bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-01. BRAIN METASTASES FROM ENDOMETRIAL CARCINOMA: TUMOR GENETIC ALTERATIONS IN A CASE SERIES AND META-ANALYSIS
Authors: Chapman Emily , Tsankova Nadejda , Sebra Robert , Germano Isabelle
Published: December 2020

INTRODUCTION

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the world. While most patients (80%) can be cured with a hysterectomy, the remaining 20% who are diagnosed with advanced or recurrent disease have worse survival rates and limited adjuvant treatment options. Discovery of novel targets and pathways is needed for better understanding of the pathogenesis and treatment development for this disease. The aim of this study is to review clinical characteristics and genetic signatures of histologically proven EC brain metastasis (BM).

METHODS

For the period 2000-2019 the medical records of patients with histological diagnosis of EC BM at our Institution were reviewed. Data were collected and analyzed for age, time interval between EC and EC BM diagnoses, tumor molecular and genetic signatures, and outcome. Immunohistochemistry and sequencing was performed as published. A meta-analysis was also performed for the same time period. Data presented as mean+SD and analyzed by t-test and Chi square.

RESULTS

There were 6 BM from 5 patients meeting our cohort entry criteria and a total 123 cases reported in the literature. The mean age was 57.6+11.7 (range 39-69) consistent with reported data. The time interval between EC and EC BM diagnoses was 145.7+119.7 (range 33.1-275.7), significantly longer than reported (19.4+27.8; range 0-156; p< 0.05). All BM in our cohort were metachronous, while only 59% were in the literature. Whereas all FIGO grades are reported in the literature (I=20%; II=6%; III=42%; IV=32%), only I and III were found in our cohort (I=60%, III=40%). Tumor microsatellite instability genes MSH2 and MSH6 gene were intact, whereas MLH1 and PMS2 showed mutations. PD-L1 expression was low. EC BM genomic reports were not found in the literature.

CONCLUSIONS

Our study brings insights on the genomic alteration burden on EC BM. Information-driven genomic testing will continue to lead patient-centered therapeutic approaches.
PATH-03. CLINICAL UTILITY OF NEXT GENERATION SEQUENCING IN IDH-WILDTYPE GLIOBLASTOMA: THE DANA-FARBER CANCER INSTITUTE EXPERIENCE
Authors: Jane Lim-Fat Mary , Youssef Gilbert , Touat Mehdi , Iorgulescu Bryan , Woodward Eleanor , Whorral Sydney , Allen Marie , Vogelzang Jayne , Pisano William , Rahman Rifaquat , Chukwueke Ugonma , Mcfaline-Figueroa Jose , Nayak Lakshmi , Lee Eudocia , Batchelor Tracy , Chiocca E Antonio , Meredith David , Santagata Sandro , Reardon David , Beroukhim Rameen , Bi Wenya Linda , Ligon Keith , Wen Patrick
Published: December 2020

BACKGROUND

Comprehensive next generation sequencing (NGS) is available through many academic institutions and commercial entities, and is incorporated in practice guidelines for glioblastoma (GBM). We retrospective evaluated the practice patterns and utility of incorporating NGS data into routine care of GBM patients at a clinical trials-focused academic center.

METHODS

We identified 1,011 consecutive adult patients with histologically confirmed GBM with OncoPanel testing, a targeted exome NGS platform of 447 cancer-associated genes at Dana Farber Cancer Institute (DFCI), from 2013-2019. We selected and retrospectively reviewed clinical records of all IDH-wildtype GBM patients treated at DFCI.

RESULTS

We identified 557 GBM IDH-wildtype patients, of which 227 were male (40.7%). OncoPanel testing revealed 833 single nucleotide variants and indels in 44 therapeutically relevant genes (Tier 1 or 2 mutations) including PIK3CA (n=51), BRAF (n=9), FGFR1 (n=8), MSH2 (n=4), MSH6 (n=2) and MLH1 (n=1). Copy number analysis revealed 509 alterations in 18 therapeutically relevant genes including EGFR amplification (n= 186), PDGFRA amplification (N=39) and CDKN2A/2B homozygous loss (N=223). Median overall survival was 17.5 months for the whole cohort. Seventy-four therapeutic clinical trials accrued 144 patients in the upfront setting (25.9%) and 203 patients (36.4%) at recurrence. Altogether, NGS data for 107 patients (19.2%) were utilized for clinical trial enrollment or targeted therapy indications. High mutational burden (>17mutations/Mb) was identified in 11/464 samples (2.4%); of whom 3/11 received immune checkpoint blockade. Four patients received compassionate use therapy targeting EGFRvIII (rindopepimut, n=2), CKD4/6 (abemaciclib, n=1) and BRAFV600E (dabrafenib/trametinib, n=1).

CONCLUSION

While NGS has greatly improved diagnosis and molecular classification, we highlight that NGS remains underutilized in selecting therapy in GBM, even in a setting where clinical trials and off-label therapies are relatively accessible. Continued efforts to develop better targeted therapies and efficient clinical trial design are required to maximize the potential benefits of genomically-stratified data.
PATH-17. NOVEL DUAL HISTONE 3 K27M AND G34R POINT MUTATIONS IN A MIDLINE GLIOMA
Authors: Pan Peter , Bale Tejus , Miller Alexandra , Ladanyi Marc , Rosenblum Marc , Haggiagi Aya
Published: December 2020

BACKGROUND

Histone H3 alterations due to mutations on H3F3A and HIST1H3B genes, have in recent years been associated with distinct entities and tumor locations within the context of infiltrative gliomas. H3K27M is associated with a midline location and is included in the WHO 2016 as the diffuse midline glioma H3K27M-mutant, a specific diagnostic entity. H3G34R, thought to be a mutually exclusive alteration, is less common but has been associated with a cerebral hemispheric location. We report the first case to our knowledge with both of these alterations in the same tumor.

METHODS

Clinical and pathologic records of the patient were reviewed and presented.

