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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: 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 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.

BackgroundMedulloblastoma (MB) is a rare brain tumor occurring more frequently in children in whom research has been primarily focused. Treatment recommendations in adults are mainly based on retrospective data and pediatric experience; however, molecular features and treatment tolerance differ between the 2 age groups. In adults, prognostic tools are suboptimal, late recurrences are typical, and long-term sequelae remain understudied. Treatment has not adapted to molecular classification advances; thus, the survival rate of adult MB has not improved.MethodsIn 2017, the National Cancer Institute (NCI) received support from the Cancer Moonshot℠ to address the challenges and unmet needs of adults with rare central nervous system tumors through NCI-CONNECT, a program that creates partnerships among patients, health care professionals, researchers, and advocacy organizations. On November 25, 2019, NCI-CONNECT convened leading clinicians and scientists in a workshop to review advances in research, share scientific insights, and discuss clinical challenges in adult MB.ResultsWorking groups identified unmet needs in clinical trial design, tissue acquisition and testing, tumor modeling, and measurement of clinical outcomes.ConclusionsParticipants identified opportunities for collaboration; discussed plans to create a working group of clinicians, researchers, and patient advocates; and developed specific action items to expedite progress in adult MB.

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.

Objectives To provide an overview of the symptoms commonly experienced by patients with malignant glioma, and discuss the pathophysiology and interventions associated with those. Data Sources A review of published scientific literature and clinical literature, and online information from National Comprehensive Cancer Network, Oncology Nursing Society, Epilepsy Foundation of America, and the American Brain Tumor Association. Conclusion The unique symptom burden associated with a malignant glioma diagnosis often disrupts the lives of patients and their caregivers. Clinical support and interventions addressing malignant glioma-related focal deficits, seizures, headaches, venous thromboembolism, mood disturbances, fatigue, and sleep-wake disturbance can positively impact patient and caregiver experiences while living with malignant glioma. Implications for Nursing Practice Understanding the pathophysiology of these symptoms and reviewing nursing-led and supported interventions will empower the nurse in providing comprehensive care to patients with malignant glioma and their caregivers.

BACKGROUND: A unified data collection system for interrogating the clinical trajectory of patients and their molecular pathology is of significant diagnostic, research, and therapeutic importance. The NCI-NHS follows primary CNS tumor patients throughout their disease. A targeted NGS panel was developed for clinical screening of mutations in 56 genes, 21 copy number alterations, and 25 gene fusion pairs using archived FFPE tissue. Due to the nature of study, available specimens range in age and source, posing a considerable challenge to obtaining an adequate quality and quantity of nucleic acid for genomic analysis. METHODS: Tumor blocks or unstained slides were received for macrodissection of neuro-pathologist scored tumor tissue. DNA and RNA were extracted, using the Qiagen AllPrep FFPE Kit on a semi-automated QIAcube instrument, and sequenced on Ion Torrent NGS platform. RESULTS: Tissue material from 227 patients was submitted, 17(8%) were rejected for low tumor content (

BACKGROUND: Survivorship is an important area of cancer care and research. There are limited studies exploring the experience of long term survivors of CNS tumors. A recent review of quality of life in adults with CNS tumors underscored the need for studies exploring patient outcomes, including mood disturbance. This report explores mood disturbance in CNS tumor patients living greater than 5 years from diagnosis. METHODS: Patients enrolled on the NOB-NHS were included. PROMIS depression/anxiety measures were completed at study entry. T-scores >60 were considered significant. Independent sample t-tests, chi-square and Fishers Exact tests were used to identify associations with mood disturbance. Significance level was set at 0.05. RESULTS: 132 patients, primarily white (84%), males (58%), with median age 49 (22–81), were included with 59% having low grade tumors; oligodendroglioma (19%) was the most common diagnosis, 30% underwent gross total resection, 33% had had a recurrence and 27% had a poor KPS (80). Five percent were on corticosteroids and 20% on psychotropic medications. Overall, 14% and 18% reported significant depression and anxiety respectively, with 10% reporting both. More non-white [29% vs 11%; X2 (1) = 4.4, p

