bluuebunny/crossref_metadata_2025_split huggingface dataset:
INNV-01. DRAMATIC RESPONSE OF ERBB2 POSITIVE BRAIN METASTASES FROM LUNG ADENOCARCINOMA TO FAM-TRASTUZUMAB DERUXTECAN-NXKI
Authors: Thompson Tracy , Luster Sara , Savvides Panayiotis , Sio Terence , Westerlund Lynsey , Fortin-Ensign Shannon , Mrugala Maciej 
Published: November 2022

Abstract

BACKGROUND
In May 2022 the Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (FAM-TRAS) for adult patients with unresectable or metastatic Her-2 positive breast cancer who have received prior Her-2-based regimen and developed recurrence withing 6 months of completing therapy. Efficacy of the drug was established in the DESTINY-BreastO3 study. It has been suggested that fam-trastuzumab deruxtecan crosses blood-brain barrier, similarly to trastuzumab and another drug conjugate trastuzumab-DM1. CNS responses in patients with Her2 positive metastatic breast cancer have been reported. ERBB2 is a receptor tyrosine kinase from the family of EGFR/ERBB/HER family of kinases and its alterations can serve as a biomarker and actionable target in solid tumors. Here we present a case of CNS metastases from ERBB2 positive lung adenocarcinoma treated successfully with FAM-TRAS alone.

METHODS
Case report.

RESULTS
50 y old man presented with a persistent cough. CT chest showed RUL nodule and peribronchial lymphadenopathy. Biopsy was positive for adenocarcinoma. Molecular testing has shown ERBB2 exon20 insertion, TP53 pathogenic variant, PDL1 positive (1%), and BRACA1 mutation. The patient had a solitary brain metastasis at the time of the initial diagnosis. He was started on FAM-TRAS and CNS response was seen while lung disease progressed. He was switched to immunotherapy but developed pneumonitis and therapy was stopped. He subsequently developed innumerable brain metastases and was restarted on FAM-TRAS. After 2 doses, dramatic response in CNS was seen with lung disease was stable.

CONCLUSIONS
This case demonstrates the critical importance of molecular testing in neuro-oncology in the era of novel systemic therapies, many with good blood-brain barrier penetration. Systemic therapies for brain metastases can be successfully implemented in the right clinical setting and they can allow for the deferral of radiotherapy. ERBB2 mutations can guide clinicians when choosing therapy for many solid tumors, including those with brain metastases.
INNV-10. OVERCOMING CHALLENGES AND OPTIMIZING PATIENT OUTCOMES WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY
Authors: Gage Gwyn P , Frongillo Peggy , Thomas Anne , Adams Nichelle Renae 
Published: November 2022

Abstract

BACKGROUND
Tumor Treating Fields therapy (TTFields; 200 kHz) is a noninvasive, locoregional, antimitotic treatment approved for newly diagnosed glioblastoma (ndGBM), recurrent GBM, and malignant pleural mesothelioma, and is being investigated in a range of solid tumors.

METHODS
Healthcare professionals (HCPs) specializing in radiation oncology, neuro-oncology, and medical oncology as well as patients with GBM and caregivers were asked to complete online surveys between October–December 2021 (HCPs) and July–September 2021 (patients/caregivers).

RESULTS
Overall, n=130 HCPs and n=50 patients/caregivers responded to the surveys. The majority (68%) of HCPs considered TTFields therapy + temozolomide a standard of care for ndGBM, yet only 35% of HCPs report strongly recommending it as a treatment option. Barriers to recommendation of TTFields therapy included the need for additional patient services and practice support with training, prescription process etc., and guidance on insurance coverage (31% for each), the need to increase patient awareness (20%), and lack of patient testimonials (20%). HCP perceptions of patient barriers were often higher than reported by patients themselves; time wearing device (46% vs 35%); treatment visibility (37% vs 24%), concerns with shaving head (37% vs 18%), and concerns with carrying device (34% vs 18%). Awareness of resources provided by the device manufacturer was relatively low (HCP: peer-peer knowledge exchange program [25%], TTFields therapy product brochures [16%–30%]; patient: webcasts [15%], patient website [23%], educational videos [25%–26%], educational brochures [26%–27%], buddy program [29%], and dedicated support service information [32%]), despite the desire for support.

