bluuebunny/crossref_metadata_2025 huggingface dataset:
IMMU-26. RADIATION AND TEMOZOLOMIDE UP-REGULATES CD70 EXPRESSION AND ENHANCES CAR T- CELL RECOGNITION IN GBM
Authors: Na Meng , Jin Linchun , Tao Haipeng , Hou Alicia , Karachi Aida , Lin Zhiguo , Deleyrolle Loic , Sayour Elias , Mitchell Duane , Huang Jianping
Published: November 2019

BACKGROUND

Glioblastoma (GBM) is a recalcitrant brain cancer in the clinic. The therapeutic effect of using standard care (SC), such as surgery, radiation and/or temozolomide (TMZ) is dismal. CAR T-cell therapy has been increasingly recognized in the field as an innovative therapeutic approach for this malignancy. We identified CD70 as a glioma marker, and show that CD70CAR T cells recognize CD70+ GBMs and mediated regression of established tumors. Since recurrent GBMs that had been heavily treated by the SC treatments expressed a relatively higher level of CD70 than primary tumors, we thus hypothesize that these modalities may help to enhance the expression of CD70 and therapeutic effect of the CD70CAR T cell therapy in GBM.

OBJECTIVE

To determine if radiation or TMZ treatments could influence the CD70 expression of GBM, and the CD70CAR T-cell recognition.

METHODS

CD70 expression on GBM cell lines, including primary GBMs (CD70+ or CD70-) and U87 (CD70+), were assessed after treating with escalated doses of irradiation or TMZ. The protein and gene expression were determined by FACS or qRT-PCR analysis, respectively, at 4, 24, 48, and 120 hours post irradiation or TMZ treatment. Tumor recognition post-treatment was also carried out. Paired samples using an RNA-seq dataset from TCGA before and after tumor recurrence were evaluated for the CD70 expression.

RESULTS

CD70 expression was markedly increased by irradiation or TMZ treatment in a dose-dependent manner (beginning at 24 hours) in vitro in CD70+ GBMs, and a slight increased in the CD70— GBMs. The treatments enhance CD70CAR T cell recognition. Up-regulation of CD70 was found in the paired GBM patients.

CONCLUSION

This study demonstrates that the irradiation or TMZ treatment significantly up-regulates CD70 expression on GBMs and the CAR-T cell recognition, providing a rationale to combine CD70CAR-T cell therapy with SC for enhanced therapeutic efficacy in GBM.
IMMU-40. CANCER IMMUNOEDITING SHAPES THE IMMUNE ESCAPE SIGNATURE AND CLONAL ARCHITECTURE IN GLIOMAS
Authors: Lamszus Katrin , Mohme Malte , Maire Cecile , Riecken Kristoffer , Alawi Malik , Fehse Boris , Westphal Manfred
Published: November 2019

Immunotherapeutic strategies are increasingly important in neuro-oncology, and the elucidation of escape mechanisms which lead to treatment resistance is crucial. Understanding heterogeneous clonal dynamics and emergence of immune escape variants during cancer immunoediting can yield valuable insights into the adaptive processes governing treatment resistance. We applied a recently developed multicolor labeling strategy termed optical barcoding to compare in vivo clonality in an immunocompetent vs immunodeficient environment. Optically barcoded GL261 glioma cells were implanted in parallel into the brains of i) wildtype (wt) C57BL/6 mice, ii) immunodeficient Pfp-/- Rag2-/- mice or iii) PD1-/- mice and tumor growth was monitored. Ex vivo analysis of individual tumor clones revealed that tumors in immunocompetent mice had a profoundly different clonal architecture compared to immunodeficient mice. Whereas tumors in pfp-/- rag2-/- mice exhibited a highly polyclonal composition, immunoedited tumors in wt and PD1-/- mice showed reduced clonality with emergence of immune escape clones, independent of in vitro proliferation rates. Survival of wt mice was significantly longer than of Pfp-/- Rag2-/- mice and was even more prolonged in PD1-/- mice. Immunoediting in immunocompetent mice was further associated with striking differences in vascularity and invasiveness. Time-course microarray analyses, flow-cytometric phenotyping of tumor-infiltrating immune cells and immunostaining highlighted the role of PD-L1 and other immunosuppressive mediators as mechanisms to adapt to T-cell infiltration and IFN-ɣ production. Furthermore, RNAseq profiling of FACS-separated tumor cells, T cells and macrophages/microglia allowed the identification of IFN-ɣ-mediated T-cell-shaped gene expression signatures and of new pathways potentially involved in the immune escape of gliomas. To conclude, the process of cancer immunoediting during tumor evolution not only shapes gene expression profiles and growth patterns, but also has a profound impact on the intratumoral clonal heterogeneity in malignant gliomas.
IMMU-43. POLYAMINE METABOLISM REGULATES MYELOID IMMUNE SUPPRESSION IN GLIOBLASTOMA
Authors: Miska Jason , Lee Chang Catalina , Rashidi Aida , Han Yu , Lopez-Rosas Aurora , Lesniak Maciej S
Published: November 2019

