bluuebunny/crossref_metadata_2025 huggingface dataset:
NIMG-67. DISAPPEARING DOTS – TRANSIENT LATE ENHANCING LESIONS YEARS AFTER BRAIN RADIOTHERAPY
Authors: Pan Peter , Padilla Oscar , Buss Elizabeth , Elliston Carl , Wang Tony , Joanta-Gomez Adela , Lignelli-Dipple Angela , Iwamoto Fabio , Kreisl Teri , Welch Mary , Haggiagi Aya , Donovan Laura , Barbaro Marissa , Bruce Jeffrey , Canoll Peter , Lassman Andrew
Published: December 2020

BACKGROUND

Late-delayed radiation effects appear 6 months to years following radiotherapy. We characterize a species of small enhancing lesions in the late-delayed phase of post-radiotherapy that are distinct from the classic descriptions of radiation necrosis or pseudoprogression associated with mass effect and edema. These “disappearing dots” are small, do not exert mass effect nor edema, and spontaneously resolve.

METHOD

We retrospectively describe a series of cases with “disappearing dots” following brain radiotherapy.

RESULTS

There were 10 cases (4 men), median age 42 years (range 29-63). Diagnoses were glioblastoma (3); low grade astrocytoma, anaplastic astrocytoma, and anaplastic oligodendroglioma (2 each); and solitary fibrous tumor (1). All patients received 54-60 Gy (Gray) of external beam radiotherapy, except one (proton beam therapy to 60 cobalt Gray equivalent). Disappearing dots appeared at a median of 27 months (range 5-197) post-radiotherapy. Lesions were relatively small (~< 1 cm3), peri-ventricular, and within the radiotherapy field. Most enlarged before resolving. Advanced MR imaging and fluorodeoxyglucose (FGD)-PET results were inconsistent. Lesions persisted a median of 8.5 months (range 1-49) before spontaneous resolution. All were asymptomatic. Biopsy in one case revealed treatment effects rather than recurrent tumor.

CONCLUSIONS

Asymptomatic small periventricular enhancing lesions can develop and remit spontaneously, years following brain radiotherapy. Such disappearing dots should be part of the differential diagnosis along with tumor recurrence. of new enhancing lesions in the late-delayed phase post-radiotherapy.
PATH-08. EVALUATION OF MISMATCH REPAIR GENE EXPRESSION BY IMMUNOHISTOCHEMISTRY MAY DETECT EARLY PHASE OF MMR DEFICIENCY IN RECURRENT GLIOMAS
Authors: Higuchi Fumi , Matsuda Hadzki , Uzuka Takeo , Kim Phyo , Ueki Keisuke
Published: December 2020

BACKGROUND

Mismatch Repair (MMR) Deficiency is common in recurrent gliomas from IDH-mutant and IDH-wild-type tumors. Emergence of MMR deficit is strongly associated with the chemotherapy using TMZ, and it is considered to be a key mechanism of acquiring resistance to TMZ. Several studies showed MMR protein loss detected by immunohistochemistry was well concordant with molecular genetics sequencing data, and sometimes even more reliable in detecting MMR functional deficit. Here we evaluated Mismatch Repair protein expression by immunohistrochemistry for the pairs of primary and recurrent gliomas.

METHODS

We investigated the expression of 4 MMR proteins (MLH1/MSH2/MSH6/PMS2) in 37 cases of paired primary-recurrent gliomas (7 grade II & III astrocytomas, 16 grade II & III oligodendrogliomas, and 14 glioblastomas). Clinical information including history of chemo-radiotherapy after primary surgery were collected retrospectively.

RESULTS

Except for one case of GBM, all primary tumors retained 4 MMR proteins. 10 of 37 recurrent tumors lost one or more MMR protein expression (4 GBM 3 astrocytoma, 3 oligodendroglioma), including one case in which primary tumor already had MSH2/MSH6 loss. 2 recurrent GBM lost MMR protein expression homogenously, while in other 8 tumors, the patterns of MMR protein loss were heterogenous. 8 of 10 tumors that lost MMR protein expression were recurrence after TMZ treatment.

CONCLUSION

Although the interpretation of the heterogenous loss of MMR protein expression is somewhat difficult, the immunohistochemical evaluation of MMR proteins appears to be feasible, and may be able to detect early phase of MMR deficiency and the rise of hypermutator phenotype.
PATH-11. PROGNOSTIC SIGNIFICANCE OF EPIGENETIC SUBTYPES AND CpGs ASSOCIATED WITH PROGRESSION TO G-CIMP LOW IN THE EORTC RANDOMIZED PHASE III INTERGROUP CATNON
Authors: Tesileanu C Mircea S , van den Bent Martin , Sabedot Thais , Sanson Marc , Brandes Alba , Wick Wolfgang , Clement Paul , Erridge Sarah , Vogelbaum Michael , Nowak Anna , Baurain Jean , Mason Warren , Wheeler Helen , Weller Michael , de Heer Iris , Dubbink Hendrikus , Kros Johan M , Aldape Kenneth , Wesseling Pieter , Golfinopoulos Vassilis , Gorlia Thierry , Baumert Brigitta , Noushmehr Houtan , French Pim
Published: December 2020

BACKGROUND

Uncontrolled studies have suggested that methylation-based epigenetic subtypes can be used for prognostication of glioma. We used the prospective randomized CATNON trial to validate the clinical relevance of these epigenetic subtypes.

METHODS

The phase III CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant TMZ. CNV data and methylation data were derived from Infinium MethylationEPIC arrays. Epigenetic subtyping and risk of progression to G-CIMP low were determined from random forest models and 7 specific CpGs (PMID: 29642018). IDH1/2 status was determined with a glioma-tailored NGS panel. Overall survival (OS) was measured from date of randomization.