CONCLUSION
Increasing awareness of existing HCP and patient support programs and resources continues to be critical in overcoming barriers to TTFields therapy initiation to optimize patient outcomes.
PATH-01. EVALUATION OF RAMAN SPECTROSCOPY AS A DIAGNOSTIC TOOL IN NEUROPATHOLOGY FOR TUMOR CLASSIFICATION
Authors: Georg Klamminger Gilbert , Mombaerts Laurent , Jelke Finn , Slimani Redouane , Mirizzi Giulia , Klein Karoline , Husch Andreas , Hertel Frank , Mittelbronn Michel , Borgmann Felix Kleine 
Published: November 2022

Abstract

BACKGROUND
Raman spectroscopy (RS) has shown its applicability in neurooncological diagnostics ranging from intraoperative tumor identification to peri- and postoperative tissue analyses. In the present study, we applied RS to track changes in the molecular vibrational status of a broad spectrum of formalin fixed paraffin-embedded (FFPE) intracranial neoplasms (primary brain tumors, meningiomas, brain metastases) and evaluated its potential as an additional method in the neuropathology toolbox, considering specific challenges when employing RS on FFPE tissue. Material and

METHODS
We examined 82 cases of intracranial neoplasms (679 individual measurements) by RS and applied a machine learning pipeline for recognition of spectral properties. The discrimination potential of the machine learning algorithms was evaluated using standard performance metrics such as AUROC and AUPR values, macro and weighted average of accuracy, precision, recall, and f1 scores. To address occurring misclassifications and further evaluate our models we searched for important Raman bands usable for tumor identification.

RESULTS
Using our trained machine learning model, we differentiated between different types of gliomas and determined the primary origin in case of a brain metastasis. We further spectroscopically diagnosed tumor types solely based on biopsy fragments of necrosis, something not possible by means of light microscopy. During the validation process we confirmed a high complexity within the spectroscopic data, possibly resulting not only from biological tissue which has undergone a rough chemical procedure but also from residual components of the fixation/paraffination process.

CONCLUSIONS
Our study demonstrates possibilities and limits of RS as a potential diagnostic tool in neuropathology, considering accompanying difficulties in the vibrational spectroscopic examination of FFPE tissue.
PATH-09. SUBTYPE-ASSOCIATED RNA SPLICING CONTROLLED BY GLIOMA DRIVER MUTATIONS REGULATES GLIOMAGENESIS
Authors: Song Xiao , Huang Tianzhi , Tiek Deanna , Miki Shunichiro , Goenka Anshika , Iglesia Rebeca , Furnari Frank , Hu Bo , Hu Bo 
Published: November 2022

