,27-dihydroxycholesterol). Differentially expressed genes were integrated across RNA sequencing of human medulloblastomas (n=458) or the Math1-Cre SmoM2 mouse genetic model of Hedgehog-associated medulloblastoma. Mechanistic studies validating Hedgehog target genes were performed using CRISPR interference, genetic gain-of-function, molecular biology, quantitative immunofluorescence, or cell biology approaches. RNA sequencing after treatment with Hedgehog pathway agonists identified a core gene expression program comprised of 155 genes driving lipid synthesis, metabolism, signaling, adhesion, or angiogenesis. Integration of transcriptomic datasets revealed a conserved gene expression program driving cellular responses to ciliary Hedgehog signals in human or mouse medulloblastomas, including known target genes such as Gli1 or Ptch1, and novel target genes such as Hsd11b1 or Retnla. Retnla is a regulator of sterol synthase expression, and Hsd11b1 is a sterol synthase that opposes the action of Hsd11b2, a driver and druggable dependency underlying Hedgehog-associated medulloblastoma. In support of these findings, mechanistic studies demonstrated Retnla drives expression of Hsd11b2, and showed Hsd11b1 negatively regulates the Hedgehog pathway.
CSIG-30. EPIGENETIC REACTIVATION OF BAI1 BLOCKS ONCOGENIC IGF1R SIGNALLING IN MEDULLOBLASTOMA
Authors: Yamamoto Takahiro , Osuka Satoru , Van Meir Erwin
Published: November 2022

Medulloblastoma (MB) is the most aggressive pediatric brain tumor and a better understanding of this disease is warranted to develop new therapeutic approaches. Brain-specific Angiogenesis Inhibitor 1 (BAI1/ADGRB1) is an orphan seven-transmembrane G protein-coupled receptor predominantly expressed in the brain and epigenetically silenced in MB formation. MDM2 is an E3 ubiquitin ligase that leads to the proteosomal degradation of multiple proteins. We previously found that BAI1 can prevent MDM2 nuclear activity by trapping it at the cell surface, and in the process suppress tumor formation by stabilizing p53. Since MDM2 also ubiquitinates cell surface proteins, we hypothesized that its membrane trapping might increase the degradation of oncogenic tyrosine kinase receptors. To explore this idea, we examined IGF1R, a known cell surface MDM2 target and found that BAI1 negatively regulates IGF1R at the protein level. In contrast, BAI1 expression did not change the protein expression levels of other RTKs (INSR, EGFR). Using co-immunoprecipitation assays we confirmed that MDM2 interacts with both BAI1 and IGF1R in MB cells. In addition, the interaction between IGF1R and β-Arrestin, which is crucial for ubiquitination and down-regulation of IGF1R by acting as an adaptor for MDM2, was increased with BAI1 expression. To examine the impact of BAI1 overexpression on IGF1 receptor signaling, we examined its downstream signaling mediators (Stat3, Akt, Erk). Stat3 and Akt phosphorylation were suppressed upon BAI1 expression, while Erk signaling was activated but through a mechanism independent from IGF1R expression. As IGF1R is known to drive radiation resistance, we examined whether BAI1 could radiosensitize the cells and found that this was indeed the case. Altogether, our data indicate that reactivating BAI1 in MB has dual anti-tumor effects by stabilizing p53 and blocking IGF1R signalling.
CSIG-32. ABL1 AND 2 DRIVE MEDULLOBLASTOMA PROLIFERATION AND ADHESION IN LEPTOMENINGEAL DISSEMINATION
Authors: Thompson Eric , Jones Jill , Kornaherns Reb , Zhang Steven
Published: November 2022

INTRODUCTION

The molecular mechanisms that drive leptomeningeal dissemination (LD) of medulloblastoma (MB) are largely unknown. The Abelson (ABL) family kinases, originally identified as oncogenes in leukemia, play an important role in lung cancer cell migration, invasion, cell adhesion, and chemotherapy resistance. The objective of this work was to elucidate the role of ABL kinases in MB LD.

METHODS

ABL1 and ABL2 mRNA expression of patient specimens was analyzed. shRNA knockdowns of ABL1/2 and pharmacologic inhibition of ABL1/2 were used for in vitro and in vivo analyses of MB LD.

RESULTS

ABL1 and ABL2 levels were significantly higher in MB patients with LD than without (p=2.6x10-10 and 7.2x10-7, respectively) and overall survival was significantly reduced in patients with high ABL1 and 2 expression (p=0.019 and 0.00027, respectively). In vitro pharmacologic inhibition and genetic knockdown of ABL1 and ABL2 in Group 3/4 MB resulted in statistically significant cell death, decreased adhesion to vitronectin (a key leptomeningeal extracellular matrix [ECM] protein), decreased migration through ECM extract, and decreased c-myc expression in multiple MB cell types. In mouse models of MB LD, ABL1/2 knockdown significantly decreased LD as determined by bioluminescence and improved overall survival (p=0.0044). Pharmacologic inhibition of ABL1/2 using nilotinib resulted in improved median overall survival (64 vs. 76.5 days).

