Aggressive Grade Research Articles

Pre-operative predictive factors of grade II and III meningiomas

Purpose:Meningiomas are the most common primary intracranial tumors. They are graded into three pathologic grades. Surgical gross total resection is the definitive treatment of meningiomas, but follow-up or stereotactic radiosurgery is sometimes advised for asymptomatic, incidentally diagnosed meningiomas. For a decision making, pre-operative prediction of Grade II and III meningiomas which are more aggressive clinically, is important. We have reviewed our intracranial meningioma series, based on their clinical, radiological, and location, to analyze the predictive factors of Grade II and III meningiomas. Patients and Methods:The clinical, radiological, operative and pathological reports of patients who were operated for intracranial meningiomas between September 1986 and July 2019 have been reviewed retrospectively from our patient database. Their age, sex, tumor location, absence or presence of peritumoral edema, and the pathological grade of meningiomas have been noted. The predictive effect of age, sex, peritumoral edema and location of tumor is analyzed statistically for pathological grade. Results:There were 1401 patients with intracranial meningiomas, 1015 of them were female, 386 were male (female/male=2.6). Their mean age was 52.2 years. There were 1219 Grade I, 164 Grade II, and 18 Grade III meningiomas. Male sex, and non-skull base location were predictive for Grade II and III meningiomas. Conclusion:While advising conservative treatment (follow-up, or stereotactic radiosurgery) for asymptomatic, incidental meningiomas, it should be kept in mind that male sex, and/or non-skull base location are risk factors for the more aggressive Grade II and III meningiomas.

BIOM-51. FACTORS ASSOCIATED WITH DECLINING SEX DISCREPANCY IN MENINGIOMA WITH INCREASING TUMOR AGGRESSIVENESS: RETROSPECTIVE REVIEW OF A RURAL PENNSYLVANIA COHORT

Abstract INTRODUCTION Meningioma is the most common benign primary brain tumor in adults comprising 37% of all primary CNS tumors. Approximately 81.1% of meningiomas are grade I, 16.9% - grade II, and 1.7% - grade III. While females are 2.5 times more likely to have meningiomas, males more commonly have aggressive grades. Loss of progesterone receptor (PR) and presence of androgen receptor (AR) are associated with tumor aggressiveness. We observed a declining sex-discrepancy with increasing tumor grade. We present an ongoing assessment of a rural population to define potential factors contributing to this observation. METHODS We completed a single institutional retrospective review of 406 pathology confirmed meningiomas in rural Northeast Pennsylvania. We compared WHO grade, hormone receptors, and proliferative indices between males and females. We further evaluated tumor location and comorbid endocrine disease for possible association. RESULTS Our patient cohort had a high frequency of aggressive tumors 73.5% (n= 297) grade I, 24% (n= 99) grade II, and 2.5% (n= 10) grade III. The ratio of females versus males was 3.1:1, 1.3:1, and 1:1 in grades I, II, and III respectively. Factors contributing to closing the sex-gap were: (1) grade II: males expressed less PR than females (76% vs 94%); (2) grade III: females expressed less AR than males (0% vs 100%), while PR expression remained equivalent; and (3) males had higher tumor proliferative indices compared to females (7% and 22% vs 2% and 14%), grades I and II respectively. There was no relationship determined for tumor location or comorbid endocrine disease between the sexes. CONCLUSION The association between declining sex discrepancy in meningioma with increasing tumor aggressiveness is potentially related to the expression PR, AR, and increased tumor proliferation indices with increasing meningioma grade.

