CNS Malignancies Research Articles

Preoperative Stereotactic Radiosurgery for Glioblastoma.

Simple SummaryStereotactic radiosurgery (SRS) is a multidisciplinary neurosurgical and radiation technique that allows for the delivery of a highly conformal dose of ionizing radiation with minimal radiation exposure to surrounding healthy tissues. SRS has been shown to be associated with excellent rates of local tumor control for multiple tumor types. Additionally, SRS has been shown to augment the effects of anti-tumor immunity. However, there is a paucity of evidence exploring the role of preoperative SRS in glioblastoma (GBM). To date, limited preclinical evidence has suggested that preoperative SRS has the potential to enhance anti-tumor immune responses and improve patient outcomes in glioma. In this review, we provide an overview of GBM and the role of preoperative radiosurgery in its management.Glioblastoma is a devastating primary brain tumor with a median overall survival of approximately 15 months despite the use of optimal modern therapy. While GBM has been studied for decades, modern therapies have allowed for a reduction in treatment-related toxicities, while the prognosis has largely been unchanged. Adjuvant stereotactic radiosurgery (SRS) was previously studied in GBM; however, the results were disappointing. SRS is a highly conformal radiation technique that permits the delivery of high doses of ionizing radiation in 1–5 sessions while largely sparing surrounding healthy tissues. Furthermore, studies have shown that the delivery of ablative doses of ionizing radiation within the central nervous system is associated with enhanced anti-tumor immunity. While SRS is commonly used in the definitive and adjuvant settings for other CNS malignancies, its role in the preoperative setting has become a topic of great interest due to the potential for reduced treatment volumes due to the treatment of an intact tumor, and a lower risk of nodular leptomeningeal disease and radiation necrosis. While early reports of SRS in the adjuvant setting for glioblastoma were disappointing, its role in the preoperative setting and its impact on the anti-tumor adaptive immune response is largely unknown. In this review, we provide an overview of GBM, discuss the potential role of preoperative SRS, and discuss the possible immunogenic effects of this therapy.

In Vitro Evaluation of the Cytotoxic Effect of Streptococcus pyogenes Strains, Protegrin PG-1, Cathelicidin LL-37, Nerve Growth Factor and Chemotherapy on the C6 Glioma Cell Line.

Brain cancer treatment, where glioblastoma represents up to 50% of all CNS malignancies, is one of the most challenging calls for neurooncologists. The major driver of this study was a search for new approaches for the treatment of glioblastoma. We tested live S. pyogenes, cathelicidin family peptides and NGF, assessing the oncolytic activity of these compounds as monotherapy or in combination with chemotherapeutics. For cytotoxicity evaluation, we used the MTT assay, trypan blue assay and the xCELLigence system. To evaluate the safety of the studied therapeutic approaches, we performed experiments on normal human fibroblasts. Streptococci and peptides demonstrated high antitumor efficiency against glioma C6 cells in all assays applied, surpassing the effect of chemotherapeutics (doxorubicin, carboplatin, cisplatin, etoposide). A real-time cytotoxicity analysis showed that the cell viability index dropped to 21% 2–5 h after S. pyogenes strain exposure. It was shown that LL-37, PG-1 and NGF also exhibited strong antitumor effects on C6 glioma cells when applied at less than 10−4 M. Synergistic effects for combinations of PG-1 with carboplatin and LL-37 with etoposide were shown. Combinations of S. pyogenes strain #7 with NGF or LL-37 demonstrated a cytotoxic effect (56.7% and 57.3%, accordingly) on C6 glioma cells after 3 h of exposure.

Population-based analysis of radiation-induced gliomas after cranial radiotherapy for childhood cancers.

