bluuebunny/crossref_metadata_2025_split huggingface dataset:
PATH-45. OUTCOMES OF AN IRRADIATION SPARING APPROACH IN MEDULLOBLASTOMA BY SUBGROUP IN YOUNG CHILDREN: AN INSTITUTIONAL REVIEW
Authors: Ronsley Rebecca , Yip Stephen , Dunham Christopher , Hukin Juliette , Finlay Jonathan 
Published: November 2023

Abstract

OBJECTIVE
To describe disease outcomes including overall survival and relapse patterns by subgroup in young pediatric patients treated for medulloblastoma with an irradiation-sparing approach.

METHODS
Retrospective analysis of clinical outcomes including treatment, relapse and salvage therapy and late effects in children treated for medulloblastoma with a radiation-sparing approach at British Columbia Children’s Hospital (BCCH) between 2000 and 2020.

RESULTS
There were 30 patients (median age 2.8 years, 60% male) treated for medulloblastoma with a radiation-sparing approach at BCCH. Subgroups included Sonic Hedgehog (SHH, (n=14), Group 3 (n=7), Group 4 (n=6) and indeterminate status (n=3). Three and 5-year event-free survival (EFS) and overall survival (OS) were 49.0% (30.2 and 65.4%) and 42.0% (24.2-58.9%) and 62.5% (42.4 and 77.2%) and 66.0% (95% CI 46.0-80.1%) and 62.5% (95% CI 42.5 and 77.2%) respectively, with a median follow up of 9.5 years. Relapse occurred in 12/25 patients following a complete response, of whom six (Group 4: n=4, Group 3: n=1, unknown: n=1) were successfully salvaged with craniospinal axis (CSA) RT and remain alive at a median follow up of seven years. Disease/treatment-related morbidity included endocrinopathies (n=8), hearing loss n=16), and neurocognitive abnormalities (n=9).

CONCLUSIONS
This radiation sparing treatment approach for young patients with medulloblastoma resulted in a durable cure in most patients with SHH subgroup medulloblastoma. In those patients with Group 3 and 4 medulloblastoma, relapse rates were high; however, most Group 4 patients were salvaged with RT.
PATH-46. A NOVEL POT1-TPD PRESENTATION: A GERMLINE POT1 MUTATION DISCOVERED IN A PATIENT WITH NEWLY DIAGNOSED POSTERIOR FOSSA EPENDYMOMA
Authors: Gilene Stephen , Raskin Scott , Roy Somak , Knapke Sara 
Published: November 2023

Abstract

INTRODUCTION
POT1 tumor predisposition (POT1-TPD) is an autosomal dominant disorder characterized by increased lifetime malignancy risk. Melanoma, angiosarcoma and chronic lymphocytic leukemia are the most frequently reported malignancies. Other related cancers include gliomas. Protection of telomeres protein 1 is part of the shelterin protein complex to maintain/protect telomeres. Proposed mechanisms for oncogenesis with POT1 loss of function include telomere elongation and DNA damage response causing genomic instability. Ependymomas are a heterogeneous group comprising 12% of pediatric brain tumors and are locally aggressive with frequent recurrence.

CASE PRESENTATION
A healthy 3-year-old male presented with worsening vertigo, headaches, and emesis. Radiographic studies demonstrated a midline posterior fossa mass in the fourth ventricle. Following a gross total resection, pathology demonstrated a posterior fossa ependymoma, group A. Next generation sequencing (NGS) using our institution’s clinically validated panel, “CinCSeq”, demonstrated a POT1 splice site variant (c.1164-1G &gt;A; variant allele frequency 46%). Paired germline testing via the molecular characterization initiative confirmed this variant as a heterozygote in the patient. Genetic testing confirmed a germline mutation in his mother who has a history of multiple nevi. He completed treatment with focal proton radiotherapy with no evidence of disease recurrence to date.