RESULTS

A 39-year-old man presented with acute right face, arm, and leg numbness and mild weakness; examination was notable for right lower motor neuron facial nerve palsy and numbness, along with numbness and subtle slowing of rapid alternating movements in the left arm and leg. A non-enhancing left thalamic mass was identified and stereotactically biopsied. Infiltrative glial neoplasm with moderately-increased cellularity was seen, with ovoid cells, enlarged nuclei, apoptotic bodies, and mitotic figures. No necrosis or microvascular proliferation seen. Immunostain was positive for H3K27M. O6-methylguanine-methyltransferase (MGMT) promoter was not methylated. Next-generation sequencing showed dual in cis H3 point mutations in K27M (HIST1H3B c.83A >T) and G34R (HIST1H3B c.103G >C). Additional alterations were noted in NF1, PIK3CA, ATRX, FGFR3, and NSD1. Isocitrate dehydrogenase (IDH1/2) mutations were not identified.

CONCLUSION

This case of a young man with a midline glioma is novel for carrying both H3K27M and H3G34R alterations and indicates these alterations are not mutually exclusive. The interaction seen here suggests H3K27M dominance for a midline phenotype.
PATH-22. COMPREHENSIVE ANALYSIS OF DIVERSE LOW-GRADE NEUROEPITHELIAL TUMORS WITH FGFR1 ALTERATIONS REVEALS A DISTINCT MOLECULAR SIGNATURE OF ROSETTE-FORMING GLIONEURONAL TUMOR
Authors: Lucas Calixto-Hope G , Gupta Rohit , Doo Pamela , Wood Matthew , Grafe Marjorie , Lee Han , Kleinschmidt-Demasters B K , Bush Nancy Ann Oberheim , Taylor Jennie , Clarke Jennifer , Butowski Nicholas , Kline Cassie , Reddy Alyssa , Banerjee Anurhada , Mueller Sabine , Hervey-Jumper Shawn , Aghi Manish , Chang Edward , Theodosopoulos Philip , Roland Jarod , Auguste Kurtis , Sun Peter , Raffel Corey , Gupta Nalin , Lee Julieann , Phillips Joanna , Pekmezci Melike , Bollen Andrew , Tihan Tarik , Chang Susan , Berger Mitchel , Perry Arie , Solomon David
Published: December 2020

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined, nor are the histopathologic features of pilocytic astrocytomas with FGFR1 alterations versus those harboring the more common BRAF mutations or fusions. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and PA are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis refines the classification and histopathologic spectrum of LGNET with FGFR1 alterations.
PATH-30. CLINICAL AND GENETIC CHARACTERISTICS OF HISTONE H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMAS IN ADULTS
Authors: Schulte Jessica , Buerki Robin , Lapointe Sarah , Molinaro Annette , Zhang Yalan , Villanueva-Meyer Javier , Perry Arie , Phillips Joanna , Tihan Tarik , Bollen Andrew , Pekmezci Melike , Butowski Nicholas , Bush Nancy Ann Oberheim , Taylor Jennie , Chang Susan , Theodosopoulos Philip , Aghi Manish , Hervey-Jumper Shawn , Berger Mitchel , Solomon David , Clarke Jennifer
Published: December 2020

BACKGROUND

“Diffuse midline glioma, H3 K27M-mutant” is a new tumor entity established in the 2016 WHO Classification of Tumors of the CNS that comprises a set of diffuse gliomas arising in midline structures that is molecularly defined by a recurrent K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited. Given the more frequent origin in the thalamus or spinal cord in adults versus the brainstem in children, gliomas with this mutation may encompass a heterogeneous population of tumor subtypes that vary based on patient age, anatomic site of origin, and concurrent genetic alterations.

METHODS

The 60 patients included were 18 years or older at initial diagnosis, during the period of 2014-2019 at UCSF. Cases were identified using immunohistochemistry with a H3 K27M-mutant specific antibody and/or next-generation sequencing of histone 3 genes H3F3A, HIST1H3B and HIST1H3C. Targeted NGS was performed on tumors from 21 patients, utilizing an UCSF institutional panel or a variety of commercial sources.

RESULTS

Patients presented primarily in the 3rd decade of life, and 57% of tumors were located in the thalamus. Genomic profiling revealed p.K27M mutations exclusively in H3F3A and an absence of mutations in HIST1H3B or HIST1H3C, which are present in approximately one-third of pediatric diffuse midline gliomas. Additionally, these adult H3 K27M-mutant diffuse midline gliomas are universally IDH-wildtype, and have frequent mutations in TP53, PPM1D, FGFR1, NF1, and ATRX. The overall survival of this adult cohort is longer than historical averages for both H3 K27M-mutant diffuse midline glioma in children and IDH-wildtype glioblastomas in adults.

CONCLUSIONS

Together, these findings indicate that H3 K27M-mutant diffuse midline glioma represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in children versus adults.
PATH-32. CLINICAL AND MUTATIONAL PROFILES OF ADULT MEDULLOBLASTOMA GROUPS
Authors: Wong Gabriel Chun-Hei , Huang Queenie Junqi , Poon Manix Fung Man , Chung Nellie Yuk-Fei , Wong Queenie Hoi-Wing , Zhang Zhen-Yu , Shi Zhi-Feng , Chen Hong , Chan Aden Ka-Yin , Li Kay Ka-Wai , Ng Ho-Keung
Published: December 2020

INTRODUCTION

Adult medulloblastomas are clinically and molecularly understudied due to their rarity.

METHODS

We studied a cohort of 101 adult medulloblastomas grouped by Nanostring assay. We performed targeted sequencing on exonic regions of 69 genes implicated in medulloblastoma, and Sanger sequencing for TERT promoter hotspot mutations.