CONCLUSIONS

ABL1 and ABL2 are preferentially expressed in patients with MB LD at diagnosis and are associated with poor survival. Both genetic inactivation and pharmacologic inhibition of ABL1 and 2 decreased MB LD in vitro and in vivo, likely via reduction of c-myc signaling. This preliminary work suggests a key role for ABL1/2 in driving MB LD.
CSIG-33. BCOR LOSS PROMOTES RETINOBLASTOMA GROWTH AND DISSEMINATION BY MODULATING INSULIN-LIKE GROWTH FACTOR 2
Authors: Eberhart Charles , Alaali Lujain , Lee Su Chan
Published: November 2022

While loss of RB function is the most common genetic alteration in the pediatric embryonal eye tumor retinoblastoma, mutations leading to BCL-6 corepressor (BCOR) loss of function are the second most common alteration. BCOR mutations are found in more aggressive tumors, and are associated with metastasis and poor prognosis. We investigated the effects of BCOR loss or overexpression in retinoblastoma cells in order to better understand its functional role, and to determine if it represents a new therapeutic target in these tumors. Six established retinoblastoma cell lines were examined, and BCOR protein was most highly expressed in WERI-RB1, but absent in Y79 and two other lines. BCOR knock down in WERI-RB1 cells using shRNA caused markedly increased migration and proliferation. BCOR was also knocked out in these cells using CRSPR, resulting in more than three-fold increased size of intraocular murine xenografts and extensive extraocular extension of tumors. In terms of mechanism, BCOR loss of function induces IGF2 transcription, resulting in an activation of IGF1R and the ERK signaling pathway. In contrast, overexpressing BCOR in Y79 retinoblastoma cells with no baseline protein had opposite effects on IGF2. Targeting IGF2/IGF1R signaling pharmacologically using Lincitinib inhibited proliferation and migration in BCOR-negative retinoblastoma cells. Increased IGF2 transcription was regulated at least in part by hyper methylation of CCCTC-binding factor (CTCF)-binding regions in the IGF2/H19 imprinting control region (ICR), suggesting that BCOR knock down promotes increased methylation at this site. In summary, our studies revealed that BCOR loss promotes the growth and invasion of retinoblastoma cells in vitro and in vivo, at least in part via modulating IGF2 transcription, suggesting new potential therapeutic targets for these aggressive childhood tumors of the eye.
RADT-01. GAMMA KNIFE STEREOTACTIC RADIOSURGERY FOR PATIENTS WITH 10 OR MORE BRAIN METASTASES AT INITIAL CNS PRESENTATION
Authors: DePaoli Bradley , Khaleghi Serena , Duffy Edward , Hall Michael , Rivers Charlotte
Published: November 2022

Stereotactic radiosurgery (SRS) is an established treatment modality for patients with up to 10 brain metastases. Previous guidelines have recommended whole brain radiation therapy (WBRT) for patients with > 10 brain metastases, but many providers and patients have opted for SRS in an attempt to minimize neurocognitive toxicity. There is growing literature supporting SRS in patients with ≥ 10 brain metastases in both the up-front and salvage settings. Data remains limited in how to best manage patients with ≥ 10 brain metastases at their first central nervous system (CNS) presentation. A retrospective review was performed on all patients with ≥ 10 brain metastases at their first CNS presentation treated with Gamma Knife SRS since 2010 at our institution. Patients with prior surgery for neurological symptoms were included, but patients who had received prior CNS radiation were excluded. Patients could be treated in a single stage or as many stages necessary to treat all metastases. Demographics and clinical data were collected. Descriptive statistics were used to summarize variables. 91 patients were identified with a median age of 64 years old. The median brain metastases treated was 13 with a range of 10-57. Local failure was 11% and occurred at a median 10.8 months. Distant failure was 51.6% and occurred at a median 2.7 months. 30.8% of patients required repeat SRS and 18.7% of patients required salvage WBRT. Median survival was 7.2 months. 1-year and 2-year overall survival were 34.8% and 16.5%, respectively. Radiation necrosis occurred in 4.4%. Grade 2 toxicity occurred in 36.3% and Grade 3+ toxicity occurred in 7.7%. There were no grade 5 toxicities and only 5.5% of patients died from clear neurological causes. Upfront SRS provides acceptable local control, survival, and toxicity in patients with ≥ 10 metastases at CNS presentation and can be considered for first-line treatment.
RADT-03. GOLDILOCKS AND THE THREE DOSES OF RADIOSURGERY FOR SMALL BRAIN METASTASES
Authors: Kutuk Tugce , Kotecha Rupesh , Tolakanahalli Ranjini , Appel Haley , Hall Matthew , Wieczorek D Jay , Lee Yongsook , McDermott Michael , Ahluwalia Manmeet , Gutierrez Alonso , Mehta Minesh , Tom Martin
Published: November 2022

INTRODUCTION

The optimal dose for single-fraction radiosurgery (SRS) for small brain metastases (BM) (< 2 cm) has not been established considerable variability in dose selection.

METHODS

Consecutive patients diagnosed with intact BM < 2 cm in maximum dimension treated with SRS to prescription doses of 24, 22, or 20 Gy on the Gamma Knife® between 3/2019-1/2021 were reviewed. Institutional dosing prescriptions were: 24 Gy for < 10 lesions, 22 Gy for 10-20, and 20 Gy for >20). Endpoints included freedom-from-local-failure (FFLF) and radionecrosis on a per-lesion basis calculated from date of SRS to event. Univariable and multivariable analyses were performed using the Kaplan-Meier method and Cox proportional hazards regression.

RESULTS

133 patients with 863 BM met inclusion criteria. Prescription dose was 24 Gy for 416 (48.2%) lesions, 22 Gy for 266 (30.8%), and 20 Gy for 181 (21.0%). 20 Gy was associated (all p< 0.001) with younger age, presence of extracranial-disease, progressive extracranial-disease, lung primary, higher number of BM per SRS course (median 17 for 20 Gy, 14 for 22 Gy, 6 for 24 Gy), and smaller per-lesion tumor volume. With a median follow-up of 15 months, 76 (8.8%) LFs occurred. Actuarial 1-year FFLF was 91.2% (95%CI: 88.6-94.8%) for 24 Gy, 92.5% (89.1-95.9%) for 22 Gy, and 77.9% (71.2-84.6%) for 20 Gy (p< 0.001). On multivariable analysis, factors independently associated with adverse FFLF (all p< 0.05) were male sex, presence of extracranial-disease, breast or lung primary, and 20 Gy prescription dose (HR: 2.52, 95%CI: 1.34-4.76). The cumulative 1-year radionecrosis rate was 7.0% for 24 Gy, 4.0% for 22 Gy, and 3.8% for 20 Gy (p=0.035).