Abstract
Dysregulated RNA alternative splicing (AS) is a hallmark of cancer and has been studied in cancers including glioma. However, whether the dysregulated AS and the regulating RNA-binding proteins (RBPs) drive gliomagenesis and the role of glioma driver mutations in shaping the RBP/AS landscape have not been studied. Here we describe two AS-defined glioma subtypes that correlate with IDH1 mutation, tumor grade, and patient prognosis. Oncogenic AS isoforms are exclusively associated with AS subtype 2, IDH1 wild-type gliomas. Modulation of representative AS isoforms or subtype-associated RBPs regulate glioma stem-like cell (GSC) tumorgenicity. With a human induced pluripotent stem cell-derived glioma model system, we demonstrate that specific glioma driver mutations are involved in shaping the subtype-associated AS. Lastly, we target a sub2-associated RBP with anti-sense oligonucleotides to inhibit GSC tumorigenicity. Our data establish relationships between glioma driver mutations and AS programs and identify dysregulated RBP/AS network as a therapeutic vulnerability.
PATH-11. THE LONGITUDINAL EVOLUTIONARY TRAJECTORY OF OLIGODENDROGLIOMA IS DRIVEN BY TREATMENT-ASSOCIATED GENETIC ALTERATIONS
Authors: Varn Frederick , Ye Gordon , Ghospurkar Padmaja , Wade Taylor , Khasraw Mustafa , Lipp Eric S , Hermes Beth , Elliott Carol , Costello Joseph F , Hong Chibo , French Pim , Vallentgoed Wies , Padovan Marta , Ng Ho-Keung , Li Kay , Gan Hui , Westcott Kerryn , Vaubel Rachael , Horbinski Craig , McCortney Kathleen , Paek Sun Ha , Moon Hyo-Eun , LaViolette Peter , Lowman Allison , Barnholtz-Sloan Jill , Wesseling Pieter , Verhaak Roel 
Published: November 2022

Abstract
Oligodendroglioma is a subtype of diffuse glioma defined by a mutation in the isocitrate dehydrogenase (IDH) genes and a co-deletion of chromosome arms 1p and 19q. These tumors primarily occur in adult patients in their third and fourth decade of life and are universally fatal due to an inevitable recurrence that follows a treatment regimen of surgical resection and an optional combination of alkylating chemotherapy and/or radiation therapy. While initially slow growing, recurrent tumors exhibit increasingly aggressive phenotypes that become progressively more difficult to treat with conventional therapy. Currently, the molecular mechanisms and cellular phenotypes that drive this recurrence remain unknown. To understand these factors, we assembled a cohort of matched initial and recurrent oligodendroglioma samples from over 100 patients and performed whole-genome sequencing and whole-exome sequencing on each of them. To link these molecular profiles to cell state changes, we additionally performed bulk and single-nucleus RNA-sequencing on a subset of these tumor pairs. In nearly 40% of alkylating chemotherapy-treated patients, recurrent tumors presented with hypermutation that corresponded with an increase in neoplastic cell proliferation. Additionally, while individual somatic alterations specific to recurrence were relatively rare, we observed a subset of tumors that acquired deletions in the cell cycle regulator CDKN2A following treatment with radiotherapy. Acquisition of either of these features associated with shorter patient survival and higher grade at recurrence, implicating cell cycle dysregulation as a mechanism of treatment resistance and increased tumor severity. Together, these results indicate that oligodendrogliomas evolve in a treatment-specific manner following chemo- and radiation therapy and highlight key pathways that can be targeted to delay the onset of recurrence.
PATH-12. DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT: A COMPREHENSIVE SEQUENCING AND HIGH-RESOLUTION GENOME-WIDE COPY NUMBER ANALYSIS
Authors: Trejo-Lopez Jorge , Kollmeyer Thomas , Praska Corinne , Raghunathan Aditya , Giannini Caterina , Vaubel Rachael , Nguyen Aivi , Jentoft Mark , Donev Kliment , Zheng Gang , DiGuardo Margaret , Kipp Benjamin , Jenkins Robert , Ida Cristiane 
Published: November 2022