RESULTS

Median age was 27 (range 19-63), and 9.5% were metastatic at diagnosis. SHH accounted for 50% of cases. Unlike previous studies, Group 3 comprised a significant proportion (14%) of adult medulloblastomas, comparable to WNT (19%) and Group 4 (18%). Median follow-up was 51.1 months. Median OS and PFS were 102 and 99 months respectively. In contrast to paediatric medulloblastomas, molecular groups had no prognostic impact in adults, for both OS (p=0.956) and PFS (p=0.162). Most frequently mutated genes were TERT (including promoter, mutated in 35% cases), chromatin modifiers KMT2C (32%) and KMT2D (31%), TCF4 (31%), PTCH1 (26%) and DDX3X (24%). Adult WNT patients showed enrichment of TP53 mutations (6/15 WNT cases), and 3/6 TP53-mutant WNT tumours were of large cell/anaplastic histology. 5 WNT cases harboured concurrent CTNNB1 and PTCH1 mutations. Adult SHH medulloblastomas had frequent upstream pathway alterations (PTCH1 and SMO mutations) and seldom downstream alterations (SUFU mutations, MYCN amplifications). TERT promoter mutations were found in 71% of adult SHH patients, and were restricted to this group. Adult Group 3 patients lacked hallmark MYC amplifications, but had recurrent mutations in KBTBD4 and NOTCH1. Adult Group 4 patients had recurrent mutations in TCF4 and chromatin modifier genes. Overall, amplifications of MYC and MYCN were rare (3%) in adult medulloblastomas.

CONCLUSIONS

We identified distinct clinical and mutational characteristics of adult medulloblastomas that will inform their treatment and risk stratification. Importantly, molecular groups were not prognostic in adult medulloblastoma, TP53 mutations were enriched in adult WNT, and MYC amplifications were absent in adult Group 3.
QOLP-05. OLANZAPINE FOR REFRACTORY CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING IN MALIGNANT GLIOMA PATIENTS
Authors: Patel Mallika , Peters Katherine , Lipp Eric , Low Justin , Herndon James , Broadwater Gloria , Johnson Margaret , Randazzo Dina , Kim Jung-Young , Affronti Mary
Published: December 2020

INTRODUCTION

Malignant glioma (MG) patients often experience chemotherapy-induced nausea and vomiting (CINV). Olanzapine has recently been added to national anti-emesis guidelines for patients on moderately/highly emetogenic chemotherapy. In this retrospective study, we investigated the use of olanzapine for refractory-CINV (R-CINV) in MG patients.

METHODS

In this chart review, we queried adult MG patients with KPS ≥ 70 who received olanzapine from January 2019-March 2020. Patients were included if they were prescribed olanzapine for CINV. Data on nausea/vomiting improvement, olanzapine dosing/schedule, number of refractory anti-emetic trials, concomitant corticosteroid use, and demographics were collected.

RESULTS

We identified 21 MG patients who were prescribed olanzapine, with 9 of those patients receiving olanzapine specifically for CINV. Seven patients had WHO grade IV glioma, and 2 patients had anaplastic astrocytoma (WHO grade III). Five of 9 patients (55.6%) were male, all were Caucasian and median age was 54 years. Patients tried an average of 3 anti-emetics prior to initiating olanzapine for R-CINV. Only one patient was taking concomitant corticosteroids; which is not in concordance with national anti-emesis guidelines. Four of 9 patients (44.4%) achieved control of R-CINV with olanzapine. The olanzapine dose and key biomarkers (IDH-status, MGMT promoter methylation) were similar between those experiencing R-CINV and those without symptoms.

CONCLUSIONS

In this study, we find that approximately half of patients with R-CINV achieved improved nausea and vomiting control with the addition of olanzapine. The lack of corticosteroid use for anti-emesis in MG continues to make this population challenging to manage. The relatively high success rate in patients that had failed, on average, 3 anti-emetics, suggests that olanzapine may be a potent addition to the anti-emetic toolkit for MG patients. These results inspire further large-scale research to validate this observation and define the optimal role for olanzapine in treating R-CINV in MG patients.
QOLP-10. MONITORING TRENDS IN PATIENT DISTRESS IN GLIOBLASTOMA USING THE PHQ4 QUESTIONNAIRE
Authors: Huan Vo Anh , Hambelton Connor , Popp Lauren , Dew Verda , Turchan Maria , Gallamore Sofia , Fu Rochelle , Neuwelt Edward , Ambady Prakash
Published: December 2020

OBJECTIVE

To identify the trend of distress over time and whether palliative care (PC) referral and visit affected distress level in glioblastoma (GBM) patients.

BACKGROUND

GBM patients experience significant distress due to their prognosis and neurologic involvement. All subjects in the neuro-oncology clinic at our institution routinely receive the Patient Health Questionnaire-4 (PHQ4) which is a validated screening tool that comprises a section for generalized anxiety disorder (GAD2) and a depression screen (PHQ2).

DESIGN

This prospective study was approved by the institutional review board. GBM patients who started radiation therapy on 1/1/2019 or later were included. Patients with a GAD2 or PHQ2 of 3 or above were categorized as present for anxiety or depression. A logistic mixed-effects model was used to test the trend of anxiety or depression over time and the impact of PC referral and visit.

RESULT

131 PHQ4 questionnaires from 39 newly diagnosed GBM patients (mean age: 59.9yrs ± 15.0; 23M/16F) at the pre-radiation, post radiation and at least every 2 months thereafter were reviewed. Before radiation, 54.8% of patients reported anxiety, higher than at 1-month post radiation (23.5%), 2-3 months (41.4%), 4-6 months (20.0%), and after 6 months (25.0%). This temporal trend is significant (P = 0.0385) after adjusting for patient characteristics such as age, gender and performance status. The proportions of anxiety were not different among visits without PC referral (23.7%), with PC referral and no PC visit (42.4%), and with PC visit (32.4%, P = 0.64). We did not identify a similar temporal trend in depression.