Tumor-associated myeloid cells, which consist of tumor associated macrophages and myeloid-derived suppressor cells (MDSCs), make up a majority of cellular infiltrates in glioma. Glioma infiltrating MDSCs highly express arginase-1 (Arg-1), a catabolic enzyme thought to deplete arginine from the tumor microenvironment. Despite being a well-known marker of immunosuppressive cells, the metabolic reasons for this choice are not clear. Examination of MDSC phenotype in murine glioma models using: RNA-seq, bulk metabolomics, and Carbon-13 arginine flux revealed that two separate pathways of arginine catabolism converge on the generation of ornithine. Ornithine is the prerequisite substrate for the de-novo generation of polyamines, a group of nitrogen-rich metabolites with foundational importance to all mammalian, bacterial, and plant biology. Importantly, we found that the rate-limiting step of polyamine generation, ornithine decarboxylase 1 (ODC1), is dramatically upregulated by glioma infiltrating MDSCs, suggesting de-novo polyamine generation is important for MDSC function. Treatment with a specific inhibitor of de-novo polyamine synthesis, difluoromethylornithine (DMFO), inhibited the immunosuppressive function of in-vitro generated glioma associated MDSCs. However, DFMO only exerted effects before differentiation, as DFMO treatment post-generation did not change their suppressive functions. This suggests that the generation of the polyamine pool is critical to immune suppression by MDSCs. Interestingly the expression of the rate limiting step of polyamine degradation (SAT1) is inversely correlated with (ODC1) during MDSC differentiation, suggesting that utilization of this polyamine pool may be required for the suppressive functions of these cells. Inhibition of SAT1 after MDSC generation blunted MDSC mediated T-cell suppression. The results of this study show that the role of arginine metabolism in tumor infiltrating MDSCs is to generate pools of polyamines which maintain MDSC function in glioma. Therapeutic targeting of this pathway may be a novel and powerful tool to combat immunosuppression in glioma.
IMMU-45. CAR-T TREATMENT OF NOVEL MOUSE MODEL OF EGFRVIII+ GBM MIRRORS CLINICAL TRIAL OUTCOMES AND PROVIDES A SYNGENEIC PLATFORM FOR THE INVESTIGATION OF CAR-T MECHANISMS OF ACTION
Authors: Chuntova Polly , Yamamichi Akane , Naka Ryosuke , Hou Yafei , Okada Hideho
Published: November 2019

Despite the recent successes in cancer immunotherapy, brain tumors continue to present a significant challenge due to the unique relationship between the CNS and the immune system. Adoptive cell transfer of chimeric antigen receptor T-cells (CAR-T cells) targets tumor-associated and tumor-specific antigens. Multiple clinical trials testing CAR-T cells in the brain tumor setting have demonstrated the feasibility and safety, but also highlighted the limitations and continued need for treatment improvement. These challenges include recurrence of tumor cells that do not express the target antigens and induction of immuno-regulatory mechanisms, such as PD-L1 expression within the tumor. In this study, we used a murine GBM cell line (SB28), engineered to express the tumor-specific neoantigen human epidermal growth factor receptor variant III, to study the in vivo effects of EGFRvIII-CAR T-cells in a novel fully immunocompetent mouse model. SB28 cells have been shown to recapitulate key characteristics of human GBM, such as aggressive growth, low mutation burden, and resistance to immune checkpoint blockade therapy, and therefore, allow us to investigate many clinically relevant questions and variations in treatment protocol. Intravenous administration of CAR-transduced murine T-cells in EGFRvIII-expressing SB28 tumors showed survival benefit only when preceded by a lymphodepleting regimen. Despite prolonging survival, EGFRvIII-CAR-T cells were not curative, and the recurrent tumors displayed profound antigen loss, similar to post-treatment human tumor samples. Preliminary mechanistic studies revealed upregulation of IFNγ-inducible molecules, such as PD-L1 on tumor cells and tumor-infiltrating myeloid cells, as well as the emergence of a small, but discreet population of activated antigen presenting cells. Currently ongoing studies are aimed at delineating the exact molecular and cellular changes in the tumor microenvironment in response to the EGFRvIII-CAR T-cell treatment, in combination with clinically relevant therapies targeting the largely immunosuppressive tumor myeloid compartment
IMMU-50. SYSTEMIC ADOPTIVE TRANSFER IMMUNOTHERAPY WITH TCR-TRANSDUCED T-CELLS TARGETING NY-ESO-1 FOR MENINGIOMA
Authors: Sun Matthew , Orpilla Joey , Contreras Erick , Treger Janet , Molaie Donna , Tsang Jonathan , Antonios Joseph , Wang Anthony , Liau Linda , Prins Robert , Everson Richard
Published: November 2019

INTRODUCTION

The lack of immunotherapeutic antigen targets selectively expressed on meningiomas have historically hindered its immunotherapy development. However, recent literature showed that in meningiomas, NY-ESO-1 is the most frequently expressed Cancer-Testis(CT)-antigen, which is a group of proteins silent in somatic cells but reactivated in cancers. NY-ESO-1 also has higher expression in higher-grade meningiomas. Decitabine is known to upregulate CT-antigens and augment immunotherapy. To evaluate systemic adoptive transfer for meningiomas, we tested the efficacy of NY-ESO-1 T-cell-receptor(TCR)-transduced T-cells in vitro and in vivo, and the role of decitabine in meningioma immunotherapy.

METHODS

NY-ESO-1 TCR-Transduced T-cells were generated by double-transfection with supernatants from PG-13 retroviral packaging cell line encoding HLA-A*0201–restricted NY-ESO-1(157 – 165)-specific TCR. In vitro cytolysis was measured using the xCelligence Real-Time Cell Analyzer System. We utilized human meningioma cells SF1335(Grade I, HLA-A2.1 positive) and CH157(Grade III, HLA-A2.1 negative) in vitro and in vivo.

RESULTS

CH157 and SF1335 have high and low NY-ESO-1 expression, respectively. Decitabine upregulated NY-ESO-1 mRNA expression in SF1335 by 6-fold after 2 days and by 100-fold after 9 days, with similar effect on protein expression. Co-culturing CH157, CH157-HLA-A2.1(CH157 transduced with HLA-A2.1 vector), SF1335, and decitabine-pretreated-SF1335 cells individually with NY-ESO-1 TCR transduced T-cells at a ratio of 1:1 resulted in 0%, 65%, 20% and 40% cytolysis at 10hours, respectively. Systemic(intravenous) adoptive transfer of TCR-transduced T-cells significantly increased overall survival in NSG mice with intracranial xenografts of CH157-HLA-A2.1 (p=0.04) and SF1335(not treated with decitabine) (p=0.06).