Abstract
Diffuse hemispheric glioma, H3 G34-mutant (DHG_H3G34) is a novel tumor type in the 2021 WHO CNS classification. We describe a comprehensive sequencing and high-resolution genome-wide copy number analysis of a series of cases clinically tested by a single laboratory (2018-2022). Cases included tumors from 47 unique patients (1 reportedly recurrent) that had an H3-3A G34 mutation detected using an 187-gene mutation and fusion targeted neuro-oncology NGS panel (n=47). A subset (n=18) of cases was also tested Oncoscan chromosomal microarray. Median age at testing was 20 years (range, 12-50). H3-3A G34 mutations included G34R (n=44; 94%), G34V (n=2) and a novel G34E variant considered to be likely clinically relevant (n=1). All DHG_H3G34 were hemispheric tumors, and one tumor was multifocal with midline involvement. Concurrent mutations recurrently involved ATRX (n=38), TERT promoter (n=3; mutually exclusive with ATRX mutations), TP53 (n=43), PDGFRA (n=26), PTEN (n=5), NF1 (n=4, all patients over 20 years), PIK3CA (n=4) and CDKN2A (n=3). The single recurrent tumor also had an MSH6 mutation, and in addition to 3 other cases, had increased number of sequence variants suggestive of a high tumor mutational burden. A single case also showed an FGFR3::FAM184B (exon 17::exon 2) fusion. All cases with available chromosomal microarray data had unbalanced genomes with multiple chromosomal gains/losses, and regions of copy-neutral loss of heterozygosity. The most frequent recurrent (at least 50% of cases) abnormalities were losses involving 3q, 4q, 10q, 13q and 18q, and 17p copy-neutral loss of heterozygosity encompassing TP53 (all but one case had concomitant TP53 mutation), a pattern reminiscent of IDH-mutant astrocytomas. Oncogene amplifications (PDGFRA and PIK3CA) were detected in 3 (of 18) cases. CDKN2A/B deletion was observed in 8 cases (2 homozygous). In conclusion, we describe additional sequence and copy-number abnormalities in DHG_H3G34, expanding the spectrum of genetic changes associated with this novel tumor type.
PATH-14. MOLECULAR ANALYSIS OF ASTROCYTOMAS WITH A DOMINANT PILOMYXOID MORPHOLOGY
Authors: Ritacco Samantha , Decker Brennan , Killian J Keith , Williams Erik , Lechpammer Mirna 
Published: November 2022

Abstract
Pilomyxoid astrocytomas (PMAs) are tumors of infancy occurring in the hypothalamic chiasmatic region, with somewhat worse prognosis than pilocytic astrocytomas (PAs). We report molecular findings in PAs with a dominant pilomyxoid histomorphology across the various age groups and CNS locations. Foundation Medicine comprehensive genomic profiling (CGP) (FoundationOne, FoundationOneCDx, FoundationOneHeme) were performed during routine clinical care. A retrospective cohort analysis was done to evaluate the genomic characteristics of PMAs. 57 PMAs were identified, of which 6 occurred in patients &lt; 12 months old (10.5%); 14 in 1-3 year old (24.6%); 15 in 4-10 y.o. (26.3%); 12 in 11-20 y.o. (21.1%), and 10 occurred in young adults 21-39 y.o. (17.5%). 30/57 (52.6%) were female and 27/57 (47.4%) male. 55 PMAs occurred in the brain and 2 in the spinal cord. Tumors were categorized by notable rearrangements and point mutations. The common fusion, KIAA1549:BRAF, was detected in 23/57 samples (40.4%). BRAF fusions with other gene partners (BRAF, TAX1BP1) occurred in 2, and BRAF V600E mutations in 4 patients. An additional 4 patients had FGFR1 fusions (FGFR1, TACC1) and 14 had FGFR mutations. Other alterations included 3 NF1 mutations, 2 NTRK family receptor tyrosine kinase fusions, 2 RAF gene fusions, 2 other (ATRX, ALK) alterations, and 1 VUS. Tumor Mutational Burden was under 10 mut/Mb for all patients. In this cohort of 57 PMAs, MAPK pathway genetic alterations were dominant drivers, similar to other PAs. We also observed other frequent genetic alterations not involving BRAF, including FGFR and NTRK gene family members that have FDA approved targeted inhibitors. While these also likely cause MAPK pathway activation, these non-BRAF variants are less common in PAs. Our report contributes to growing evidence that PMAs harbor a distinct molecular alteration profile, which is becoming increasingly important in the context of the evolving targeted therapeutics landscape.
PATH-19. CLINICAL AND MOLECULAR FEATURES OF GLIOBLASTOMA, IDH-WILDTYPE ARISING IN THE SETTING OF LI FRAUMENI SYNDROME
Authors: Kibe Yuji , Ohka Fumiharu , Motomura Kazuya , Aoki Kosuke , Maeda Sachi , Yamaguchi Junya , Nishikawa Tomohide , Mizutani Kosuke , Shimizu Hiroki , Hiramatsu Taku , Suzuki Kazuaki , Saito Ryuta 
Published: November 2022