RESULTS

Methylation analysis was performed on 654 tumors: 440 were IDH1/2mt, 204 IDH1/2wt and of 10 IDH1/2 status was unknown; 8 IDH1/2mt were 1p/19q codeleted. Based on methylation, tumors were classified as G-CIMP high (n=409), G-CIMP low (n=19), codel-like (n=18), mesenchymal-like (n=107), classic-like (n=48), and PA-like tumors (n=53). Median OS between these epigenetic subtypes varied considerably: codel-like 9.1 yrs, G-CIMP high 9.5 yrs, G-CIMP low 2.8 yrs, mesenchymal-like 1.3 yrs, classic-like 1.6 yrs, and PA-like 2.8 yrs. The difference in OS of the IDH1/2mt astrocytoma subgroup patients was prominent [G-CIMP low vs G-CIMP high: HR 4.12, 95% CI 2.37-7.19, p < 0.001]. Within the IDH1/2mt G-CIMP high astrocytoma patients, 115 tumors were predicted to have risk of progression to G-CIMP low and patients with such tumors indeed had poorer survival [risk vs no-risk: HR 1.59, 95% CI 1.10-2.31, p = 0.02]. Median OS in G-CIMP high tumors with (n=37) and without (n=366) CDKN2A/B HD was 3.3 yrs versus not reached [p< 0.001], in G-CIMP low tumors it was 1.2 yrs (n=6) versus 4.4 yrs (n=12) [p=0.008].

CONCLUSIONS

In IDH1/2mt anaplastic astrocytoma, G-CIMP status and CDKN2A/B HD are of independent prognostic value.
PATH-13. CHARACTERIZING TEMPORAL GENOMIC HETEROGENEITY IN PEDIATRIC LOW-GRADE GLIOMAS
Authors: Lazow Margot , Schafer Austin , Hoffman Lindsey , Osorio Diana , Boué Daniel , Rush Sarah , Wright Erin , Lane Adam , DeWire Mariko , Smolarek Teresa , Sipple Jared , Taggert Heather , Reuss Jaime , Salloum Ralph , Hummel Trent , de Blank Peter , Pillay-Smiley Natasha , Sutton Mary , Asher Anthony , Stevenson Charles , Drissi Rachid , Finlay Jonathan , Fouladi Maryam , Fuller Christine
Published: December 2020

BACKGROUND

Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence.

METHODS

Fluorescence in situ hybridization, mutation-specific immunohistochemistry, exome analyses, and/or targeted sequencing were performed on paired tumor samples from diagnostic and subsequent surgeries.

RESULTS

Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status occurred in 10 patients (40%), with acquisition of CDKN2A deletion in seven (including three who received chemotherapy [two with temozolomide] and one who received radiation) and loss in three (including one who received targeted therapy and radiation). A trend toward shorter time to progression was observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration (median: 5.5 versus 14.0 months [p=0.078]).

CONCLUSIONS

Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.
PATH-14. FHL1 INTERACTS WITH SP1 TO REGULATE EGFR EXPRESSION IN GLIOBLASTOMA
Authors: Sun Lili , Li Ming
Published: December 2020

The four and a half LIM domain 1 (FHL1) has been considered as a tumor suppressor protein in multiple cancers. Here, we show that FHL1 plays a tumor-promoting role in glioblastoma, the most common and incurable brain cancer. Overexpression of FHL1 promotes the growth, migration, and invasion of GBM cells in vivo and in vitro. In contrast, FHL1 silencing exhibits the opposite effects. Mechanically, FHL1 upregulates EGFR expression and activates the downstream AKT / ERK1 / 2 / STAT3 signaling pathways. We further demonstrated that SP1 can also be induced by FHL1 expression, and FHL1 interacts with SP1 to upregulate EGFR expression at both mRNA and protein levels, leading to glioblastoma malignancy. Clinically, FHL1 is highly expressed in glioblastoma and shows positive correlation with EGFR and SP1 in GBM specimens. Our results suggest the key role of FHL1 in the expression of EGFR and highlight the translation potential of inhibiting FHL1 as a treatment for glioblastoma.
PATH-23. GENOMIC LANDSCAPE OF IDH-MUTANT PRIMARY GLIOBLASTOMAS SHOWS DISTINCT CLINICAL AND MOLECULAR FEATURES AND THAT CDKN2A SHOULD BE SUPPLEMENTED WITH MGMTp AND G-CIMP FOR PRECISE PROGNOSTICATION
Authors: Wong Queenie Hoi-Wing , Wong Gabriel Chun-Hei , Chan Aden Ka-Yin , Poon Wai Sang , Chan Danny Tat-Ming , Chen Hong , Zhang Zhen-yu , Noushmehr Houtan , Jones Chris , Grabovska Yura , Mackay Alan , Chow Chit , Kwan Johnny Sheung Him , Chung Nellie Yuk-Fei , Huang Queenie Junqi , Poon Manix Fung-Man , Shi Zhi-feng , Li Kay Ka-Wai , Ng Ho-Keung
Published: December 2020