Primary CNS tumor patients are highly symptomatic, with 40% of brain tumor patients reporting 3 moderate-severe symptoms. The five most commonly reported are fatigue, drowsiness, difficulty remembering, disturbed sleep in brain and in spine patients, pain, numbness, leg weakness, and autonomic dysfunction (bowel and sexual dysfunction). Twenty-five percent reported interference with activity and mood. These reports are limited to primarily white patients, with limited studies exploring in more diverse samples. Fifty patients self-identified as non-white are included in this report of symptom burden (MD Anderson Symptom Inventory-Brain and Spine Tumor), depression and anxiety (PROMIS measures). Descriptive statistics, and standardized classification of severe symptoms and mood are used to describe the sample characteristics Chi-square and Fishers exact test were used to identify associations. Significance level was set at p< 0.05. The majority of patients were male(62%), Black/African American(38%). Median age 40(range 14–69), 44% had a gross total resection at diagnosis. Glioblastoma was the most common diagnosis(40%) with 1/3 having a poor(KPS 80) and a recurrence, and 56% having completed treatment. All spine and 34% of brain tumor patients had at least three symptoms rated as moderate-severe. The top five among brain tumor patients were weakness in arms/legs, fatigue, disturbed sleep, difficulty remembering, and feeling irritable and 57% reported moderate-severe activity related interference from symptoms. Fourteen percent of patients reported having moderate-severe depression and anxiety symptoms at study entry. Diagnosis other than glioblastoma was associated with depression symptoms (X2(1)= 5.4, p< 0.04), but no associations between clinical and demographic factors were found with interference, depression, or anxiety. Minority populations are highly symptomatic, but differences in symptoms reported as most severe were found when compared to historical data which is a restricted patient demographic. Future studies exploring symptom prevalence, underlying risk and treatment in diverse populations are warranted.

BACKGROUND: Biomarkers of response to immunotherapy are critical to evaluate efficacy and ultimately select patients most likely to benefit from this potentially toxic treatment. Peripheral blood mononuclear cells (PBMC) are easily collected and offer abundant lymphocytes, yet the molecular determinants of cells relevant to a therapeutic response have not been determined. To identify such cells, likely rare, we developed four state-of-the-art flow cytometry assays that quantify 65 unique proteins on single-cells for comprehensive, high-throughput proteomic interrogation of PBMC and tumor-infiltrating lymphocytes. Our goal is to identify biomarkers and predictors of response to immunotherapy as well as to find potential peripheral correlates of immune responses to the tumor itself. METHODS: Molecular determinants of B, NK, DC, classical T, invariant T, NKT, and MAIT immune cell lineages and differentiation stages, as well as functional markers including cytokines, cytokine receptors, activation/senescence markers, proliferation, and markers of cytotoxicity were chosen as potential biomarkers of response. Proteomic analyses were performed on PBMC from healthy donors and patients with GBM who received checkpoint blockade therapy. RESULTS: Changes in cellular composition, cell differentiation and functional status were quantified in this comprehensive analysis of healthy donor and patient PBMC. Cellular expression patterns varied by cell activation and differentiation status; highlighting the importance of detailed subset analyses. Potential biomarkers were selected using linear discriminant analysis to identify proteomic differences between healthy donor and patient, as well as longitudinal patient PBMC samples. CONCLUSIONS: Using cutting-edge flow cytometry, we generated a comprehensive analysis of molecular and cellular changes that occur in PBMC in response to immune checkpoint blockade. Additionally, we identify sources of interpatient variation that may obscure subtle proteomic changes. This technological advance provides high-throughput proteomic analysis of live lymphocytes, which can then be sorted for downstream molecular analyses: a critical step in biomarker validation and discovery.

BACKGROUND: Body image is an important psychosocial issue in cancer patients, including those with primary brain tumors (PBT). Investment in physical appearance is associated with depression and quality-of-life (QoL) outcomes in non-CNS malignancies. Therefore, examination of body image investment is warranted to better understand factors involved in body image disturbance in the PBT population. METHODS: A cross-sectional survey of 100 PBT patients was conducted as part of an IRB approved prospective protocol. Participants completed the 10-item Body Image Scale (BIS), and the 20-item Appearance Schemas Inventory-Revised (ASI-R) which includes self-evaluative and motivational salience subscales. Potential BIS and ASI-R scores ranged from 0–30 and 1–5 respectively. Cronbach’s alpha assessed reliability. Pearson’s correlation coefficients assessed relationships between questionnaires. Significance level was p< 0.05. RESULTS: Patients were mostly male (56%) with a median age of 48 (range 23–74). Glioblastoma was the most common diagnosis (32%). Median time from initial diagnosis was 5 years (range 0–22), and 64% of patients had a KPS≥ 90. Median BIS score was 5 (range 0–27), ASI-R composite score was 2.9 (range 1.5–4.7), self-evaluative subscale score was 2.6 (range 1.2–4.5), and motivational subscale score was 3.4 (range 1.9–5.0). BIS was significantly correlated with ASI-R composite (r=0.53, 95%CI: 0.37 to 0.65), ASI-R self-evaluative (r=0.65, 95%CI: .52 to .75), but not ASI-R motivational (r=0.14, 95%CI: -0.06 to 0.33, p=0.17) scores. Increased severity of altered body image was correlated to increased negativity of the patient’s belief about their appearance. Cronbach’s alpha for the ASI-R composite, self-evaluative and motivational subscales were 0.87, 0.85, and 0.81 respectively. CONCLUSIONS: Body image and investment are important QoL issues for PBT patients. The ASI-R demonstrated good internal consistency in this population. While there was significant correlation between BIS and ASI-R composite and self-evaluative scores, this was not true with the motivational score.