Abstract

INTRODUCTION
Li Fraumeni Syndrome (LFS) is a rare autosomal dominant tumor predisposition syndrome caused by germline alterations of the TP53. Brain tumors are included in LFS core cancers. Choroid plexus carcinomas and medulloblastomas tend to occur in pediatric LFS patients, while gliomas tend to occur in adult LFS patients. There are few previous reports about gliomas arising in the setting of LFS. Here, we report clinical and molecular features of three cases of glioblastoma, IDH-wildtype arising in the setting of LFS.

RESULTS
Mean age at diagnosis was 40 years (range: 32-45). Two patients were male. Two patients had medical history of multiple tumors and family history of brain tumors. Magnetic resonance imaging of each patients revealed a left cerebellar peduncle lesion with faint contrast-enhancement, a right parietal lobe lesion with nodular contrast-enhancement and two lesions in the pons (no enhancement) and right parietal lobe (ring enhancement), respectively. All patients underwent chemotherapy including temozolomide and/or bevacizumab combined with radiation therapy (60Gy) after surgery. Mean progression free survival was 10.4 months (range: 5.1-17.0). All patients were admitted to palliative care mean 17.3 months (range: 14.4-21.4) after diagnosis. All patients harbored heterozygous germline mutations of TP53. Whole exome sequencing and copy number analysis of tumor tissues revealed TP53 mutation and PDGFRA amplification in all patients. However, EGFR amplification, the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10-) and mutations of IDH, H3F3A, BRAF and TERT promoter were not detected in all tissues.

CONCLUSION
We experienced three cases of glioblastoma, IDH-wildtype arising in the setting of LFS. Although tumor locations and radiographic features were varied, all clinical courses were poor. Notably, all tumor tissues harbored TP53 mutation and PDGFRA amplification, while no tumor tissues harbored TERT promoter mutation, EGFR amplification and 7+/10-.
PATH-22. CLINICAL FEATURES AND MOLECULAR CHARACTERIZATION OF LEPTOMENINGEAL DISEASE IN PATIENTS WITH HIGH GRADE GLIOMA
Authors: Shoaf Madison , Chow Frances , Xiu Joanne , Glantz Michael , Aulakh Sonikpreet , Ashley David , Lipp Eric S , Lopez Giselle , Sumrall Ashley , Walker Phillip , Spetzler David , Nicolaides Theodore , Peters Katherine B 
Published: November 2022

Abstract

INTRODUCTION
Leptomeningeal disease (LMD) is a challenging complication of high grade glioma (HGG) and critical questions remain unanswered regarding clinicopathologic risk factors, molecular associations, and optimal treatment.

METHODS
Patients with molecularly-profiled HGG (Caris Life Sciences; Phoenix, AZ) with LMD at two institutions were included. Medical records were reviewed for clinicopathological characteristics, treatment, and outcome. Kaplan-Meier estimates of patient survival were performed on censored data using Cox’s proportional hazard model.