There have only been rare studies of IDH-mutant primary glioblastomas (IDH-mutant astrocytoma IV); there were one or two studies on secondary glioblastomas. In a cohort of 70 cases, we conducted clinical analysis, methylation profiling, RNA sequencing, targeted sequencing, and TERTp seqeuncing on available FFPE tissues. Median follow-up was 58.2 months (n= 60). IDH-mutant primary glioblastomas had longer median OS (30.4 months) and median PFS (25.9 months) than IDH-mutant secondary glioblastomas as in the literature or established databases. MGMTp methylated cases had better OS (p= 0.001) and it was an independent prognosticator. We previously showed G-CIMP to be an independent prognostic marker for IDH-mutant glioblastomas (NOA 2019). Although CDKN2A deletion was an independent prognostic marker for poorer OS (p= 0.036) and PFS (p= 0.005), MGMTp methylation had a trend of superseding CDKN2A deletion (p= 0.055) for prognostication and G-CIMP subgroups could similarly partially supersede CDKN2A deletion (p= 0.582). Hence, CDKN2A deletion should be supplemented with these two biomarkers for finer prognostication. Targeted sequencing (n= 55) showed that there were more ATRX (35/55, 64%), TP53 (31/55, 56%), KMT2D (18/55, 33%), POLE (11/55, 20%) and MSH6 (7/55, 13%) mutations, but fewer TERTp (3/69, 4%) and PTEN (1/55, 2%) mutations than IDH-wildtype glioblastomas as from literature and databases. CNVs revealed by methylomes (n= 53) and mutations (n= 55) showed that there were more PDGFRA (amplification: 9/53, 17%, mutation: 10/55, 18%) alterations, but fewer MET (amplification: 3/53, 6%, mutation: 4/55, 7%) alterations and hypermutated (6/55, 11%) cases than IDH-mutant secondary glioblastomas from literature. GISTIC analysis revealed amplifications of CCND2, CDK4, MYC, and PDGFRA, deletions of CDKN2A, RB1, and chromosome 10q to be significant CNVs (q< 0.05). There were few EGFR amplifications (2/53, 4%), which was different from regular glioblastomas. RNA sequencing (n= 42) showed few fusions (4/42, 10%), which was different from IDH-mutant secondary glioblastomas.
PATH-26. INTEGRATED MOLECULAR AND CLINICAL ANALYSIS OF BRAF-MUTATED GLIOMA IN ADULTS
Authors: Schreck Karisa , Langat Pinky , Li Taibo , Bi Wenya Linda
Published: December 2020

INTRODUCTION

BRAF mutations in glioma have been recognized as a significant driver of disease in pediatric low-grade glioma, but the implications of BRAF alterations on disease trajectory and response to treatment are unknown in adult glioma. Here, we characterize a multi-institutional cohort of adults with BRAF-altered glioma.

METHODS

We identified patients aged ≥ 18 years with glioma containing BRAF alteration on sequencing in multi-institutional cohorts (Dana-Farber/Brigham Cancer Center, Johns Hopkins Hospital, GENIE, TCGA). BRAF mutations were grouped into three previously-defined classes: I (RAS-independent/dimerization-independent), II (RAS-independent/dimerization-dependent), III (RAS-dependent/dimerization-dependent).

RESULTS

We identified 198 adults with BRAF-altered glioma (median age 42 years, range 18-85 years), including 17 WHO grade I, 33 grade II, 26 grade III, 114 grade IV, and 8 others. Glioblastoma (n=115) predominated, followed by grade II-III astrocytoma (n=31), pleomorphic xanthoastrocytoma (n=18), pilocytic astrocytoma (n=12), oligodendroglioma (n=7), or other glioma (n=15). Class I mutations (BRAFV600E) comprised 49% (n=97), class II mutations 4.5% (n=9) and class III mutations 4.5% (n=9). Rearrangements occurred in 9.6% (n=19), of which canonical fusions comprised 4% (n=8), occurring primarily in pilocytic astrocytomas; copy number gains affected 13% (n=26), and other alterations 19% (n=38). All pleomorphic xanthoastrocytomas and 43.5% of glioblastoma harbored BRAFV600E. Mutation of NF1, an inhibitor of RAS/ERK signaling, was significantly associated with class II/III BRAF mutations (64.3%) and not observed in BRAFV600E-altered glioma (0%, n=62; p< 0.0001). BRAFV600E was the sole alteration in a subset of glioma with class I mutations, while others harbored multiple genomic alterations. Among 45 patients with glioblastoma and detailed clinicopathologic data, 7 received RAF-targeted therapy, with variable clinical response. Overall survival was 26 months with BRAFV600E, 21 months with class II/III mutation, and 33 months with other BRAF-alteration.

CONCLUSIONS

This large cohort of BRAF-altered adult glioma demonstrates a broad range of alterations, with implications for treatment sensitivity and patient survival.
PATH-29. COMPARATIVE ANALYSIS OF DNA METHYLATION PROFILES ASSOCIATED WITH IDH-WILDTYPE GLIOMA AND GLIONEURONAL TUMOR SUBTYPES
Authors: Singh Omkar , Aldape Kenneth
Published: December 2020

DNA Methylation profiles are highly robust and reproducible as a classification tool. Less is understood regarding the methylation differences that exist among gliomas and glioneuronal tumors. To address this, we analyzed differentially methylated probes (DMPs) of gliomas and glioneuronal tumors compared to normal brain white matter controls. After filtering (Δbeta >0.3, logFC >±1) of significant probes we observed that low grade glioma/glioneuronal tumors (LGGs) had significantly fewer DMPs (Hyper/Hypo) as compared to GBMs. For example, posterior fossa pilocytic astrocytomas (PA’s) showed 2861 DMPs (1916 hypo/945 hyper) versus 9653 for GBM-RTKI ((6563/3090) respectively, while tumors such as PXA and anaplastic PA showed intermediate changes between LGG’s and GBMs. Hypomethylated and hypermethylated probes were analyzed for gene ontology and KEGG pathway enrichment, with LGG subtypes showing hypomethylated probes/genes associated with cell adhesion, blood vessel development and viral infection (P-value = 10-7). In contrast, hypomethylated probes in GBM subtypes were enriched for plasma membrane and cell periphery gene ontologies (P-value = 10-52). With respect to hypermethylated probes, LGG subtypes showed enrichment for myelination, glial cell differentiation and sphingolipid metabolism (P-value = 10-5) while DNA-binding transcription factor activity was seen in GBM subtypes (P-value=10-35). Examples of the most significantly hypermethylated genes in GBM included the transcription factors, GATA3 and PAX9. Intermediate-grade gliomas such as anaplastic PA and PXA showed enrichment of hypermethylated genes similar to GBM, but of lower significance (P-values = 10-6 and 10-4). Overall, understanding of cancer-associated DNA methylation changes in glioma subtypes suggests a hierarchy of biological changes that may underlie the pathogenesis of these tumors and interestingly, highlight tumor types such as PXA and anaplastic PA as having intermediate methylation changes, between benign LGG and GBM. Hypermethylation of transcription-factor genes will be investigated in GBM and compared with changes in gene expression to understand possible roles in the pathogenesis.
PATH-35. A SCALABLE MOLECULARLY INTEGRATED CLASSIFIER FOR MENINGIOMA OUTPERFORMS WHO CLASSIFICATION
Authors: Linda Bi Wenya , Driver Joseph , Tavakol Sherwin , Hoffman Samantha , Woodward Eleanor , Abedalthagafi Malak , Al-Mefty Ossama , Ligon Keith , Beroukhim Rameen , Ligon Azra , Dubuc Adrian , Dunn Ian , Santagata Sandro
Published: December 2020