CONCLUSIONS

NY-ESO-1 TCR-transduced T-cells induce NY-ESO-1 and HLA-A2.1-specific cytolysis in meningioma in vitro, and systemic adoptive transfer confers a statistically significant survival benefit in vivo for meningiomas with high NY-ESO-1 expression. Decitabine upregulates NY-ESO-1 expression and increases tumor cytolysis by TCR-transduced T-cells in meningiomas. Targeting NY-ESO-1 may be a clinically feasible immunotherapeutic strategy to treat aggressive meningiomas.
INNV-08. VALIDATION OF READIBAND™ ACTIGRAPH AND ASSOCIATED SLEEP/WAKE CLASSIFICATION ALGORITHMS IN PREDICTING CANCER-RELATED FATIGUE IN HIGH GRADE GLIOBLASTOMA
Authors: Tipps Megan , Hultman Meghan , Banerji Nilanjana , Jackson Kelsey , Liu Minda , Ellenberger Amy , Sanville Emily , Trusheim John
Published: November 2019

INTRODUCTION

Standard care for glioblastoma consists of maximal surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide. Fatigue and sleep disturbances are among the most common side-effect reported by these patients. Monitoring long-term sleep patterns and fatigue levels in this population would allow for comparison between iatrogenic sleep disturbances, disease progression, treatment tolerance, and self-reported levels of fatigue. Wearable actigraph devices provide a potential alternative approach to polysomnography for long-term sleep monitoring. Here, we describe initial results from the implementation of the Readiband™ Sleep Tracker (Fatigue Science) for monitoring sleep patterns and fatigue in newly diagnosed glioblastoma patients.

PATIENTS AND METHODS

Patients with primary glioblastoma were prospectively enrolled and asked to wear the Readiband™ Sleep Tracker for a maximum of twelve months or until disease progression. Data regarding alertness levels and sleep patterns were collected from Fatigue Science. Patients were also asked to report fatigue levels and sleep quality via the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Pittsburg Sleep Quality Index (PSQI) questionnaires, respectively. Demographic, pathologic, and clinical information was abstracted from electronic medical records.

RESULTS

The Readiband™ data includes sleep/wake assessments, as well as sleep quality, sleep efficiency, and alertness scores. The overall sleep patterns reported by Readiband™ align with self-reported sleep times and sleep quantity. In addition, the SAFTE™ alertness scores show a positive correlation with FACIT-F (r=0.80) scores, and the sleep quality scores generated by Readiband™ show a negative correlation with PSQI (r=-0.83) scores.

CONCLUSION

The Readiband™ Sleep Tracker is a convenient and viable approach for monitoring sleep and fatigue in glioblastoma patients. Our preliminary findings suggest that actigraph measures can be used to monitor sleep quality and predict fatigue in this population. The study is ongoing to understand implications of sleep patterns on disease progression and treatment tolerance in primary glioblastoma.
INNV-12. OUTCOMES IN A REAL-WORLD PRACTICE FOR PATIENTS WITH PRIMARY GLIOBLASTOMA: IMPACT OF A SPECIALIZED NEURO-ONCOLOGY CANCER CARE PROGRAM
Authors: Banerji Nilanjana , Hultman Meghan , Tipps Megan , Liu Minda , Bruns Patricia , Trusheim John
Published: November 2019

INTRODUCTION

Standard care for newly diagnosed glioblastoma consists of maximal surgical resection followed by radiotherapy with concurrent and adjuvant temozolomide. Prognosis for glioblastoma still remains poor, with a reported median survival of 14.6 months. Published data indicate that optimal outcomes in this population require involvement of an experienced team providing multidisciplinary care. We report here the outcomes in a real-world setting for glioblastoma patients treated at a specialized neuro-oncology cancer care program.

PATIENTS AND METHODS

Data from fifty consecutive patients with primary glioblastoma pursuing care at the Givens Brain tumor Center were analyzed. Coordinated medical care was provided by dedicated neuro-oncology and surgical clinicians, supplemented by care from nurse coordinators, social workers, care guides, genetic counselors, and other specialties. Demographic, pathologic, and clinical information was abstracted from electronic medical records.

RESULTS

Median patient age was 58 (range, 23–80) years and 26% were ≥65 years of age. Gross total resection was achieved in 91.5% patients, with 56% of resections performed in the Institution’s iMRI suite. A majority of patients received radiation and chemotherapy. In accordance with cancer program guidelines, 48% of the cases were presented at multidisciplinary tumor conferences. A LifeCourse™ care guide was utilized by 30% of the patients. Bevacizumab was used as second-line therapy with/without carboplatin in 63.2% patients. Optune treatment was administered to 27 patients. Additionally, eligible patients enrolled in clinical trials both at primary and recurrent stages. Median progression-free survival (PFS) and overall survival (OS) was 9.1 (range, 2.2–30.5) months and 19.4 (range, 4.6–31.8) months, respectively. End-of-life hospice care was elected by 48% patients.

CONCLUSION

PFS and OS in this real-world settings were comparable to outcomes noted in controlled clinical trials. These results indicate that efficient, quality care may be achieved with a multidisciplinary treatment approach, producing exceptional survival rates in patients with glioblastoma.
INNV-21. IN NEWLY-DIAGNOSED GLIOBLASTOMA, FRAILTY/SARCOPENIA PREDICTS 30D MORBIDITY & 30D, 90D, AND OVERALL MORTALITY AS ACCURATELY AS CURRENT STANDARDS
Authors: Zakaria Hesham , Chandra Ankush , Macki Mohamed , Robin Adam , Walbert Tobias , Chang Victor , Kalkanis Steven , Lee Ian
Published: November 2019

INTRODUCTION

Identification of novel prognostic biomarkers for glioblastoma (GBM) could stratify patients between aggressive or palliative treatments. Frailty, as measured by sarcopenia (lack of muscle mass), has been proven to predict survival in cancers. We evaluate whether the frailty/sarcopenia phenotype (FSP) predicts morbidity and mortality in GBM, and compare it to other survival markers.