CONCLUSION

For BM < 2 cm, we propose a testable hypothesis that 22 Gy prescription dose may represent the “Goldilocks zone”- superior to 20 Gy regarding LF and superior to 24 Gy concerning radionecrosis.
RADT-07. RADIOGRAPHIC “NECROSIS" FOLLOWING SINGLE-FRACTION SRS AND IMMUNE CHECKPOINT INHIBITION IS ASSOCIATED WITH IMPROVED SURVIVAL IN PATIENTS WITH BRAIN METASTASES: AN INTERNATIONAL MULTICENTER STUDY
Authors: Lehrer Eric , Ahluwalia Manmeet , Gurewitz Jason , Bernstein Kenneth , Kondziolka Douglas , Wei Zhishuo , Niranjan Ajay , Lunsford L Dade , Fakhoury Kareem , Rusthoven Chad , Mathieu David , Trudel Claire , Malouff Timothy , Ruiz-Garcia Henry , Bonney Phillip , Hwang Lindsay , Yu Cheng , Zada Gabriel , Patel Samir , Deibert Christopher , Picozzi Piero , Franzini Andrea , Attuati Luca , Prasad Rahul , Raval Raju , Palmer Joshua , Lee Cheng-Chia , Yang Huai-che , Jones Brianna , Green Sheryl , Sheehan Jason , Trifiletti Daniel
Published: November 2022

OBJECTIVE

Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are commonly utilized in the management of brain metastases. Treatment-related imaging changes (TRIC) are a frequently observed clinical manifestation and are commonly classified as radiographic radiation necrosis. However, these findings are not well characterized and may predict for response to SRS and ICI.

METHODS

The diagnosis-specific graded prognostic assessment was used to guide variable selection. TRIC were determined based upon MRI, PET/CT, or MR spectroscopy and a consensus by local clinical providers was required.

RESULTS

The analysis included 697 patients with 4,536 brain metastases across 11 institutions in 4 countries. The median follow-up after SRS was 13.6 months. The median age was 66 years, 54.1% of patients were male, and 57.3%, 36.3%, and 6.4% were non-small cell lung cancer, melanoma, and renal cell carcinoma (RCC) histology, respectively. TRIC were observed in 9.8%. On univariable analysis, Karnofsky Performance Status (KPS) (hazard ratio [HR]: 0.98; p < 0.001), presence of TRIC (HR: 0.67; p = 0.03), female sex (HR: 0.67; p < 0.001), and prior resection (HR: 0.60; p = 0.03) were associated with improved OS. On multivariable analysis, KPS (HR: 0.98; p < 0.001) and the presence of TRIC (HR: 0.66; p = 0.03) were associated with improved OS. A V12 Gy ≥ 10 cm3 (Odds Ratio [OR]: 2.78; p < 0.001), prior whole brain radiation therapy (OR: 3.46; p = 0.006), and RCC histology (OR: 3.10; p = 0.01) were associated with an increased probability of developing TRIC. The median OS in patients with and without TRIC was 29.0 and 23.1 months, respectively (log-rank p = 0.03).

CONCLUSION

TRIC following ICI and SRS are associated with a median OS benefit of approximately 6 months. Further prospective study is warranted to further elucidate the role and etiology of this common clinical scenario.
RADT-10. THE LOST METASTASES: DEEP LEARNING’S POTENTIAL IN RADIOSURGERY QUALITY ASSURANCE
Authors: Bang Charmin , Chartrand Gabriel , Pawlowski Sophie , Emiliani Ramon , Markel Daniel , Bahig Houda , Samak Alexandre , Rajakesari Selvan , Lavoie Jérémi , Ducharme Simon , Roberge David
Published: November 2022

Introduction

Identifying, segmenting, measuring, and following multiple brain metastases treated with radiosurgery can be time consuming and error prone. Machine learning has shown promise for automated detection and segmentation. Recently, a U-Net inspired model combining volume aware loss functions and volume aware sampling methods was trained in an industrial-academic partnership. A total of 530 clinically annotated T1 gadolinium MRIs were used. Initial validation showed a high sensitivity (91%) with an average of 0.66 false positives per MRI. The goal of the present work was to characterize those “false positives” which may represent clinically undetected metastases.

METHODS

The images used for model development were clinically annotated for radiosurgery planning. Lesions had first been identified by a radiologist, second by clinicians during tumor board review, third by the treating radiation oncologist and the treating neurosurgeon (potentially after segmentation by a trainee) and finally by fellow radiation oncologists during quality assurance rounds. Despite these multiple checks, 10 patients (2%) had brain lesions considered potential clinical misses when all “false positives” were manually reviewed by a single investigator. Further detailed review including prior and subsequent imaging was used to arbitrate the nature of these lesions.

RESULTS

Among the 10 cases, four were confirmed as undetected metastases: two lesions required subsequent radiosurgery and 2 patients died prior to further imaging. The six other lesions were adjudicated as true “false positives” (typically vascular).

CONCLUSION

The multi-tier radiosurgery workflow at our institution left very few unidentified brain metastases (0.8%). Despite this low error rate, our AI algorithm still detected two lesions that required further treatment. Future investigations will focus on potential roles of AI in simplifying and accelerating our workflow. It also remains to be established if more undetected metastases would be seen in community settings where workflows include fewer sequential imaging reviews.
RADT-17. A CASE OF RECURRENT GLIOBLASTOMA EFFECTIVELY TREATED WITH TUMOR-TREATING-FIELDS(TTFS)
Authors: Geng Xin , Ji Hongming , Cheng Rui
Published: November 2022