CONCLUSION

Our data suggests that anxiety is more prevalent than depression in this cohort. This study identifies subjects to be at a greatest likelihood of experiencing anxiety at the pre-radiation time point. Focused interventions at this time point may help improve the patient’s overall quality of life.
RADT-01. THE EFFICACY AND SAFETY OF TWO-STAGED STEREOTACTIC RADIOSURGERY FOR LARGE POSTERIOR FOSSA METASTASES: POST-TREATMENT VOLUMETRIC CHANGES IN TUMOR SIZE, PERI-TUMORAL EDEMA, AND FOURTH VENTRICLE
Authors: Hori Yusuke , Muhsen Baha’eddin , Joshi Krishna , Wei Wei , Borghei-Razavi Hamid , Chao Samuel , Mohammadi Alireza , Barnett Gene , Suh John , Angelov Lilyana
Published: December 2020

INTRODUCTION

Two-staged stereotactic radiosurgery (2-SSRS) delivers a high radiation dose to large (≥2 cm) brain metastases to achieve improved tumor control. However, treating large posterior fossa metastases (LPFM) with SRS is challenging because of the potential risk of increased peritumoral edema (PTE) and compression to brain stem and/or obstructive hydrocephalus of the fourth ventricle (4V).

METHODS

21 patients (22 LPFM) treated with 2-SSRS were retrospectively reviewed. Volumetric analysis for tumor, PTE, and 4V volume was assessed for objective response. We defined local failure (LF) as ≧ 71.5% of volumetric increase, equivalent to ≧ 20% increase in maximum diameter (RECIST criteria). Kaplan-Meier estimated overall survival (OS), time-to-local failure, and linear mixed model estimated and compared measurements between time points.

RESULTS

The median age was 61 years (range: 39–79 years), and nine patients (42.9%) were female. The most common primary cancer was NSCLC (47.6%), followed by breast (14.3%) and renal (14.3). Median OS was 13 months (95% CI: 6–24 months) with median follow-up 18 months (range 7–42 months). The median tumor, PTE and 4V volumes at diagnosis were 7.43 cm3, 18.9 cm3, and 0.95 cm3 respectively. At the first follow-up (median 51 days after the second session), mean tumor (–59%, p< 0.0001) and PTE (–47%, p=0.0008) volumes decreased, while mean 4V volume (+35%, p=0.001) increased. Significant volumetric changes were maintained at second (median 179 days after the second session) follow-up for tumor (–43%, p=0.01) and 4V (+44%, p=0.002), but not for PTE (+8%, p=0.87). Tumor LC rate was 83% (95% CI: 64–100%) at 1 year, and no patient developed the post-treatment hydrocephalus requiring CSF diversion or required surgical resection for tumor progression.

CONCLUSIONS

This is the first report documenting detailed time courses and excellent safety/ efficacy of 2-SSRS for LPFM. Additional studies with longer follow-ups are needed.
RADT-05. CLINICAL OUTCOMES OF PROTON CRANIOSPINAL IRRADIATION FOR PATIENTS WITH LEPTOMENINGEAL CARCINOMATOSIS
Authors: Ari Wijetunga N , Mohammed Nader , Yamada Yoshiya , Wolden Suzanne , Seidman Andrew , Yu Helena , Kris Mark , Malani Rachna , Pentsova Elena , Boire Adrienne , Yang T Jonathan
Published: December 2020

Leptomeningeal carcinomatosis (LC) is a devastating complication of metastatic tumors. Radiotherapy (RT) is integral to LC treatment, and proton craniospinal irradiation (CSI) may make RT more effective by targeting the entire central nervous system (CNS) compartment. We evaluated outcomes in patients treated with proton CSI for LC. We identified 56 patients treated with proton CSI for LC between 2018 and 2020 at our institution. Data on patient demographics, disease and treatment history, cerebrospinal fluid circulating tumor cells (CSF CTCs), and gene alterations were collected. Kaplan Meier analysis and Cox regression models were used to compare correlates with CNS time to progression (TTP), CNS progression-free survival (PFS) and overall survival (OS). Most patients had non-small cell lung cancer (NSCLC, n=27, 48%) or breast cancer (n=21, 38%). The median age was 58 (30-77), and median KPS was 80 (60-90). The median RT dose was 30Gy (25-36). The median follow-up was 12 months (1-22), with 26 (46%) patients alive at the last follow-up. Of 35 (63%) patients who progressed, 6 (11%) progressed in the CNS, 13 (23%) progressed systemically, and 16 (29%) progressed in both. The median TTP, PFS and OS was 8 months (1-21), 6 months (1-21) and 8 months (1-22), respectively. No difference in PFS (7 vs. 6 months, p=0.6) and OS (8 vs. 7 months, p=0.3) was observed between patients with NSCLC and breast cancer. Of patients alive at 3 months, 79% showed stable or improved functional status after CSI. Decreased CSF CTCs immediately post CSI had significantly improved PFS (8 vs. 5 months with no CTC decrease, HR=0.3, p=0.02). Lastly, we identified genetic correlates with survival outcomes. Proton CSI appears to be a promising treatment for LC in select patients, resulting in prolonged CNS disease control and survival. A randomized trial is currently underway to assess its efficacy prospectively.
RADT-09. TYPE AND TIMING OF SYSTEMIC THERAPY USE PREDICT SURVIVAL IN PATIENTS WITH BRAIN METASTASES TREATED WITH RADIATION THERAPY
Authors: Fan Kevin , Lalani Nafisha , Levasseur Nathalie , Krauze Andra , Gondara Lovedeep , Willemsma Kaylie , Nichol Alan
Published: December 2020

PURPOSE

We aimed to investigate whether systemic therapy (ST) use around the time of brain radiotherapy (RT) predicts overall survival for patients with brain metastases (BM). We also aimed to validate the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) in a population-based cohort.

METHODS

We used provincial RT and pharmacy databases to retrospectively review all adult patients in British Columbia, Canada, who received a first course of RT for BMs between 2012 and 2016. We used a randomly selected subset with complete baseline data to develop a multivariate analysis (MVA)-based nomogram including ST use to predict survival after RT and to validate the DS-GPA.