Cranial radiotherapy (RT) used for pediatric CNS cancers and leukemias carries a risk of secondary CNS malignancies, including radiation-induced gliomas (RIG). Our aim was to characterize the epidemiology of RIG. This retrospective study used SEER data (1975-2016). Cohort 1 included patients diagnosed with glioma as a second malignancy ≥2 years after receiving treatment for a first malignancy diagnosed at 0-19 years, either a primary CNS tumor (1a, n = 57) or leukemia (1b, n = 20). Cohort 2 included patients who received RT for a pediatric CNS tumor and died of presumed progressive disease >7 years after diagnosis, since previous studies have documented many missed RIGs in this group (n = 296). Controls (n = 10 687) included all other patients ages 0-19 years who received RT for a first CNS tumor or leukemia. For Cohort 1, 0.77% of patients receiving cranial RT developed RIG. 3.39% of patients receiving cranial RT for primary CNS tumors fell in cohort 2. Median latency to RIG diagnosis was 11.1 years and was significantly shorter for cohort 1b than 1a. Median OS for cohort 1 was 9.0 months. Receiving surgery, radiation, or chemotherapy were all associated with a nonstatistically significant improvement in OS (P .1-.2). A total of 1.8% of all brain tumor deaths fell in cohort 1, with 7.9% in cohort 2. A total of 1%-4% of patients undergoing cranial RT for pediatric cancers later developed RIG, which can occur 3-35 years after RT. Given the substantial and likely underestimated impact on overall CNS tumor mortality, RIG is deserving of increased attention in preclinical and clinical studies.

Smart biomaterials to enhance the efficiency of immunotherapy in glioblastoma: State of the art and future perspectives.

Glioblastoma multiform (GBM) is considered as the most lethal tumor among CNS malignancies. Although immunotherapy has achieved remarkable advances in cancer treatment, it has not shown satisfactory results in GBM patients. Biomaterial science, along with nanobiotechnology, is able to optimize the efficiency of immunotherapy in these patients. They can be employed to provide the specific activation of immune cells in tumor tissue and combinational therapy as well as preventing systemic adverse effects resulting from hyperactivation of immune responses and off-targeting effect. Advance biomaterials in this field are classified into targeting nanocarriers and localized delivery systems. This review will offer an overview of immunotherapy strategies for glioblastoma and advance delivery systems for immunotherapeutics that may have a high potential in glioblastoma treatment.

Development of a Semiautomated Search Tool to Identify Grading From Pathology Reports for Tumors of the CNS and Prostate Cancers.

This study demonstrates the functionality of semiautomated algorithms to classify cancer-specific grading from electronic pathology reports generated from military treatment facilities. Two Perl-based algorithms are validated to classify WHO grade for tumors of the CNS and Gleason grades for prostate cancer. Case-finding cohorts were developed using diagnostic codes and matched by unique identifiers to obtain pathology records generated in the Military Health System for active duty service members from 2013 to 2018. Perl-based algorithms were applied to classify document-based pathology reports to identify malignant CNS tumors and prostate cancer, followed by a hand-review process to determine accuracy of the algorithm classifications. Inter-rater reliability, sensitivity, specificity, positive predictive values (PPVs), and negative predictive values were computed following abstractor adjudication. The high PPV for the Perl-based algorithms to classify CNS tumors (PPV > 98%) and prostate cancer (PPV > 99%) supports this approach to classify malignancies for cancer surveillance operations, mediated by a hand-reviewed semiautomated process to increase sensitivity by capturing ungraded cancers. Early detection was pronounced where 33.6% and 50.7% of malignant records retained a CNS WHO grade of II or a Gleason score of 6, respectively. Sensitivity metrics met criteria (> 75%) for brain (79.9%, 95% CI, 73.0 to 85.7) and prostate (96.7%, 95% CI, 94.9 to 98.0) cancers. Semiautomated, document-based text classification using Perl coding successfully leveraged identification of WHO and Gleason grades to classify pathology records for CNS tumors and prostate cancer. The process is recommended for data quality initiatives to support cancer reporting functions, epidemiology, and research.

