bluuebunny/crossref_metadata_2025 huggingface dataset:
PATH-18. MORE UNUSUAL FEATURES IN H3 K27M-MUTANT GLIOMAS
Authors: DeMasters B K , Guzman Samuel , Ormond David
Published: November 2023

Diffuse midline glioma, H3 K27M-altered, WHO grade 4 is an infiltrating midline glioma; however, H3 K27M mutation can also be seen in midline circumscribed, non-infiltrating gliomas and rarely in non-midline tumors. We report 2 unusual examples. A 37-year-old female developed a right posterior frontal infiltrating glioma; resection showed infiltrative tumor with brisk mitotic activity, elevated MIB-1 (20%), negative p53 expression, ATRX retention, but no necrosis or microvascular proliferation. Molecular workup showed neither IDH1/2/TERT promoter mutations or co-deletion 1p, 19q; further testing showed gain of whole chromosome 7 + loss of whole chromosome 10, meeting molecular criteria for glioblastoma. Recurrent tumor 2 years later in the same area prompted re-resection again of infiltrating tumor devoid of necrosis or microvascular proliferation; molecular testing now revealed a H3F3A (p.K28M) mutation. Both tumors showed protein expression by H3 K27M IHC+. She succumbed post-therapy at 3 ½ years. A 30-year-old woman developed a circumscribed, non-enhancing third ventricular mass; resection demonstrated circumscribed, non-infiltrating glioneuronal tumor with monotonous rounded tumor nuclei, synaptophysin IHC+, negative GFAP, H3 K27M IHC+, and low MIB-1. Molecular testing identified alterations in H3F3A p. K28M and FGFR1 p.N546K. She was treated, but lost to follow-up, until she re-presented 5 years later with hemorrhagic left frontal lobe tumor contiguous with the midline, with dorsal midbrain and 4th ventricular involvement. After resection, tumor now showed infiltrative features, necrosis and microvascular proliferation, diffuse GFAP IHC+, retention of nuclear ATRX, p53 (20%), MIB-1 (22%), and H3 K27M IHC+. New tumor had no FGFR1 alteration or PDGFRA amplification to suggest radiation-induced tumor, instead manifesting PTPRZ1-MET fusion. She survives at 5 years. These cases offer new insights into survival of a non-midline example and transformation of a circumscribed, non-infiltrating tumor to secondary infiltrating H3 K27-altered tumor with new molecular alterations, possibly representing second independent tumor development.
PATH-20. IDH MUTANT ASTROCYTOMAS WITHOUT RECEIVING ADJUVANT TREATMENT DO NOT DEVELOP HYPERMUTATION OR SPECIFIC GENE MUTATION AND MYC, CDKN2A AND PDGFRA ARE INVOLVED IN MALIGNANT TRANSFORMATION
Authors: Li Kay Ka-Wai , Shi Zhi-Feng , Kwan Johnny Sheung-Him , Chan Danny Tat-Ming , Ng Ho-Keung
Published: November 2023

It is known that temozolomide treatment induces hypermutation and malignant transformation in IDH-mutant astrocytomas at recurrences and “wait-and-see” after resection is acceptable post-operative management. Although a small number of adjuvant-treatment-naive IDH-mutant low-grade astrocytomas have been embedded in well known series of longitudinal gliomas, little specific information is available about the natural evolution of IDH-mutant astrocytoma without selection pressures of temozolomide and irradiation. We studied 19 patients for tissues from primary and recurrent IDH-mutant 1p19q non-deleted Grade 2 gliomas and where no alkylating therapy or radiation was given between primary tumors and malignantly transformed recurrences (2 patients with multiple recurrences). Mean and median follow-ups were 123.1 and 138.8 months. We performed FISH for amplifications for MYC, PDGFRA, homozygous deletion (HD) for CDKN2A and for Alternative Lengthening for Telomeres (ALT). In the paired tumors from 12 patients, panel sequencing was performed. ATRX, p53, IDH mutations and ALT co-occurred in both primary and recurrent tumors for the same patients. MYC was found in tumors from 5/19 patients, three of which were found in the recurrences but not primary tumors. PDGFRA amplification was seen in tumors from six patients, four only in recurrences. Tumors from 11/19 patients showed either CDKN2A HD, MYC or PDGFRA amplification at recurrences. No hypermutated tumors could be found. Only 131 of a total 255 mutations were acquired in the recurrences. NOTCH1 mutation was found only in tumors from 2 patients. No recurrence-specific mutation was identified. p53 mutations when occurring in the primary tumors were associated with a shorter PFS (p=0.011). No mutation of the mismatch repair genes was found and only one POLE mutation was found. CONCLUSION: IDH-mutant low grade astrocytomas not being treated with temozolomide or irradiation do not develop hypermutation or specific gene mutation for their natural evolution and malignant transformation.
PATH-21. GPX4 IS CRUCIALLY IMPLICATED IN THE PATHOBIOLOGY OF GLIOBLASTOMA AND A PUTATIVE ACTIONABLE TARGET
Authors: Purkait Suvendu , Behera Minakshi , Sahu Rabi N , Ghosh Amit
Published: November 2023