EPID-12. TREATMENT OUTCOMES OF MIDLINE GLIOMAS WITH H3K27 M: OUR BARROW NEUROLOGICAL INSTITUTE EXPERIENCE

Abstract BACKGROUND H3 K27M glioblastoma is an aggressive grade IV tumor located in midline structures, added in 2016 by the WHO. Current outcomes are poor. The rarity of these tumors presents a challenge for definitive research on developing optimal treatments. METHODS We conducted a case series of 12 patients at the Barrow Neurological Institute who were diagnosed with biopsy-proven H3 K27M glioblastoma. The clinical status of these patients was followed from dates of first and last contact. Factors included first line treatment, best response to first line treatment, recurrences, second line treatments, response assessment criteria for all treatment rounds, any discovered metastases, and vital status by date of last contact. RESULTS Of the initial 12 patients, 5 were lost to follow-up before meaningful clinical outcomes could be recorded. Of the remaining 7, all underwent temozolomide and radiation as components of first-line treatment. After first-line treatment, 1/7 (14.2%) had partial response, 3/7 (42.8%) had stable disease, and 3/7 (42.8%) had progressive disease. 4 patients elected to undergo second line treatment: 2 underwent bevacizumab with lomustine, 1 underwent bevacizumab and irinotecan, and 1 underwent surgery with carmustine. Of the 2 who underwent bevacizumab and lomustine, 1 (50%) improved from progressive to stable disease and 1 (50%) stayed at stable disease. Of the 1 patient who underwent bevacizumab and lomustine, outcome worsened from stable to progressive disease. Of the 1 patient who underwent surgery and carmustine, outcome improved from progressive to stable disease. CONCLUSIONS H3 K27M is a highly aggressive tumor with poor outcomes. This case series demonstrates that multiple treatment rounds with chemotherapy and radiation therapy may benefit patients, with bevacizumab/lomustine and surgery/carmustine appearing to lead to promising outcomes. Further research is needed to establish evidence-based protocols so quality of life and survival time in these patients may improve.

CBIO-19. LOW GLOBAL HISTONE H4 ACETYLATION LEVELS REVEAL CANDIDATE QUIESCENT CELL POPULATIONS IN GLIOMA AND DISTINGUISH TUMORS BY GRADE

Abstract Current standard of care therapy for glioblastoma (GBM) includes cytoreduction followed by ablative therapies that target rapidly dividing cell types. However, the presence of quiescent-like/G0 states, therefore, represents a natural reservoir of tumor cells that are resistant to current treatments. Quiescence or G0 phase is a reversible state of “stasis” cells enter in response to developmental or environmental cues. To gain insight into how glioblastoma cells might regulate G0-like states, we performed a genome-wide CRISPR-Cas9 screen in patient-derived GBM stem-like cells (GSCs) harboring a G0-reporter to identify genes that when inhibited trap GSCs in G0-like states. Among the top screen hits were members of the Tip60/KAT5 histone acetyltransferase complex, which targets both histones (e.g., H4) and non-histone proteins for acetylation. NuA4 functions as a transcriptional activator, whose activities are coordinated with MYC in certain contexts, and also participates in DNA double-strand break repair by facilitating chromatin opening. However, currently little is known about the roles for NuA4 complex in GBM biology. Through modeling KAT5 function in GSC in vitro cultures and in vivo tumors, we find that KAT5 inhibition causes cells to arrest in a G0-like state with high p27 levels, G1-phase DNA content, low protein synthesis rates, low rRNA rates, lower metabolic rate, suppression of cell cycle gene expression, and low histone H4 acetylation. Interestingly, partial inhibition of KAT5 activity slows highly aggressive tumor growth, while increasing p27hi H4-aclow populations. Remarkably, we that low grade gliomas have significantly higher H4-aclow subpopulations and generally lower H4-ac levels than aggressive grade IV tumors. Taken together, our results suggest that NuA4/KAT5 activity may play a key role in quiescence ingress/egress in glioma and that targeting its activity in high grade tumors may effectively “down grade” them, thus, increase patient survival.

Gene Expression Signatures Identify Biologically Homogenous Subgroups of Grade 2 Meningiomas.

IntroductionMeningiomas are the most common brain tumor, with prevalence of approximately 3%. Histological grading has a major role in determining treatment choice and predicting outcome. While indolent grade 1 and aggressive grade 3 meningiomas exhibit relatively homogeneous clinical behavior, grade 2 meningiomas are far more heterogeneous, making outcome prediction challenging. We hypothesized two subgroups of grade 2 meningiomas which biologically resemble either World Health Organization (WHO) grade 1 or WHO grade 3. Our aim was to establish gene expression signatures that separate grade 2 meningiomas into two homogeneous subgroups: a more indolent subtype genetically resembling grade 1 and a more aggressive subtype resembling grade 3.MethodsWe carried out an observational meta-analysis on 212 meningiomas from six distinct studies retrieved from the open-access platform Gene Expression Omnibus. Microarray data was analyzed with systems-level gene co-expression network analysis. Fuzzy C-means clustering was employed to reclassify 34 of the 46 grade 2 meningiomas (74%) into a benign “grade 1-like” (13/46), and malignant “grade 3-like” (21/46) subgroup based on transcriptomic profiles. We verified shared biology between matching subgroups based on meta-gene expression and recurrence rates. These results were validated further using an independent RNA-seq dataset with 160 meningiomas, with similar results.ResultsRecurrence rates of “grade 1-like” and “grade 3- like” tumors were 0 and 75%, respectively, statistically similar to recurrence rates of grade 1 (17%) and 3 (85%). We also found overlapping biological processes of new subgroups with their adjacent grades 1 and 3.ConclusionThese results underpin molecular signatures as complements to histological grading systems. They may help reshape prediction, follow-up planning, treatment decisions and recruitment protocols for future and ongoing clinical trials.