The clinical behavior of meningiomas often belies their histopathologic grade. Increasing data suggest that molecular features augment classic World Health Organization (WHO) classification in predicting recurrent risk. We investigated the influence of histopathology, chromosome copy number, and treatment on meningioma outcome to construct a simple, scalable, molecularly integrated classifier. METHODS: We analyzed 684 meningiomas with genome-wide chromosomal copy-number profiling for clinical features, pre-/post-operative tumor volume, histopathology, and recurrence. We devised a point-based molecularly-integrated classification system (IC 1-3), incorporating mitotic count and nine common molecular alterations consistently associated with risk of recurrence across four independent statistical tests. We used brier curves, time-dependent area-under-the-curve, and average precision to assess model performance. We added treatment variables, including primary or recurrent status, tumor size, and extent of resection, to the Integrated class to formulate a nomogram of recurrence risk at 5 years. RESULTS: The Integrated Class significantly associated with recurrence in a multivariate model (IC Class 2 vs 1: HR 3.60, 95% CI 2.19-5.91; Class 3 vs 1: HR 5.15, 95% CI 3.28-8.09) and outperformed WHO grade in predicting recurrence (by integrated brier score, 0.093 vs 0.178, internally and independently validated). WHO Grade I and IC-1 exhibited 86% concordance, 31.5% between Grade II and IC-2, and 64% between Grade III and IC-3. WHO grade I meningiomas with IC 2-3 fared significantly worse than WHO grade II-III meningiomas with IC-1 designation. Each additional molecular feature incrementally strengthens the classifier, allowing for application of single-arm FISH or combinatorial genome-wide signatures based on available resources. Intriguingly, receipt of adjuvant radiation in newly diagnosed WHO Grade II-III or IC 2-3 meningiomas was associated with greater propensity for recurrence, after controlling for extent of resection. CONCLUSION: We present a scalable, molecularly-integrated classification for meningioma that better predicts recurrence compared to classic histopathologic grades to aid in clinical management.
PATH-36. SYNCHRONOUS TTF-1-POSITIVE TUMORS AND PITUITARY ADENOMAS. ARE WE SENDING INSUFFICIENT TUMOR TISSUE FOR PATHOLOGY?
Authors: Rubino Franco , Eichberg Daniel , shah Ashish , Luther Evan , Lu Victor , Saad Ali , Komotar Ricardo , Ivan Michael
Published: December 2020

BACKGROUND

Tumors of the posterior pituitary are a distinct group of low-grade neoplasms arising from the sellar region. According to the most recent World Health Organization (WHO) guidelines, these tumors are grouped based on TTF-1 immunostain positivity. The coexistence of a posterior and anterior pituitary tumors is statistically extremely unlikely.

OBJECTIVE

In this study, we present a case of a 41-year-old woman suffering from Cushing syndrome with the presence of two pituitary masses on MRI. Also, the relevant literature is systematically reviewed.

METHODS

Two databases (PubMed and Google Scholar) and crossed references were systematically reviewed for TTF-1 pituitary tumors with coexisting pituitary adenoma or increased pituitary serum hormone levels. A literature review was performed according to PRISMA guidelines. Also, one patient from our institution is reported. Data regarding demographic features, type of anterior and posterior pituitary tumor, clinical features of the patients and lab results, MRI findings, and pathology results were extracted.

RESULTS

Seventeen retrospective case reports and case series were identified and included. Twenty-four patients were analyzed (including the reported case). The mean age was 46 ± 16 years, with a male-to-female ratio of 0.33:1. Pituicytomas and granular cell tumors were the only posterior pituitary tumors reported in 19 (79%) and 5 (21%) cases, respectively. There are only eight cases reported (including our patient) with a confirmed pituitary adenoma and a TTF-1 pituitary tumor (one GCT with GH-secreting adenoma, five pituicytoma with ACTH-secreting adenoma, one with GH-secreting adenoma and one with a null type adenoma).

CONCLUSION

We presented the eighth reported case of a TTF-1 pituitary tumor coexisting with a pituitary adenoma. We think that improving the amount of the tissue specimen available for pathology evaluation could increase the incidence of these very rare tumors.
PATH-37. IDENTIFYING HIGH-RISK PATIENTS FOR WHO GRADE I MENINGIOMA RECURRENCE USING HISTOPATHOLOGICAL FEATURES AND THE MIB-1 INDEX
Authors: Haddad Alexander , Young Jacob , Kanungo Ishan , Sudhir Sweta , Chen Jia-Shu , Raleigh David , Magill Stephen , McDermott Michael , Aghi Manish
Published: December 2020

BACKGROUND

In this study, we identify clinical, radiographic, and histopathologic prognosticators of overall, early, and post-median recurrence in World Health Organization (WHO) grade I meningiomas. We also determine a clinically relevant cutoff for MIB-1 to identify patients at high risk for recurrence.