RESULTS

In our 3095-patient cohort, the median overall survival (OS) of the 999 recipients of ST after RT was 5.0 months (CI 4.1-6.0) longer than the OS of the 2096 non-recipients of ST after RT (p< 0.0001): targeted therapy (HR 0.42, CI 0.37-0.48), hormone therapy (HR 0.45, CI 0.36-0.55) and cytotoxic chemotherapy (HR 0.71, CI 0.64-0.79). The OS of patients who discontinued ST after RT was 0.9 months (CI 0.3-1.4) shorter than the OS of those who did not receive ST before nor after RT (p< 0.0001). A MVA in the 200-patient subset demonstrated that the traditional baseline variables: cancer diagnosis, age, performance status, presence of extracranial disease, and number of BMs predicted survival, as did the novel variables: ST use before RT and ST use after RT. The MVA-based nomogram had a bootstrap-corrected Harrell’s Concordance Index of 0.70. In the 179 patients within this subset with DS-GPA-compatible diagnoses, the DS-GPA overestimated OS by 6.3 months (CI 5.3- 9.8) (p= 0.0006).

CONCLUSIONS

The type and timing of ST use around RT predict survival for patients with BMs. A novel baseline variable “ST planned after RT” should be prospectively collected to validate these findings in other cohorts.
RADT-13. EARLY CONCURRENT IMMUNOTHERAPY WITH STEREOTACTIC RADIOSURGERY IS ASSOCIATED WITH PROLONGED SURVIVAL AND DECREASED DISTANT BRAIN FAILURE IN PATIENTS WITH NEWLY DIAGNOSED MELANOMA BRAIN METASTASES (MBM)
Authors: Augustyn Alexander , Patel Roshal , Ludmir Ethan , Haydu Lauren , Guha-Thakurta Nandita , Bishop Andrew , Chung Caroline , Ghia Amol , McAleer Mary Frances , McGovern Susan , Wang Chenyang , Woodhouse Kristina , Yeboa Debra , Ferguson Sherise , Kim Betty , Glitza Isabella , Li Jing
Published: December 2020

INTRODUCTION

We evaluated outcomes of patients with newly diagnosed MBM treated with concurrent immune checkpoint inhibition (ICI) and stereotactic radiosurgery (SRS) (concurrentTx), defined as treatment delivery within 30 days of each other.

METHODS

Screening of 2,617 melanoma patients who received ICI (anti-CTLA4/anti-PD1/both) between 2011-2019 identified 151 pts who received concurrentTx for MBM. Among these, 51 had newly-diagnosed MBM and received no prior ICI or SRS, and were included in the current study. Overall survival (OS) and distant brain failure (DBF) were estimated using the Kaplan-Meier method. Incidence of radiation necrosis (RN) was captured.

RESULTS

Median follow up from treatment initiation (either ICI or SRS, whichever occurred first) was 37 months. Median OS was 30 months. Median interval between ICI/SRS was 12 days (range: 1-29). Twenty-two patients received ICI first and 29 received SRS first, without differences in OS (p=0.22), DBF (p=0.91), or development of RN (p=0.86). However, the interval between ICI and SRS was significant. Patients who received concurrentTx 1-11 days apart (n=25, “early”) experienced a significant improvement in OS and DBF compared to 12-29 days apart (n=26, “delayed”) (p=0.01, HR 2.8; 95%CI 1.3-6.2 for OS and p=0.02, HR 2.5; 95%CI 1.2-5.6 for DBF). OS and DBF at 36 months were 67% vs. 26% and 60% vs. 27%, respectively, for the early vs. delayed groups. Time to concurrentTx as a continuous variable was significantly associated with DBF (p=0.02), but not OS (p=0.06). Although not significant, more patients developed RN in the early (26.0%) versus delayed (3.8%) group (p=0.07). No additional patient or treatment differences were identified.

CONCLUSIONS

Early concurrentTx was associated with prolonged OS and improved DBF in newly diagnosed MBM patients who did not receive prior CNS-directed therapy. This finding suggests therapeutic synergism related to combined early treatment and should be validated in a prospective clinical trial.
RADT-17. RADIOTHERAPY IN THE MANAGEMENT OF OPTIC NERVE SHEATH MENINGIOMAS: AN INTERNATIONAL SYSTEMATIC REVIEW AND META-ANALYSIS OF EIGHTEEN STUDIES
Authors: Vaishnav Yash J , Singh Raj , Didwania Prabhanjan , Lehrer Eric J , Bakaeva Tatiana , Harris Timothy , Migliori Michael E , Trifiletti Daniel M
Published: December 2020

INTRODUCTION

Optic nerve sheath meningiomas (ONSMs) are often managed with radiotherapy (RT) with the goal of achieving radiographic local control (LC) to prevent further decline in visual acuity (VA); however, reports on outcomes are limited to small retrospective series. Thus, we aimed to perform a systematic review and meta-analysis of outcomes for patients with ONSM treated with RT.

METHODS

A PICOS/PRISMA/MOOSE selection criteria was utilized to identify studies for inclusion. Primary outcomes were stable or improved VA and radiographic LC at last follow-up. The secondary outcome was incidence of radiation-induced retinopathy. Weighted random effects meta-analyses using the DerSimonian and Laird methods were conducted to characterize effect sizes. Mixed effects regression models were used to examine potential correlations between gross tumor volume (GTV) and outcomes.

RESULTS

In total, 381 patients with ONSM across 18 published studies were included. Of these, 332 and 386 treated ONSMs had information on VA or LC, respectively. Median age was 46.75 (range: 9-87), median/mean GTV was 2.905cc (range: 0.28-26.3), and median follow-up was 51.15 months (range: 1-248.4 months). The estimated LC rate at last follow-up was 100% (95% CI: 98-100%), and the estimated proportion of patients with stable or improved VA at last follow-up was 89% (95% CI: 84-93%). The rate of chronic radiation retinopathy was estimated to be 7% (95% CI: 5-11%). GTV was significantly associated with VA (p=0.014) with estimated VA rates of 96.4%, 91.4%, and 80.5% for GTVs of 2.0, 3.0, and 4.0ccs, respectively.