Ion Channels as Therapeutic Targets in High Grade Gliomas.

Simple SummaryGlioblastoma multiforme is an aggressive grade IV lethal brain tumour with a median survival of 14 months. Despite surgery to remove the tumour, and subsequent concurrent chemotherapy and radiotherapy, there is little in terms of effective treatment options. Because of this, exploring new treatment avenues is vital. Brain tumours are intrinsically electrically active; expressing unique patterns of ion channels, and this is a characteristic we can exploit. Ion channels are specialised proteins in the cell’s membrane that allow for the passage of positive and negatively charged ions in and out of the cell, controlling membrane potential. Membrane potential is a crucial biophysical signal in normal and cancerous cells. Research has identified that specific classes of ion channels not only move the cell through its cell cycle, thus encouraging growth and proliferation, but may also be essential in the development of brain tumours. Inhibition of sodium, potassium, calcium, and chloride channels has been shown to reduce the capacity of glioblastoma cells to grow and invade. Therefore, we propose that targeting ion channels and repurposing commercially available ion channel inhibitors may hold the key to new therapeutic avenues in high grade gliomas.Glioblastoma multiforme (GBM) is a lethal brain cancer with an average survival of 14–15 months even with exhaustive treatment. High grade gliomas (HGG) represent the leading cause of CNS cancer-related death in children and adults due to the aggressive nature of the tumour and limited treatment options. The scarcity of treatment available for GBM has opened the field to new modalities such as electrotherapy. Previous studies have identified the clinical benefit of electrotherapy in combination with chemotherapeutics, however the mechanistic action is unclear. Increasing evidence indicates that not only are ion channels key in regulating electrical signaling and membrane potential of excitable cells, they perform a crucial role in the development and neoplastic progression of brain tumours. Unlike other tissue types, neural tissue is intrinsically electrically active and reliant on ion channels and their function. Ion channels are essential in cell cycle control, invasion and migration of cancer cells and therefore present as valuable therapeutic targets. This review aims to discuss the role that ion channels hold in gliomagenesis and whether we can target and exploit these channels to provide new therapeutic targets and whether ion channels hold the mechanistic key to the newfound success of electrotherapies.

DEC2 Serves as Potential Tumor Suppressor in Breast Carcinoma.

Background Identification of new biomarkers can facilitate the development of effective therapeutic strategies in breast cancer (BC). Data from previous studies have revealed that differentiated embryonic chondrocyte gene (DEC) 1 and DEC2 might involve in the progression of various cancer types. We explored the expression profiles and function of DEC1/2 in BC patients in this study. Methods The mRNA expression of DEC1/2 in BC patients and cell lines were taken from the Oncomine and Cancer Cell Line Encyclopedia database. The prognostic impacts of DEC1/2 were mined from the bc-GenExMiner and Kaplan–Meier plotter database. The impact of DEC1/2 genomic alterations on patient survival was calculated by cBioPortal. DEC2 protein expressions were confirmed by Western blotting (WB) in 10 pairs of BC samples. In addition, DEC2 sgRNA was constructed to confirm its affection on cell viability, invasion, and colony formation. Results The DEC1 and DEC2 mRNA levels are both lower in BC tissues than normal tissues. DEC1/2 expression was high in progesterone receptor (PR) positive BC patients (P = 0.0023), but low in human epidermal growth factor receptor 2 (HER2) positive patients (P < 0.0001). Lower DEC2 mRNA level has significant association with more aggressive pathogenic grade (P < 0.0001) and worse overall survival (OS) of BC patients (P = 5.2 × 10−6). Subgroup analysis showed that low DEC2 level was correlated with worse OS in estrogen receptor (ER) positive BC (P = 0.008). DEC2 (P = 0.00029) alteration was significantly correlated with worse OS in BC patients. WB results also confirmed the lower DEC2 protein levels in BC samples than their paired normal tissues. And, DEC2 silencing by sgRNA resulted in a significant increasing in cell viability, invasion, and colony formation. Conclusion DEC2 might serve as a tumor suppressor, and its disfunction may involve in the tumorigenesis and indicate bad clinical outcomes in BC patients.

Longitudinal Associations Linking Elementary and Middle School Contexts with Student Aggression in Early Adolescence.