BACKGROUND

Glioblastoma(GBM) is the most common malignant primary brain tumor with a dismal prognosis. Glutathione-mediated inhibition of the ferroptotic form of cell death is crucially implicated in various malignancies, which is principally regulated by glutathione peroxidase 4 (GPX4). However, there is limited data on GBM. The present study evaluated the expression of GPX4 in GBM and its implications in tumor biology, clinical outcome, and therapeutic potentials.

METHODS

The mRNA and protein expression was assessed by qRT-PCR and immunohistochemistry, respectively, in 75 cases of adult hemispheric GBMs (IDH wild type). For comparison, 21 lower-grade astrocytomas (IDH-mutant, grade-2/3) [LGA] and 20 cases were also evaluated. In-vitro analysis was performed on U87MG and LN229 glioma cell line.

RESULTS

The mRNA expression of GPX-4 was significantly higher in GBM than LGA, and normal brain (NB) [p-values 0.028, and 0.001, respectively]. Normal brain cases were negative for GPX4. Almost half of the GBMs (49.3%) showed strong immunoreactivity, which was higher than LGAs (23.8%) [p-value -0.04]. Inhibition of GPX-4 in-vitro by 1S-RSL3 & FIN56 was associated with decreased cell survival, proliferation, migration, invasion, and increased cell death. GPX-4 expression was not significantly associated with overall survival in GBM.

CONCLUSION

GPX-4 is crucial for the tumor cells' survival and aggressive biological behavior. Considering its immune-positivity only in the neoplastic cell and strong positivity in GBM it may be a useful adjunct to the diagnosis. The present study emphasized its role as a potential therapeutic target in the form of 1S-RSL3 & FIN56.
PATH-24. A CASE SERIES OF LONGER THAN EXPECTED SURVIVAL IN IDH-WILDTYPE, MGMT-UNMETHYLATED GLIOBLASTOMA PATIENTS
Authors: Lomax Jerica , Kong Xiao-Tang , Bota Daniela
Published: November 2023

Despite interventions with surgery, radiation, and chemotherapy, Glioblastoma (GBM) remains a difficult cancer to treat. Only 6.9% of patients survive five years post-diagnosis1 and the median overall survival is reported to be in the range of 14-15 months.2Glioblastoma patients who harbor an IDH-mutation have a known improved survival rate over their IDH-wildtype counterparts and under the recent WHO 2021 Classification of CNS tumors, IDH-mutational status is now an established criteria for the classification of high-grade gliomas. MGMT methylation status is also a well-described prognostic factor in GBM. MGMT methylated patients have a more favorable prognosis and better response to conventional treatment with temozolomide.3 It is rare but there are some IDH-wildtype, MGMT-unmethylated GBM patients who survive longer than 4 years. Therefore, it is important to identify other potential favorable factors for longer survival in the unfavorable cohort of patients with IDH-wildtype and MGMT-unmethylated GBM. Case Series: Eighty-five GBM patients who had next generation sequencing completed at the University of California, Irvine were reviewed. Of 85 patients, 4 patients (4.7%) were IDH-wildtype, MGMT-unmethylated and lived longer than 4 years. We evaluated the pathology, clinical characteristics, treatment course, and molecular findings of these 4 long term GBM survivors with IDH-wildtype and MGMT-unmethylated status. Discussion: This case series of 4 cases of patients with IDH-wildtype, MGMT-unmethylated GBM with longer than expected survival did not reveal a ubiquitously prevalent molecular marker for long term survival based on review of next-generation sequencing results. 2 out of the 4 patients harbored an uncommon MTAP copy number loss mutation, which may warrant further investigation into the significance of this mutation on prognosis. 3 out of 4 patients received a vaccine-based intervention through clinical trial which may support ongoing investigation into the additional benefit this specific population of GBM patients may have from vaccine-based therapy.
PATH-27. DROPLET DIGITAL PCR ENHANCES DETECTION OF HOTSPOT MUTATIONS IN CIRCULATING TUMOR DNA FROM CEREBROSPINAL FLUID OF PATIENTS WITH HIGH-GRADE GLIOMA
Authors: Tartaro Marlene , Nandakumar Subhiksha , Hertz Charli Ann , Holle Bridget , Hill Katherine , Lapshina Maria , Farina Andrea , Arcila Maria , Miller Alexandra , Mellinghoff Ingo
Published: November 2023