The patient was admitted to our hospital due to sudden headache in February 2021, and the head MRI showed "right frontal mass". On February 8, 2021, a large right forehead mass resection was performed under general anesthesia. The postoperative pathology showed: Glioblastoma (WHO grade IV). Regular chemotherapy with temozolomide was given postoperatively. In June 2021, the re-examination of the head MRI examination considered the possibility of recurrence, and tumor-treating-fields(TTFs) was started. Subsequently, the head MRI was reviewed every 2 months, and it was seen that the lesions gradually shrank. At present, the patient is generally in good condition without headache and other discomfort, and has obtained 15 months of PFS since the operation.
RADT-19. CHEMORADIATION (CRT) TREATMENT WITH OR WITHOUT CONCURRENT TUMOR-TREATING FIELDS (TTFIELDS) IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Cappelli Louis , Kayne Allison , Pan Peter , Cordova James , Huang Jiayi , Wang Tony , Alnahhas Iyad , Shi Wenyin
Published: November 2022

OBJECTIVES

Standard of care for newly diagnosed glioblastoma after resection includes concurrent temozolomide (TMZ) and radiation therapy followed by adjuvant TTF with maintenance TMZ. Preclinical studies suggest TTF and radiotherapy work synergistically. We evaluate the benefit of concurrent TTF with CRT vs adjuvant TTF with TMZ after CRT.

METHODS

Concurrent TTF with CRT patients were enrolled in a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). For the comparison control of adjuvant TTF, adult patients with newly diagnosed GBM that had a KPS ≥ 60 who received treatment with CRT and adjuvant TMZ + TTF from three institutions were included. The adjuvant TTF cohort excluded patients who progressed during CRT or did not receive TMZ. PFS and OS were compared between groups.

RESULTS

A total of 87 patients were included in this study, of which 30 received concurrent TTF with CRT. Median patient age was 58 in the concurrent TTF group and 59 in the adjuvant TTF group. The median KPS in both groups was. MGMT methylation was present in 33.3% of the concurrent TTF and 32.0% in the adjuvant TTF group. 40% received GTR in the concurrent group and 38% received GTR in the adjuvant group. Multifocal disease was appreciated in 40% of patients in the concurrent TTF group. There was no significant difference in median OS (p=0.38) or PFS (p=0.76).

CONCLUSIONS

There was no difference in OS or PFS between concurrent or adjuvant TTF treatment groups. However, the adjuvant TTF group is expected to be a better prognosis due to the elimination of patients that progressed or declined after initial CRT. The current study suggested concurrent TTF treatment achieved outcomes to that of a better prognosis group. The survival benefit of concurrent TTF with CRT vs adjuvant TTF is being tested in the phase 3 TRIDENT EF-32 clinical trial (NCT04471844).
RADT-22. RISING UTILIZATION AND REDUCED MEDICARE SPENDING OF SHORT-COURSE RADIATION THERAPY FOR PRIMARY CNS TUMORS IN ELDERLY ADULTS
Authors: Tringale Kathryn , Miller Alexandra , Beal Kathryn , Yang Jonathan , Pike Luke , Imber Brandon
Published: November 2022

INTRODUCTION

For elderly/frail glioma patients, shortening radiotherapy from 6 to 3 weeks (short-course RT [SC-RT]) is non-inferior to standard long course (LC-RT) though usage is estimated to be < 20%. We analyzed real-world utilization of SC-RT with/without systemic therapy in Medicare beneficiaries treated with RT for primary CNS tumors using CMS data on radiation episodes.

METHODS

Radiation modality, year, age (65-74, 75-84, ≥ 85), and site-of-care (freestanding vs hospital-affiliated) were evaluated. Utilization of SC-RT (11-20 fractions) vs LC-RT (21-30 fractions) and systemic therapy was evaluated by multivariable logistic regression. Medicare spending over the 90-day episode was analyzed using multivariable linear regression (adjusted β coefficients reported).

RESULTS

From 2015-2019, 9,572 episodes were included (2,966 [31%] SC-RT). SC-RT utilization increased (27% in 2015, 34% in 2019; OR 1.2 per year [95%CI:1.1-1.2]) and was associated with older age (age ≥ 85 vs 65-74, OR 7.0 [95%CI:5.7-8.7], hospital-affiliated sites (OR 1.2 [95%CI:1.1-1.4]), conventional RT (vs IMRT OR 2.8 [95%CI 2.4-3.3]), and lack of systemic therapy (OR 1.2 [95%CI:1.1-1.3]; p < 0.001 for all). Rise in SC-RT was concentrated in hospital-affiliated sites (interaction p = 0.005). Most (6,629, 69%) received systemic therapy with no differences by site-of-care (p = 0.34). Systemic therapy utilization increased over time (67% in 2015, 71% in 2019; OR 1.1 per year [95%CI:1.1-1.1]) and was less likely for older patients, conventional RT, and SC-RT (p-value < 0.001 for all). SC-RT significantly reduced spending vs LC-RT (β=$8,416, 95%CI:8,317-8,515), while spending modestly increased with systemic therapy usage (β=$316, 95%CI:220-409).

CONCLUSIONS

While most Medicare beneficiaries received LC-RT for primary brain tumors, SC-RT utilization increased in hospital-affiliated centers; despite high-level evidence, discrepancy in SC-RT implementation by site-of-care persists and necessitates further investigation. Given RT course length had a greater impact on Medicare spending than systemic therapy, increased use of SC-RT in appropriate populations reflects an opportunity to increase high value care.
RADT-31. 68GA-DOTATATE PET VERSUS MRI-BASED TREATMENT PLANNING FOR POST-OPERATIVE AND INTACT MENINGIOMA: A DOSIMETRIC ANALYSIS
Authors: Perlow Haley , Prasad Rahul , Siedow Michael , Gokun Yevgeniya , McElroy Joseph , Matsui Jennifer , Cadieux Catherine , Eiler Daniel , Odou Sean , Addington Mark , Ivanidze Jana , Bovi Joseph , Kleefisch Christopher , Zoller Wesley , Palmer Joshua
Published: November 2022

Background

Nearly all meningiomas express somatostatin receptor 1/2 (SSTR1/SSTR2); therefore, SSTR ligands such as 68Ga-DOTATATE can be utilized for meningioma radiotherapy treatment planning. Incorporation of 68Ga-DOTATATE PET assists with target delineation and may reduce the dose to organs-at-risk (OARs). We hypothesize that 68Ga-DOTATATE PET-based treatment plans will reduce dose to OARs when compared to MRI-based plans.