Growing up in poverty increases youth risk for developing aggressive behavior problems, which, in turn, are associated with a host of problematic outcomes, including school drop-out, substance use, mental health problems, and delinquency. In part, this may be due to exposure to adverse school contexts that create socialization influences supporting aggression. In the current study, 356 children from low-income families (58% White, 17% Latinx, 25% Black; 54% girls) were followed from preschool through seventh grade. Longitudinal data included measures of the school-level contexts experienced by study participants during their elementary and middle school years, including school levels of poverty (percentage of students receiving free or reduced-price lunch) and academic achievement (percentage of students scoring below the basic proficiency level on state achievement tests). Regression analyses suggested little impact of these school-level contexts on teacher or parent ratings of aggression in fifth grade, controlling for child baseline aggression and demographics. In contrast, school-level contexts had significant effects on child aggression in seventh grade with unique contributions by school-level achievement, controlling for child fifth grade aggression and elementary school contexts along with baseline covariates. These effects were robust across teacher and parent ratings. Findings are discussed in terms of understanding the school-based socialization of aggressive behavior and implications for educational policy and prevention programming.

Bidirectional Associations between Popularity, Popularity Goal, and Aggression, Alcohol Use and Prosocial Behaviors in Adolescence: A 3-Year Prospective Longitudinal Study

Adolescents’ popularity and popularity goal have been shown to be related to their aggression and alcohol use. As intervention efforts increasingly aim to focus on prosocial alternatives for youth to gain status, it is essential to have a comprehensive understanding of how popularity and popularity goal are associated with aggression and substance use as well as prosocial behaviors over time. The current study examined the bidirectional associations of aggression (overt and relational aggression), alcohol use, and prosocial behavior with popularity and popularity goal in adolescence across 3 years using cross-lagged panel analyses. Participants were 839 Dutch adolescents (Mage = 13.36, SD = 0.98; 51.3% girls). The results indicated that popularity was consistently positively associated with popularity goal, but popularity goal did not significantly predict subsequent popularity. Popularity positively predicted elevated aggression and alcohol use, but lower levels of prosocial behavior. For the full sample, alcohol use and overt aggression in grade 7 both predicted subsequent popularity in grade 8. However, when considering gender differences, overt aggression no longer was a significant predictor of popularity. These results were discussed in terms of the dynamic interplay between popularity, popularity goal, and behaviors, and in terms of implications for prevention and intervention efforts.

Rare male cancers: Effect of social deprivation on a cohort of penile cancer patients

Background: Penile cancer is a rare disease, with approximately 600 cases diagnosed every year in the UK. In this study, we assessed the impact of social deprivation on penile cancer, concentrating on incidence, disease factors, surgical treatment and mortality within our ‘Supranetwork’ population. Methods: All cases of penile cancer in the West of Scotland were identified from the uro-oncology multidisciplinary team meetings over a 10-year period covering January 2008 to December 2017. Patients underwent treatment within the remit of a centralised service, and social deprivation was determined using the Scottish Index of Multiple Deprivation (SIMD), which is the Scottish government’s official tool to identify areas of multiple deprivations. Results: A total of 278 patients were identified, with an age range of 27–97 years ( M=64 years). The incidence of penile cancer in SIMD category 1 (most deprived) is 7.2/100,000 population at risk compared to 2.8/100,000 population at risk in SIMD category 5 (least deprived). Histologically, a higher proportion of aggressive grade 3 cancers (45% vs. 16%, p=0.03) and more advanced N2/N3 nodal disease (63% vs. 33%, p=0.04) was found in SIMD category 1 compared to SIMD category 5, suggesting higher incidence of delayed presentation with more advanced and aggressive disease in the most deprived populations. Conclusions: The level of social deprivation shows a significant association with penile cancer incidence, tumour grade and stage at time of diagnosis, with a resulting disproportionate impact on morbidity and mortality in the most deprived cohort of patients. Public awareness and efforts to increase earlier diagnoses of penile cancer in these ‘hard to reach’ men should be an important step in improving overall outcomes from penile cancer.

Quiescent stem cell marker genes in glioma gene networks are sufficient to distinguish between normal and glioblastoma (GBM) samples

