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Purpose: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. Patients and Methods: This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. Results: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12–24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. Conclusions: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.

PURPOSE: Resting state functional magnetic resonance imaging (rsfMRI) is an emerging tool to explore the functional connectivity of different brain regions. We aimed to assess the disruption of functional connectivity of the Default Mode Network (DMN), Dorsal Attention Network(DAN) and Fronto-Parietal Network (FPN) in patients with glial tumors. METHODS: rsfMRI data acquired on 3T-MR of treatment-naive glioma patients prospectively recruited (2015–2019) and matched controls from the 1000 functional-connectomes-project were analyzed using the CONN functional toolbox. Seed-Based Connectivity Analysis (SBCA) and Independent Component Analysis (ICA, with 10 to 100 components) were performed to study reliably the three networks of interest. RESULTS: 35 patients with gliomas (17 WHO grade I-II, 18 grade III-IV) and 70 controls were included. Global increased DMN connectivity was consistently found with SBCA and ICA in patients compared to controls (Cluster1: Precuneus, height: p < 10(−6); Cluster2: subcallosum; height: p < 10(−5)). However, an area of decreased connectivity was found in the posterior corpus callosum, particularly in high-grade gliomas (height: p < 10(−5)). The DAN demonstrated small areas of increased connectivity in frontal and occipital regions (height: p < 10(−6)). For the FPN, increased connectivity was noted in the precuneus, posterior cingulate gyrus, and frontal cortex. No difference in the connectivity of the networks of interest was demonstrated between low- and high-grade gliomas, as well as when stratified by their IDH1-R132H (isocitrate dehydrogenase) mutation status. CONCLUSION: Altered functional connectivity is reliably found with SBCA and ICA in the DMN, DAN, and FPN in glioma patients, possibly explained by decreased connectivity between the cerebral hemispheres across the corpus callosum due to disruption of the connections.

Purpose Body image (BI) is an important issue for cancer patients, as patients with BI concerns are susceptible to depression, anxiety, difficulty coping, and poor quality of life (QoL). While this concern has been documented in patients with other malignancies, no data exists of this QoL issue in patients with primary brain tumors (PBT). Methods A cross-sectional survey of 100 PBT patients was conducted on an IRB approved prospective protocol using structured questionnaires. Participants completed the body image scale (BIS), Appearance Scheme Inventory Revised (ASI-R), MD Anderson Symptom Inventory Brain Tumor (MDASI-BT), and Patient-Reported Outcomes Measurement Information System (PROMIS) Depression, Anxiety, and Psychosocial Impact Positive measures. Results The prevalence of clinically significant body image dissatisfaction (BIS ≥ 10) was 28% (95% CI 19–37%), median BIS score was 5 (range 0–27). The median ASI-R composite score was 2.9 (range 1.5–4.7). BIS was significantly correlated with the ASI-R (r = 0.53, 95% CI 0.37 to 0.65). The mean PROMIS Depression score was 48.4 (SD = 8.9), PROMIS Anxiety score was 49.4 (SD = 9.9), and PROMIS Psychosocial Illness Impact Positive score was 48.9 (SD = 9.7). BIS was significantly correlated with age, and trended with BMI and sex. The PROMIS Psychosocial Illness Impact Positive and PROMIS Anxiety scores were the most strongly related to BIS. Conclusions This study, the first to explore altered body image in PBT patients, revealed clinically significant body image dissatisfaction in nearly 1/3 of patients, similar to other malignancies. These findings underscore the potential contribution of disease and treatment-related body image concerns on psychosocial wellbeing in patients with PBT.

Histone mutations occur in approximately 4% of different cancer types. In 2012, mutations were found in the gene encoding histone variant H3.3 (H3F3A gene) in pediatric diffuse intrinsic pontine gliomas and pediatric hemispheric gliomas. Tumors with mutations in the H3F3A gene are generally characterized as histone mutated gliomas (HMGs) or diffuse midline gliomas. HMGs are a rare subtype of glial tumor that is malignant and fast growing, carrying a poor prognosis. In 2017, the Beau Biden Cancer Moonshot Program appropriated $1.7 billion toward cancer care in 10 select areas. The National Cancer Institute (NCI) was granted support to focus specifically on rare central nervous system (CNS) tumors through NCI-CONNECT. Its mission is to address the challenges and unmet needs in CNS cancer research and treatment by connecting patients, providers, researchers, and advocacy organizations to work in partnership. On September 27, 2018, NCI-CONNECT convened a workshop on histone mutated midline glioma, one of the 12 CNS cancers included in its initial portfolio. Three leaders in the field provided an overview of advances in histone mutated midline glioma research. These experts shared observations and experiences related to common scientific and clinical challenges in studying these tumors. Although the clinical focus of this workshop was on adult patients, one important objective was to start a collaborative dialogue between pediatric and adult clinicians and researchers. Meeting participants identified needs for diagnostic and treatment standards, disease biology and biological targets for this cancer, disease-specific trial designs, and developed a list of action items and future direction.