BACKGROUND: Body image dissatisfaction is associated with difficulty coping and adjustment in patients with other solid tumors. Although PBT patients may be at increased risk due to the visible disfigurement and debilitating nature of the disease, there is limited research in this patient group. The purpose of this report is to present the qualitative analysis of data captured on the NOB-NHS Body Image Study. METHODS: 100 patients participated by completing structured questionnaires and open-ended responses. Seventy-two patients provided open-ended feedback exploring, How have the changes affected you? within the Feedback Form. Qualitative analysis software (MAXQDA) allowed for text coding of response data to identify recurrent themes. RESULTS: The sample was primarily white (82%), males (58%) median age=50 (range 23–74), diagnosed with glioblastoma (36%). Only 10 (8%) indicated no body image issues. Five dominant themes (lifestyle changes, symptom effects, negative & positive outlook, changes in appearance) characterized participant description of body image since their diagnosis. A number of patients (28%) expressed a hindrance within their lifestyle (altered mobility, independence, activity, and changes in relationships) contributing to this theme. Participants described symptom effects (weight gain, fatigue, pain, vision changes) contributing to dissatisfaction throughout the disease trajectory. Specific changes in appearance (hair loss, indentation on head, skin dryness) were also problematic factors affecting adjustment and coping. An ascribed negative outlook (9%) (self-conscious, feeling ashamed or vulnerable) magnified awareness of long-term permanent changes, but some (8%) described the implementation of a positive outlook (using exercise and hope) allowing for acceptance of these changes. CONCLUSION: These findings offer insight from the patients perspective on identified physical, mental and treatment-related factors regarding body image concerns and the scope of issues faced by PBT patients. Understanding patient concerns allows for a multidimensional approach in management of key areas with the goal of improving overall quality of life.

Background Immune checkpoint inhibitors (ICPIs) are being investigated in clinical trials for patients with glioblastoma. While these therapies hold great promise, management of the patients receiving such treatment can be complicated due to the challenges in recognizing immune-related adverse events caused by checkpoint inhibitor treatment. Brain imaging changes that are the consequence of an inflammatory response may be misinterpreted as disease progression leading to inappropriate premature cessation of treatment. The aim of this study was to, by way of a series of cases, underscore the challenges in determining the nature of contrast-enhancing masses that develop during the treatment of patients with glioblastoma treated with ICPIs. Case presentation We reviewed the clinical course and management of 4 patients on ICPIs who developed signs of tumor progression on imaging. These findings were examined in the context of Immunotherapy Response Assessment in Neuro-Oncology (iRANO) guidelines. Although all 4 patients had very similar imaging findings, 2 of the 4 patients were later found to have intense inflammatory changes (pseudoprogression) by pathologic examination. Conclusions A high index of suspicion for pseudoprogression needs to be maintained when a patient with brain tumor on immunotherapy presents with worsening in an area of a pre-existing tumor or a new lesion in brain. Our findings strongly suggest that pathological diagnosis remains the gold standard for distinguishing tumor progression from pseudoprogression in patients receiving immunotherapy. There is a large unmet need to develop reliable non-invasive imaging diagnostic techniques. Trial registration ClinicalTrials.gov NCT02311920. Registered 8 December 2014.

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.