Grade 4 glioma or GBM has poor prognosis and is the most aggressive grade of glioma. Accurate diagnosis and classification of tumor grade is a critical determinant for development of treatment pathway. Extensive genomic sequencing of gliomas, different cell types, brain tissue regions and advances in bioinformatics algorithms, have presented an opportunity to identify molecular markers that can complement existing histology and imaging methods used to diagnose and classify gliomas. ‘Cancer stem cell theory’ purports that a minor population of stem cells among the heterogeneous population of different cell types in the tumor, drive tumor growth and resistance to therapies. However, characterization of stem cell states in GBM and ability of stem cell state signature genes to serve as diagnostic or prognostic molecular markers are unknown. In this work, two different network construction algorithms, Weighted correlation network analysis (WGCNA) and Multiscale Clustering of Geometric Network (MEGENA), were applied on publicly available glioma, control brain and stem cell gene expression RNA-seq datasets, to identify gene network regulatory modules associated with GBM. Both gene network algorithms identified consensus or equivalent modules, HuAgeGBsplit_18 (WGCNA) and c1_HuAgeGBsplit_32/193 (MEGENA), significantly associated with GBM. Characterization of HuAgeGBsplit_18 (WGCNA) and c1_HuAgeGBsplit_32/193 (MEGENA) modules showed significant enrichment of rodent quiescent stem cell marker genes (GSE70696_QNPbyTAP). A logistic regression model built with eight of these quiescent stem cell marker genes (GSE70696_QNPbyTAP) was sufficient to distinguish between control and GBM samples. This study demonstrates that GBM associated gene regulatory modules are characterized by diagnostic quiescent stem cell marker genes, which may potentially be used clinically as diagnostic markers and therapeutic targets in GBM.

Abstract D001: Can small area estimates explain variation in cancer outcomes? 500 cities’ tobacco use estimates and prostate cancer mortality in Philadelphia

Abstract Background: Prostate cancer is the most common cancer in U.S. men, and racial disparities in incidence and mortality persist. Tobacco use has been associated with aggressive histologic grade and mortality; however, population-based cancer registries have limited data on lifetime tobacco use or SHS exposure. Community-level small-area estimates calculated from individual-level survey data offer a useful tool for understanding neighborhood effects, and estimating individual behaviors when direct observation is not feasible. Methods: This project used data on all 2005-2014 incident prostate cancer cases in Philadelphia, a city with high burden from both tobacco use and poverty. Using multi-level models, the odds of death from prostate cancer were estimated in relation to individual case characteristics (age, race, year of diagnosis, and tumor histologic grade) and Census tract-level estimates of tobacco use, using CDC’s 500 Cities small area estimates. Mediation analyses were used to examine whether tobacco use plays a role in the relationship between race and both aggressive histologic grade and prostate cancer related mortality. Results: From 2005-2014, 6% of the 10621 cases died from prostate cancer. Cases residing in Census tracts with higher estimated proportion of adults who smoke were more likely to have aggressive grade tumors, and more likely to die from their cancer. Analyses revealed that aggressive grade partially mediated the relationship between tobacco use and cancer death, and that tobacco use partially mediated the relationship between black race and cancer death. Conclusions: Findings support the utility of small area estimates for investigating area-level influences in exploratory studies. Citation Format: Ann C Klassen, Russell McIntyre, Maxwell Boamah, Scott Keith, Loni Tabb, Charnita Ziegler-Johnson. Can small area estimates explain variation in cancer outcomes? 500 cities’ tobacco use estimates and prostate cancer mortality in Philadelphia [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D001.

Del-1 and MFG-E8 expression to differentially modulate prognosis of patients with triple-negative breast cancer.

e13093 Background: Del-1 was previously found to be prognostic biomarker in early breast cancer patients. Del-1 shares both structural and functional homology with Milk fat globule-epidermal growth factor-factor VIII (MFG-E8). To date, the biological functions of Del-1 and MFG-E8 have not been sufficiently compared in side-by-side experiments. MFG-E8 is a secreted glycoprotein from macrophages that promotes clearance of apoptotic cells. In this study, we investigated the function of MFG-E8 and Del-1 and prognosis in a large cohort of EBC patients. Methods: The MFG-E8 levels were measured using a qRT-PCR in breast cancer cells (MDA-MB-231, Hs578T, MCF7, SK-BR3, and T-47D), and tissues from 20 patients with EBC. The effects of MFG-E8 and Del-1 on cell proliferation, migration, and invasion were determined using MTT, wound healing, and Matrigel Transwell assays. The expressions of MFG-E8 and Del-1 protein were detected by immunohistochemical staining in 436 tumor tissues. The relationship between MFG-E8, Del-1 expression levels and clinicopathological features were evaluated. Results: MFG-E8 and Del-1 levels were significantly elevated in MDA-MB-231 and Hs578T cell lines (p &lt; 0.001). Given that MFG-E8 and Del-1 share similar protein structure, we wanted to explore the effect of dual knockdown of MFG-E8 and Del-1 in migration and invasion assay. As expected, knockdown of Del-1 alone decreased cell migration in TNBC cell lines, but dual knockdown of MFG-E8 and Del-1 showed reduction was restored. Dual knockdown of MFG-E8 and Del-1 showed consistent result in invasion assay. Down-regulation of Del-1 inhibited TNBC cells invasion and recovered by the MFG-E8 knockdown. Interestingly, for the 436 patients, Del-1 high- and MFG-E8 low- expression shows correlation with aggressive histologic grade, high Ki-67 (p &lt; 0.001 and p = 0.042, respectively) and shorter survival outcome (distant disease free survival p = 0.028, breast cancer specific survival p = 0.001). Conclusions: Overall, these findings suggest that MFG-E8 and Del-1 protein expression could be a prognostic marker for patients in triple negative breast cancer (TNBC). Thus, MFG-E8 reduction may contributes to tumorigenesis by increasing Del-1. However, functions of Del-1 and MFG-E8 have not yet been thoroughly analyzed, further studies are required.