METHODS

In 257 patients undergoing initial diagnostic surgery for GBM, FSP was defined by temporalis muscle thickness from preoperative MRI; patients were grouped into tertiles (thirds) based on size, which corresponded to the severity of FSP. Morbidity and mortality hazard ratios were calculated from surgery using multivariate analysis, accounting for age, gender, past medical history, tumor focality / laterality / eloquence / volume, extent of resection, MGMT / IDH status, and initiation of postoperative chemo/radiation. Morbidity was defined as any of these events within 30d: DVT, PE, SSI, UTI, MI, urinary retention, ileus, readmission.

RESULTS

FSP at diagnostic surgery predicted any morbidity (OR2.98, P= 0.005) at 30d. FSP at diagnostic surgery was the only risk factor associated with 30d mortality (OR10.0, P= 0.030), and was also strongly associated with 90d mortality (OR25.0, P= 0.003). FSP at diagnostic surgery was associated with decreased overall survival (OR0.41, P< 0.001) at a level comparable to other mortality predictors, including temozolomide/EBRT (OR0.27), gross total resection (OR0.54), favorable MGMT (OR0.44) or IDH (OR0.44) mutations. Kaplan-Meier curves display overall survival based on severity of FSP.

CONCLUSION

FSP is a preoperative, simple, accurate, and non-invasive methodology to predict 30d morbidity & 30-day, 90-day, and overall mortality from diagnosis in GBM. FSP is independent of age (not an age surrogate), demographic, oncologic, genetic, surgical, and therapeutic factors. Mortality prediction is comparable to temozolamid/EBRT, total resection, MGMT, and IDH. It is a low cost, intuitive, and potentially universal methodology to guide treatment decision making.
INNV-33. BARRIERS TO ACCRUAL AND ENROLLMENT IN BRAIN TUMOR TRIALS
Authors: Lee Eudocia , Chukwueke Ugonma , Hervey-Jumper Shawn , DeGroot John , Leone Pablo , Armstrong Terri , Chang Susan , Arons David , Oliver Kathy , Verble Kay , Musella Al , Willmarth Nicole , Alexander Brian , Bates Amanda , Doherty Lisa , Galanis Evanthia , Gaffey Sarah , Halkin Thomas , Friday Bret , Fouladi Maryam , Lin Nancy , Macdonald David , Mehta Minesh , Penas-Prado Marta , Vogelbaum Michael , Sahebjam Solmaz , Sandak David , van den Bent Martin , Weller Michael , Reardon David , Wen Patrick
Published: November 2019

BACKGROUND

A major impediment to improving neuro-oncology outcomes is poor clinical trial accrual.

METHODS

We convened a multi-stakeholder group including Society for Neuro-Oncology, Response Assessment in Neuro-Oncology, patient advocacy groups, clinical trial cooperative groups, and other partners to determine how we can improve trial accrual.

RESULTS

We described selected factors contributing to poor trial accrual and possible solutions. We focused on patient and community factors, disparities, physician and provider factors, clinical trial factors, and site and organizational factors

CONCLUSIONS

We will implement strategies with the intent to double accrual to neuro-oncology trials over the next 5 years.
INNV-34. PATTERNS OF FAILURE AND DEVELOPMENT OF A NOVEL PROGNOSTIC SCORING SYSTEM IN ELDERLY PATIENTS WITH GLIOBLASTOMA – FOLLOW UP ON 10 YEAR ANALYSIS OF THE BC CANCER AGENCY POPULATION
Authors: Zeng Jonathan , DeVries Kimberly , Krauze Andra
Published: November 2019

PURPOSE

Glioblastomas (GBM) are the most common primary brain tumour recurring in most patients despite maximal management. Patient selection for appropriate treatment modality remains challenging resulting in heterogeneity in management. We examined the patterns of failure and developed a scoring system for patient stratification to optimise clinical decision making.

METHODS

822 adults (BC Cancer Agency registry) diagnosed 2005–2015 age ≥60 with histologically confirmed GBM ICD-O-3 codes (9440/3, 9441/3, 9442/3) were reviewed. Univariate and Kaplan-Meier analysis were performed. Performance status (PS), age and resection status were assigned a score, cummulative maximal (favorable) score of 10 and minimum (unfavorable) score of 3. Patterns of failure were further analysed in the subset of patients with radiographic follow-up.

RESULTS

PS score of 3(KPS >80, ECOG 0/1), 2 (KPS 60–70, ECOG 2), 1 (KPS < 60, ECOG 3/4) (median OS 11, 6, 3 months respectively), age score and resection status were prognostic for OS with PS resulting in the most significant curve separation (p< 0.0001). Biopsy as compared to STR/GTR resulted in poorer OS in patients over 70 (age score 1/2) but had less impact in patients younger than 70 (age scores 3/4). The median OS for cumulative scores of 9/10 (123 patients), 7/8 (286 patients), 5/6 (313 patients), and 3/4 (55 patients) were 14, 8, 4 and 2 months respectively (p< 0.0001) allowing for stratification into 4 prognostic groups. 133 patients had >3 MRIs following diagnosis allowing for clinical and radiographic analysis of progression. Clinical/radiographic progression occurred within 3 months (29%/45%), 6 months (50%/66%), 9 months (70%/81%). Progression type (radiographic, clinical, both was not associated with OS.

CONCLUSION

Our novel prognostic scoring system is effective in achieving patient stratification and may guide clinical decision making. Early radiographic progression appears to precede clinical deterioration and may represent true progression in the elderly.
MNGI-05. COMBINED MULTIMODAL TREATMENT REGIMEN IN RECURRENT MENINGIOMAS
Authors: Carrillo Jose , Wagle Naveed , Barkhoudarian Garni , Kelly Daniel , Heng Annie , Gill Jaya , Juarez Tiffany , Kesari Santosh
Published: November 2019