Combined PET/MRI may be highly beneficial for radiotherapy treatment planning in terms of tumor delineation and characterization. To standardize tumor volume delineation, an automatic algorithm for the co-segmentation of head and neck (HN) tumors based on PET/MR data was developed. Ten HN patient datasets acquired in a combined PET/MR system were available for this study. The proposed algorithm uses both the anatomical T2-weighted MR and FDG-PET data. For both imaging modalities tumor probability maps were derived, assigning each voxel a probability of being cancerous based on its signal intensity. A combination of these maps was subsequently segmented using a threshold level set algorithm. To validate the method, tumor delineations from three radiation oncologists were available. Inter-observer variabilities and variabilities between the algorithm and each observer were quantified by means of the Dice similarity index and a distance measure. Inter-observer variabilities and variabilities between observers and algorithm were found to be comparable, suggesting that the proposed algorithm is adequate for PET/MR co-segmentation. Moreover, taking into account combined PET/MR data resulted in more consistent tumor delineations compared to MR information only.

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.

2031 Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) 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 days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm 1) or metronomic (MN; 50mg/m2/d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264.

Background. Combined positron emission tomography (PET)/magnetic resonance imaging (MRi) is highly promising for biologically individualized radiotherapy (RT). Hence, the purpose of this work was to develop an accurate and robust registration strategy to integrate combined PET/MR data into RT treatment planning. Material and methods. Eight patient datasets consisting of an FDG PET/computed tomography (CT) and a subsequently acquired PET/MR of the head and neck (Hn) region were available. Registration strategies were developed based on CT and MR data only, whereas the PET components were fused with the resulting deformation field. Following a rigid registration, deformable registration was performed with a transform parametrized by B-splines. Three different optimization metrics were investigated: global mutual information (GMi), GMi combined with a bending energy penalty (BEP) for regularization (GMi BEP) and localized mutual information with BEP (LMi BEP). Different quantitative registration quality measures were developed, including volumetric overlap and mean distance measures for structures segmented on CT and MR as well as anatomical landmark distances. Moreover, the local registration quality in the tumor region was assessed by the normalized cross correlation (nCC) of the two PET datasets. Results. LMi BEP yielded the most robust and accurate registration results. For GMi, GMi BEP and LMi BEP, mean landmark distances (standard deviations) were 23.9 mm (15.5 mm), 4.8 mm (4.0 mm) and 3.0 mm (1.0 mm), and mean nCC values (standard deviations) were 0.29 (0.29), 0.84 (0.14) and 0.88 (0.06), respectively. Conclusion. accurate and robust multimodal deformable image registration of CT and MR in the Hn region can be performed using a B-spline parametrized transform and LMi BEP as optimization metric. With this strategy, biologically individualized RT based on combined PET/MRi in terms of dose painting is possible.

BACKGROUND: The use of molecular diagnostics is an integral component of CNS cancer care. The NIH NOB PBTP includes 80 alterations (55 mutations/copy number variations and 25 gene fusions) identified as relevant to the primary CNS patient population. We have previously reported on the diagnostic utility. Identified therapeutic target results from the PBTP are reported here. METHODS: PBTP results from patients enrolled on the NOB NHS are reported. Targetable alterations were defined using the NCI MATCH trial list. The proportion of cases with identified alterations based on recognized diagnostic histology and recurrence are reported. RESULTS: 190/282 (67%) PBTPs reported significant alterations; 132 from initial diagnosis and 58 recurrent samples;10 had two sequential samples analyzed. Astrocytoma, grade 2–4 (126/190, 66%), was the most common histologic tumor type. Over 60% of cases had a unique alteration profile, appearing only once in the data set. At diagnosis 74% had 1–3 alterations. At recurrence 45% had >3, and 9% had > 7 alterations. New and increasing alterations were seen in 80% (8/10) of sequential cases, with 1 case showing an entirely different alteration pattern. Targetable alterations were identified in 87/190 (46%) PBTP results. Exclusively in astrocytomas, EGFR (19%), and CDK4/CDK6 (12%) were found. Less frequent were: BRAF (5%) (8 astrocytomas, 2 pleomorphic xanthoastrocytoma), FGFR (3%) (5 GBM, 1 rosette-forming glioneuronal tumor), MET (3%) (3 GBM, 1 anaplastic oligodenroglioma, 1 anaplastic ependymoma), PTCH1 (3%) (3 astrocytoma, 1 ependymoma, 1 medulloblastoma), NTRK (2%) (2 astrocytomas, 1 oligodendroglioma). CONCLUSIONS: The PBTP has demonstrated diagnostic and therapeutic utility, with actionable targets found in nearly half of analyzed samples. The profile and number of alterations was higher at recurrence, underscoring the need for contemporary resampling and analysis. Importantly, 2/3 of the results showed a unique alteration profile highlighting the unique nature of each patients tumor.