CONCLUSIONS

RT was well-tolerated in the treatment of ONSM with excellent LC achieved. Nearly 90% of patients noted either stability or improvement in VA. Larger ONSMs were found to be associated with poorer VA. Incidences of radiation-induced retinopathy were limited and estimated to be less than 10%.
RADT-23. IMPACT OF REIRRADIATION UTILIZING STEREOTACTIC RADIOSURGERY ON RECURRENT GLIOBLASTOMA
Authors: Patrick O’Dell , Nickols H , LaRocca R , Sinicrope K , Sun D , Spalding A
Published: December 2020

BACKGROUND

Patients who have recurrent glioblastoma have limited treatment options. We conducted a retrospective review of patients with recurrent glioblastoma treated with standard initial radiation and temozolomide with tumor treating fields to investigate whether reirradiation using radiosurgery would be associated with improved outcomes.

METHODS

We reviewed the records of 54 consecutively treated patients with recurrent glioblastoma with ECOG 0 or 1 at recurrence and conducted Kaplan-Meier analysis with Log-rank testing to determine significance between groups.

RESULTS

We identified 24 patients who were treated without radiation therapy (control) while 30 patients underwent re-irradiation using radiosurgery (ReSRS) with a median total dose of 25Gy in five fractions. All patients had completed standard initial therapy, and there was no difference in the time to recurrence between the two groups (10 months for control, 15 months for ReSRS, [P = 0.17, HR for progression 0.65 (95% CI 0.38-1.13)]. A larger proportion of patients in the control arm (54%) had subtotal or gross total resection of the recurrence compared with the ReSRS group (44%, P < 0.05). The majority of patients had recurrence confirmed with biopsy (18/22 in control group, 25/31 in the ReSRS group). MGMT methylation status did not differ between control vs ReSRS (29% vs. 27%). ReSRS was associated with improved median survival from the time of first recurrence of 11.6 months versus 3.8 months in the control arm [P< 0.0001, HR for death 0.33 (95% CI 0.18-0.6)].

CONCLUSIONS

In a group of patients with high performance status diagnosed with recurrent glioblastoma, reirradiation with stereotactic radiosurgery was associated with nearly one year median survival after recurrence. Additional analyses are warranted to determine the impact of concurrent systemic therapies with irradiation and underlying tumor or patient factors to predict outcomes.
RADT-24. HIGH ABSORBED DOSES OF RHENIUM-186 NANOLIPOSOMES (RNL) IN RECURRENT GBM: A PHASE 1 STUDY
Authors: Brenner Andrew , Floyd John , Bao Ande , Phillips William , Awasthi Vibhudutta , Patel Toral , Weinberg Jeffrey
Published: December 2020

INTRODUCTION

While external beam radiation therapy (EBRT) remains a central component of the management of primary brain tumors, it is limited by tolerance of the surrounding normal brain tissue. Nanoliposomal BMEDA-chelated-186Rhenium (RNL™) permits the delivery of beta-emitting radiation of high specific activity with excellent retention in the tumor. We report on the phase 1 results in recurrent glioma.

METHODS

A phase 1 dose-escalation study of RNL in recurrent glioma utilizing a standard 3 + 3 design was undertaken to determine the maximum tolerated dose of RNL following stereotactic biopsy. RNL is administered with the BrainLab Flexible Catheter by convection enhanced delivery (CED) with placement guided using iPlan Flow and the Varioguide system. Infusion is followed under whole body planar imaging and SPECT/CT. Repeat SPECT/CT imaging is performed immediately following, and at 1, 3, 5, and 8 days after RNL infustion to obtain dosimetry and distribution.

RESULTS

Thirteen patients have been treated to-date, 12 were recurrent glioblastoma, and 54% failed treatment with bevacizumab. The infused dose was progressively increased from 1.0 mCi to 13.4 mCi and the volume of infusate from 1.0 mL to 5.28 mL using 1 – 2 CED catheters. The mean absorbed dose to the distribution volume was 175 Gy (CI 97 – 254). The maximum absorbed dose to the tumor volume was 593 Gy. The mean retention of the administered dose at 24 hours was 61.4% (CI 45.4 – 77.5). The therapy has been well tolerated and no dose-limiting toxicity has been observed with no treatment related adverse effects despite markedly higher absorbed doses than EBRT in patients with prior treatment. The plan is to increase the dose to 22.3 mCi and the infusate volume to 8.8 mL.

CONCLUSION

Intratumoral RNL can deliver up to twenty times the absorbed dose of radiation administered by EBRT without significant toxicity.
RADT-25. EVALUATING LYMPHOCYTE COUNTS IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS RECEIVING CHEMORADIATION
Authors: Hammoudeh Lubna , Lim-Fat Mary Jane , Cagney Daniel , Aizer Ayal A , Tanguturi Shyam , Arvold Nils , Mcfaline-Figueroa Jose , Chukwueke Ugonma , Reardon David , Lee Eudocia , Nayak Lakshmi , Rinne Mikael , Ligon Keith , Wen Patrick , Alexander Brian , Rahman Rifaquat
Published: December 2020

BACKGROUND

Glioblastoma (GBM) patients are treated with chemotherapy, radiation therapy (RT) and often corticosteroids, which can all contribute to lymphopenia. We examined lymphopenia with respect to incidence, predictors, and association with progression-free survival (PFS) and overall survival (OS).

METHODS

We reviewed 349 newly diagnosed adult GBM patients treated at our institution in the temozolomide (TMZ) era with available lymphocyte and RT records. Data was reviewed from diagnosis through the chemoradiation (CRT) phase, defined as the period upto 6 weeks after RT. Linear regression and Cox proportional hazards modeling were used to evaluate outcomes.