Ad-RTS-hIL-12(Ad) is a gene therapy candidate conditionally expressing IL-12 under the transcriptional control of veledimex(V) acting via the RheoSwitch Therapeutic System® gene switch. Veledimex plasma and tumor PK demonstrated a dose-response relationship and crossing the BBB. PD-1+ T-cells were increased in tumor biopsy samples after treatment with Controlled-IL-12 in a phase-l study. This finding was the rationale for conducting 2 trials of Controlled-IL-12 in combination with PD-1-inhibitor to enhance T-cell-mediated anti-tumor effects. Data from two completed phase-I studies (presented in SNO2020), and an ongoing phase-II study of Controlled-IL-12 with cemiplimab study for the treatment of recurrent glioblastoma (rGBM) will be discussed. Ziopharm has conducted 3 phase-I (NCT02026271/NCT03679754 (monotherapy), NCT03636477 (combination with nivolumab)) and one phase-ll (NCT04006119) multicenter, open-label, single-arm trial in subjects with rGBM is evaluating Ad (single intratumoral injection, 2 x 1011-viral-particles, Day0) with oral V dosing (20mg, Days 0-14) with cemiplimab infusions (350 mg IV) on Days -7, 15, then Q3W. Systemic biomarkers (serum cytokines, and immune-activation-markers), local effects (tumor cytokines, T-cell immunobiology, pathology), neoepitope, and imaging will be assessed. Subject characteristics (Controlled IL-12 monotherapy (n=75); combination (Controlled IL-12 with anti-PD-1s) (n=61) were consistent across all 3 studies. Safety profiles were comparable between monotherapy and in combination with anti-PD-1s. Adverse reactions (ARs) after nivolumab or cemiplimab were consistent with labeling of anti-PD-1s. ARs related to Controlled IL-12 were all manageable and reversible with no synergistic toxicities in combination with anti-PD-1s. Increases in serum cytokine levels and pathology findings consistent with immune-mediated anti-tumor effect were observed in subjects who received Controlled-IL-12 monotherapy and in combination with anti-PD-1s. Final survival data and results from neoepitope analysis will be presented. Further investigation is warranted to understand the impact of monotherapy vs. combination, concurrent steroids use and unifocal vs. multifocal disease on overall survival in subjects with rGBM receiving Controlled-IL-12.

Progression (PD) in medulloblastoma (MB) represents a diagnostic challenge due to imaging heterogeneity among/within patients. SHH (Sonic hedgehog)-MB is thought to recur mostly within the tumor bed (TB). In children, DWI restriction (DWIr) is more sensitive than contrast enhancement(CE) for first PD. Whether this is applicable to adults is unknown. METHODS Retrospective review of adults (age ≥18) with MB enrolled to Natural History study at NCI-NOB. Descriptive statistics of imaging at diagnosis and PD(CE, T2/FLAIR signal without CE, DWIr) and imaging patterns for each PD. RESULTS:14 adults with MB: 5 diagnosed in childhood (8–16 yrs), 9 as adults (18–45 yrs); Subtypes: 7 SHH, 3 non-WNT/non-SHH, 4 unknown. Eleven experienced ≥1 PD (6/7 SHH, 2/3 non-WNT/non-SHH, 3/4 unknown); median PD of 5 (range 1–9). Median age at first PD 31 years (range 10–46) with 5 first PDs >5 years after diagnosis. In 10 patients with available baseline MRI, 9 had CE, and 8 DWIr (2 without DWI sequences). Of 48 total PDs, the commonest patterns were: brain LMD alone (n=14), TB alone or distant brain parenchyma alone (each n=7), distant brain parenchyma with brain LMD (n=6), and TB with either distant brain parenchyma or LMD (n=3). Of the 82 PD lesions, 23% (n=14) of brain lesions lacked DWIr, and 37% (n=23) had T2/FLAIR signal without CE. PD tissue confirmation obtained at 18 time points:16 cases with confirmed recurrence had heterogeneous characteristics; in 12 with brain PD: CE in 5, T2/FLAIR without CE in 3 (unknown: 4). 2 CE lesions revealed meningioma (one- atypical meningioma- had DWIr). CONCLUSIONS Imaging findings in adult patients with MB are highly heterogeneous. Despite high specificity of DWIr for PD in children, it failed for 23% of brain lesions across multiple patients. Most SHH-MB had PD outside the TB, unlike what is widely accepted in the literature.