BACKGROUND: There is increasing interest in the use of immunotherapy in rare CNS tumors, but limited experiences in the clinical evaluation of imaging findings and treatment toxicity in these patients. A phase II clinical trial of Nivolumab, a PD-1 inhibitor, in eleven rare CNS tumors was developed by NCI-Connect program. The purpose of this report is to describe both patient-reported outcome (PRO) and standardized assessment of these patients treatment toxicities and correlate with imaging findings. METHODS: Patients were evaluated using standardized CTCAE (version 4.0) for toxicity grading and M.D. Anderson Symptom Inventory-Brain/Spine Tumor Module (MDASI-BT/SP) for PRO scoring. The item change scores (>1 point) in individual symptoms, overall symptom burden, and interference from symptoms were calculated at the time of imaging changes and classified as improved, stable or worsened. RESULTS: Of thirteen patients, male (n=10), median age 43 (24–74), brain location (n=10), spine location (n=4), the most common diagnosis was Ependymoma (n=4). An average of 4 cycles of nivolumab was received, with three grade 3 or higher adverse events: one grade 3 colitis and two grade 3 lymphopenia. Radiographic disease progression was declared in all, confirmed by pathological diagnosis in 8/13. Per MDASI-BT/SP, mean symptom severity was stable in all cases; interference score was worse in 3/8 cases. Significant worsening in disease-related symptoms included walking (50%) and pain (25%). Autonomic function worsened in 2/3 spine patients; concentration/memory and seizures worsened in 60% and 20% respectively in brain tumor patients. CONCLUSION: Nivolumab was well tolerated with no CNS specific adverse events. MRI changes were not associated with change in symptom burden, but was associated with significant worsening in patient-reported interference, specifically in walking, pain, seizures, cognitive or autonomic symptoms. Evaluation of cardinal symptoms associated with progression on immunotherapy may be meaningful diagnostic adjuncts in patients with rare CNS tumors.

BACKGROUND: BRAF V600E-mutations are rare but noteworthy in primary brain tumors given their potential as a targetable mutation and the lack of efficacious therapies for glioblastoma. BRAF V600E mutations may serve as a prognostic marker in pediatric and low-grade gliomas, and are associated with improved survival in young adults with glioblastoma; however, its prognostic significance in adults >35 years is uncertain given the very small number of patients evaluated to date. METHODS: Patients aged >18 with WHO III-IV glioma and a BRAF V600E mutation were identified from the National Institutes of Health, the Johns Hopkins Hospital, and a previous publication (PMID:27503138). Paired control cases were identified at each institution based on age, sex, degree of resection, performance status at diagnosis/first encounter, MGMT and IDH status, and first-line treatment. Log-rank test was used to compare survival curves. RESULTS: The present cohort consisted of 23 patients (6 from each institution and 11 from a published cohort) with median age of 39 (range 20–70 years), 78% female, and 87% with a glioblastoma diagnosis. No tumors had an IDH mutation. 39% of patients were aged >50 years. All but one were treated with radiation and temozolomide at diagnosis (exception went into hospice and died shortly thereafter). The median overall survival was 33.4 ± 8.4 months in all patients. For 13 patients aged 35 or older, median survival was 34.5 ± 12.1 months compared to 18.0 ± 3.0 months in case-matched controls (p=0.03). Two patients were treated with dabrafenib and trametinib; one is still on therapy (26 months), the other progressed after 8 months. CONCLUSIONS: Adults aged >35 with BRAF V600E mutation may have improved survival compared with matched controls, similar to results in young adults. BRAF V600E mutations occur in patients with glioblastoma aged >50 years and testing in this population should be considered as well.