EXTH-78. WP1874, A HIGHLY POTENT UNIQUE DNA BINDING AGENT WITH ENHANCED CNS UPTAKE

Abstract As part of our drug discovery program, we have developed structure-based modular designs of unique DNA-binding agents. The approach combines DNA intercalating and DNA “minor-groove-binding” modules. We have discovered compound WP1244 that potentially binds up to 10 bp long sequences of DNA. The unique and intriguing feature of WP1244 is its high CNS uptake combined with the picomolar to low nanomolar cytotoxicity against ependymoma and glioblastoma multiforme (GBM) cell lines and demonstrated in vivo activity in the orthotopic model of GBM. To improve water solubility and develop an IV formulation, we have synthesized WP1874, a mesylate salt of WP1244, and initiated its preclinical characterization. WP1874, similarly to its parental compound, shows high cytotoxicity in ependymoma, GBM, and medulloblastoma cell lines with IC50 in low nanomolar range and it was up to 100 to 200 times more potent than doxorubicin. Interestingly, WP1874 does not appear to be cytotoxic against normal kidney cells (VeroC1008) with IC50 > 10 μM. Preliminary pharmacokinetic and biodistribution studies performed in CD-1 mice with intact brains revealed enhanced penetration of WP1874 to the brain with Cmax 1.5-fold greater than in plasma. Respectively, WP1874 Cmax in the brain was 2.3 ug/g (~2.0 μM) vs. 1.5 μg/ml (1.3 μM) in plasma. Acute toxicity in intravenously administered WP1874 was LD50 >15mg/kg. No mortalities or any apparent toxicity symptoms were recorded for six intravenous weekly doses of WP1874 at 2.5 or 5 mg/kg in CD-1, Balb/c, or nude athymic mice. Intraperitoneal administration was well-tolerated up to 5 mg/kg given three times a week for four cycles. High CNS uptake, excellent cytotoxicity against different brain cancer cell lines, and low toxicity in vivo and in vitro against normal cells warrant further investigation of WP1874 as a mechanically unique potential anticancer agent against CNS malignancies.

EPID-08. IMPORTANCE OF THE INTERSECTION OF AGE AND SEX TO UNDERSTAND VARIATION IN INCIDENCE AND SURVIVAL FOR PRIMARY MALIGNANT GLIOMAS

Abstract BACKGROUND Gliomas are the most common type of malignant brain and other CNS tumors, accounting for 80.8% of malignant primary brain and CNS tumors. They cause significant morbidity and mortality. This study investigates the intersection between age and sex to better understand variation of incidence and survival for glioma in the United States. METHODS Incidence data from 2000-2017 were obtained from the Central Crain Tumor Registry of the United States, which obtains data from the CDC’s National Program of Cancer Registries and NCI’s Surveillance Epidemiology and End Results Program (SEER), and survival data from the CDC’s NPCR Registries. Age-adjusted incidence rates and rate ratios per 100,000 were generated to compare male-to-female incidence by age group. Cox proportional hazard models were performed by age group, generating hazard ratios to assess male-to-female survival differences. RESULTS Overall, glioma incidence was higher in males. Male-to-female incidence was lowest in ages 0-9 years (IRR: 1.04, 95% CI:1.01 - 1.07, p=0.003), increasing with age, peaking at 50-59 years (IRR:1.56, 95% CI: 1.53 - 1.59, p< 0.001). Females had worse survival for ages 0-9 (HR:0.93, 95% CI:0.87-0.99), though male survival was worse for all other age groups, with the difference highest in those 20-29 years (HR:1.36, 95% CI:1.28-1.44). Incidence and survival differences by age and sex also varied by histological subtype of glioma. CONCLUSION To better understand the variation in glioma incidence and survival, investigating the intersection of age and sex is key. The current work shows that the combined impact of these variables is dependent on glioma subtype. These results contribute to the growing understanding of sex and age differences that impact cancer incidence and survival.

IMMU-50. GLIOBLASTOMA MANIPULATES HEMATOPOIETIC STEM CELL DIFFERENTIATION OUTCOMES AND DRIVES ALTERED IMMUNE RECONSTITUTION