Molecular profiling of circulating tumor DNA (ctDNA) from cerebrospinal fluid (CSF) has the potential to enhance diagnosis, prognosis, and longitudinal monitoring for glioma patients through a minimally invasive approach. We previously detected somatic mutations from gliomas in CSF samples using MSK-IMPACT™, a 505-gene FDA-authorized next-generation DNA sequencing panel, and detected tumor-derived mutations in 50% of samples of patients with high-grade gliomas (HGG). To investigate whether we could enhance sensitivity of CSF ctDNA profiling and biomarker detection, we tested MSK-IMPACT™ pre-capture NGS residual DNA libraries from 43 CSF ctDNA samples by droplet digital PCR (ddPCR) for detection of key recurrent alterations in IDH1, BRAF, TERT, H3F3A, and TP53 using previously validated probes. Residual libraries contained a median of 18.0ng of DNA library (range, 0.0153-18.0ng). Of the 7 samples positive for IDH1 R132H, TERT C228T, or TERT C250T mutations in MSK-IMPACT™, we found that ddPCR accurately detected all mutations (7/7, 100%), confirming sensitivity of ddPCR in CSF ctDNA. We also tested 36 mutation-negative samples by MSK-IMPACT™ for the corresponding undetected mutations, of which 7 were tested for two mutations. Overall, ddPCR detected 41.9% (18/43) of previously undetected mutations. Specifically, we found that ddPCR rescued hotspot mutations such as BRAF V600E (2/3, 66.7%), IDH1 R132G/H (3/8, 37.5%), TERT C228T (11/26, 42.3%), and TERT C250T (2/4, 50.0%). Collectively, our results suggest that a combined-modality approach involving MSK-IMPACT™ and ddPCR enables comprehensive assessment of limited CSF ctDNA samples with high sensitivity and provides a minimally invasive methodology to molecularly profiling glioma.
PATH-31. RECURRENT COPY NUMBER CHANGES IN GLIOBLASTOMA, IDH-WILDTYPE: ARE OTHER +7/-10 PATTERNS CLINICALLY RELEVANT?
Authors: Choate Lauren , Pazdernik Vanessa , Kollmeyer Thomas , Praska Corinne , Jenkins Robert , Ida Cristine
Published: November 2023