METHODS

All treatment plans were rendered on computed tomography (CT) planning datasets, using RapidArc and 6MV photon energy. Two arcs were positioned on the coplanar axis with alternated collimator settings of 0 and 90 degrees to promote MLC sparing with a third unique vertex arc chosen independently to spare normal brain tissue and associated organs at risk (OAR). For MRI structures, a 1 cm expansion from the gross tumor volume (GTV) created a clinical treatment volume (CTV)60. A 2 cm expansion created a CTV54. For PET structures, a 1 cm expansion from the GTV created a CTV60. A 3 mm isotropic expansion created planning treatment volumes (PTVs). Plans were optimized such that Dmax to brainstem remained limited to 60Gy or less and Dmax to optic structures was limited to 54Gy or less.

RESULTS

18 meningioma patients were included (9 post-operative, 9 intact). The mean PTV volume using MRI was 258 ccs (306 ccs for post-operative, 210 ccs for intact), and the mean PTV volume using PET was 60 ccs (97 ccs for post-operative, 91 ccs for intact). The mean radiation dose to both optic nerves, the optic chiasm, both hippocampi, and the brainstem was reduced favoring PET-based treatment plans for both post-operative and intact patients.

CONCLUSION

Our study shows that incorporation of 68Ga-DOTATATE PET can reduce dose to OARs for post-operative and intact patients, and this difference may translate to reduced toxicity. 68Ga-DOTATATE PET guided radiation treatments are worthy of future prospective investigation.
RADT-33. INTRATUMORAL HEMORRHAGE IN VESTIBULAR SCHWANNOMAS FOLLOWING GAMMA KNIFE STEREOTACTIC RADIOSURGERY
Authors: Bin-Alamer Othman , Fogg David , Wei Zhishuo , Duehr James , Mallela Arka , Niranjan Ajay , Lunsford L Dade , Abou-Al-Shaar Hussam
Published: November 2022

INTRODUCTION

Intratumoral hemorrhage (ITH) is a rare occurrence in vestibular schwannomas (VS) resulting in worsening vestibular and cranial nerve deficits. Scarce data described the occurrence, management, and outcomes of ITH after stereotactic radiosurgery (SRS).

OBJECTIVE

The aim of this study is to delineate the incidence, presentation, management, and outcomes of ITH in VS patients following SRS.

METHODS

A total of 2058 patients with VS underwent Gamma Knife radiosurgery (GKRS) at the University of Pittsburgh Medical Center between 1987 and 2022. The authors identified patients with ITH. Their presentation, management, clinical, and imaging outcomes are reported and analyzed.

RESULTS

A total of 1902 VS patients had sufficient clinical and imaging follow-up data. Five Koos III (n = 1) and IV (n = 4) VS patients developed ITH after GKRS, resulting in a cumulative incidence rate of 0.26%. The age at presentation ranged from 62 to 79 years, and 3 of the patients were males. The time from VS diagnosis to GKRS ranged from 1-13 months, and the time from GKRS to ITH ranged from 2-130 months. Three patients had bleeding risk factors. One patient required urgent surgical intervention due to the ITH volume, while the other four patients initially were observed. Three remained stable and required no delayed intervention. Histopathological analysis revealed multiple fragments of S-100–positive cells, hemorrhage, and hemosiderin-laden macrophages. At last follow-up, 4 patients had clinically improved, and one remained stable.ConclusionVS ITH following SRS is a rare complication with a cumulative incidence rate of 0.26%. Patient-tailored management is vital based on patient presentation, acuity, and ITH size and characteristics.
RADT-36. MANAGEMENT OF PATIENTS WITH METASTATIC CENTRAL NERVOUS SYSTEM (CNS) GERMINOMA; A LITERATURE REVIEW
Authors: Abu-Arja Mohammad , Shatara Margaret , Okcu M Fatih , McGovern Susan , Su Jack M , Abdelbaki Mohamed
Published: November 2022

BACKGROUND

No consensus exists on the optimal irradiation volume/dose for patients with metastatic CNS germinoma. We reviewed the literature for a potential association between different treatment modalities and survival.

METHODS

We searched PubMed for studies on patients with primary metastatic CNS germinoma including detailed survival outcome data. We used the Kaplan-Meier method to estimate event-free survival (EFS) rates and log-rank test for comparison among treatment modalities.

RESULTS

We identified 124 patients from 38 studies published between 1990 and 2021. The median age of presentation was 15 years (range: 1.5–47 years). Treatment modalities included: chemotherapy only (n = 5), radiotherapy only (n = 31), and radio-chemotherapy (n = 88). Radiotherapy modalities included: craniospinal irradiation (CSI) (n = 69), whole-brain irradiation (WBI) (n = 19), whole ventricular irradiation (WVI) (n=16), focal and spine irradiation (n = 5), focal irradiation only (n = 9), and not specified (n = 1). The median focal irradiation dose was 36.6 Gy (range:19.5-59.8 Gy). The median doses for CSI, WBI, and WVI were 24 Gy (range: 10.8-49 Gy). Eighteen patients relapsed, 111 were alive without disease, 2 were alive with disease, and 12 died of disease. The median follow-up time was 5 years in survivors. Four patients who received only chemotherapy relapsed. Five-year EFS rates were similar in patients who received chemo-radiotherapy and radiotherapy alone (89%, 95%CI 81-97%, vs 88%, 95%CI 74-100%, p = 0.6). Patients who were treated with CSI had a longer 5-year EFS compared to patients treated with other modalities (92%, 95%CI 84-100% vs 80%, 95%CI 64-94% p = 0.03). EFS was similar in patients treated with CSI whether they received ≥ 24 Gy or less.