Abstract INTRODUCTION Bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) give rise to the cellular components of the immune system. Unfortunately, immune reconstitution from HSPCs are negatively impacted by solid cancers, including high-grade gliomas. For example, an expansion of myeloid progenitor cells has been previously described across several cancers that originate outside the CNS. A similar expansion of MDSCs coupled with diminished T cell function has also been described in the peripheral blood of patients with newly-diagnosed GBM. Alterations in both lymphoid and myeloid compartments due to CNS malignancy led us to determine how intracranial gliomas impact HSPCs in both their capacity to reconstitute the immune compartment and in their cell fate determination. This is important to better understand the impact of gliomas on immunity and how we can leverage these findings to better develop cellular immunotherapeutics. METHODS HSPCs were isolated from bone marrow of C57BL/6 mice with orthotopic KR158B glioma, or age-matched naïve mice. Experiments were conducted to compare relative changes in: gene expression (RNA-sequencing), precursor frequencies, cell fate determination, and cellular function of cells derived from HSPCs of glioma-bearing mice. RESULTS RNA-sequencing revealed 700+ genes whose expression was significantly up- or downregulated in HSPCs from glioma-bearing mice, particularly those involved with stemness and metabolic activity. Importantly, HSPCs from glioma-bearing mice expressed upregulation of genes involved in myelopoiesis relative to naïve mice. This was coupled with an expansion of granulocyte macrophage precursors (GMPs), the progenitors to gMDSCs. Next, differentiation assays revealed that HSPCs from glioma-bearing mice had higher propensity of differentiating into MDSC under homeostatic conditions relative to controls both in vitro and in vivo. Furthermore, mice bearing intracranial gliomas possess an expansion of MDSCs which are more suppressive on T cell proliferation and hinders T cell-mediated tumor cell killing relative to MDSCs derived from naïve control mice.

EXTH-54. PHOTODYNAMIC ONCOLYTIC VIROTHERAPY INCORPORATING GENETICALLY ENGINEERED PHOTOSENSITIZER KILLERRED FOR THE TREATMENT OF CENTRAL NERVOUS SYSTEM MALIGNANCIES

Abstract BACKGROUND Photodynamic therapy (PDT) is a targeted cancer therapy utilizing tumor-specific accumulation of photosensitizers and generation of reactive oxygen species (ROS) upon receiving specific light. The deadly CNS malignancies, high-grade gliomas and malignant meningioma, represent excellent candidates for this therapeutic method due to accessibility to light irradiation at the time of surgery. On the other hand, oncolytic virotherapy using a genetically engineered oncolytic herpes simplex virus (oHSV), has been intensively investigated as a multi-mechanistic therapy against these tumors. One of the advantages of oHSV is its ability to incorporate therapeutic transgenes. Our study aims to address our hypothesis that incorporating KillerRed, the first fully genetically encoded photosensitizing fluorescent protein, into oHSV will establish photodynamic oncolytic virotherapy that enhances tumoricidal efficacy as a novel treatment approach to CNS neoplasms. METHOD The optical properties of the intracellular KillerRed protein expressed in cells were determined by scanning by a multi-mode microplate reader to determine the optimal irradiation wavelength. In vitro efficacy of KillerRed-mediated PDT was tested using human glioblastoma and malignant meningioma cell lines. oHSV G47delta expressing KillerRed was constructed by a bacterial artificial chromosome-based method. KillerRed-transduced cells were confirmed to express red fluorescence, followed by irradiation by an amber color LED. Cell death and viability were assessed by DAPI staining and MTS assay, respectively. ROS generation post light treatment was assessed by DCF-DA cellular ROS assay. RESULTS KillerRed had an excitation peak at 580-585nm in transduced cells. Light irradiation by an amber LED after infection with G47delta-KillerRed induced increased cell growth inhibition and death compared with virus infection without light or light alone. Increased ROS production was observed following KillerRed PDT. CONCLUSION G47delta-KillerRed enables a combination of oncolytic virus therapy and PDT to augment tumor killing. This approach is being tested in in vivo mouse models using potent focused laser irradiation.

EPID-20. THE RISING INCIDENCE AND PREVALENCE OF BRAIN TUMOURS: A CANADIAN EPIDEMIOLOGICAL STUDY

Abstract BACKGROUND Primary malignant brain tumours account for over one third of all brain tumours and are associated with high morbidity and mortality. The purpose of this paper is to estimate the rate and trends of incidence and prevalence for primary malignant CNS tumours in Canada from 1992 to 2017. METHODS An epidemiological study using publicly available data from Statistics Canada: Canadian Cancer Registry (CCR) from 1992 to 2017 for all of Canada was conducted. Incidence and prevalence per 100,000, age-standardized incidence, and age-standardized prevalence per 100,000 person-years of primary malignant CNS tumours were calculated and stratified by sex and age: pediatric (0-19), adult (20-64), and elderly ( >64) populations. RESULTS During the study period, incidence and prevalence increased by 27.3% and 28.8%, respectively. Males accounted for 56% of all diagnoses and experienced decreased survival compared to females one year after diagnosis (p-value = 0.04). Age-standardized rates of incidence and prevalence were highest in elderly populations. CONCLUSIONS Overall, the incidence of primary malignant CNS tumours has increased from 1992 to 2017 with males and the elderly disproportionately affected. Increased healthcare resources and awareness are needed to better identify and deliver evidence-based care for these patients.