Increasing recognition of the symptom burden and functional limitations among primary brain tumor (PBT) patients has led to proposing clinical outcomes assessments as an additional measure of a treatment’s effectiveness. The RANO-PRO Collaborative recommended core symptoms for evaluation in clinical care and research for malignant glioma are weakness, walking, seizures, communication, memory, and treatment-specific symptoms. We evaluated these symptoms using the MDASI-Brain Tumor (BT) in the PBT patient sample of the NCI-NOB Natural History Study, in relation to disease progression, by descriptive statistics, and independent- and paired-samples t-tests. The sample included 434 PBT patients (59% male, median age=50 (18–83), 82% white, 43% with a prior recurrence). In the 60% with a malignant glioma, weakness, walking, seizures, difficulty remembering, and fatigue were significantly worse in the group with progression at time of imaging compared to the group with stable disease (p< 0.05). In a subset of 114 patients with progression after study entry, reported severity in all symptoms (except seizures) significantly worsened from study entry to time of progression (-1.7< mean difference< -0.1, p< 0.02, 0.3< r< 0.5). Walking, weakness, difficulty remembering, and fatigue each had a difference greater than 1-point, the minimally important difference for MDASI-BT. No one core symptom accounted for the severity change; each was reported by 17%-35% of patients as their largest change in severity. Utilizing the symptom with the largest change increased the magnitude of the worsening and its effect size (mean difference=-2.9, r=0.5). The analysis was repeated in the larger PBT sample with similar statistical findings but with smaller mean differences. RANO-PRO Collaborative core symptoms were shown to worsen at time of progression on imaging, highlighting the importance of continual symptom assessment and validating this core symptom group. Further analysis will focus on degree of change with each core symptom and validation in other datasets.

BACKGROUND: The standard of care for unresectable intrahepatic cholangiocarcinoma (ICC) is palliative systemic chemotherapy with cisplatin and gemcitabine. The use of hepatic arterial infusion (HAI) floxuridine (FUDR) with systemic chemotherapy may improve outcomes. We conducted a phase 1 study of HAI FUDR with systemic gemcitabine and oxaliplatin. METHODS: We enrolled patients in three cohorts: FUDR 0.16 mg/kg/day ×14 days (Cohort 1), FUDR 0.12 mg/kg/day ×14 days with gemcitabine 1,000 mg/m(2) on days 1, 8, 15 (Cohort 2), and FUDR 0.10 mg/kg/day ×14 days with gemcitabine 800 mg/m(2) days 1, 15 and oxaliplatin 85 mg/m(2) days 1, 15 (Cohort 3). The primary endpoint was the recommended phase 2 dose (RP2D). Dose limiting toxicities (DLTs) were assessed during cycle 1. Secondary objectives were response rate and survival. RESULTS: We enrolled 24 patients, 6 male, age range 42–81 years (median 64). No DLTs were observed in Cohort 1. In Cohort 2, the addition of gemcitabine 1,000 mg/m(2) days 1, 8, 15 resulted in grade 3 LFT elevation in 2 patients; for subsequent patients, the gemcitabine dose was reduced to 800 mg/m(2). No DLT were observed in Cohort 3. Most patients experienced stable disease (SD) or partial response (PR). Conversion to resectable disease occurred in all cohorts. CONCLUSIONS: Administration of FUDR via HAI pump in combination with systemic gemcitabine and oxaliplatin is well-tolerated in patients with unresectable cholangiocarcinoma. Preliminary analysis suggests a high rate of response and disease control, with some patients proceeding to resection. Based on Cohort 3, the RP2D is FUDR 0.10 mg/kg/day ×14 days, with gemcitabine 800 mg/m(2) days 1, 15 and oxaliplatin 85 mg/m(2) days 1, 15 for future studies. Future studies of this promising regimen will utilize this dosing schedule.