DISCUSSION
To our knowledge, this represents the first documented pediatric ependymoma with a familial, germline POT1 mutation. Somatic POT1 mutational frequency as determined by NGS in 60,000 solid tumors occurs at a rate of 2.94%. 45/60,000 were ependymomas with 1 non-benign POT1 mutation. Alterations of telomere maintenance have been reported in infratentorial ependymomas through increased human telomerase reverse transcriptase (hTERT) expression. This case sheds light on potential new mechanisms/predispositions for ependymoma development and the expanding phenotype of POT1-TPD. We recognize the POT1 mutation may have been discovered incidentally in this case. Further research into an association between POT1 and ependymomas is needed to advance our understanding.
PATH-49. COMPREHENSIVE RNA-SEQ ANALYSIS REVEALS NOVEL SUBTYPES OF MENINGIOMAS AND PREDICTS PATIENT OUTCOME.
Authors: Nayanga Thirimanne H , AlmironBonnin Damian , Nuechterlein Nicholas , Arora Sonali , Jensen Matt , Parada Carolina Da Silva , Szulzewsky Frank , English Collin , Chen William , Sievers Philipp , Nassiri Farshad , Wang Justin , Patel Akash , Raleigh David , Zadeh Gelareh , Aldape Kenneth , Klisch Tiemo J , Sahm Felix , Ferreira Manuel , Holland Eric 
Published: November 2023

Abstract

OBJECTIVE
Meningiomas are the most common intracranial tumor in humans. While most tumors are benign, some are malignant and ultimately lethal. Current grading systems based on WHO grade do not provide adequate risk stratification, therefore, better characterizations of the biology of aggressive meningiomas are needed. METHOD: We obtained 12 datasets from 9 institutions and 5 countries in North America, Europe and Asia and combined them with ~300 tumors sequenced from the University of Washington to create a set of ~1300 meningioma tumors. Raw sequencing data was aligned to hg38, batch corrected and then dimension reduction of normalized counts was performed to create a UMAP landscape. Differential expression analysis and gene set enrichment analysis were performed to elucidate the underlying biology of meningioma subtypes.

RESULTS
The analysis revealed nine distinct meningioma subtypes through unsupervised clustering. Clinical metadata, DNA sequencing, copy number alterations, and gene-fusion data effectively correlated with these identified clusters. These subtypes exhibited specific biological signatures. Notably, regional distribution of time to recurrence identified subtypes as well as intra-cluster differences of meningiomas with varying patient outcomes. The most aggressive subtype, characterized by higher WHO grades, frequent tumor recurrences, and shorter time to recurrence, exhibited elevated proliferation rates and RNA expression resembling embryonic limb development. To facilitate clinical applications, we developed a cross-validated nearest-neighbors-based algorithm that accurately mapped new patients onto this UMAP landscape, achieving a remarkable 95% accuracy.

CONCLUSION
Our study highlights the utility of RNA sequencing in discerning meningioma heterogeneity and provides a valuable tool in predicting tumor biology and patient prognosis. The integration of our UMAP landscape with patient data offers an effective approach for personalized treatment strategies.
PATH-50. GENETIC AND EPIGENETIC PROFILING OF MENINGIOMAS TO GAIN INSIGHTS INTO MOLECULAR HETEROGENEITY AND RISK STRATIFICATION.
Authors: Suri Vaishali , Singh Jyotsna , Suri Ashish , Sharma M C 
Published: November 2023

Abstract

BACKGROUND
Meningiomas are slow-growing CNS tumors, with most being benign (WHO grade 1) and having indolent behavior. Limited data on molecular profiling of meningiomas and its clinical implications have hindered the implementation of effective therapies and new treatments. Aims & Objectives: Perform DNA methylation profiling, copy number analysis, and targeted sequencing in meningiomas. MATERIALS &

METHODS
208 meningiomas, grade 1 (n=109), grade 2 (n=83), and grade 3 (n=16)were assessed for pTERT mutation, CDKN2A homozygous deletion, and H3K27me3 expression. Additionally, 35 diagnostically challenging meningiomas underwent DNA methylation profiling, copy number analysis, and targeted sequencing.