Meningiomas are the most common primary brain tumor, subsequent tumor progression can be problematic for surgical treatment options based upon location. Currently there is limited activity of various single agent medical therapies. We evaluated a combined treatment modality in recurrent Meningiomas. Patients were consented to NOC study protocol JWCI-17–0401 in this retrospective analysis. Treatment consisted of combination Octreotide LAR, Everolimus, Hydroxyurea, and Mifepristone. Patient characteristics in the combined treatment meningioma group (n=12) had a median age 60, 50% male, 47% WHO grade I, 37% WHO grade II, 11% WHO grade III, 67% skull base location, median number of recurrences is 2.2, with median number of surgeries of 1.7. Total comparison meningioma patients (n=19) with median age 62, 42% male, 42% WHO grade I, 50% WHO grade II, 17% WHO grade III, 58% skull base location, median number of recurrences is 2.2, with median number of surgeries of 2.2. Median PFS in recurrence prior to initiation of multimodal combined therapy, mPFS=283 days. Median PFS with subsequent multimodal combined therapy, mPFS=318 days. Multimodal therapy may prolong mPFS in recurrent meningiomas. Our pilot data supports further clinical trials in combined multimodal treatments.
MNGI-08. PHARMACOKINETIC ANALYSIS OF 68GA-DOTATOC IN MENINGIOMAS USING PET/CT FOR ASSESSMENT OF SOMATOSTATIN RECEPTORS AND CORRELATION WITH ANGIOGENESIS, INFLAMMATION AND PROLIFERATION
Authors: Bashir Asma , Bitsch Vestergaard Mark , Binderup Tina , Broholm Helle , Marner Lisbeth , Ziebell Morten , Fugleholm Kåre , Kjær Andreas , Law Ian
Published: November 2019

BACKGROUND

A quantitative correlative analysis between 68Ga-DOTATOC accumulation using PET/CT and somatostatin receptor subtype 2 (SSTR2) in meningiomas was conducted. The possible contributions of angiogenesis and inflammation were investigated as well.

METHODS

Fifteen patients with newly (n = 12) and recurrent (n = 3) meningiomas were prospectively assigned to a 60-minute dynamic 68Ga-DOTATOC PET/CT scan prior to surgery. PET data included measurements of maximum and mean standardized uptake value (SUVmax, SUVmean) with/without normalisation to different reference tissues, and quantitative measures derived from kinetic modeling using a reversible two-tissue compartment model with the fractional blood volume (VB) included in the model. The SSTR2-expression was determined by immunohistochemistry and quantitative polymerase chain reaction (qPCR), while biomarkers of inflammation (macrophage-specific marker CD68, interleukin-18 [IL18]) and angiogenesis (endothelial marker CD34, vascular endothelial growth factor-A [VEGF-A]), were assessed by qPCR only.

RESULTS

Twelve patients (80%) were diagnosed with World Health Organization (WHO) grade I meningioma and three with WHO grade II (20%). No significant differences in SSTR2-expression was seen between WHO grades or subtypes (P ≥ 0.05; Mann-Whitney, Kruskal-Wallis). Upon stratification of patients based on the median SUVs (SUVmax, 20.9; SUVmean, 9.9), SSTR2-expression was seven-fold increased in patients with SUVs above the medians compared to patients with SUVs below the medians. Spearman’s rank correlation coefficient revealed significant correlations between SSTR2-expression, and SUVmean (r = 0.532, P = .041) and mean tumor-to-neck muscle ratio (TNMRmean) (r = 0.593, P = .020). 68Ga-DOTATOC uptake was additionally associated with VB and VEGF-A (P < 0.01), while no association with inflammatory biomarkers were found. In univariate linear regression analysis, SUVmean and TNMRmean remained the optimal surrogate biomarkers for SSTR2-expression (P < .0001).

CONCLUSIONS

68Ga-DOTATOC accumulation in meningiomas is more complex than previously reported, and may not be limited to the SSTR2-density but also be associated with the vascular component.
PATH-01. MGMT METHYLATION CUTOFF VALUE IN QUANTITATIVE ANALYSIS RELATED TO PROGNOSIS OF NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Adachi Jun-ichi , Shirahata Mitsuaki , Suzuki Tomonari , Mishima Kazuhiko , Nishikawa Ryo
Published: November 2019

BACKGROUND

MGMT promoter methylation is an important biomarker related to glioblastoma therapeutic response and prognosis. There are qualitative and quantitative methods as assays for MGMT methylation. Although the qualitative method is common, there is a disadvantage that low or high methylation cannot be distinguished. The quantitative method is an excellent method for evaluating methylation of tumors characterized by intratumoral heterogeneity like malignant glioma, but cutoff value of methylation that defines the prognosis of glioblastoma is unknown. Therefore, we examined the cutoff value of quantitative MGMT methylation assay determining the prognosis in glioblastoma.

METHODS

180 newly diagnosed glioblastoma which underwent radiotherapy and temozolomide treatment after tumor removal in our department were included. MGMT methylation was quantitatively analyzed by methylation-specific high resolution melting (MS-HRM) analysis. For each level of methylation, progression-free survival (PFS) and overall survival (OS) were calculated and statistically analyzed.

RESULTS

In the low MGMT methylation cases in which the proportion of methylation was 25% or less in PFS and 30% or less in OS, no difference was observed in PFS and OS as compared with those of unmethylated cases. The cutoff value of MGMT methylation most contributing to survival was calculated to be 35% by the survival classification and regression tree method.

CONCLUSION

The prognosis for MGMT hypomethylated group is as poor as unmethylated one. In the quantitative MS-HRM method, we found that the value of MGMT methylation of 35% is useful as a cut off determining the prognosis of glioblastoma.
PATH-02. A COMBINATION OF MGMT METHYLATION AND NFKBIA COPY NUMBER ALTERATION REFINES PROGNOSTICATION OF IDH-WT GLIOBLASTOMAS
Authors: Umehara Toru , Arita Hideyuki , Yoshioka Ema , Shofuda Tomoko , Kinoshita Manabu , Kodama Yoshinori , Kagawa Naoki , Okita Yoshiko , Nonaka Masahiro , Uda Takehiro , Fukai Junya , Sakamoto Daisuke , Mori Kanji , Kishima Haruhiko , Kanemura Yonehiro
Published: November 2019

INTRODUCTION

Recent studies have reported that NFKBIA deletion (dNFKBIA) was potentially associated with worse prognosis in glioblastoma (GBM) patients. However, no consensus has been reached to its universal prognostic value. Here, we investigated the survival impact of dNFKBIA using two primary IDH wild-type GBM cohorts: an original Japanese cohort and a dataset from The Cancer Genome Atlas (TCGA). Additionally, prognostic impact of a combination of NFKBIA copy number and MGMT methylation status was evaluated.