METHODS

A retrospective review of WHO grade I meningioma patients with available MIB-1 index data who underwent treatment at our institution from 2007-2017 was performed. Univariate and multivariate analyses, and recursive partitioning analysis (RPA), were used to identify risk factors for overall, early (within 24 months), and post-median (greater than 24 months post-treatment) recurrence.

RESULTS

A total of 239 patients were included. The mean age was 60.0 years, and 69.5% of patients were female. The average follow-up was 41.1 months. All patients received surgery and 2 patients each received either adjuvant radiotherapy or gamma knife treatment. The incidence of recurrence was 10.9%, with an average time to recurrence of 33.2 months (6-105 months). Posterior fossa tumor location (p=0.004), MIB-1 staining (p=0.008), nuclear atypia (p=0.003), and STR (p< 0.001) were independently associated with an increased risk of recurrence on cox-regression analysis. RPA for overall recurrence highlighted extent of resection, and after gross total resection (GTR), a MIB-1 index cutoff of 4.5% as key prognostic factors for recurrence. Patients with a GTR and MIB-1 >4.5% had a similar incidence of recurrence as those with STR (18.8vs.18.6%). Variables independently associated with early recurrence on binary logistic regression modeling included STR (p=0.002) and nuclear atypia (p=0.019). RPA confirmed STR as associated with early recurrence. MIB-1 index (p=0.010) was identified as an independent predictor of post-median recurrence using similar methods.

CONCLUSIONS

STR, posterior fossa location, nuclear atypia, and elevated MIB-1 index are prognostic factors for WHO grade I meningioma recurrence. Moreover, MIB-1 index >4.5% is prognostic for recurrence in patients with GTR.
PATH-39. ASSOCIATIONS OF GENOMIC SUBGROUP WITH RECURRENCE IN LOW-GRADE MENINGIOMAS
Authors: Youngblood Mark , Miyagishima Danielle , Jin Lan , Gupte Trisha , Li Chang , Duran Daniel , Montejo Julio , Zhao Amy , Sheth Amar , Tyrtova Evgeniya , Özduman Koray , Iacoangeli Francesco , Peyre Matthieu , Boetto Julien , Pease Matthew , Avşar Timuçin , Huttner Anita , Bilguvar Kaya , Kilic Türker , Pamir M Necmettiin , Amankulor Nduka , Kalamarides Michel , Erson-omay Zeynep , Gunel Murat , Moliterno Jennifer
Published: December 2020

Up to 80% of meningiomas are classified as clinically low-grade, however, a subset of these ‘benign’ cases will ultimately recur and require additional treatment. The role of molecular subgroup in meningioma recurrence has not been thoroughly investigated, despite correlations of this variable with other clinical features. Indeed, epigenetic and transcriptional evidence supports involvement of distinct oncogenic processes within each subgroup, and as shown in other brain tumors, this may result in divergent clinical courses. In the present study, we classified 429 meningiomas into six established molecular subgroups based on genomic driver, and investigated associations of each subgroup with tumor recurrence. At two years of follow-up, we observed differences in progression free survival curves among relatively aggressive (NF2-loss, PI3K-activated, Hedgehog-activated) and quiescent (KLF4-mutant, SMARCB1-mutant, POLR2A-mutant) subgroups (log rank p = 4.3 x 10-2), with the former group recurring at a rate 14x higher. We found PI3K-activated meningiomas recurred significantly earlier than other subgroups (average time to recurrence of 19.2 months; p = 2.2 x 10-2), though we observed an intermediate long-term outcome relative to the Hedgehog and NF2 lesions. Overall, Hedgehog tumors recurred significantly more frequently than other low-grade meningiomas (adj. p = 3.1 x 10-2), and this subgroup was found to be an independent predictor of progression free survival using cox proportional hazards modelling (HR = 3.1; p = 2.4 x 10-2). By contrast, the aggressiveness of NF2 meningiomas was found to depend upon gender, WHO grade, and elevated Ki-67 index, and this subgroup was not an independent prognostic predictor. Our results suggest molecular subgroup is predictive of recurrence in low-grade meningiomas, and thus is an important consideration in post-operative management decisions. Routine genotyping to detect Hedgehog and PI3K mutant lesions may identify patients that would benefit from closer follow-up and consideration of adjuvant therapies.
PATH-44. AN UNUSUAL PRESENTATION OF A PEDIATRIC MIDLINE H3K27M-MUTANT TUMOR WITH DISSEMINATED CRANIOSPINAL LEPTOMENINGEAL DISEASE
Authors: Navarro Ralph , Golub Danielle , Hill Travis , McQuinn Michelle , Kim Nora , Tang Karen , Livingston Stephanie , Cooper Benjamin , Gardner Sharon , Nicolaides Theodore , William Christopher , Zagzag David , Hidalgo E Teresa
Published: December 2020

BACKGROUND

H3K27M-mutant midline lesions were recently reclassified by the WHO as “Diffuse Midline Glioma” (DMG) based on their molecular signature. DMG is one of the most common and most lethal pediatric brain tumors; terminal progression is typically caused by local progression or secondary leptomeningeal dissemination. H3K27M mutations have also been infrequently associated with a histologically diverse set of lesions, particularly spinal masses with early leptomeningeal spread, but the role of H3K27M in these atypical lesions remains poorly understood.