Glioblastoma (GBM), IDH-wildtype (WT) is currently defined as an IDH-WT and H3-WT diffuse astrocytic glioma with molecular diagnostic features including whole +7/−10, TERT promoter (TERTp) mutation, and EGFR amplification and/or morphological diagnostic features such as necrosis and microvascular proliferation. To further understand the diversity of copy number signatures of GBM, IDHWT and evaluate the diagnostic utility of other recurrent copy number changes, we analyzed paired chromosomal microarray and next-generation sequencing mutational profiling data from 418 adult IDH-WT and H3-WT tumors with GBM morphological diagnostic features. The most common molecular features were TERTp mutations (85%), CDKN2A/B heterozygous/homozygous deletion (78%/66%), +7/-10 (63%), EGFR amplification (41%), +19 (36%), PTEN mutations (35%), partial -13 (33%), partial -14 (33%), +20 (32%), TP53 mutations (32%), and partial -22 (29%). At least one molecular diagnostic biomarker was present in 92% (n=385) of cases, and 29% (n=121) of cases had all three. The +7/-10 biomarker was the most frequent chromosomes 7/10 copy number change (68%, n=265). Other +7/-10 patterns were seen in 30% (n=125) of cases and included isolated +7 or -10, combinations of +7 and -10 with partial +7, partial -10 or 10 copy neutral loss of heterozygosity (cnLOH). Overall, 93% (390/418) of cases had whole and other chromosome 7/10 copy number changes. In comparison to tumors with +7/-10, tumors with other +7/-10 patterns were significantly enriched for partial 13 loss (Bonferroni adjusted p=0.04) but were not associated with significant difference in patient overall survival (p=0.30, 158/418 had available survival data). Our findings reiterate and expand the spectrum of copy number changes associated with GBM, IDH-WT. The similar overall survival rates between cases with the +7/-10 biomarker and those with other +7/-10 patterns suggest that other +7/-10 patterns may be functionally equivalent to +7/-10 and diagnostically relevant as a molecular diagnostic biomarker for this tumor type.
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

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

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 >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

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

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

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

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

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

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 >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 >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

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

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< 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< 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.
NIMG-23. COMBINATION OF ADC MRI AND FET PET FOR THE ASSESSMENT OF QUANTITATIVE TUMOR PRESENCE IN DIFFUSE GLIOMA
Authors: Tjin Joe Kaithlyn Tjong , Wesseling Pieter , Barkhof Frederik , Beliën Jeroen , Yaqub Maqsood , Pouwels Petra , Verhaak Roel , Reijneveld Jaap , Rozemuller Annemieke , Vandertop Peter , Boellaard Ronald , Barthel Floris , Hamer Philip de Witt , van de Giessen Elsmarieke , Verburg Niels
Published: November 2023

BACKGROUND

Local treatment of diffuse glioma is currently guided by standard MRI sequences. Yet, the combination of apparent diffusion coefficient (ADC) and O-(2-[18F]-fluoroethyl)-L-tyrosine positron emission tomography (FET PET) (ADC/FET) detects qualitatively assessed histopathological tumor presence more accurately than standard MRI imaging. It is unknown whether this is similar for quantitatively assessment of tumor presence. This study compares the diagnostic accuracy of standard imaging and ADC/FET for detecting quantitatively assessment of tumor presence in diffuse glioma.

METHODS

Fifteen patients with newly diagnosed diffuse glioma were retrospectively included. Pre-operative MRI and FET PET imaging were available. Multiregional image-guided stereotactic biopsies were acquired before craniotomy. Quantitative imaging data from regions-of-interests (ROIs) centered at the biopsy locations was obtained. For each biopsy sample, semi-automatic cellularity and proliferation index, as well as DNA methylation-based tumor purity, was determined. Linear mixed models were used to evaluate which modalities were significant independent predictors for each tumor presence marker, and fitness was assessed using Bayesian Information Criterium.

RESULTS

125 biopsies were analyzed (75 from eight high grade and 50 from seven low grade gliomas). Cellularity was associated with T1 weighted MRI (p = 0.033), ADC (p = 0.016) and ADC/FET (p < .001), with ADC/FET as best fit. ADC/FET was the only modality associated with proliferation index (p = 0.003) and with tumor purity (p < .001).

CONCLUSION

Combined ADC and FET PET is stronger associated with cellularity, proliferation index and tumor purity than standard MRI imaging. These findings may pave the way towards ADC/FET-guided local treatment of diffuse gliomas.
NIMG-26. DIFFERENTIATION OF IDH-WILDTYPE GLIOBLASTOMA AND TUMEFACTIVE MULTIPLE SCLEROSIS USING PRE-OPERATIVE BRAIN MRI AND DEEP LEARNING: RIGOROUS AND UNBIASED EXPERIMENTAL DESIGN AND ANALYTICAL APPROACH
Authors: Conte Gian Marco , Decker Paul , Kosel Matthew , Kollmeyer Thomas , McCarthy Christina , Sagen Jessica , Nikanpour Yalda , Fereidan-Esfahani Mahboubeh , Erickson Bradley , Jenkins Robert , Lachance Daniel , Tobin W Oliver , Eckel-Passow Jeanette
Published: November 2023