Visceral obesity and cell cycle pathways serve as links in the association between bisphenol A exposure and breast cancer.

It has been identified that bisphenol A (BPA) exposure causes developmental toxicity in breast cells. However, the exact molecular mechanisms underlying the association between exposure to BPA and breast cancer remain unclear. The aim of the present study was to investigate the BPA-regulated signaling pathways associated with the aggressiveness and the development of breast cancer. Microarray technology and functional gene set analyses were used to evaluate BPA and breast cancer-associated biomarkers and pathways in a discovery-driven manner. Using individual dataset analyses, it was indicated that two BPA-associated gene sets, the visceral obesity pathway, involved in visceral fat deposits and the metabolic syndrome, and the cell cycle pathway, involved in cyclins and cell cycle regulation, were significantly associated with a high grade of aggressiveness and the development of estrogen receptor (ER)-positive breast cancer (between P<0.05 and 0.0001). The pooled analysis indicated that the most significant pathway was G1/S checkpoint regulation, and the cyclin and cell cycle regulation pathway for BPA-associated ER-positive cancer. Cancer cell signaling pathways were associated with healthy breast cells developing into breast cancer. The visceral obesity and the cell cycle pathways were indicated to link BPA exposure to breast cancer. The results of the present study demonstrate a significant association between breast cancer and BPA-regulated gene pathways.

Ependymoma Pediatric Brain Tumor Protein Fingerprinting by Integrated Mass Spectrometry Platforms: A Pilot Investigation.

Ependymoma pediatric brain tumor occurs at approximate frequencies of 10–15% in supratentorial and 20–30% in posterior fossa regions. These tumors have an almost selective response to surgery and relative and confirmed resistance to radiotherapy and chemotherapic agents, respectively. Alongside histopathological grading, clinical and treatment evaluation of ependymomas currently consider the tumor localization and the genomic outlined associated molecular subgroups, with the supratentorial and the posterior fossa ependymomas nowadays considered diverse diseases. On these grounds and in trying to better understand the molecular features of these tumors, the present investigation aimed to originally investigate the proteomic profile of pediatric ependymoma tissues of different grade and localization by mass spectrometry platforms to disclose potential distinct protein phenotypes. To this purpose, acid-soluble and acid-insoluble fractions of ependymoma tumor tissues homogenates were analyzed by LC-MS following both the top-down and the shotgun proteomic approaches, respectively, to either investigate the intact proteome or its digested form. The two approaches were complementary in profiling the ependymoma tumor tissues and showed distinguished profiles for supratentorial and posterior fossa ependymomas and for WHO II and III tumor grades. Top-down proteomic analysis revealed statistically significant higher levels of thymosin beta 4, 10 kDa heat shock protein, non-histone chromosomal protein HMG-17, and mono-/uncitrullinated forms ratio of the glial fibrillary acidic protein (GFAP) fragment 388–432 in supratentorial ependymomas—the same GFAP fragment as well as the hemoglobin alpha- and the beta-chain marked grade II with respect to grade III posterior fossa ependymomas. Gene ontology classification of shotgun data of the identified cancer and the non-cancer related proteins disclosed protein elements exclusively marking tumor localization and pathways that were selectively overrepresented. These results, although preliminary, seem consistent with different protein profiles of ependymomas of diverse grade of aggressiveness and brain region development and contributed to enlarging the molecular knowledge of this still enigmatic tumor.

Imaging growth as a predictor of grade of malignancy and aggressiveness of IDH-mutant and 1p/19q-codeleted oligodendrogliomas in adults.