RESULTS
there were 199 adult and 9 pediatric cases, (mean age 44.5 years). The tumors were located in basal (53%) ,convexity (42%),and 5% in other locations.pTERT C228T mutation was detected in 4.8% and CDKN2A deletion in 2.4% cases. Loss of H3K27me3 expression was found in a significant proportion of tumors across all three grades. Methylation profiling identified four distinct molecular subgroups: Malignant, Intermediate, Benign A, and Benign B. Intermediate, Benign A, and Benign B subgroups included both WHO grade 1 and grade 2 cases. Mutations showed a strong association with specific methylation subgroups (NF2, AKT1, SMO, TRAF7, and pTERT). Loss of chromosome 22q was observed in all subgroups. 1p/14q co-deletion was predominantly seen in the malignant and intermediate subgroups (50%). CDKN2A loss was mainly observed in the malignant subgroup (50%). The DKFZ classifier successfully classified 71% of cases with an acceptable score. Methylation profiling significantly influenced PFS in WHO grade 1 and 2 meningiomas (p=0.0051).

CONCLUSIONS
Genome-wide DNA methylation profiling reveals clinically distinct molecular subgroups and heterogeneity within the same grade of meningiomas and is particularly valuable for identifying high-risk cases and predicting prognosis in WHO grade 1 and 2 meningiomas. The pTERT mutation serves as a significant and cost-effective marker for risk stratification in meningiomas.
PATH-52. MENINGIOMA MOLECULAR GROUPS PREDICT RESPONSE TO SURGERY AND RADIOTHERAPY
Authors: Wang Justin , Patil Vikas , Landry Alexander , Ajisebutu Andrew , Liu Jeff , Yakubov Rebeca , Gao Andrew , Cohen-Gadol Aaron , Wilson Christopher , Chotai Silky , Holland Eric , Barnholtz-Sloan Jill , Tabatabai Ghazaleh , Makarenko Serge , Yip Stephen , Sahm Felix , Mansouri Sheila , Wei Qingxia , Aldape Kenneth , Nassiri Farshad , Zadeh Gelareh 
Published: November 2023

Abstract

INTRODUCTION
Aside from surgery, radiotherapy (RT) remains the only accepted treatment for meningiomas. However, patient selection for adjuvant RT remains controversial. We aimed to evaluate whether novel molecular and methylation groups could more accurately predict outcomes following surgery and adjuvant RT compared to WHO grade using a large clinical-molecular dataset. Method: We utilized publicly available, clinically annotated molecular datasets of meningiomas and generated de novo DNA-methylation and RNA-sequencing data. Meningiomas were classified into different molecular and methylation groups based on the methodologies of their original publications (Nassiri et al. [2021], Bayley et al.[2022], Choudhury et al.[2022], Sahm et al.[2017]) and progression-free survival (PFS) following surgery with and without adjuvant RT were analyzed.

RESULTS
A total of 2029 meningiomas from 11 different institutions with adjuvant RT data were included. Adjuvant RT was associated with improved PFS in WHO grade 1 meningiomas following subtotal resection(STR) and WHO grade 2 meningiomas following gross total resection(GTR) or STR. Multivariable analysis using Cox proportional hazards regression models showed that having a meningioma belonging to a hypermetabolic (MG3)(HR 3.63, 95%CI 1.47-8.99), or proliferative (MG4)(HR 7.24, 95%CI 2.84-18.49) molecular group were associated with worse PFS following surgery and adjuvant RT when controlling for age, gender, WHO grade, and extent of resection. Meningiomas belonging to DKFZ MC-intermediate, MC-malignant and UCSF hypermitotic methylation groups were also associated with worse outcomes. These relationships held true even in subgroup analysis with only WHO grade 2 meningiomas and following propensity score matching for the same clinical covariates above. Nearly all molecular and methylation classifications predicted 5-year PFS including following surgery and adjuvant RT (area under the curve [AUC] 0.61-0.72) better than WHO grade (AUC 0.51).