EPID-21. EPIDEMIOLOGY AND RISK FACTORS OF PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS IN CHILDREN AND ADULTS IN THE MIAMI CANCER INSTITUTE (MCI) COHORT

Abstract BACKGROUND Many epidemiological studies assess risk factors and incidence of primary CNS tumors in the United States; few describe the incidence in specific geographic locations. Environmental or ethnic/racial factors may affect the incidence of primary CNS tumors. Miami-Dade County (MDC) is an ethnically-diverse US county, with 69.4% Hispanic, 12.9% White Non-Hispanic, 15.5% Black Non-Hispanic, Asian 1.6%, 0.3% Native, and 0.3% other. We characterized primary CNS tumors at Miami Cancer Institute (MCI) relative to national reports. METHODS We reviewed electronic medical records for all patients (n=1221) diagnosed with CNS tumors at MCI from 2017 to 2021. Descriptive and statistical analyses assessed environmental and clinical variables. RESULTS Malignant CNS tumors account for 74% of MCI primary CNS tumors. Diffuse gliomas (41%), meningiomas (26%), and embryonal tumors (5%) were the most common histologies; embryonal tumors most common at younger ages (median: 18 years). The most abundant histological subtypes were glioblastoma (54%), benign meningioma (92%), and medulloblastoma (73%), respectively. Ethnic/racial composition of glioma patients at MCI was 55.9% Hispanic, 24.6% White Non-Hispanic, 6.4% Black Non-Hispanic, 1.8% Other Non-Hispanic, 1.3% Asian, 10% unreported, comparable to MDC. Compared to national averages, the age distribution at MCI was higher among lower grade gliomas (range: 15-96, Median: 61 years), yet lower for malignant gliomas (range: 1-93, median: 47 years). The incidence of malignant CNS tumors did not differ by gender; benign primary CNS tumors were significantly more frequent in females (245/324, 76%; p< 0.001). Smoking history did not associate with incidence of primary CNS tumors; 793/1221 (65%) self-reported as non-smoker. CONCLUSION The ethnic/racial composition and incidence of primary CNS tumors by histology at MCI significantly differs from national CBTRUS database (Ostrom et al). This cohort will be further characterized by genetic profiles, race, diet, allergies, family history, substance use, clinical trial enrollment, therapeutic modalities, and overall survival rate.

Isolated headache is not a reliable indicator for brain cancer: the 2-week wait pathway for suspected CNS malignancies

The UK uses the 2-week-wait (2WW) pathway for rapid access to cancer services. It is unclear whether this is effective for brain cancer. We retrospectively analysed all 2WW referrals for brain cancer between 2009 and 2016 in a district general neurology department. We compared clinical presentations to national guidelines and diagnoses of brain cancer. Of the 153 cases analysed, four brain cancers were identified: two glioblastomas and two metastases. Headaches were the most common referral. The end diagnosis was mostly migraine. The highest positive predictive value was for behavioural/personality change (5.3%) and sub-acute neurological deficit (3.2%). There was no significant association between any symptom(s) and brain cancer. The 2WW pathway is not effective in the diagnosis of brain cancer. Resources are better directed towards clinical research and treatment trials. Headache remains the most common reason for referral although it is not yet a reliable indicator of brain cancer.