BACKGROUND: Emotional distress, including anxiety and depression, is associated with significant morbidity. Studies in CNS tumor patients have been limited by small non-diverse samples. The NOB-NHS includes screening for depression and anxiety patients undergoing longitudinal care in the NOB. In a previously reported pilot study, anxiety(11%) and depression(15%), and association with performance status and use of psychotropic medications were reported. This report attempts to validate these findings in a larger more diverse cohort. METHODS: All patients(n= 269) enrolled in the NOB-NHS were screened for depression and anxiety using PROMIS measures. Descriptive statistics and standardized classification of moderate-severe depression and anxiety are used to describe the sample characteristics. Emotional Distress was defined as PROMIS T scores-> 60 on depression, anxiety, or both scales. Chi-square and Fishers exact tests were used to identify associations. Significance level was set at p< 0.05. RESULTS: The sample was primarily white(82%), males(61%), 54 months(0–398) from diagnosis, with a median age of 49(21–81), good performance status(KPS 90, 75%) and a high-grade neoplasm(63%) with glioblastoma(30%) the most common diagnosis. Significant emotional distress was present in 19% of the sample. Poor performance status(28%) and use of psychotropic medications(32%) were both significantly associated with emotional distress(X(2)(1)= 4.8, p< 0.03 and X(2)(1)= 7.4,p< 0.01), respectively. Past recurrence(25%), progression/pseudo-progression on MRI(26%), female gender(23%), corticosteroid use(28%) and non-glioblastoma(21%) had higher incidence of distress, although not significant. Tumor location, age and disease status was not associated with emotional distress in this sample. CONCLUSION: This is one of the largest reported cohorts using screening measures for emotional distress in this population and confirms earlier findings of association with functional status and psychotropic medications. Future studies will investigate longitudinal trends, diagnostic referrals, and emotional distress phenotypes, including genomic predisposition, to improve individual patient/population care.

BACKGROUND: Multinodular and vacuolating neuronal tumor of the cerebrum (MVNT) is a rare, recently described neoplasm in the 2016 World Health Organization (WHO) classification with 14 cases reported to date. MVNTs usually present with epilepsy or are discovered incidentally. Median age of diagnosis is 44.9 years (22 to 71 years), and the most common location is the temporal lobe (~65%). METHODS/ RESULTS: After reviewing 282 patients enrolled in our natural history study between September 2016 and August 2017, we uncovered two additional cases: the first patient is a 39-year-old woman and the other is a 57-year-old man. The tumors were localized in the left temporal and left frontal lobes respectively. Gross total resection was performed in both cases. Histological features were consistent with the 2016 WHO classification and other published reports. A CNS specific molecular panel revealed a BRAF p.Leu597Arg missense mutation in our first patient, a mutation that was recently reported in one other MVNT but has not been detected in any other primary CNS neoplasm within our database. The second patients lesion was found to have MAP2K1 p.Gln56Pro missense mutation. Our literature review found 2 cases with BRAF and 5 cases with MAP2K1 mutations in MVNT. MAPK pathway alterations reported in other glioneuronal tumors include BRAF p.Val600Glu mutations as well as BRAF fusions, neither of which have been reported in MVNTs to date. CONCLUSIONS: MVNT while rare, will likely be increasingly recognized. Our results suggest that the BRAF p.Leu597Arg missense mutation, (now described in two cases) and the MAP2K1 p.Gln56Pro missense mutation, may be useful diagnostic adjuncts to histopathological features and in differentiating this entity from more commonly epilepsy associated glioneuronal tumors.

The author used qualitative research methods to explore an 8th-grade mathematics teacher's personal definition of cooperative learning and the enactment of cooperative learning in his classroom according to that definition. Data collection involved interviews and classroom observations. The author used coding schemes and descriptive statistics for data reduction and analysis. Constructivist psychology provided the theoretical groundwork for conclusions based on consistency across interview and observational data. Results revealed that while the teacher implemented a research-based model of cooperative-learning instruction, he adapted the model for use in his classroom. Results also identified the teacher's prior experience and teaching context as factors that influenced his implementation of cooperative-learning instruction.

Qualitative research methods were employed to explore variations in teacher implementation of a research-based model of cooperative learning. Participants included five middle school math and science teachers who were trained in the Johnson, D.W. and Johnson, R.T. [Johnson, D. W., & Johnson, R. T. (1983). The socialization and achievement crisis: Are cooperative learning experiences the answer? Applied Social Psychology, 4, 199-124.] model of cooperative learning. Implementation was examined via interview and observation. Principles from cognitive psychology defined constructs for study, which included teacher concepts, plans, and enactment of cooperative learning in the classroom. Study design included features characteristic of ethnographic inquiry: prolonged engagement, purposeful sampling, persistent observation, multiple source data collection, and recursive interpretation. Triangulation of data sources revealed that relationships between concepts, plans and enactment were mediated by teaching style, teaching context, and degree of teaching expertise. Findings suggest that when attempting to implement cooperative learning lessons, teacher may benefit from attention to teacher and student roles, curricular requirements, instructional time, and classroom management skills. Findings further demonstrate the important contributions of qualitative research to the cooperative learning literature.

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