RESULTS

Median age was 60 years (range, 19-90); 86% had KPS ≥ 70, 30% had gross total resection (GTR), and 91% received TMZ. Prior to RT, 60% (205/341) patients had a lymphocyte measurement < 1.0 x 1000 cells [K]/μL and 15% (50/341) had < 0.5 K/μL. During the CRT phase of therapy, 83% (270/324) had at least one lymphocyte measurement < 1.0 K/μL, 42% (135/324) < 0.5 K/μL, and 5% (16/324) < 0.2 K/μL. Older age was associated with lower lymphocytes pre-RT, while subtotal resection, TMZ use, and RT dose was associated with lower lymphocyte counts during CRT (p< 0.05). On multivariable analysis (MVA), age (AHR 1.03, p< 0.01), KPS > 70 (AHR 0.35, p< 0.01), MGMT status (AHR 0.47, p< 0.01), GTR (AHR 0.67, p=0.03), TMZ (AHR 0.27, p< 0.01) and lymphopenia during CRT (AHR 1.80, p< 0.01) were significantly associated with OS. Pre-RT lymphocyte level was associated with PFS on UVA (HR 0.81, p=0.03) but not on MVA (p=0.27). Lymphocyte count during CRT was not associated with PFS (p=0.24).

CONCLUSION

Lymphopenia is common in GBM, and chemoradiation-related lymphopenia was associated with inferior OS relative to patients without lymphopenia. Further characterization of the mechanism and optimal treatment of patients with lymphopenia are warranted to improve outcomes.
RADT-38. ADJUVANT RADIOTHERAPY FOR INTRACRANIAL ATYPICAL AND MALIGNANT MENINGIOMAS IN ADULT PATIENTS
Authors: Unterberger Ansley , Kondajji Aditya , Kulinich Daniel , Duong Courtney , Yang Isaac
Published: December 2020

BACKGROUND

Meningiomas, the most common primary brain tumor, account for more than one third of all primary CNS tumors. High-grade meningiomas, WHO grade II and III, comprise between 16%-24% of total meningiomas and are more aggressive, recur more frequently, and portend a worse prognosis than WHO grade I meningiomas. Adjuvant radiation of high-grade meningiomas, while not uncommon, remains variably described in current literature. To assess our institution’s radiation protocol, we examined our cohort of over 200 high-grade meningiomas.

METHODS

We queried our hospital’s EHR system for surgically resected meningiomas from January 2013 to December 2019. Of 286 results identified, 24 patients met the inclusion criteria: 1) histologically confirmed WHO grade II or III meningioma, 2) primary resection coupled with adjuvant radiation therapy, and 3) no chemotherapy. Only one WHO grade III meningioma met inclusion criteria. Patients with NF2 were excluded. Patient demographics, radiation dosage, fraction number, and dates of surgery, radiation onset, recurrence, and most recent follow-up were recorded.

RESULTS

Median age at surgery was 56.2 years (± 11.1, range 37.8 – 81.7), and males comprised 70.8% (n = 17) of the population. Only FSRT or IMRT were employed. The most frequent dosage was 55.8 Gy across 31 fractions with a median time to radiation of 2.7 months (± 3.0, range 1.0 – 12.6). 5 out of 24 patients experienced recurrence, which did not include the WHO III tumor. Median time to recurrence was 3.0 years (± 2.0, range .3 – 5.8). Median follow up was 3.5 years (± 2.2, range .3 – 9.3).

CONCLUSIONS

A fraction of our population experienced recurrence, regardless of grade II or grade III pathology. FSRT remains a safe and effective adjuvant therapy for high-grade meningioma after surgical resection. Future prospective studies comparing differing radiation modalities should be conducted.
RTID-04. A RANDOMIZED PHASE II TRIAL TO COMPARE THE EFFICACY OF STANDARD VERSUS COMBINATION THERAPY (PERAMPANEL, MEMANTINE PLUS STANDARD) IN THE TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED GBM-A STUDY DESIGN
Authors: Kong Xiao-Tang , Albala Bruce , Du Senxi , Kong Xiao-Tang , Bota Daniela
Published: December 2020

BACKGROUND

Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults with poor prognosis. Effective treatment is urgently needed. Recent studies demonstrated neurogliomal synaptic communication through AMPA and NMDA receptors promotes glioma invasion and progression in vitro and in vivo. Therefore, dual blocking AMPA and NMDA receptor therapy is a potential enhancing strategy to prevent and to treat GBM progression given the two blockers act through different anti-glioma mechanisms.

OBJECTIVE/HYPOTHESIS

We hypothesize that adding AMPA blocker Perampanel (An anti-seizure medication) and NMDA blocker Memantine (An anti-dementia medication) to standard temozolomide plus radiation therapy (Stupp’s regimen) for the treatment of newly diagnosed GBM may prevent tumor progression. It may also reduce the frequency of onset/recurrence of seizure episodes and possibly improve radiation related cognition impairment.

STUDY DESIGN

This is a randomized, active controlled, open label, two arm phase II study of efficacy of treatment of GBM with combination therapy (dual AMPA and NMDA receptor blockers plus standard therapy) versus standard therapy. In the combination therapy arm, patients take Perampanel 2 mg daily and Memantine 5 mg bid, starting from -14 days to +14 days from initiation of concurrent chemo-radiation therapy. Titrating up at a 2 mg increment for Perampanel and 5 mg bid increment for Memantine until reaching MTD. If the patient has AE >= grade 2, then reduce doses at a decrement of 2 mg for Perampanel and decrement of 5 mg bid for Memantine. In the standard therapy arm, the patients are treated with Stupp’s regimen.