CONCLUSION

CSI is required to achieve prolonged relapse-free survival (RFS). CSI dose of < 24 Gy may be sufficient to achieve sustained RFS. Future trials are needed to evaluate the potential role of neoadjuvant chemotherapy in reducing the dose/volume of irradiation in patients with metastatic CNS germinoma.
RADT-38. INCIDENCE OF HEARING IMPAIRMENT AFTER DEFINITIVE PROTON BEAM THERAPY FOR MALIGNANCIES OF THE BRAIN AND BASE OF SKULL
Authors: Gaito Simona , Hwang Eunji , Aznar Marianne , Ahern Verity , Twaithes David , France Anna , Sitch Peter , Indelicato Daniel J , Holtzman Adam , Pan Shermaine , Smith Ed , Whitfield Gillian
Published: November 2022

AIM

Aim of the project is to report the incidence of moderate/severe (G ≥ 3) long-term hearing impairment (HI) and to identify risk factors in patients treated for malignancies of the brain and base of skull with definitive Proton Beam Therapy (PBT) within the Proton Overseas Programme (POP).

METHODS

Clinical and treatment-related data from patients’ files stored in a national database and curated by a dedicated outcomes unit were extracted and analysed. Clinical toxicity data from the POP were graded as per Common Terminology Criteria for Adverse Events (CTCAE 4.0). Dosimetric data (Dmean to the cochlear structures) were extracted from the Treatment Planning System Proknow. For the purpose of this analysis, patients with radical definitive PBT only were selected.

RESULTS

Between 2008 - 2018, 229 UK patients received radical PBT overseas for Craniopharyngioma (104 patients;45.4%), Chordoma (60; 26.2%), Chondrosarcoma (53;23.1%), Meningioma (7;3%), Pituitary Adenoma (5;2.1%). Median age was 17 years (1-77). Median prescription dose was 55.8 Gy (45-75.8). Median dose to the Left and Right cochleas were 14.18 Gy (0-85.15) and 12.55 Gy (0-77.50), respectively. Eight patients developed G ≥ 3 HI (3.5%). Of those, 7 had received dose escalated treatments for radioresistant tumours (chordomas or condrosarcomas). In 4/8, the HI was bilateral. The median cochlear dose for the structures who developed G ≥ 3 HI was 48.99 Gy (10-76.87).

CONCLUSIONS

Incidence of G ≥ 3 HI in this patient population compares with historical cohorts, and, as expected, is higher in patients who receive dose escalated treatments for radioresistant tumours of the base of skull. Median dose in those who developed HI supports the use of dose constraints used in the clinical PBT practice.
RADT-41. IATROGENIC INFLUENCE ON PROGNOSIS OF RADIATION-INDUCED CONTRAST ENHANCEMENTS IN PATIENTS WITH GLIOMA WHO 1-3 FOLLOWING PHOTON AND PROTON RADIOTHERAPY
Authors: Eichkorn Tanja , Lischalk Jonathan , Deng Maximilian , Elisabetta Sandrini , Eva Meixner , Regnery Sebastian , Held Thomas , Bauer Julia , Bahn Emanuel , Semi Harrabi , Juliane Hoerner-Rieber , Klaus Herfarth , Juergen Debus , Laila Koenig
Published: November 2022

Radiation-induced contrast enhancement (RICE) is a common side effect following radiotherapy for glioma, but both diagnosis and handling are challenging. Due to the potential risks associated with RICE and its challenges in differentiating RICE from tumor progression, it is critical to better understand how RICE prognosis depends on iatrogenic influence. We identified 99 patients diagnosed with RICE who were previously treated with either photon or proton therapy for World Health Organization (WHO) grade 1-3 primary gliomas. Post-treatment brain MRI-based volumetric analysis and clinical data collection was performed at multiple time points. The most common histologic subtypes were astrocytoma (50%) and oligodendroglioma (46%). In 67%, it was graded WHO grade 2 and in 86% an IDH mutation was present. RICE first occurred after 16 months (range: 1 - 160) in median. At initial RICE occurrence, 39% were misinterpreted as tumor progression. A tumor-specific therapy including chemotherapy or re-irradiation led to a RICE size progression in 86% and 92% of cases, respectively and RICE symptom progression in 57% and 65% of cases, respectively. A RICE-specific therapy such as corticosteroids or Bevacizumab for larger or symptomatic RICE led to a RICE size regression in 81% of cases with symptom stability or regression in 62% of cases. RICE progression went along with a worsening in progression-free survival (p = 0.04). While with chemotherapy and re-irradiation a RICE progression was frequently observed, anti-edematous or anti-VEGF treatment frequently went along with a RICE regression. For RICE, correct diagnosis and treatment decisions are challenging and critical and should be made interdisciplinarily.
CTIM-06. EVALUATING THE ASSOCIATION BETWEEN PERIPHERAL BLOOD IMMUNOLOGIC RESPONSE AND THERAPEUTIC RESPONSE TO IMMUNE CHECKPOINT INHIBITION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA AND GLIOSARCOMA
Authors: Watowich Matthew , Yaghi Nasser , Briceno Nicole , Ahn Susie , Wall Kathleen , Evans Karen , Polskin Lily , Komlodi-Pasztor Edina , Sahebjam Solmaz , Watanabe Masashi , Gilbert Mark
Published: November 2022