CONCLUSIONS
Molecular classification improves clinical outcome prediction for meningiomas following surgery and adjuvant radiotherapy, supporting the rationale for molecularly informed treatment decisions and potential clinical trial stratification.
PATH-55. "UNRAVELING THE COMPLEXITIES OF RECURRENT PLEOMORPHIC XANTHOASTROCYTOMA: INSIGHTS FROM ABERRANT IMMUNOHISTOCHEMISTRY AND BRAF V600E MUTATION."
Authors: Ferrer Marisol , Kahl Susana , Nallino Belén , Nallino José , Fauceglia Juan Gil , Ferrer Jaime 
Published: November 2023

Abstract

INTRODUCTION
Pleomorphic xanthoastrocytoma (PXA) is a rare brain tumor that accounts for less than 0.3% of primary central nervous system (CNS) tumors, with an annual incidence of less than 0.7 cases per 100,000 population. PXAs typically express glial fibrillary acidic protein (GFAP), and S100 is often diffusely positive in these tumors. Objetive: To present a long-term multi-recurrence of PXA spanning 12 years which exhibits unusual histological features and an aberrant immunophenotype profile. Patient and methods: We reevaluted the primary tumor, performed a wide panel of immunohistochemistry ( Benchmark Gx Roche) and add molecular testing of BRAFp.V600E mutation and CDKN2 deletion.

RESULTS
The tumor present fibrillar and epitheliod features in the first recurrence and rhabdoid morphology in the subsequent two resections. All of them were characterized by the absence of GFAP and S100 expression with focal myogenin positivity. This variation in immunohistochemistry adds to the diagnostic challenge in identifying the tumor correctly.The patient's clinical history and the molecular results played a crucial role in defining the diagnosis and guiding treatment decisions. After complete surgical resection the patient received anti-BRAF treatment and has shown an excellent clinical response thus far.

CONCLUSIONS
This case highlights the extreme pleomorphism of PXA, as evidenced by the unusual histological features and aberrant immunophenotype observed. It emphasizes the diagnostic challenge presented when morphological and immunohistochemical characteristics deviate from the usual pattern. Molecular biology techniques, including genetic testing, are crucial in such cases to aid in accurate diagnosis, guide treatment decisions, and improve patient outcomes.
NIMG-06. BRAINSTEM NON-ENHANCING DIFFUSION-RESTRICTING T2 FLAIR HYPERINTENSITY AFTER EGFR TYROSINE KINASE INHIBITORS: AN EARLY SIGN OF LEPTOMENINGEAL DISEASE?
Authors: Kaur Jaspreet , Pham Nhat-Long , Ilyas Omer , Mo Fan , Bao Silin , Yuen Carlen 
Published: November 2023

Abstract
Leptomeningeal disease (LMD) is a late complication of non-small cell lung cancer (NSCLC) patients and carries poor prognosis. The discovery of EGFR mutations as actionable drivers launched a new treatment paradigm with EGFR tyrosine kinase inhibitors (TKIs) for NSCLC patients, including those with LMD. LMD is characterized by leptomeningeal enhancement on post-contrast MRI. Adverse effects of EGFR TKIs are well described, but little is known about non-enhancing LMD in this patient population. Previously described only in case studies, this rare and novel imaging abnormality is characterized by non-enhancing band-like diffusion-restricting T2 hyperintensity surrounding the brainstem and is thought to be an early marker of LMD. Positive CSF cytology confirms the diagnosis. The mechanism is unknown, but is thought to be a result of highly cellular tumor invasion and subsequent capillary microinfarctions. Early evidence suggests that NSCLC patients with non-enhancing cerebral hemispheric LMD carry improved overall survival compared to those with contrast-enhancing disease. We present a case of a 75-year-old female with NSCLC brain metastases responsive to 3 EGFR inhibitors and non-enhancing brainstem LMD. Three CSF cytologic examinations were negative for malignant cells. She remains clinically and radiographically stable at 8-month follow-up. This case is significant because it contributes to the small existing body of literature for this atypical radiographic finding. We propose that non-enhancing LMD in NSCLC patients being treated with EGFR TKIs is a potential surrogate marker for response to treatment.
NIMG-07. LONG-TERM FOLLOW-UP OF SCHWANNOMA GROWTH BEHAVIOR IN ADULT SCHWANNOMATOSIS PATIENTS USING WHOLE-BODY MRI
Authors: Ly Ina , Merker Vanessa , Cai Weni , Bredella Miriam , Thalheimer Raquel , Da Jennifer , Herr Hamilton , Silverman Danielle , Orr Christina , Chang Connie , Harris Gordon , Plotkin Scott R , Jordan Justin T 
Published: November 2023