P.164 The Rising Incidence and Prevalence of Brain Tumours: a Canadian epidemiological study

Background: Primary malignant brain tumours account for over one third of all brain tumours and are associated with high morbidity and mortality. The purpose of this paper is to estimate the rate and trends of incidence and prevalence for primary malignant CNS tumours in Canada from 1992 to 2017. Methods: An epidemiological study using publicly available data from Statistics Canada: Canadian Cancer Registry (CCR) from 1992 to 2017 for all of Canada was conducted. Incidence and prevalence per 100,000, age-standardized incidence, and age-standardized prevalence per 100,000 person-years of primary malignant CNS tumours were calculated and stratified by sex and age: pediatric (0-19), adult (20-64), and elderly (>64) populations. Results: During the study period, incidence and prevalence increased by 27.3% and 28.8%, respectively. Males accounted for 56% of all diagnoses and experienced decreased survival compared to females one year after diagnosis (p-value = 0.04). Age-standardized rates of incidence and prevalence were highest in elderly populations. Conclusions: Overall, the incidence of primary malignant CNS tumours has increased from 1992 to 2017 with males and the elderly disproportionately affected. Increased healthcare resources and awareness are needed to better identify and deliver evidence-based care for these patients.

HIGH GRADE GLIOMA OF CENTRAL NERVOUS SYSTEM: SINGLE CENTER TREATMENT EXPERIENCE

To evaluate characteristics and treatment responses of patients with high grade gliomas (HGG) in our center. Medical files of patients with malignant CNS tumors between 1987-2020 were analyzed retrospectively. There were 44 patients with HGG. Diagnosis of patients as follows: 21 pons glioma, 2 anaplastic astrocytoma, 11 anaplastic ependimoma, 7 glioblastoma multiforme, 1 glioblastoma, 2 gliomatosis cerebri. The median age at diagnosis was 6,5 yrs (7 – 17 yrs), M/F:25/19. Age distribution: <5 yrs 12 patients, 5-10 yrs 18 patients, 10-18 yrs 14 patients. The most frequent complaints for pons gliomas: cranial nerve paralysis (52%), visual impairment (48%), headache (38%), power loss (43%) and speech disorder (30%). Surgery was performed to extrinsic component of mass in 3 patients of pons gliomas.For other HGG: 7 subtotal resection and 16 gross total resection had performed.7 patients died before RT. And other 37 patients received radiotherapy. RT total doses varied between 50-60 Gy.7 patients were not received chemotherapy, 3 of them died before chemo, and others received only RT. For other HGGs, platin based regimens used for the first line treatment. Temozolamide, bevacizumab, irinotecan as the other options. Median progression free survival time was 6 mos (2weeks-25 mos) for pons gliomas, for other gliomas median progression free survival time was 14 mos(0 -74 mos).For pons gliomas: Event free survival rate for 6 mos was 75%, for one year 17%;one year, 18 mos, and two years overall survival rates were 84%,52% and 10%respectively.For other HGGs: Event free survival rate for one year and two years were 57% and 17% respectively. One year and two years overall survival rates were 73% and 36% respectively. High grade glioma is a group of tumors in which still the helplessness experienced in treatment. Despite radiotherapy and chemotherapy, prognosis is very poor. The progression free and overall survival rates of patients were similar to literature. With new developments in molecular pathology, as the use of molecular target therapies, the progression free survival rates newly will improve.

Availability and role of clinical pharmacists in ambulatory neuro-oncology.

Outpatient clinics treating neuro-oncology patients are becoming more multidisciplinary. Utilization of all team members is critical for the holistic care of these complex patients. Specifically, the role of clinical pharmacist (CP) in the ambulatory clinic remains undefined and will likely evolve as more therapeutics are developed for CNS malignancies. We queried the Society for Neuro-Oncology (SNO) membership about the availability of a CP in their ambulatory setting and, if present, the role of that CP. In an IRB-exempt study, we surveyed the SNO community and analyzed responses to queries about CPs in the ambulatory setting. Of the 65 SNO members who responded, 52 were clinical members. Of these 52 clinicians, the majority were physicians (88.5%, n = 46). Of these physicians, most were in academic practices (93.5%, n = 43). Over half of the 52 clinical respondents (51.9%, n = 27) reported that they saw ≥30 primary brain tumor patients per month, thus typifying busy clinics. Despite having busy clinics, only 12 (28.6%) of 42 providers with access to a CP reported that their CP was solely dedicated to neuro-oncology patients. For the respondents who had access to a CP, only ~two-thirds of those CPs had direct patient interaction. The top 3 roles of the CP included medication review, chemotherapy dosing/modifications, and practice guideline development; none of which involve direct patient interaction. We found that while our surveyed population of SNO clinical members have demanding outpatient practices, most do not have the support or expertise of dedicated neuro-oncology CPs.