We quantified the spontaneous imaging growth rate of oligodendrogliomas. We assessed whether (i) it discriminates between World Health Organization (WHO) grade II and grade III oligodendrogliomas, and (ii) grade III oligodendrogliomas with neo-angiogenesis are associated with more fast growth rates (≥8 mm/y). This work employed a retrospective bicentric cohort study (2010-2016) of adult patients harboring a newly diagnosed supratentorial oligodendroglioma, isocitrate dehydrogenase (IDH) mutant and 1p/19q codeleted (WHO 2016 classification), with a minimum of 2 available MRIs before any treatment (minimum 6-week interval) to measure the spontaneous tumor growth rate. We included 108 patients (age 44.7 ± 14.1 y, 60 males). The tumor growth rate was higher in grade III oligodendrogliomas with neo-angiogenesis (n = 37, median 10.4 mm/y, mean 10.0 ± 6.9) than in grade III oligodendrogliomas with increased mitosis count only (cutoff ≥6 mitoses, n = 18, median 3.9 mm/y, mean 4.5 ± 3.2; P = 0.004), and higher than in grade II oligodendrogliomas (n = 53, median 2.3 mm/y, mean 2.8 ± 2.2; P < 0.001). There was increased prevalence of fast tumor growth rates in grade III oligodendrogliomas with neo-angiogenesis (54.1%) compared with grade III oligodendrogliomas with increased mitosis count only (11.1%; P < 0.001), and in grade II oligodendrogliomas (0.0%; P < 0.001). The tumor growth rate trends did not differ between centers (P = 0.121). Neo-angiogenesis (P < 0.001) and mitosis count at ≥9 (P = 0.013) were independently associated with tumor growth rates ≥8 mm/year. A tumor growth rate ≥8 mm/year was the only predictor independently associated with shorter progression-free survival (P = 0.041). The spontaneous tumor growth rate recapitulates oligodendroglioma aggressiveness, permits identification of grade III oligodendrogliomas preoperatively when ≥8 mm/year, and questions the grading by mitosis count.

Phosphoproteomic and Kinomic Signature of Clinically Aggressive Grade I (1.5) Meningiomas Reveals RB1 Signaling as a Novel Mediator and Biomarker.

Most World Health Organization (WHO) grade I meningiomas carry a favorable prognosis. Some become clinically aggressive with recurrence, invasion, and resistance to conventional therapies (grade 1.5; recurrent/progressive WHO grade I tumors requiring further treatment within 10 years). We aimed to identify biomarker signatures in grade 1.5 meningiomas where histopathology and genetic evaluation has fallen short. Mass spectrometry (MS)-based phosphoproteomics and peptide chip array kinomics were used to compare grade I and 1.5 tumors. Ingenuity Pathway Analysis (IPA) identified alterations in signaling pathways with validation by Western blot analysis. The selected biomarker was evaluated in an independent cohort of 140 samples (79/140 genotyped for meningioma mutations) by tissue microarray and correlated with clinical variables. The MS-based phosphoproteomics revealed differential Ser/Thr phosphorylation in 32 phosphopeptides. The kinomic profiling by peptide chip array identified 10 phosphopeptides, including a 360% increase in phosphorylation of RB1, in the 1.5 group. IPA of the combined datasets and Western blot validation revealed regulation of AKT and cell-cycle checkpoint cascades. RB1 hyperphosphorylation at the S780 site distinguished grade 1.5 meningiomas in an independent cohort of 140 samples and was associated with decreased progression/recurrence-free survival. Mutations in NF2, TRAF7, SMO, KLF4, and AKT1 E17K did not predict RB1 S780 staining or progression in grade 1.5 meningiomas. RB1 S780 staining distinguishes grade 1.5 meningiomas, independent of histology, subtype, WHO grade, or genotype. This promising biomarker for risk stratification of histologically bland WHO grade I meningiomas provides insight into the pathways of oncogenesis driving these outlying clinically aggressive tumors.

Is there a correlation between the aggressiveness of chronic asymptomatic prostatitis National Institutes of Health category IV and the Gleason score in patients with prostate cancer?

