bluuebunny/crossref_metadata_2025_split 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

Abstract

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 (~&lt; 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

Abstract

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

Abstract

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 &lt; 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&lt; 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

Abstract

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

Abstract
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

Abstract
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&lt; 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

Abstract

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&lt; 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

Abstract
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 &gt;0.3, logFC &gt;±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

Abstract
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

Abstract

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.