The ability of positron emission tomography-computerized tomography (PET-CT) to accurately detect bone marrow involvement (BMI) has been suggested in Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL), but its abilities in other histologies is less established. The aim of this retrospective study was to confirm the role of PET-CT in detecting BMI in DLBCL and HL, and to explore its usefulness in other subtypes. Of the 149 newly diagnosed patients, common subtypes included DLBCL, follicular lymphoma (FL) and HL. In DLBCL, the sensitivity and specificity of PET-CT at diagnosis were 75% and 92%. In FL, the sensitivity and specificity of PET-CT were 67% and 85% at diagnosis, and 73% and 89% at relapse. In HL, the sensitivity and specificity were 100% and 74%. PET-CT was able to detect BMI in patients with negative biopsies. Most of the patients in which PET-CT failed to identify BMI were already advanced stage by imaging. In this analysis, PET-CT was highly accurate for detecting BMI at diagnosis in DLBCL and HL and highly specific in FL at diagnosis and relapse. Results also suggested the diagnostic advantage of PET-CT over bone marrow biopsy in detecting BMI. Prospective evaluation is necessary and may eliminate biopsies in future patients.

Introduction: Liquid biopsies, especially plasma cell-free circulating tumor DNA (ctDNA), provide a potential opportunity to be a noninvasive biomarker for the diagnosis and monitoring of glioblastoma (GBM) patients. Previously, we detected TERT promoter hotspot mutations (C228T and C250T) in ctDNA of IDH wild-type (IDHwt) TERT promoter mutant GBM patients with 100% specificity using mutation-specific droplet digital PCR (ddPCR) assays. Here, we examine the association between mutant TERT ctDNA levels and clinical outcomes in newly diagnosed GBM patients undergoing chemoradiation. Methods: We analyzed 76 serially collected plasma samples from 17 patients with suspected IDHwt GBM based on MRI before surgery. Twenty mL of whole blood was collected in EDTA tubes at predetermined times: pre- and postoperatively, at the end of chemoradiation, and 1, 3, and 6 months from the end of chemoradiation. TERT promoter mutations C228T or C250T were identified in FFPE tumor samples using ddPCR assays specific for these mutations. Plasma samples were analyzed for the patient’s tumor TERT mutation using the ddPCR assays. The analytically validated thresholds for positive ctDNA detection were 1.5 and 1.7 copies/mL for C228T and C250T, respectively. Results: Sixteen of 17 (94%) IDHwt tumors had TERT mutations (10 C228T, 6 C250T) with MGMT methylated, unmethylated, or unknown status in 10, 5, and 1, respectively. Fourteen of the 16 patients (87.5%) had detectable mutant ctDNA at one or more time points (range 1.66 to 22.13 copies/mL). Of the 2 patients with undetectable ctDNA, one had diffuse and non-avidly enhancing disease and the other only had pre/postop plasma samples collected. Six patients had detectable ctDNA preop, and most had a dominant rim-enhancing mass with additional nonenhancing or enhancing lesion(s). Ten patients had detectable ctDNA up to 4 days postop, half of whom had undergone gross total resection. For 3 of 5 patients for whom there was a question of pseudoprogression versus true progression, ctDNA kinetics matched the clinical outcome. One patient with MGMT unmethylated multifocal GBM achieved ctDNA zeroconversion at 6 months post radiation (RT), and did not progress for another five months. Another patient was negative at all time points until their 3-month post RT follow-up, at which time they developed a recurrence. Another patient achieved zeroconversion at the end of RT but developed a borderline positive ctDNA at 6 months after RT, 2 months before documented radiographic progression. Conclusions: In this pilot, prospective ctDNA monitoring study of IDHwt GBM, TERT mutant ctDNA was detected at one or more time points in the majority of patients. ctDNA kinetics were associated with clinical outcomes for some patients. These data suggest that additional, larger studies could refine how ctDNA monitoring may be used to enhance the clinical management of IDHwt GBM patients. Citation Format: Christine Cordova, Mahrukh M. Syeda, Broderick Corless, Jennifer M. Wiggins, Amie Patel, Sylvia C. Kurz, Malcolm Delara, Zacharia Sawaged, Minerva Utate, Dimitris Placantonakis, John Golfinos, Jessica Schafrick, Joshua S. Silverman, Rajan Jain, Matija Snuderl, David Zagzag, George Karlin-Neumann, David Polsky, Andrew S. Chi. Longitudinal detection of TERT-mutant plasma cell-free circulating tumor DNA in newly diagnosed glioblastoma patients [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr A65.