METHOD

The Japanese cohort was collected from cases registered in Kansai Molecular Diagnosis Network for CNS tumors (KNBTG). The survival impact of dNFKBIA and/or unmethylated MGMT (uMGMT) were analyzed for 212 KNBTG cases and 265 TCGA cases. The hazard ratio (HR) and p-value were computed using Cox regression analysis.

RESULTS

dNFKBIA was less frequently observed in KNBTG (47 cases, 22.2%) than in TCGA (84 cases, 31.7%). dNFKBIA was associated with unfavorable prognosis in KNBTG (HR 1.52, p = 0.031), while this was not validated in TCGA (HR 1.14, p=0.406). uMGMT was a common adverse prognostic factor in KNBGT (HR 1.72, p = 0.001) and TCGA (HR 1.50, p = 0.008) cohort. When stratified by NFKBIA status, uMGMT was also associated with shorter survival in NFKBIA deleted cases both in KNBTG (HR 1.87, p = 0.002) and TCGA (HR 1.59, p = 0.014). On the other hand, MGMT status was not significantly associated with prognosis in NFKBIA intact cases in either KNBTG (HR 1.45, p = 0.279) or TCGA (HR 1.55, p = 0.131).

DISCUSSION

Although the prognostic value of dNFKBIA in IDH wild-type GBM patients was not validated in TCGA cohort, our results indicated that the prognostication based on MGMT methylation was potentially interacted by NFKBIA status.
PATH-07. MITOTIC INDEX THRESHOLDS DO NOT PREDICT CLINICAL OUTCOME FOR IDH-MUTANT ASTROCYTOMA
Authors: Yoda Rebecca , Marxen Troy , Longo Lauren , Ene Chibawanye , Wirsching Hans-Georg , Keene Dirk , Holland Eric , Cimino P J
Published: November 2019

Current histological grading recommendations for isocitrate dehydrogenase (IDH)-mutant astrocytoma are imprecise and not reliably predictive of patient outcome, while somatic copy number alterations are emerging as important prognostic biomarkers. One explanation for this relative underperformance of histological grading is that current criteria to distinguish World Health Organization (WHO) grade III anaplastic astrocytomas from lower-grade diffuse astrocytomas (WHO grade II) are vague (‘increased mitotic activity’). This qualitative approach ensures diagnostic uncertainty and a broad ‘gray zone’ where both diffuse and anaplastic designations can reasonably be assigned. Thus, we hypothesized that interobserver variability and lack of defined mitotic thresholds for IDH-mutant astrocytomas underlies poor predictive accuracy of current histologic grading approaches. To test this hypothesis, we quantified total mitotic figures and maximum mitotic activity per ten high-powered fields in an institutional cohort of IDH-mutant astrocytomas. In our cohort, there was no mitotic activity threshold that was reflective of clinical progression-free or overall survival. Furthermore, in a multivariate Cox regression model consisting of mitotic activity, molecular markers, and clinical characteristics, only CDKN2A deletion was identified as a relevant variant for poor overall survival. We conclude that lack of defined mitotic figure thresholds may not contribute to underperformance of histological grading for IDH-mutant astrocytomas. This study supports the shift towards ‘molecular grading’ to replace traditional histological grading for IDH-mutant astrocytomas.
PATH-20. INVESTIGATION OF CLINICALLY AGGRESSIVE SPINAL CORD EPENDYMOMA THROUGH METHYLATION ANALYSIS
Authors: Briceno Nicole , Abdullaev Zied , Vera Elizabeth , Blumental De Abreu Francine , Quezado Martha , Pack Svetlana , Xi Liqiang , Raffeld Mark , Gilbert Mark , Aldape Kenneth , Armstrong Terri
Published: November 2019

Spinal ependymoma is a rare, often low-grade tumor, for which the clinical course and prognosis has been poorly defined. Classification has relied on histological criteria, as there are few defining molecular mutations, causing controversy in diagnosis and grading. DNA methylation analysis with the brain tumor classifier was used on tumor tissue from 37 patients identified from the Neuro-Oncology Branch Natural History Study and selected Collaborative Ependymoma Research Network (CERN) Tissue Repository. These were histologically diagnosed with non-myxopapillary spinal ependymoma (92% grade II and 8% grade III), with 12 designated “poor performers” (50% male, median age 30 years) defined by a progression free survival of less than two years (median 7 months) with at least one recurrence. Alternatively, the 25 “good performers” (56% male, median age 43 years) had no progression with a follow-up time greater than 5 years (median 84 months). Methylation classification matched to “spinal ependymoma” in 33% of the poor performer cases while 8% matched myxopapillary or RELA-fusion ependymoma and 50% were no-match. For the good performers, 52% agreed with histological diagnosis, 28% matched myxopapillary and 20% were no-match. Interestingly, we noted high-level MYCN amplification by copy number analysis in two (17%) cases, neither of which matched to a defined methylation class, and both of which were in the poor performers group. Overall, methylation results reveal complex biology in conventional spinal cord ependymomas, most evident in an increase of no-match cases in the poor performers group. Of importance, the no-match cases contain evidence of a potentially new diagnostic entity characterized by both a poor prognosis and MYCN amplification. For further elucidation of this entity, a larger cohort of patients with expanded clinical criteria has been identified for further testing.
PATH-23. PROGNOSTIC AND RADIOGRAPHIC CORRELATES OF A PROSPECTIVELY COLLECTED MOLECULARLY PROFILED COHORT OF IDH-WILDTYPE ASTROCYTOMAS
Authors: Lin Andrew , Bale Tejus , Mellinghoff Ingo , Tabar Viviane , Schaff Lauren , Jonathan Yang T , Young Robert , Taylor Barry , Rosenblum Marc , Jonsson Philip
Published: November 2019

BACKGROUND

In the molecular era, the relevance of tumor grade for prognostication of IDH-wildtype (WT) astrocytomas has been debated. It has been suggested that lower-grade gliomas with molecular features of glioblastoma, IDH-WT have a similar prognosis to glioblastoma and should be considered for the same clinical trials.