Clinical management of IDH wildtype glioblastoma (GBM) and tumefactive multiple sclerosis (tMS) is drastically different. GBM requires maximal safe resection followed by chemoradiation, while tMS outcome is worsened by surgery and radiotherapy. Misdiagnosis of brain lesions may expose patients to unnecessary anxiety, surgery, or radiotherapy. Noninvasive methods to help with accurate diagnosis of tumor and non-tumor etiologies are needed. tMS subjects were identified by the Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology (CMSAN). GBM subjects were matched to tMS by age at diagnosis, index MRI date, and sex. Inclusion criteria included one cm minimal lesion size and pre-operative post-contrast T1 and T2 images available for analysis. To identify potential experimental design bias, MRI technology and clinical characteristics were compared across groups. A 3D-DenseNet121 was used to develop a classification model using prespecified parameters: 600 epochs, batch size 16, learning rate 10-3, cross entropy loss, and AdamW optimizer. The stopping rule was defined as three sequential epoch cross entropy loss < 0.02. Five-fold cross validation (CV) was utilized to obtain an unbiased estimate of predictive performance (overfitting) and sensitivity of the 3D-DenseNet121 algorithm was evaluated. 224 subjects (114 GBM, 110 tMS) were analyzed: 40% male, median age 46. After one round of CV, the average unbiased estimate of sensitivity and specificity for predicting GBM from the final classification model was 0.86 and 0.73, respectively. To assess the reproducibility of the deep learning algorithm (3D-DenseNet121), the exact same CV folds were rerun resulting in average sensitivity and specificity of 0.82 and 0.75, respectively. Obtaining unbiased estimates of model performance using internal validation is critical before evaluating a final model on an external dataset. Understanding sensitivity of a deep learning algorithm is important for model validity. Differentiation of GBM and tMS appears reasonable with MRI; external validation is in progress.
NIMG-28. DIFFUSION DIFFERENCES IN LOW TO HIGH GRADE GLIOMA TRANSFORMATION
Authors: Flatley Michael , Duenweg Savannah , Lowman Allison , Bobholz Samuel , Stebbins Margaret , Winiarz Aleksandra , Nath Biprojit , Kyereme Fitzgerald , Connelly Jennifer , Coss Dylan , Krucoff Max , Banerjee Anjishnu , LaViolette Peter
Published: November 2023

PURPOSE

Apparent diffusion coefficient (ADC) maps offer tremendous insight into cellularity and local tissue environment. Proliferation of tumor cells results in increased local cellularity and cell density, thus impairing the free diffusion of water molecules. Therefore, hypointense ADC signals are thought to reflect regions of increased cellularity, and are useful imaging markers for distinguishing neoplastic cellular processes. In this study, we tested the hypothesis that changes in ADC intensity over the course of disease progression differ in progressing gliomas within the tumor-delineated region.

METHODS

Sixty-three glioma patients from our brain bank were separated into two groups. Group 1 included patients with Grade 1-3 gliomas at surgical diagnosis and progressed to a Grade 4 glioma at autopsy. The second group of patients were those with an initial and final Grade 4 glioma diagnosis. Contrast-enhancing tumor regions on MRI sequences were annotated with an established machine-learning algorithm for each patient on their initial and final MRIs. Average ADC intensity within the contrast enhancing regions was extracted and change in signal intensity between the first and last MRI was calculated for each patient. Finally, the mean intensity difference between Group 2 and Group 1 were evaluated using a linear mixed model.

RESULTS

We report a negative mean difference between the Group 2 and Group 1s change in ADC intensity over time (p=0.03).

CONCLUSIONS

These findings suggest changes in cellularity, identified by ADC, are greater in patients who progress from low-to-high grade gliomas. With these results, it may be concluded that change in ADC hypointensity, as a proxy for cellularity, may be a defining imaging characteristic to identify progressing gliomas.
NIMG-29. ADVANCED MRI BIOMARKERS PREDICT EARLY RESPONSE TO TUMOR TREATING FIELDS IN GLIOBLASTOMA
Authors: Schmainda Kathleen , Prah Melissa , Connelly Jennifer
Published: November 2023

BACKGROUND

Tumor-treating fields (TTFields) is a novel US FDA-approved antimitotic treatment modality for patients with newly diagnosed and recurrent glioblastoma, shown to improve both OS and PFS (Stupp et al 2015). Yet, how to best monitor response to TTfields remains unclear. Conventional (anatomic) MRI is unreliable, often showing initial early radiographic progression followed by tumor regression and clinical benefit, thereby delaying confirmation of response. To address this limitation, we evaluate the utility of quantitative (physiologic) MRI biomarkers.