CASE PRESENTATION

A 15-year-old girl was found to have a T2/FLAIR-hyperintense and heterogeneously contrast-enhancing thalamic mass accompanied by severe leptomeningeal enhancement along the entire neuraxis. Initial infectious workup was negative, and open intracranial biopsy was inconclusive. Follow-up spinal arachnoid biopsy was diagnostic for H3K27M neuroepithelial tumor, thereafter classified as DMG. Biopsy also showed focal p53 immunopositivity, variable immunoreactivity for GFAP and synaptophysin, and an increased proliferation index, altogether suggestive of a glioneuronal origin. She received craniospinal irradiation (CSI) to 41.4Gy with a boost to the thalamic lesion to 54Gy. Imaging 1-month post-radiation demonstrated significant treatment response only with residual enhancement at the conus.

CONCLUSIONS

This case report describes the unique presentation of an H3K27M-mutant midline lesion with significant craniospinal leptomeningeal spread on admission and atypical glioneuronal histopathological markers. Given her avid leptomeningeal disease, spinal dural biopsy could have been considered earlier given its diagnostic yield in classifying the lesion as DMG. This lesion, however, additionally demonstrated synaptophysin positivity. Per extensive literature review, this histopathology is also potentially consistent with diffuse leptomeningeal glioneuronal tumor (DLGNT). This patient’s uniquely marked treatment response to CSI is also not typically observed in DMG, further supporting the possibility of an alternative molecular identity. In atypical DMG cases, particularly with early leptomeningeal spread, additional consideration of clinical and histopathological context is warranted for accurate diagnosis and prognostication.
PATH-45. CLINICAL UTILITY OF COMBINED NEXT GENERATION SEQUENCING AND CHROMOSOMAL MICROARRAY ANALYSIS FOR THE DIAGNOSIS AND MANAGEMENT OF ADULT GLIOMAS
Authors: Praska Corinne , Kollmeyer Thomas , Fritcher Emily Barr , Voss Jesse , McKenna Michelle , Balcom Jessica , Pryzbylski Amber , Pasion Romela , Kipp Benjamin , Raghunathan Aditya , Vaubel Rachael , Passow Jeanette Eckel , Lachance Daniel , Ida Cristiane , Giannini Caterina , Jenkins Robert
Published: December 2020

BACKGROUND

Molecular parameters have been incorporated into the 2016 WHO Classification of CNS Tumors and subsequent cIMPACT-NOW updates to facilitate clinical management of glioma patients. However, there have been few reports of the overall clinical utility of comprehensive genetic testing in adult glioma patients. We report the results of sequencing and chromosomal microarray analysis of adult gliomas seen at the Mayo Clinic and through the Mayo Clinic Laboratories (MCL) reference practice.

METHODS

A consecutive series of 379 Mayo Clinic adult glioma patients were consented to receive targeted next generation sequencing and chromosomal microarray analysis, regardless of standard clinical ordering practices. Known diagnostic, prognostic, and predictive alterations were annotated for each case. These results were compared to the larger MCL reference practice of 2400 adult glioma samples that received one or both tests clinically.

RESULTS

Of the consecutive Mayo Clinic cases, 67% had alterations that fell into at least one of the diagnostic, prognostic, and/or predictive categories. Molecular testing generated diagnostic, prognostic, and predictive information in 44%, 34%, and 36% of cases, respectively. Diagnostically, molecular testing mainly aided in arriving at a final integrated diagnosis, and only a small number of cases (n= 5; 1%) had a change in diagnosis. The consecutive cases represent the typical distribution of adult glioma types (47% IDH-wildtype glioblastoma/astrocytoma, 22% IDH-mutant astrocytoma/glioblastoma, 13% IDH-mutant 1p/19q-codeleted oligodendroglioma, and 18% other tumor types). The MCL practice is enriched in tumors with atypical molecular patterns (37% IDH-wildtype glioblastoma/astrocytoma, 17% IDH-mutant astrocytoma/glioblastoma, 18% IDH-mutant 1p/19q-codeleted oligodendroglioma, and 29% other tumor types).

CONCLUSIONS

Molecular testing provides useful diagnostic, prognostic, and predictive information for the clinical management of adult glioma patients. While the current guidelines for ordering molecular testing are effective for diagnostic purposes, additional prognostic and predictive information can be gleaned from comprehensive molecular testing of adult gliomas.
QOLP-01. OUTCOME ASSESSMENT OF MULTIDISCIPLINARY BRAIN TUMOR BOARD MEETING RECOMMENDATIONS FOR BRAIN METASTASIS: IS THERE A GAP?
Authors: Santos-Pinheiro Fernando , Bovi Joseph , Peltier Wendy , Connelly Jennifer , Mueller Wade , Straza Michael , Puckett Lindsay , Crabb Marianne , Leuck Julianne , Zwagerman Nathan , Thompson Jonathan , Schultz Christopher , Lindstedt Jennifer , Roller-Voigt Kimberly , Nelson Ariel , Bichler Sarah , Leutenegger Alexandra , Erlitz Tracy , Brausch Carolyn , Saeed Hina , Hahn Dustin , Santos-Pinheiro Fernando
Published: December 2020

BACKGROUND

Brain metastasis (BM) is the most common form of brain cancer affecting 20-40% of cancer patients. Advancements in cancer therapy has prolonged survival but BM incidence has increased. BM management requires a multidisciplinary approach to individualize care via an ever-growing sum of surgical, radiation, and systemic therapy options. Consensus is achieved by multidisciplinary tumor board meeting (MTBm). Nevertheless, BM diagnosis predicts poor prognosis. Palliative Care (PC) is essential for proper BM management. Yet, formal PC assessment may not be available for MTBm. We evaluated whether MTBm consensus recommendations were followed.

