bluuebunny/crossref_metadata_2025_split 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

Abstract

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&lt; 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

Abstract

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 (&gt;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

Abstract

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 &gt;T) and G34R (HIST1H3B c.103G &gt;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

Abstract
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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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&lt; 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

Abstract
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.