METHODS

Patients with newly diagnosed or recurrent IDH wildtype glioblastoma who underwent MRI with DSC-MRI perfusion imaging at 1-2, 3-4 and 5-6 months after TTField treatment were retrospectively identified for this study. Delta T1 (dT1) images were created from standardized (calibrated) pre- and post-contrast T1-weighted images, from which an enhancing lesion volume was objectively determined. Standardized and leakage-corrected relative cerebral blood volume (sRCBV) images were created from the DSC-MRI data. Together, dT1 and sRCBV were used to generate class maps of fractional tumor burden (FTB), which identify highly-vascular and avascular (treatment effect) regions within contrast-enhancement. Kaplan-Meier survival analysis was performed to determine if positive versus negative changes in these metrics, at each time-point relative to pre-treatment values, are predictive of survival.

RESULTS

20 patients with newly diagnosed (n=17) or recurrent (n=4) IDH wildtype glioblastoma with a mean TTField compliance of 74.9% were identified. At 1-2 months no metric predicted a survival difference, consistent with the known 4-week delay in tumor stabilization following TTField therapy. At months 3-4 and 5-6 decreasing dT1-determined enhancing volumes showed a survival benefit (p=0.0081, p=0.03). Likewise, a decreasing percentage of highly-vascular tissue, determined from FTB class maps, demonstrated a survival benefit (p=0.0013).

CONCLUSIONS

Quantitative MRI metrics, including dT1-derived enhancing volumes and FTB/sRCBV-defined regions of high vascularity, demonstrate an ability to provide early indicators of response to TTField treatment.
NIMG-37. FUNCTIONAL MRI AND DTI TRACTOGRAPHY AS ADJUNCTS TO IMPROVE THE PREDICTIVE VALUE OF TMS FOR CORTICAL LANGUAGE SITES
Authors: Muir Matthew , Prinsloo Sarah , Noll Kyle , Kumar Vinodh , Traylor Jeffrey , Prabhu Sujit
Published: November 2023

Surgeons must maximize the extent of resection while minimizing postoperative neurological morbidity in patients with eloquent gliomas. Transcranial magnetic stimulation (TMS) has emerged as a novel non-invasive technique to map the functional language cortex. However, multiple studies have documented the plethora of false positives that decrease the predictive value of TMS for intraoperative functional sites. Here we hypothesize that diffusion tensor imaging (DTI) tractography and functional magnetic resonance imaging (fMRI) can serve as adjuncts to identify true positive TMS preoperatively and increase the positive predictive value (PPV). We used a distortion correction algorithm to overlay the postoperative MRI with the preoperative surgical plan and correlated the resection versus preservation of certain structures with functional outcomes measured by pre to postoperative change in the Western Aphasia Battery (WAB) score in a cohort of 61 patients with language eloquent gliomas. We found that the resection of TMS points alone does not correlate with aphasic surgical deficits. We then seeded DTI tractography with TMS points and investigated the effect of progressively increasing fractional anisotropic (FA) thresholds. We found that the resection of TMS points with connecting white matter tracts identified at the 50%, 75%, and 85% FA thresholds strongly correlated with surgical deficits. (r=.38, p=.002; r=.61, p< .001, r=.54, p< .001) The PPV increased with increasing FA thresholds. The highest PPV was 50% at the 75% and 85% FA thresholds while the highest negative predictive value was 98% at the 75% FA threshold. We then combined fMRI with TMS and DTI tractography by only using fMRI-colocalized TMS points for tractography seeding. The PPV increased to 63% but the correlation coefficient with aphasic deficits stayed at .61. This study shows that adjunctive modalities can significantly increase the predictive value of TMS for preoperatively identifying true positive cortical sites of language function.