RESULTS

Our weekly MTBm discussed 157 BM cases during 2019 (median age: 64 years [range 28-91], male/female: 82/75). The most common primary diagnosis was lung (n=49, 31%), breast (n=24, 15%), melanoma (n=16, 10%). The majority was newly diagnosed BM (n=143, 91%). MTBm recommendations were divided into three not-mutually-exclusive categories: surveillance/workup (n=78, 50%), BM-directed treatment (n=101, 64%) and GOC discussion (n=7, 4%). MTBm recommendations were fully followed in 113 cases (72%), partially in 13(8%), and not followed in 25(16%). Of the 38 patients whose recommendations were partially/not followed, the main reason was transition to hospice/death (n=26, 68%). Of the 101 patients recommended treatment, 68% (n=68) fully followed it, yet 31% (n=21) of them died within 3 months; for those living longer than 3 months (n=47, 69%), median KPS at 3 months was 70 (range 30-90). Of the entire cohort (n=157), only 20 (13%) established consistent PC follow-up (>1 outpatient visit) and 69 cases (44%) transitioned to hospice/died within 6 months, 30 of which (43%) still completed surgery (n=6) or radiotherapy (n=24) within this period.

CONCLUSION

Periodic assessment of MTBm recommendations is relevant for sensible BM management. Balancing treatment while focusing on QoL in a patient population with limited survival is challenging. PC assessment at MTBm could close this gap.
QOLP-03. NEURO-ONCOLOGY PALLIATIVE CARE SURVEY OF PHYSICIANS IN SUB-SAHARAN AFRICA
Authors: Tadipatri Ramya , Azadi Amir , Cowdrey Madison , Fongue Samuel , Smith Paul , Razis Evangelia , Boccia Maria , Fonkem Ekokobe
Published: December 2020

BACKGROUND

Early access to palliative care is a critical component of treating patients with advanced cancer, particularly for glioblastoma patients who have low rates of survival despite optimal therapies. Additionally, there are unique considerations for primary brain tumor patients given the need for management of headaches, seizures, and focal neurological deficits.

METHODS

We conducted a survey of 109 physicians in Sub-Saharan Africa in order to determine level of understanding and skill in providing palliative care, types of palliative care therapies provided, role of cultural beliefs, availability of resources, and challenges faced. Demographic data including age, gender, and prior training was collected and analyzed using ANOVA statistical testing.

RESULTS

Among the participants, 48% felt comfortable in providing palliative care consultations, 62% have not had prior training, 52% believed that palliative care is only appropriate when there is irreversible deterioration, 62% expressed having access to palliative care, 49% do not have access to liquid opioid agents, 50% stated that cultural beliefs held by the patient or family prevented them from receiving, palliative care, and 23% stated that their own beliefs affected palliative care delivery. Older providers (age > 30) had a clearer understanding of palliative care (p = 0.004), were more comfortable providing consultation (p = 0.052), and were more likely to address mental health (p < 0.001).

CONCLUSIONS

Palliative care delivery to glioblastoma patients in Sub-Saharan Africa is often delayed until late in the disease course. Barriers to adequate palliative care treatment identified in this survey study include lack of training, limited access to liquid opioid agents, and cultural beliefs. Challenges most often identified by participants were pain management and end-of-life communication skills, but also included patient spirituality and psychological support, anxiety and depression, terminal dyspnea, ethics, and intravenous hydration and non-oral feeding.
QOLP-06. PHENOMENOLOGICAL EXPLORATION OF THE LIVED EXPERIENCE OF QUALITY OF LIFE FOR PATIENTS WITH GLIOBLASTOMA AND THEIR PRIMARY CARE PARTNERS
Authors: Tierney Meghan , Peden-McAlpine Cynthia
Published: December 2020

INTRODUCTION

Quality of life (QOL) should be included among the important outcomes of brain tumor treatment. QOL is often reduced to a measure of treatment tolerability, resulting in a lack of understanding of how patients experience this phenomenon. There is also limited knowledge surrounding the meaning of QOL for family care partners. The research (in progress) aims to explore the meaning of lived experience of QOL during treatment for glioblastoma (GBM) for both patients and their primary care partners. It will also examine similarities and differences in QOL perceptions within patient-care partner dyads.

METHODS

Using a phenomenological approach, this study is recruiting patients receiving treatment for GBM and their care partners. Participants complete a timeline depicting significant events impacting QOL from the time of the patient’s diagnosis to the present. They then complete an individual, unstructured interview describing their experience of QOL. Interviews are recorded and transcribed. The research team reviews and completes a thematic analysis on transcripts.

RESULTS

Numerous themes are emerging from the data. One theme among patients is: Feeling Uncertain About the Future. Patients discussed feeling uncertain about their prognosis during their course of treatment. They talked about the need to adjust to multiple changes in their lives over time. This uncertainty extended to concern for their QOL in the future. One theme among care partners is: Challenges in Relationship with Spouse. Care partners reported relationship conflict stemming from both personality changes in their spouse and role changes resulting in increased responsibilities for the care partner.

CONCLUSION

This study is providing insight into the meaning and experience of QOL for patients undergoing treatment for GBM, along with meaning and experience of QOL for their care partners. The findings will have implications for clinical practice and generate insights for future research.
QOLP-09. HEALTH ECONOMIC EVALUATION OF LOW-GRADE GLIOMA MANAGEMENT: A SYSTEMATIC REVIEW
Authors: Hamidi Nima , Fernandez Ajay , Tuohy Kyle , Mansouri Alireza
Published: December 2020

BACKGROUND

Diffuse low-grade gliomas (DLGGs, WHO Grade II gliomas) comprise 13-16% of all primary brain tumors. Although there has been a paradigmatic shift toward upfront maximal safe resection (MSR) for these heterogeneous tumors, it is important to consider the health economic perspective of this approach, compared with the traditional watch-and-wait approach, as well.

OBJECTIVE

To conduct a systematic review of the health economic literature on the range of DLGG management options.

METHODS

Following the PRISMA guidelines, Medline, EMBASE, The Central Registration Depository (CRD), EconPapers, and EconLit were searched for ‘cost-effectiveness’, ‘health economics’ and ‘Low-grade glioma’. Grade I tumors were excluded. Pre-specified variables were extracted. All currencies were converted to USD.