Immune checkpoint inhibition (ICI) has failed to demonstrate significant efficacy in glioblastoma. With the underlying hypothesis that generation of an immune response in peripheral is necessary for a brain tumor response, we are enrolling patients with newly diagnosed glioblastoma on an ICI immunotherapy clinical trial with longitudinal monitoring of immune function. The purpose of this work is to improve patient selectivity for response to ICI treatment by identifying peripheral immunologic response via immunophenotyping and functional analyses. Currently, 10 of a planned 48 patients have been treated with combination nivolumab and ipilimumab (NCI-21-C-0015). We analyzed blood samples of the first two patients, from pretreatment through cycle 5 of combination ICI to confirm methods used in this clinical trial. Longitudinal evaluation of immunologic response using comprehensive flow cytometric analysis and an in vitro T cell stimulation paradigm with nivolumab and ipilimumab supplementation, serving as an ex vivo predictor of immune response, are reported. Immunophenotyping via flow cytometry successfully documented patients’ peripheral immune cell phenotypes, and ELISpot and in vitro stimulation assays successfully measured patients’ immune cell functional capacitance. Both patients analyzed have shown increased proportions of effector/memory phenotypes within peripheral T cells, and a decrease in peripheral lymphocyte/monocyte ratio during treatment, potentially indicating lymphocyte sequestration in bone marrow or recruitment to the tumor microenvironment. ELISpot analysis documented interferon-γ production capability of T cell is maintained during treatment. Moreover, preliminary analysis of patients’ T cell proliferative capacity in PBMC utilizing in vitro anti-CD3 stimulation indicated T cells become increased in proliferative capability during treatment. These findings support the feasibility of longitudinal assessments, demonstrating that immunologic responsiveness and functionality can be detected with these blood monitoring strategies. Additional patients’ samples will be tested to allow confirmation of trends in immunologic response, and correlations with patient outcomes will be reported at time of presentation.
CTIM-08. A PILOT STUDY OF ABEMACICLIB WITH BEVACIZUMAB IN RECURRENT GLIOBLASTOMA PATIENTS WITH LOSS OF CDKN2A/B OR GAIN OR AMPLIFICATION OF CDK4/6
Authors: Murillo Jennifer , Pan Edward , Youssef Michael , Raslan Omar , Maher Elizabeth , Bachoo Robert
Published: November 2022

The recurrence rate for glioblastomas is essentially 100% and median overall survival (OS) for recurrent glioblastoma patients is usually poor, approximately 6-8 months from first recurrence. There is an unmet need in recurrent glioblastomas for novel therapeutic options with favorable safety profiles and potentially longer OS.

PURPOSE

The goal was to assess the impact of treating recurrent Glioblastoma patients whose tumors harbor loss of CDKN2A and/or CDKN2B, and/or copy gains or amplifications of CDK4 and/or CDK6 with dual therapy Abemaciclib with Bevacizumab.

METHODS

This was a single institution, pilot study (N = 10) of recurrent glioblastoma patients given the combination of Abemaciclib with Bevacizumab. Study patients received the combination of Abemaciclib at 150 mg po bid daily along with intravenous Bevacizumab at 10 mg/kg once every 2 weeks within a 28-day cycle. Staging brain MRIs with contrast were obtained every 8 weeks. Trial patients were removed from the study for significant treatment toxicities, clinical or MRI progression, patient choice, or death.

RESULTS

A total of 10 patients were enrolled in the study. There were 3 patients initially enrolled that were evaluated for safety followed by the additional 7 patients meeting clinical accrual from Jan. 2020-Sept. 2021. A total of 9 patients received at least one cycle (M = 6, F = 3). Preliminary findings revealed a median PFS of 14 weeks (range 5 weeks–25 weeks) and median OS of 20 weeks (range 5-70 weeks).

CONCLUSION

The combination of Abemaciclib with Bevacizumab compared to monotherapy Bevacizumab, surprisingly, had poorer outcomes. In a 2014 Bevacizumab study in recurrent glioblastomas, the median PFS was 13 weeks and OS 34.8 weeks compared to our combination therapy study of 14 weeks and 20 weeks, respectively. It is postulated that the use of Bevacizumab with Abemaciclib caused a drug-drug interaction that led to poor outcomes in our pilot study.
CTIM-13. LOCAL ADOPTIVE CELLULAR IMMUNOTHERAPY WITH CYTOKINE-INDUCED KILLER (CIK) CELLS FOR HIGH GRADE GLIOMAS: A PILOT STUDY WITH LONG-TERM FOLLOW-UP AND POTENTIAL FACTORS FOR SURVIVAL BENEFITS
Authors: Duan Hao , Chen Yukun , He Zhenqiang , Sai Ke , Mou Yonggao
Published: November 2022

BACKGROUND

Immunotherapy is emerging as a promising approach for the treatment of high grade gliomas (HGGs). We reported the long-term follow-up of 6 HGG patients treated by local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor cavity following operation. Meanwhile, Gene expression profiles and immune microenvironments of tumors were further compared between the long-term and short -term survivors.

METHODS

Clinicopathological characteristics and outcomes of patients were reviewed and updated. Gene expression profiles, expressions of cytokines and infiltrations of immune cells in tumors were investigated by RNA sequencing, an electrochemiluminescence assay and immunohistochemistry staining, respectively

RESULTS

Fever and symptoms of encephaledema occurred in 5 patients after local administration of CIK cells, and could be efficiently relieved by mannitol and dexamethasone. Four patients died from progressive disease during follow-up, and their overall survival ranged from 6 to 26 months. Remarkably, 2 patients have survived more than 200 months without evidence of recurrence. Comparing with the tumors of the short-term survivors, 353 genes which were highly associated with tumor microenvironment immune were differentially expressed (false discovery rate (FDR) < 0.05 and log2 fold change (FC) ≥ 1) in the tumor of the long-term survivor. Higher expressions of cytokines, especially IL-8 and IL-10, were observed in the tumor of the long-term survivor, while the infiltrations of M2 polarized macrophages were significantly higher in the tumors of short-term survivors.