PRIMARY AND SECONDARY ENDPOINTS

PFS, 12, 24 month survival rates and response duration. Safety will be assessed by CTCAE V5. We will use Kaplan-Meier estimates for survival data and a stratified log-rank test for the randomization strata.
RTID-05. INDIGO: A GLOBAL, RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF VORASIDENIB (AG-881) VS PLACEBO IN PATIENTS WITH RESIDUAL/RECURRENT GRADE II GLIOMA WITH AN ISOCITRATE DEHYDROGENASE 1/2 (IDH1/2) MUTATION
Authors: Mellinghoff Ingo , van den Bent Martin , Clarke Jennifer , Maher Elizabeth , Peters Katherine , Touat Mehdi , de Groot John , De La Fuente Macarena , Arrillaga-Romany Isabel , Wick Wolfgang , Ellingson Benjamin , Schoenfeld Steven , Liu Hua , Le Kha , Lu Min , Steelman Lori , Hassan Islam , Pandya Shuchi , Wen Patrick , Cloughesy Timothy
Published: December 2020

BACKGROUND

Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options are surgery followed by observation (“watch and wait”) for patients with lower risk for disease progression or postoperative chemoradiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (mIDH1/2) occur in approximately 80% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate. Vorasidenib, an oral, potent, reversible, brain-penetrant pan-inhibitor of mIDH1/2, was evaluated in 76 patients with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at daily doses below 100 mg. Preliminary clinical activity was observed in non-enhancing glioma patients in both studies, with an objective response rate (ORR) of 18.2% and median progression-free survival of 31.4 months in the dose escalation study.

METHODS

Approximately 366 patients will be randomized 1:1 to vorasidenib (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria: age ≥ 12 years; grade II oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed mIDH1/2 status; ≥ 1 surgery for glioma with most recent ≥ 1 year but ≤ 5 years before randomization, and no other anticancer therapy; Karnofsky performance status ≥ 80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the vorasidenib arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint: progression-free survival assessed by independent review. Secondary endpoints: safety and tolerability, tumor growth rate assessed by volume, ORR, overall survival, and quality of life. Clinical data will be reviewed regularly by an independent data monitoring committee. The study is currently enrolling patients in the US, with additional countries planned (NCT04164901).
RTID-08. A PHASE 1/2 STUDY OF SELINEXOR IN COMBINATION WITH STANDARD OF CARE THERAPY FOR NEWLY DIAGNOSED OR RECURRENT GLIOBLASTOMA (ndGBM OR rGBM)
Authors: Wen Patrick , Odia Yazmin , Mehta Minesh , Goldlust Samuel , Tamir Sharon , Shacham Sharon , Wang Hongwei , Sheehan Heidi , Li Kai
Published: December 2020

BACKGROUND

GBM is the most common and most aggressive primary brain tumor with poor prognosis and median overall survival (mOS) of patients with ndGBM and rGBM being 15 vs 5-7 months, respectively. Selinexor is a first-in class, oral, selective nuclear export inhibitor which forces nuclear retention and reactivation of many tumor suppressor proteins. Selinexor with low dose dexamethasone was recently approved for patients with triple-class refractory multiple myeloma. Additionally, selinexor monotherapy has demonstrated broad activity in other hematologic and solid malignancies. In a Phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. Preclinical GBM studies showed synergy when combining selinexor with radiation, temozolomide and lomustine.

METHOD

This is a phase 1 (PH-1) dose finding study followed by a 1:1 randomized phase 2 (PH-2; n= 350) efficacy exploration trial to independently evaluate 3 different combination regimens: Arm A: radiation +/- selinexor in uMGMT ndGBM; Arm B: radiation and temozolomide +/- selinexor in MGMT ndGBM; Arm C:omustine +/- selinexor in first relapse rGBM following frontline radiation and temozolomide. The PH-1 primary endpoint is MTD/RP2D, with secondary endpoints of ORR per modified RANO, duration of response (DOR), PFS, and OS. The PH-2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS6, ORR, DOR. For Arm C, the PH-2 primary endpoint is OS while key secondary endpoints are PFS, PFS6, ORR, DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy for arms A & B, and 80% power to detect a hazard ratio of 0.70 for arm C. We are currently enrolling patients nationwide. Clinical trial identifier: NCT04421378
STEM-14. GLIOBLASTOMA STEM CELL TARGETING CHIMERIC ANTIGEN RECEPTOR T CELLS MODIFIED USING PHAGE DISPLAY ISOLATED PEPTIDES
Authors: Potez Marine , Snedal Sebastian , Kim Jongmyung , Thorner Konrad , Ramello Maria Cecilia , Abate-Daga Daniel , Liu James
Published: December 2020

Glioblastoma (GBM) is the most aggressive primary brain tumor with high mortality rates and resistance to conventional therapy. Their resistance to conventional therapy has been attributed to the presence of cancer stem cells (CSCs), a sub-population of tumor cells capable of self-renewal and tumor initiation. Developing novel strategies to specifically target GSCs may allow more effective therapeutic strategies. Using in vivo phage display biopanning, we have identified several peptides with the potential to selectively target and bind GSCs. We wished to leverage the GSC targeting properties of the peptides to augment therapeutic delivery vehicles for the development of novel targeting strategies. We used a combination of GSC targeting peptides to modify the antigen-binding domain of chimeric antigen receptors, by arranging the peptides in tandem at the N-terminus of the CAR molecule. These tandem peptides were tested for binding to GSCs in vitro and in vivo. The functionality of the CAR-T cells was evaluated by measuring cytokine release in the supernatant after overnight co-culture through ELISA. Apoptosis was evaluated by flow cytometry with Annexin V staining. Two different GSC-targeting peptide CAR-T cells demonstrated specific targeting GSCs. Following co-culture with GSCs, GSC targeting CAR-T cells were activated with release of Interferon gamma and subsequently induced GSCs specific apoptosis. These results demonstrate the use of phage display biopanning to isolate GSC targeting peptides which may be used to develop novel GBM specific cytotoxic therapies.