RESULTS

Among 258 abstracts, 28 were selected for full-text screening, and 3 were selected for this review. A European study evaluated the role of intraoperative electrical stimulation (IES). Although IES was associated with higher direct costs upfront ($38,662.70 vs $32,116.10), this was offset by less long-term indirect costs ($12,222.30 vs $31,927.10; p=0.023), greater QALY (4.8 vs 2.9; p=0.001), and an incremental cost-effectiveness ratio (ICER) of $1,842.50. Another study evaluated the cost-effectiveness of adjuvant PCV+RT vs RT alone, finding greater QALY for the former (9.94 vs 5.17) and an ICER of $10,186 per QALY gained. A third study evaluated the cost-effectiveness of adding 18F-fluoroethyl-L-tyrosine (FET) PET to MRI, compared to preoperative MRI alone. This resulted in an ICER of $7,193.58 for the baseline scenario (lowest reimbursement) and $10,236.12 for the morbidity-adjusted reimbursement rate scenario (highest reimbursement). There were no studies evaluating the health economics of maximal upfront surgical resection to the watch-and-wait approach.

CONCLUSION

We found a limited number of studies reporting on the health economics of DLGGs. Given the paradigmatic transition toward more aggressive upfront surgical resection, DLGG-specific health economic analyses are underway.
QOLP-13. COMPARISON OF SYMPTOM BURDEN AND ASSOCIATED IMPACT ON DAILY LIFE IN GLIOBLASTOMA PATIENTS TREATED WITH AND WITHOUT TUMOR TREATING FIELDS
Authors: Tipps Megan , Tierney Meghan , Monson Caitlin , Jackson Kelsey , Banerji Nilanjana , Bruns Patricia , Trusheim John
Published: December 2020

INTRODUCTION

Clinical trials have demonstrated that the use of low intensity alternating electric fields, known as Tumor Treating Fields (TTFields), via the Optune™ device extends overall survival times in patients with glioblastoma when combined with standard chemotherapy. In addition to survival time, quality of life (QOL) is an important factor in treatment decisions for life-limiting diagnoses. Examinations of the impact of TTFields on QOL have yielded mixed RESULTS: Here, we describe patient-reported symptoms in patients with glioblastoma undergoing treatment with TTFields and compare symptom burden and associated interference with daily life to that of a historic non-TTFields cohort.

METHODS

Patients with primary glioblastoma who chose treatment with the Optune™ device were prospectively enrolled and asked to complete the brain tumor-specific MD Anderson Symptom Inventory (MDASI-BT) approximately every 8 weeks through cessation of active disease treatment. MDASI-BT assessments were examined for symptom frequency, severity, and relationships between symptom severity and interference with daily life. These results were also compared with a matched cohort of patients who did not chose TTFields treatment and completed MDASI-BT assessments as part of a previous study.

RESULTS

The most commonly reported symptoms for Optune™ users were fatigue, sleep disturbance and speaking/word finding. Fatigue and sleep disturbance were also among the symptoms rated as most severe, along with feeling drowsy/sleepy. Interference with general activities and overall enjoyment of life as both were reported as both the most common and most severe impacts on daily life. When compared with historic data from non-Optune™ users at the same point in treatment, we found no difference in either symptom burden (p=0.48) or interference scores (p=0.72).

CONCLUSION

Attention to both survival benefit and symptom experience related to treatment options can inform patient decisions and direct approaches to symptom management as well as improved QOL.
RADT-08. ADJUVANT SBRT FOR RESECTED BRAIN METASTASES: THE EFFECT OF TIMING ON LONG-TERM INTENDED-FIELD CONTROL
Authors: Bander Evan , Yuan Melissa , Reiner Anne , Panageas Katherine , Brennan Cameron , Beal Kathryn , Tabar Viviane , Moss Nelson
Published: December 2020

INTRODUCTION

Adjuvant stereotactic body radiation therapy (SBRT) improves the local control of resected brain metastases (BrM). However, the dependency of long-term outcomes on SBRT timing relative to surgery remains unclear.

METHODS

Retrospective analysis of metastasectomy-plus-adjuvant-SBRT patients at Memorial Sloan Kettering (MSK) between 2013-2016 was conducted. Kaplan-Meier methodology was used to describe overall survival (OS) and cumulative incidence in a competing-risks setting recurrence at the surgical site, other SBRT-treated sites, and elsewhere in the brain as defined by RANO-BM criteria. Recursive partitioning analysis (RPA) and competing-risks regression modeling assessed prognostic variables and associated events of interest.

RESULTS

Two hundred eighty-two patients with BrM including non-small cell lung (34%), breast (16%), melanoma (13%), and other cancers were included. Median time-to-adjuvant-SBRT (TT-SBRT) was 34 days (IQR: 27-39). Median overall survival (OS) from SBRT was 1.5 years (95% CI: 1.2-2.1) with median follow-up of 49.8 months for survivors. Local surgical recurrence, other irradiated-site, and distant progression rates were 14.3% (95%CI: 10.1-18.5), 4.9% (95%CI: 2.3-7.5), and 47.5% (95%CI: 41.4-53.6) at 5 years, respectively. TT-SBRT as a continuous variable significantly associated with surgical-site recurrence (HR 1.05 [1.02-1.07], p=0.0003), but not with distant or other irradiated-site recurrence nor OS. RPA analysis demonstrated the greatest control rate advantage with TT-SBRT < 39 days (HR for 39+ days: 2.81 [1.50-5.27], p=0.001). No association of TT-SBRT with radiation necrosis, wound complication, or development of leptomeningeal dissemination was identified.

CONCLUSIONS

Delays in initiation of post-operative SBRT can decrease its efficacy. Efforts must be made to minimize logistical, procedural, and socioeconomic factors responsible for these delays.