METHODS

We integrated prospective clinical sequencing via the FDA-approved genomic sequencing assay MSK-IMPACT from 564 patients with IDH-WT astrocytomas (26 grade II, 71 grade III, and 467 grade IV) with clinical data.

RESULTS

Compared to grade III IDH-WT astrocytomas, grade II tumors harbor fewer chromosome 7/10 alterations and EGFR amplifications (p=0.07 and 0.03), but the same frequency of TERT promoter mutation. In contrast, there is no difference in the frequency of these canonical molecular features in grade III versus grade IV IDH-WT disease. Additionally, grade II astrocytomas harbor fewer cell cycle-pathway alterations than grade III tumors (p=6.9e-7). Progression-free (PFS) and overall survival (OS) for grade II astrocytomas were significantly longer than grade III tumors (p=0.02 and p=0.008, respectively), whereas there was no difference in PFS and OS for grade III compared to grade IV tumors. Median PFS for grade II vs. III vs. IV: 19 mo vs. 11 mo vs. 9 mo; median OS: 44 mo vs. 23 mo vs. 23 mo. In lower-grade IDH-WT astrocytomas, gliomatosis is associated with grade II histology (p=0.04), the absence of cell-cycle alterations (p=0.008), and more alterations in the PI3K-AKT pathway (p=0.09).

CONCLUSION

Histologic grade has genotypic and phenotypic associations, remains prognostically important in IDH-WT astrocytomas, and should be considered when enrolling patients to clinical trials.
PATH-25. APPLICABILITY OF A NOMOGRAM INCLUDING CLINICAL AND MOLECULAR VARIABLES IN THE STRATIFICATION OF RISK GROUPS IN PEDIATRIC MEDULLOBLASTOMA
Authors: Mançano Bruna , Reis Rui , Leal Leticia , de Paula Flavia , Almeida Jr Carlos , Almeida Gisele , Matushita Marcus , Faustino Fabio , Cavalcante Carlos , Magalhães Fernanda , Oliveira Marco
Published: November 2019

Medulloblastoma is the most common type of malignant brain tumor that occurs during childhood and adolescence. Currently, this pathology comprises at least four different molecular tumor subtypes (WNT, SHH, group 3 or C and group 4 or D) which have their own molecular characteristics, distinct clinical presentations and are associated with different survival rates. The purpose is to evaluate the applicability of a nomogram that includes clinical and molecular variables in pediatric medulloblastomas in the routine of the Hospital de Cancer de Barretos. The series l consists of 85 pediatric patients from 0 to 18 years old, diagnosed with medulloblastoma attended at the Hospital de Cancer de Barretos (HCB), from January 2000 to December 2017. The molecular subgroups will be performed using the Nanostring technique. This research intends to implement a nomogram that uses several variables known and involved in the treatment and prognosis of patients, this nomogram with multiple variables will show the clinical and molecular effect of each variable to predict disease-free survival and survival overall in 3 and 5 years. Thus, we will have the opportunity to analyze these characteristics in order to improve survival and reduce morbidity and consequently mortality during treatment for the different subgroups of medulloblastomas.
PATH-29. POTENTIAL OF RAMAN SPECTROSCOPY IN ONCOLOGICAL NEUROSURGERY
Authors: Kleine Borgmann Felix , Husch Andreas , Slimani Redouane , Jelke Finn , Mirizzi Giulia , Klein Karoline , Mittelbronn Michel , Hertel Frank
Published: November 2019

Raman spectroscopy (RS) has gained increasing interest for the analysis of biological tissues within the recent years. It is a label-free, non-destructive method providing insights in biochemical properties of tumor cells. It is possible to compare RS signals with histological properties of identical tissue parts. Therefore, RS bears promising potentials in neurosurgical neurooncology. On one hand, it could potentially be used for both intraoperative tumor diagnostics and resection control. On the other hand, it could provide important knowledge on tumor biochemistry and used for a subclassification of tumors with a potential impact on personalized therapy approaches. Within our group, we analyzed over 3000 measurement points in different brain tumors ex vivo with a robotized RS system and correlated the spectral curves with histopathological results. We separated and subclassified the data by AI-based methods. Additionally, we compared the latter results with those of a handheld probe, which is potentially navigatable for in vivo, intraoperative applications. We could demonstrate, that it is possible to separate distinct tumor groups only based on RS signals, especially by using computer-based signal analysis. Furthermore, we could demonstrate the differences of the spectra of deep-frozen and formalin-fixed tissues versus non-fixed tissues. Based on our results, we will highlight the potentials of RS for intraoperative neurosurgical application in resection control for brain tumors, as well as we will focus on the potentials for brain tumor diagnostics based purely on this method or by using it as an adjunct. Those methods bear additional potentials in the field of personalized chemotherapy approaches.
PATH-31. BUILDING A RAMAN SPECTROSCOPY REFERENCE DATABASE FOR TUMOR IDENTIFICATION AND CLASSIFICATION
Authors: Kleine Borgmann Felix , Husch Andreas , Slimani Redouane , Jelke Finn , Mirizzi Giulia , Klein Karoline , Mittelbronn Michel , Hertel Frank
Published: November 2019