RESULTS
43 patients (male: 33, female: 10; median age: 56 years) were identified, comprising 41 grade 4 (glioblastoma: 38; gliosarcoma: 2; H3K27M diffuse midline glioma: 1) and 2 grade 3 tumors (astrocytoma: 1; pleomorphic xanthoastrocytoma: 1). LMD diagnosed at HGG diagnosis (n=18) versus recurrence (n=22) was associated with longer post-LMD survival [pLMD-OS: 15.3m vs. 4.8m, HR: 0.07, 95% CI: 0.02-0.29, p=0.0004] but similar overall survival [mOS: 15.3m vs. 12.3m; HR: 0.82; 95% CI: 0.36-1.85; p=0.63]. Pathology-diagnosed LMD (n=15) versus MRI-diagnosed LMD (n=26) was associated with longer post-LMD survival [pLMD-OS: 15.4m vs. 5.2m, HR: 14.9, 95% CI: 0.01-0.30, p=0.0004] but similar overall survival [mOS: 17.1m vs. 12.3m; HR: 0.66; 95% CI: 0.3-1.58; p=0.38]. Post-LMD survival was significantly prolonged for supratentorial (n=28) versus infratentorial/spinal (n=4) locations regardless of the diagnostic modality [pLMD-OS: 2.6m vs. 11.3m, HR: 14.4, 95% CI: 2.73-75.7, p=0.0017], and did not significantly differ between symptomatic (n=20) and asymptomatic (n=23) patients [pLMD-OS: 4.8m vs. 11.2m, HR: 1.75, 95% CI: 0.82-3.77, p=0.15). pTERT mutation (81%), EGFR amplification (43%), and MGMT methylation (33%) were prevalent but IDH1 mutation was rare (2.8%). Comparison with a separate glioblastoma cohort (n=1400) suggested more frequent amplification of CHIC2, MDM4, and KDR, higher mutation rates of RUNX1, APC, and RAD51C, colder tumor microenvironment (TME), and lower expression of immune checkpoint-related genes.

CONCLUSIONS
Clinicopathological characteristics affect post-LMD survival, and cohort comparison suggests molecular and TME differences in LMD-HGG tumors.
PATH-29. BIOLOGIC AND CLINICAL SIGNIFICANCE OF NEOPLASTIC AND MYELOID STATES IN DIFFUSE GLIOMAS
Authors: Mehani Bharati , Asanigari Saleembhasha , Chung Hye-Jung , Dazelle Karen , Aldape Kenneth 
Published: November 2022

Abstract

INTRODUCTION
Interactions between neoplastic cell characteristics and the immune microenvironment is an important yet understudied area in diffuse gliomas. We examined this by analyzing single cell RNAseq data (n=290,738) from 35 glioma patients (in-house and GSE182109) including 24 IDH-wildtype and 11 IDH-mutant tumors at the single cell level. Cells were assigned to specific classes, including neoplastic cell states and myeloid components, based on established methods. We used these data to develop a signature matrix to deconvolve bulk RNAseq data from TCGA diffuse gliomas.

RESULTS
Clustering of neoplastic cells revealed 4 cell states: proneural, mesenchymal, proliferative and cancer signaling. Elevated proneural cell state was, as expected, positively correlated with IDH-mutant tumors, and elevated mesenchymal cell state was correlated with IDH wildtype tumors (both p&lt; 0.01, chi-square), Among IDH-mutant tumors, 1p/19q co-deletion was associated with the proneural state. Fourteen distinct myeloid cell subtypes were identified, and among them several were enriched for either microglial or macrophage (or both) markers. We examined relationships of neoplastic cell state with myeloid cell type abundance and significant associations were identified in both IDH-mutant tumors and IDH-wildtype tumors between specific myeloid cell states and myeloid clusters. Among IDH-mutant tumors, 1p/19q-co-deletion status was positively associated with abundance of a specific microglial cell cluster but negatively associated with abundance of 3 other myeloid cell clusters, suggesting substantial microenvironmental differences based on 1p/19q status in IDH-mutant tumors. In survival analyses, a specific myeloid cluster group proved interesting, with increased abundance of this group showing improved survival in both IDH-mutant and -wildtype tumors, in a manner that was enriched in specific neoplastic cell states. Overall, results suggest specific interactions between neoplastic cell characteristics, (cell states, IDH- and 1p/19q status), with myeloid cell and highlight the need of further studies understand the biological significance of the immune cell environment in diffuse gliomas.