Abstract

BACKGROUND
The schwannomatoses include NF2-related schwannomatosis (NF2-SWN, formerly known as “NF2”) and non-NF2-related schwannomatosis (e.g. SMARCB1- and LZTR1-related schwannomatosis) and are caused by distinct germline pathogenic variants on chromosome 22. Patients may develop cranial, peripheral, and/or spinal nerve schwannomas. Except for vestibular schwannomas, the long-term growth behavior of schwannomas is unknown but this is important to guide patient surveillance and selection for treatment. Whole-body MRI (WBMRI) can detect whole-body schwannoma burden.

METHODS
16 NF2-SWN and 12 non-NF2-SWN patients with WBMRI acquired between 2007-2010 underwent a repeat WBMRI between 2018-2022. Non-vestibular schwannomas were segmented on short tau inversion recovery (STIR) sequences. Tumor volume was calculated using a 3D tumor quantification software (3DQI). Tumor growth and shrinkage were defined as a volume change ³20% over the entire study period.

RESULTS
Median time between scans was 10.3 years. Median age was 43.5 years at baseline and 54 years at follow-up. Excluding resected tumors, 102 schwannomas (49 NF2-SWN, 53 non-NF2-SWN) were analyzed. 62/102 (61%) tumors grew &gt;20% (65% NF2-SWN, 57% non-NF2-SWN); median growth was 96% in NF2-SWN and 94% in non-NF2-SWN. 24/102 (24%) tumors shrank &gt;20% (20% NF2-SWN, 26% non-NF2-SWN); median shrinkage was 49% in NF2-SWN and 40% in non-NF2-SWN. 29 new tumors developed between scans (16 NF2-SWN, 13 non-NF2-SWN). Of 32 NF2-SWN tumors exposed to systemic or radiation therapy, 63% grew and 31% shrank. Of 7 non-NF2-SWN tumors exposed to treatment, 29% grew and 42% shrank. 11 non-NF2-SWN tumors shrank spontaneously without treatment. Spontaneous tumor shrinkage was not observed in NF2-SWN.

CONCLUSIONS
About 60% of SWN-associated schwannomas grow significantly over a decade. Spontaneous shrinkage is only observed in non-NF2-SWN tumors whereas, in NF2-SWN patients, about 60% of tumors grow despite treatment, suggesting a more aggressive tumor phenotype in NF2-SWN. Correlation of MRI findings with patient-reported outcomes and hormone exposure history are ongoing.
NIMG-08. ANALYSIS OF11C-METHIONINE PET UPTAKE AND PROGNOSIS IN LOWER GRADE GLIOMAS
Authors: Tamura Kaoru , Inaji Motoki , Yamamura Toshihiro , Hara Shoko , Shimizu Kazuhide , Tanaka Yoji , Nariai Tadashi , Ishii Kenji , Maehara Taketoshi 
Published: November 2023

Abstract

PURPOSE
The 2021 WHO Classification of Tumors of the Central Nervous System incorporates molecular alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. This study aimed to assess the correlation between 11C-methionine uptake, molecular features and prognosis in newly diagnosed lower-grade gliomas (LGGs).