Brain tumor resection requires careful assessment of the nature and malignancy of the tumor tissue during intervention, as this is the basis for the decision as to how radical surgery has to be. Typically, there is no tissue available for analysis prior to the surgery. Intraoperative histopathological examination of tumor samples is time consuming and puts the patient to a significant amount of strain due to ongoing anesthesia and prolonged surgery, thus there is a need to develop faster methods for thorough diagnostics. Raman spectroscopy allows for a fast analysis of samples without the need for labeling and sample preparation, making it a useful tool for peri- and intrasurgical application. We collect Raman spectra and correlated histopathological results to build a database of different tumor types. As intrasurgical use of Raman spectroscopy will typically be applied to native specimens, the respective database has to be based on native samples as well. We collected several thousands of measurements from more than 100 patients and continue to assemble a native database. Tumors that do not occur with a high frequency are not sufficiently represented in the database. Therefore, we investigate whether it is possible to integrate fixed and frozen specimens in the collection of Raman spectra and the classifier. Fixation results in characteristic changes to the biochemistry of biological tissues. We collect pairs of spectra from native and fixed as well as from native and frozen specimens and use the difference of the spectra to create an algorithm for filtering of the specific changes in the spectra. These data can be used to train a classifier for the identification of native samples. This opens the way for assessing large collections of pathological samples in fixed and frozen state to cover any type of neoplastic disease in the database.
PATH-32. GENOMIC LANDSCAPE AND BIOLOGY OF MEDULLOBLASTOMA IN ADULTS
Authors: Goschzik Tobias , zur Mühlen Anja , Dörner Evelyn , Waha Andreas , Friedrich Carsten , Hau Peter , Pietsch Torsten
Published: November 2019

BACKGROUND

Medulloblastoma (MB) is a rare disease in adults. Only few cohorts have been studied so far.

METHODS

Histological features were evaluated and tumors were annotated to WNT-MB, SHH-MB, and non-WNT/non-SHH-MB by immunohistochemistry. Copy number alterations were analyzed by genome-wide molecular inversion probe array. MB-related genes were screened by NGS panel and Sanger sequencing in WNT- and SHH-MB.

RESULTS

The cohort of 117 tumors contained 14.5% WNT-MB, 63.2% SHH-MB, and 22.2% non-WNT/non-SHH-MB. Classic histology was found in WNT-MB, non-WNT/non-SHH-MB and 22% of SHH-MB; 78% of SHH-MB showed desmoplastic/nodular histology. In WNT-MB, CTNNB1 mutations were found in 88.2% and monosomy 6 in 52.9% of cases. In SHH-MB, PTCH1 mutations were present in 40% of cases and chromosome 9q loss including the PTCH1 locus was the most frequent copy number event in SHH-MB (50%), while SMO and SUFU mutations were found only in 15.4% and 7.7%, respectively. TERT promoter mutations were present in 92.3% of SHH-MBs. Only 2 (3%) of SHH-MB were TP53-mutated (1.7% of whole cohort). In non-WNT/non-SHH-MB, isochromosome 17q was the most frequent chromosomal alteration (84.6%). A previously published whole chromosomal aberration (WCA) signature with ≥1 WCA was found in 69.2% of cases. For 87 cases, survival data were available. WNT-MB, SHH-MB with wildtype TP53 and non-WNT/non-SHH-MB showed similar outcomes (5-year OS: 75%, 78.1% and 69.1%, respectively). Both SHH-MB patients with mutant TP53 died of disease. Patients with non-WNT/non-SHH-MB characterized by the cytogenetic WCA phenotype showed – as described in pediatric standard-risk MB – significant better overall survival compared to patients with tumors lacking WCA (p=0.02).

CONCLUSIONS

Adult MB represents four defined biological/genomic entities. While in our cohort WNT-MB and SHH-MB-TP53wt were standard risk, non-WNT/non-SHH-MB patients could be divided into two risk-groups according to the presence or absence of WCA in the tumors as previously published for childhood standard-risk MB.
PATH-34. CLINICOPATHOLOGIC, MOLECULAR AND IMMUNOLOGICAL CHARACTERIZATION OF DIFFUSE MIDLINE GLIOMAS: IS THERE A PROGNOSTIC SIGNIFICANCE?
Authors: Manjunath Niveditha , Jha Prerna , Raheja Amol , Suri Vaishali , Suri Ashish , Garg Ajay , Kaur Kavneet , Sarkar Chitra
Published: November 2019

H3K27M Diffuse Midline Gliomas (DMGs) are amongst the most fatal cancers, considered WHO grade IV irrespective of the histological features. Treatment modalities have been ineffective in prolonging survival. The aim was to determine the clinico-pathologic, molecular and immunological characteristics of DMGs in children and adults. Genetic (H3K27M, ATRX, IDH1, p53) and immune (CD3,CD8 and PD-L1) profile of 126 DMGs identified over 10 years was studied with immunohistochemistry (IHC). Sanger sequencing performed for IDH1 and H3K27M mutation. Clinico-radiologic characteristics were reviewed and survival analysis performed. Of the 126 DMGs, 49.2% H3K27M mutant and 50.8% wildtype cases (mean age 21.27 years vs. 36.23 years). 75.68% of pediatric whereas 38.20% of adults were H3K27M mutant. Brainstem (46%) was commonest site in H3K27M mutant pediatric cases while majority of adults (62%) were thalamic. H3K27M was mutually exclusive with IDH mutation in 92.5% cases, whereas p53, ATRX mutation was 56.4% and 30.6% respectively. IHC showed 95% concordance with Sanger sequencing for H3K27M mutation. PD-L1 expression was greater in elderly (>50 years), than young adults and pediatric cases (p=0.002). CD8 expression was greater in adult then pediatric cases (p=0.0001). Overall survival (OS) was not statistically significant in mutant versus wildtype cases in children (p=0.45) as well as adults (p=0.65). Tumor location showed no correlation with OS. Tumor resection independently or on correlation with H3K27M did not influence OS (p=0.505 and p=0.470). Adjuvant therapy impacted survival significantly in adults (p=0.0009) than in pediatric patients (p=0.0669) The study highlights the differences in frequency and location of pediatric and adult H3K27M mutant DMGs. Dismal prognosis in both age groups of H3K27M mutant and wild type DMGs. IHC for H3K27M mutation is an excellent substitute to Sanger sequencing. Our analysis emphasises the role of molecular characterisation for the development of effective therapeutic strategies, for different DMG subgroups.