CONCLUSION

Long-term survival of HGG patients could achieve after local administration of CIK cells into tumor cavity postoperatively. High expressions of cytokines and low infiltrations of M2 polarized macrophages in the tumors potentially benefited the CIK cell therapy.
CTIM-15. RESULTS OF A PHASE IB TRIAL OF RECOMBINANT POLIO:RHINOVIRUS IMMUNOTHERAPY FOR RECURRENT PEDIATRIC HIGH GRADE GLIOMA
Authors: Thompson Eric , Landi Daniel , Brown Michael , Friedman Henry S , McLendon Roger , Bolognesi Dani , Schroeder Kristin , Becher Oren , Friedman Allan , Walter Ashley , Threatt Stevie , Jaggers Denise , Desjardins Annick , Gromeier Matthias , Bigner Darell , Ashley David
Published: November 2022

BACKGROUND

Outcomes of recurrent pediatric high grade glioma (pHHG) are poor with a median overall survival (OS) of < 6 months. Viral immunotherapy such as the polio:rhinovirus chimera, PVSRIPO, is a novel treatment approach for recurrent pHHG. PVSRIPO is genetically engineered to prevent neurovirulence. In adults with recurrent glioblastoma treated with PVSRIPO, 21% survived > 36 months. The poliovirus receptor, CD155, is ubiquitously expressed in malignant pediatric brain tumors including pHHG.

METHODS

The primary objective of this Phase 1b clinical trial was to evaluate the safety and feasibility of PVSRIPO for recurrent pHGG. PVSRIPO was given at a single dose, 5x107 50% tissue-culture infectious dose (TCID50) administered by convection enhanced delivery (CED) to children with biopsy-confirmed recurrent pHHG between ≥ 1 and ≤ 5.5 in diameter. 3 mL of PVSRIPO was delivered at 0.5 mL/hr via a single catheter.

RESULTS

Eight patients were treated with PVSRIPO including 5 males and 3 females with a median age of 16.5 (range 9-19). Six patients had recurrent glioblastoma, 2 had recurrent anaplastic astrocytoma. The median number of previous recurrences prior to enrollment was 3.5 (range 1-5). Four patients received bevacizumab on-study for treatment-related peritumoral inflammation/edema. Six of 8 patients experienced 26 treatment related adverse events (AEs) possibly, probably, or definitely related to protocol treatment. There were no Grade 4 or 5 AEs. There were 3 Grade 3 AEs: 2 headaches and 1 seizure. There were no AEs related to biopsy or CED catheter insertion/removal. Median OS was 4.13 months (range 1.23-NA). One patient is currently alive at > 21 months. Monocyte and T cell inflammatory phenotypes and total CD4+ T cells were increased in peripheral blood after treatment.

CONCLUSIONS

CED of PVSPRIO is both safe and feasible for the treatment of recurrent pHHG. Histologic correlative results will also be presented.
CTIM-16. PHASE 1 TRIAL OF RUXOLITINIB, TEMOZOLOMIDE, AND RADIATION IN HIGH-GRADE GLIOMAS
Authors: Ahluwalia Manmeet , Khosla Atulya , Rauf Yasmeen , Murphy Erin , Chao Samuel , Suh John , Stevens Glen , Peereboom David
Published: November 2022

BACKGROUND

Ruxolitinib is a small molecule inhibitor of JAK1 (Janus kinase 1) and JAK2 and JAK3. Dysregulation of the JAK/STAT pathway is associated with increased proliferation and survival of malignant cells. Preclinical evidence supporting inhibition of the JAK-STAT pathway arrogated glioma growth led to the design of this trial.

METHODS

Newly diagnosed patients with unmethylated MGMT HGG (arm 1) received ruxolitinib and 60 Gy radiation for 6 weeks over 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 was 10 mg twice daily, level 2 (15 mg twice daily), level 3 (20 mg twice daily), and level -1 was 5 mg twice daily. Patients with methylated MGMT HGG (arm 2) received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method and compared using the log-rank test.

RESULTS

60 HGG were treated in the study and there was no dose-limiting toxicity. Survival data was calculated for 37 GBM patients. The OS for arm 1 was 18.17 months (10.15, NA) and was not reached for arm 2. The 1-year OS was 0.77 for all GBM patients, was 0.62 for arm 1 (unmethylated MGMT) and 0.93 for arm 2 (unmethylated MGMT).

CONCLUSIONS

A dose of 20 mg twice daily of ruxolitinib is safe with radiation and temozolomide. Preliminary survival data appears promising compared to the historical benchmarks for both the methylated MGMT and unmethylated MGMT groups. Genomic markers of response will be presented. A randomized phase 2 trial is planned.
CTIM-22. THE COMBINATION OF LOMUSTINE AND THE IMMUNOCYTOKINE L19TNF IS A PROMISING TREATMENT FOR RECURRENT GLIOBLASTOMA
Authors: Look Thomas , Puca Emanuele , Stucchi Riccardo , De Luca Roberto , Roth Patrick , Neri Dario , Weller Michael , Hemmerle Teresa , Weiss Tobias
Published: November 2022

Glioblastoma is the most aggressive primary brain tumor and adults and poorly immunogenic. Treatment options for recurrent glioblastoma after standard of care chemoradiation are limited Several immunotherapeutic strategies including peptide vaccination and immune checkpoint inhibition have so far failed to improve survival and except from potentially regorafenib, no other agent has demonstrated superior activity to lomustine. Therefore, there is an urgent need for more effective treatment strategies for recurrent glioblastoma. Here, we investigate a new treatment combination based on the alkylating chemotherapy lomustine and the tumor-stroma targeting antibody-cytokine fusion protein L19TNF in preclinical glioma models and patients with recurrent glioblastoma. The combination treatment with lomustine and L19TNF demonstrated strong synergistic anti-tumor activity in several immunocompetent orthotopic glioma models curing the majority of tumor-bearing mice, whereas other mono- or combination therapies for example with anti-PD1 had only limited anti-glioma activity. Investigations of the mechanism of action revealed that lomustine plus L19TNF led to intratumoral necrosis, DNA damage and triggered a strong local anti-tumor immune response with increased MHC-I expression, presentation of neoepitopes and increased abundance of tumor-infiltrating lymphoid cells. In the first patients treated within a phase I/II clinical trial (NCT04573192), the treatment was well tolerated, and durable objective tumor responses and disease stabilizations could be observed also in patients with an unmethylated MGMT promoter.