METHODS
93 newly diagnosed LGG patients (Grade 2: 39 patients, Grade 3: 54 patients) who underwent surgery at Tokyo Medical and Dental University Hospital from 2000 to 2020 and imaged preoperatively using 11C-methionine PET were retrospectively included in this study. These patients were re-classified according to the 2021 WHO classification. The tumor-to-normal ratio (T/N) of 11C-methionine uptake was calculated by dividing the mean standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain.

RESULTS
44 out of 93 gliomas were IDH wild-type tumors and re-classified as glioblastoma or pediatric-type gliomas according to the 2021 WHO classification and therefore excluded from the analysis. Remaining 49 LGGs were re-classified in two types- Oligodendrogliomas, IDH-mutant and 1p/19q- codeleted (n=25), and Astrocytomas, IDH-mutant (n=24)- following the indications provided by the 2021 WHO classification. The median T/N ratio in Oligodendrogliomas, IDH-mutant and 1p/19q- codeleted were 1.83 in grade 2 and 2.83 in grade 3, which were significantly higher than those in Astrocytoma, IDH-mutant (grade2: 1.38, grade3:1.62). Kaplan–Meier survival analysis revealed that Oligodendroglioma, IDH-mutant and 1p/19q- codeleted had significantly better outcomes regardless of WHO grade.

CONCLUSION
The results indicated that LGG categories reclassified with molecular classification correlate with the T/N ratio of methionine uptake and the prognosis.
NIMG-11. AUTOPSY-BASED RADIO-PATHOMIC MAPS OF TISSUE COMPOSITION DELINEATE IDH1 STATS IN GLIOMAS
Authors: Bobholz Samuel , Lowman Allison , Duenweg Savannah , Winiarz Aleksandra , Stebbins Margaret , Flatley Michael , Nath Biprojit , Kyereme Fitzgerald , Connelly Jennifer , Coss Dylan , Krucoff Max , Banerjee Anjishnu , LaViolette Peter 
Published: November 2023

Abstract
Isocitrate dehydrogenase 1 (IDH1) mutation status is used as an important prognostic marker for gliomas, where IDH1-wildtype patients see shorter survival than patients with an IDH1 mutation. This study uses radio-pathomic maps of cell, extracellular fluid (ECF), and cytoplasm (Cyt) density developed using conventional MRI and aligned autopsy samples to test the hypothesis that IDH1-mutant tumors differ in contrast-enhancing and non-enhancing tissue composition from IDH1-wildtype tumors. A total of 426 patients from the UCSF-PDGM data set (380 IDH1-wildtype, 46 IDH1-mutant) were included in this study. T1, T1C, FLAIR and ADC images from each patient’s pre-surgical MRI were used to generate whole brain radio-pathomic maps of cell, ECF, and Cyt density using a previously reported algorithm. This tool was trained using aligned autopsy samples as ground truth and is particularly adept at highlighting areas of tumor beyond traditional imaging signatures. The mean value from each feature map was computed for each patient both within non-necrotic contrast enhancement and non-enhancing FLAIR hyperintensity. Higher ECF density (F=15.45, p&lt; 0.001) and lower Cyt density (F=8.51, p=0.004) was observed within contrast-enhancement for IDH1 mutant patients, with no difference observed for cell density within contrast enhancement between mutation statuses (F=0.03, p=0.86). Higher cell density (F=4.16, p&lt; 0.042), Higher ECF density (F=4.65, p=0.032), lower Cyt density (F=4.48, p=0.035) was also found in patients with IDH1 mutations in the non-enhancing FLAIR hyperintense region. These results suggest that the large-scale tissue composition of IDH1-mutant tumors may differ from IDH1-wildtype tumors, suggesting differences in growth patterns and pathological composition between tumor types. Future studies examining how tissue composition post-treatment over time may elucidate how pathological characteristics evolve for each tumor type.