Sleep disturbance (SD) is a common symptom reported by PBT patients and research has demonstrated a link between sleep and stress circadian pathways. SD can impact perceived severity of other symptoms and development of psychopathology. This study explored the prevalence of moderate-severe SD in PBT patients, identifying associated clinical characteristics and co-occurrence with other tumor-related and psychological symptoms. Demographic, clinical characteristics, MDASI-Brain Tumor, and PROMIS Depression and Anxiety Short-Forms were collected at study entry. Descriptive statistics, Chi-square tests, and independent t-tests were used to report results. The sample included 424 patients (58% male, 81% Caucasian) with a median age of 49 years (range 18–81) and 58% with high-grade gliomas. Most had received treatment with surgery, radiation or chemotherapy prior to study entry, with 44% reporting a past recurrence. Moderate-severe SD (³ 5 on a 0–10 scale) was reported in 19% of patients and was associated with younger age (mean difference = 5 years), poor KPS (OR 2.2), current steroid use (OR 2.4), and tumor progression on MRI (OR 2). Those with moderate-severe SD had a higher overall symptom burden (mean difference = 2.3) and reported more moderate-severe symptoms (8 vs. 2). Patients reporting moderate-severe SD also reported higher severity in affective and cognitive symptom domains and mood-interference, with fatigue (72%), drowsiness (59%), and distress (56%) the most frequently co-occurring symptoms. Patients with moderate-severe SD also had increased prevalence of moderate-severe anxiety (32%) and depression (23%), compared to 10% in those without SD. PBT patients with moderate-severe SD are more symptomatic and have higher incidence of mood disturbance, suggesting a key role for sleep in the development of tumor-related and psychological symptoms. Future work delineating specific pathways involving sleep disturbance and co-occurring symptoms will be foundational for designing targeted sleep interventions to improve symptom burden and quality of life.

BACKGROUND Therapies targeting multiple survival pathways are desirable for high-grade gliomas. TG02 (Zotiraciclib), a CDK9 inhibitor, regulates transcription and metabolism of tumor cells and synergizes with temozolomide. A phase I/II trial was launched to test the TG02/temozolomide combined treatment in recurrent high-grade astrocytomas. Phase I results are reported here. METHODS Adults with recurrent high-grade astrocytoma, KPS≥60, adequate organ function, < 2 prior relapses were enrolled. Primary endpoint was dose limiting toxicity (DLT) in cycle1 in each arm. Bayesian optimal interval design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days1,12,15, and 26) and temozolomide, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm1) or metronomic (MN; 50mg/m2/d, Arm2) dosing schedule on a 28-day cycle. RESULTS Thirty-eight patients were evaluable; median age 50.7, KPS 90. Of 18 evaluable patients in Arm1, at TG02 dose-level 200mg, 1/6 had a DLT: Gr3 diarrhea; at dose-level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm2, at TG02 dose-level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia; at dose-level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia; at dose-level 300mg,1 of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST. TG02 dose-level of 250mg was declared as the MTD in both Arms. Using the MDASI-BT, patients with high symptom burden had increased symptoms during cycle1 but became stable as they continued treatment. CONCLUSION The combination of TG02 at the MTD of 250mg with DD or MN temozolomide was tolerated. Cohort expansion continues at the MTD in both arms. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation.

BACKGROUND Immunotherapy agents have unique symptomatic side effects; patient-reported outcomes (PROs) can help to characterize the benefits and burdens associated with therapy. Common immunotherapy-associated symptoms include pain, fatigue, shortness of breath, and irregular bowel patterns. The purpose of this study was to assess the severity of symptoms and their association with imaging changes in CNS tumor patients undergoing single agent or combination treatment with immune checkpoint inhibitors (ICIs). METHODS Patients completed the MDASI-BT or MDASI-SP at baseline and longitudinally (every 8 weeks), and results through cycle 4 are reported. Neuro-imaging was categorized as stable, possible ICI-related pseudoprogression, or progression by clinical team review. RESULTS 29 Brain Tumor (BT) and 6 Spinal Tumor patients participated; the majority of which were male (62%) and white (91%), ranging 24-74yo (mean = 46). Glioblastoma was the most common diagnosis (31%) followed by medulloblastoma (16%), with 56% of patients having greater than 2 recurrences prior to the study. At baseline, both brain and spine tumor patients reported moderate to severe fatigue (Brain=4, Spine=6) and pain (Spine=5) with shortness of breath and pain worsening over time. BT patients with pseudoprogression were more likely to report increased fatigue (87%) and pain (63%) compared to those with stable (29%) or true progressive (17%) disease on imaging. BT patients with pseudoprogression also reported worsening of cognitive (43%) and neurologic (57%) symptom burden. CONCLUSIONS In contrast to the common pseudoprogression after chemoradiation, treatment-specific symptoms were worse with ICI-related pseudoprogression by MRI where an immunologic reaction was the likely cause of the imaging worsening. These results suggest that commonly used symptom and functional assessments to distinguish true progression from pseudoprogression may not be helpful with immunotherapy. Additional studies including those with pathologic confirmation of progression or pseudoprogression combined with outcomes measures are needed to develop more accurate determinations of disease status.