We evaluated the correlation between the International Society of Urological Pathology (ISUP) grades and the aggressiveness grades of prostate inflammation in newly diagnosed prostate cancer patients with chronic asymptomatic prostatitis National Institiutes of Health (NIH) category IV (CAPNIHIV). The study comprised 357 consecutive patients with prostate cancer in whom a cancer diagnosis had been made via a prostate needle biopsy. Histological sections of the prostate biopsy specimens of the patients were reviewed and scored. Prostatic inflammation was scored using the aggressiveness grade of inflammation. The associations between the ISUP grades and the aggressiveness grades of inflammation were analyzed using logistic regression. The limitations of the study were its retrospective design and the limited number of cases. In 110 (31%) patients, CAPNIHIV was detected: 56 (51%) patients had a grade 0 aggressiveness score, 34 (31%) patients had a grade 1 aggressiveness score, and 20 (18%) patients had a grade 2 aggressiveness score. The patients who had prostatic inflammation had 1.65 times (95% confidence interval [CI] 1.05-2.61) greater likelihood of a high ISUP grade (grade ≥3) compared with the patients who did not have prostatic inflammation. The association between the ISUP grade and the aggressiveness grade of inflammation was more pronounced for a grade 2 aggressiveness score (n= 20; odds ratio 2.97; 95% CI 1.14-7.71). In prostate cancer patients with CAPNIHIV, there was a positive correlation between the inflammation aggressiveness grade and the ISUP grade. The aggressiveness of intraprostatic inflammation may be an important morphological factor affecting the Gleason score.

SCIDOT-26. THE ROLE OF TUMOR-DERIVED GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR (GM-CSF/CSF2) IN REGULATION OF MICROGLIA-DEPENDENT INVASION IN GLIOMAS

Abstract Brain resident immune cells (microglia) and peripheral macrophages accumulate in malignant gliomas and constitute for 30–50% of the tumor mass. These immune cells are polarized by factors released by glioma and become the pro-invasive, immunosuppressive cells that support tumor progression. We have previously found that tumor-derived granulocyte macrophage colony stimulating factor (GM-CSF/Csf-2) is a crucial factor controlling accumulation of microglia and macrophages in murine gliomas. The analysis of TCGA dataset revealed overexpression of the CSF2 gene (encoding GM-CSF) in a set of mesenchymal glioblastomas (most aggressive WHO grade IV gliomas) and its association with high immune gene expression. To study the role of GM-CSF in microglia-stimulated glioma invasion, we used a co-culture system, which mimics microglia interactions with tumor cells. We silenced the expression of CSF2 in glioma cells and found reduced microglia-dependent invasion of glioma cells. To translate those results into clinically relevant setting, we designed and tested humanized short peptides interfering with binding of GM-CSF to its receptor. Selected peptide effectively inhibited binding of GM-CSF to its receptor as demonstrated with different methods. We selected the non-cytotoxic peptides that potently blocked microglia-dependent glioma invasion in cell co-cultures. Blocking GM-CSF-receptor signaling pathway with a neutralizing antibody against a GM-CSF receptor also inhibited microglia-dependent invasion of glioma cells. Altogether, our results demonstrate that glioma-derived GM-CSF supports pro-tumorigenic polarization of microglia turning them into cells that facilitate glioma growth and shape the immune microenvironment. The study was supported by grant 2014/15/B/NZ3/04704 from The National Science Centre, Poland.

1411. Differentiation of Fungal Abscess of Brain From Brain Glioblastoma by MRI Scan ADC Value

BackgroundDifferentiation of Brain fungal abscess from brain glioblastoma is very important. Treatment strategies are different in both cases. Glioblastoma needs different surgical planning as compared with abscess. We hypothesized that preoperative MRI brain will help in differentiation.MethodsA retrospective study was carried out at Aga Khan University Hospital Karachi. Data from 2007 to 2017 was retrieved from Medical records using ICD-9 coding. 90 patients (47 males and 43 females; age range 10–70 years) with aggressive grade IV brain lesion and fungal abscess was selected and their preoperative MRI data were retrieved. The apparent diffusion coefficient (ADC) maps were reconstructed from diffusion-weighted imaging DWI data. The mean ADC value and standard deviation of glioblastoma and fungal abscesses were calculated. Postoperative biopsy results were used as gold standard.The analysis of data was done to test statistically significant differences between glioblastoma and fungal brain abscess. Receiver operating characteristic (ROC) curve was used to determine the cut-off point with highest accuracy that was used to differentiate malignancy from infection. The statistical analysis of data was done using SPSS® v. 19.ResultsThe mean (±standard deviation) ADC value of fungal brain abscess (826.040 ± 94.97 × 0.001 mm2/sec) was significantly lower than that of glioblastoma (1,462.800 ± 163.66 × 0.001 mm2/sec). When an ADC value of 1,200 × 0.001 mm2/s used as a cutoff value for differentiating fungal abscess from glioblastoma the best result was obtained with an accuracy of 85%, sensitivity of 81%, specificity of 88%, negative predictive value of 80%, and positive predictive value of 90%.ConclusionADC value is a noninvasive promising imaging parameter that can be used for differentiation of fungal brain abscess and glioblastoma on preoperative scan. The cut-off value with best accuracy in our study was 1,200 × 0.001 mm2/s. Disclosures All authors: No reported disclosures.