778 A Systematic Review of Surgery for Optic Pathway Glioma

Abstract Aim Optic pathway gliomas (OPG) are a rare group of primary CNS malignancies usually found in children. The contemporary role of surgery in managing OPG is unclear. This review aimed to systematically assess the contemporary role for surgery in managing OPGs with respect to survival and functional outcomes. Method A systematic review was conducted in accordance with the PRISMA guidelines. A broad search strategy was employed in the literature search of the major medical databases. Articles describing OPG patients (stratified by modified Dodge classification (mDC) location) undergoing tumour-directed surgery were included, whilst articles with <10 patients, published before 2000 and describing individual case reports, opinions or secondary research were excluded. Primary outcomes were overall survival (OS), progression-free survival (PFS), visual outcome and endocrine outcome. Results 1221 articles were originally identified, with 21 included in the qualitative synthesis. There were 13 Level II and 8 Level IV articles. 5-year OS and PFS was 94.6% and 57.8% respectively (n = 2139). Total resection of mDC I OPG was curative, with no other surgical strategy being associated with survival benefit. Surgery was not significantly associated with visual or endocrine outcome, aside from preservation of contralateral vision (p < 0.001) in one series and predicting posterior pituitary dysfunction and GH deficiency (both p = 0.05) in one cohort. Conclusions Patients undergoing surgery for OPG have excellent overall survival, but a significant proportion have disease progression and associated endocrinopathy. Although total resection of mDC I OPG appears curative, more robust evidence is required to ascertain the surgical role in OPG.

Taste disorders in children with hemoblastosis and malignant CNS tumors after treatment

Despite significant achievements in oncopediatrics there is an increasing amount of children with remote consequences of anticancer treatment. Nutritional disorders are one of the key consequences, the main factors of which are taste disorders. Despite the interest in this issue, an increase in the number of studies, the exact genesis and causal relationships of these violations have not yet been established.Objective. To study the characteristics of taste perception in children with hemoblastosis and CNS tumors after treatment. Material and methods. The authors carried out a cross-sectional study, which included 110 children with hematological malignancies (42 patients) and CNS tumors (68 patients) aged from 10 to 17 years. The after – treatment period was 2–5 years. They analyzed the nutritional screening data (body mass index and survey data). A test for the identification of four tastes (sour, bitter, salty, sweet) was carried out with the solutions in a regulated concentration according to the standard GOST ISO 3972-2014.Results. The majority of children had violations of taste: to bitter taste – 64,6%, sweet – 40%, sour – 43,7%, salty – 33,6%. Children with hemoblastosis had more disorders.Parageusia was more common in children with CNS tumors. Obese children have a greater proportion of these disorders compared to children with malnutrition and normal nutritional status. There is no relationship with the frequency of food intake, its regularity andappetite.Conclusion. The authors have confirmed the presence of nutritional disorders and problems with taste perception that persist for a long time after the end of treatment. Apparently, a significant part of them has a peripheral genesis.

OS06.4A Identification of T cell receptors targeting ZFTA-RELA fusion-positive ependymoma

Abstract BACKGROUND The oncogenic gene fusion between ZFTA (formerly C11orf95) and RELA has in recent years been highlighted as oncogenic driver event ultimately leading to malignant transformation and progression of ependymoma. Representing a genetic hallmark in 17.6% of ependymomas, ZFTA-RELA fusion-positive tumors qualified as separate diagnostic entity in the 2016 revision of the WHO classification of CNS tumors. This tumor entity mainly occurs in pediatric patients and is characterized by poor prognosis and the lack of biology-driven therapy. RESULTS De novo prediction of putative gene fusion-derived neoepitopes in malignant CNS diseases yielded several potential candidates suitable for screening. Of these, vaccination of A2.DR1-transgenic major histocompatibility complex (MHC)-humanized mice with in silico compiled peptide vaccines encompassing the ZFTA-RELA fusion sequence elicited robust antigen-specific CD4+-restricted immune responses. We identified ZFTA-RELA-reactive T cell clones by multiplexed Interferon-γ / Interleukin-2 recall response. Single-cell VDJ-sequencing of reactive T cells demonstrated a highly clonal T cell receptor (TCR) repertoire and shared clonotypes among all vaccinated animals. Matching TCRα/β chains have been assembled from single-cell sequencing data and cloned for functional testing of neoepitope-reactive TCR-transgenic T cells in vitro as well as in vivo using a transposon system-based immunocompetent, MHC-humanized ZFTA-RELA fusion-positive ependymoma model. CONCLUSION Here we identify the oncogenic ZFTA-RELA gene fusion product as a novel tumor-specific neoepitope that is recognized by MHC class II-restricted TCRs. Therapeutic efficacy of TCR-transgenic cell therapy can be further investigated using an immunocompetent MHC-humanized mouse model of ZFTA-RELA fusion-positive ependymoma. Our findings provide initial evidence for neoepitope-specific immunotherapy in pediatric CNS tumors.