BACKGROUND While rare cancers have provided insight into mechanisms of tumorigenesis and familial syndromes, patients with rare CNS tumors and providers face unique challenges, including diagnostic delays and errors, lack of standardized approaches to care/treatment, and limited social support. Scant data exists on the natural history, health status, and impact of these tumors on life quality. This report describes an innovative clinic designed to fulfill the mission of the NCI-CONNECT program: To advance our understanding and to improve approaches to care and treatment of rare CNS tumors. METHODS A specialized weekly clinic was established incorporating routine comprehensive analysis of tumor tissue, genetic counseling with individual pedigree assessment, group meetings with a health and wellness counselor and comprehensive clinical evaluation. Patients and caregivers both participated. Descriptive statistics report of NCI-CONNECT clinic patients from January 1-May 8, 2019 are presented. RESULTS 33 patients and 32 caregivers have participated to date, representing 6 of the 12 rare tumors studied in NCI-CONNECT: 19 ependymomas, 9 oligodendrogliomas, 2 PXAs, 1 papillary pineal tumor, 1 medulloblastoma, 1 gliosarcoma. The median time from receiving pathologic material to appointment was 22 days, with analysis including methylation and next generation sequencing testing. All 33 patients underwent genetic counseling, most (n=26) having at least ≥ 2 first- or second-degree relatives diagnosed with cancer (Germline mutations/genetic predisposition testing underway). 44 patients attended (33 with 8 repeat visits) the health and wellness group sessions, with education on coping/wellness techniques included. During this same period, 7 patients participated in a rare CNS basket trial using nivolumab. CONCLUSIONS We have developed an innovative clinic model to interrogate rare CNS tumors for therapeutic targets, understand individual risk, how the patient feels and functions and conduct clinical trials. This effort has the potential to accelerate our understanding of these rare tumors and provide guidance on care.

BACKGROUND A recent report examining 75 Oligodendrogliomas indicated that specific imaging features may help predict grading and guide target selection for biopsy when resection is not possible. This report attempted to validate these findings in a separate sample and evaluate interrater reliability. METHODS Two Neuro-Oncologists, blinded to radiology report and grading reviewed diagnostic pre-radiation MRI. Imaging features and reviewer interpretations were evaluated included contrast enhancement, necrosis, calcification, and restricted diffusion; examiner concordance is reported. RESULTS Sixty-two patients with diagnosis of Oligodendroglioma (50 WHO grade II, 12 WHO grade III); 54 were molecularly confirmed as IDH-mutant/1p19q co-deleted based on the NOB Natural History Study. Four patients (grade III) were excluded due to lack of imaging studies. Among 58 evaluable patients, their location was frontal (n=32), temporal (n=14), parietal (n=4), occipital (n=1), and multi-lobe (n=11). Extent of resection: gross total 9, subtotal 36, biopsy 17. Partial to extensive contrast enhancement was present in 18/58 patients (6 grade II, 33%; 12 grade III, 67%); Kappa interrater agreement k= 0.37 on grade II and k=0.50 on grade III; extensive enhancement was present in 4/58 (all grade III), k= 0.70. Necrosis noted in 7/58 patients (all grade III), k=0.61. Calcification noted in 7/17 patients reviewed (all grade III), k=1.0; restriction noted in only 2/39 patients reviewed (all grade III), k=1.0. CONCLUSIONS THE presence of extensive enhancement, necrosis, calcification and restricted diffusion were only present in grade III with substantial agreement between readers, but there was lower agreement for partial enhancement. Image reviewers commented on the variability of enhancement intensity in normal structures between scans, likely contributing to this poor concordance. Tumor areas with extensive enhancement and/or necrosis are associated with higher grade and can guide biopsy if resection is not feasible. Discrepancies in imaging interpretation may be ameliorated by implementing a standardized imaging protocol.