Importance of the intersection of age and sex to understand variation in incidence and survival for primary malignant gliomas.

BackgroundGliomas are the most common type of malignant brain and other CNS tumors, accounting for 80.8% of malignant primary brain and CNS tumors. They cause significant morbidity and mortality. This study investigates the intersection between age and sex to better understand variation of incidence and survival for glioma in the United States.MethodsIncidence data from 2000 to 2017 were obtained from CBTRUS, which obtains data from the NPCR and SEER, and survival data from the CDC’s NPCR. Age-adjusted incidence rate ratios (IRR) per 100 000 were generated to compare male-to-female incidence by age group. Cox proportional hazard models were performed by age group, generating hazard ratios to assess male-to-female survival differences.ResultsOverall, glioma incidence was higher in males. Male-to-female incidence was lowest in ages 0-9 years (IRR: 1.04, 95% CI: 1.01-1.07, P = .003), increasing with age, peaking at 50-59 years (IRR: 1.56, 95% CI: 1.53-1.59, P < .001). Females had worse survival for ages 0-9 (HR: 0.93, 95% CI: 0.87-0.99), though male survival was worse for all other age groups, with the difference highest in those 20-29 years (HR: 1.36, 95% CI: 1.28-1.44). Incidence and survival differences by age and sex also varied by histological subtype of glioma.ConclusionsTo better understand the variation in glioma incidence and survival, investigating the intersection of age and sex is key. The current work shows that the combined impact of these variables is dependent on glioma subtype. These results contribute to the growing understanding of sex and age differences that impact cancer incidence and survival.

OTHR-04. Gynecological Malignancies With Metastasis To The Central Nervous System: A Case Series and Systematic Review of the Literature

IntroductionGynecologic malignancies are an increasingly common proportion of central nervous system metastatic disease. As genetic sequencing technology improves and becomes more accessible, mutations associated with CNS metastasis are easier to elucidate. The aims of this case series and systematic literature review are to describe the patient population with CNS metastatic disease from a gynecologic primary, and to investigate why the proportion of CNS metastasis from gynecologic malignancies is increasing. Ultimately, we hope to improve understanding of this subset of metastatic CNS malignancies and improve management strategies.MethodsA literature review of articles describing patients from 1990–2020 who were diagnosed with CNS metastasis from a known gynecologic primary malignancy was performed. Demographics, cancer type, mutation characteristics, management for metastatic disease, progression free survival, number of CNS metastases, and location of metastatic disease were assessed. Inclusion criteria were age>18 years, diagnosis of primary ovarian, uterine, or cervical cancer with confirmed metastatic disease to the CNS, including brain parenchyma, leptomeninges, or intradural spinal cord or dural metastases. Exclusion criteria included pediatric population and bony metastases (e.g., bony spine metastases without evidence of meningeal/parenchymal invasion).ResultsOur review showed that patients with gynecological metastasis to the CNS generally have worse outcomes regarding overall survival, progression free survival, and quality of life than patients without CNS metastasis.DiscussionOur results infer that the reported increase in incidence of CNS metastasis from gynecologic malignancies is a reflection of improvement of detection given advances in technology, improved patient follow up, and increased overall survival of patients with gynecologic malignancies. Further characterization of mutations from gynecologic malignancies associated with brain metastasis could result in development of more treatment options for patients in the future and help determine factors that contribute to developing metastasis to the CNS of various degrees, thus, potentially inform treatment strategies.