bluuebunny/crossref_metadata_2025 huggingface dataset:
RTHP-17. APPLICATION OF EXACTRAC X-RAY IMAGE GUIDE SYSTEM IN STEREOTACTIC RADIOSURGERY FOR INTRACRANIAL NEURAL TUMORS IN PATIENTS AGED 3–14 YEARS
Authors: Cai Linbo , Xiao Qing
Published: November 2019

OBJECTIVES

To investigate the setup accuracy in stereotactic radiosurgery based on Exactrac Xray image guide system for intracranial neural tumors in patients aged between 3 and 14 years, and to discuss the related influence factors.

METHODS

Thirty seven patients with intracranial neural tumors, at the age of 314 years old, who were admitted to Guangdong Sanjiu Brain Hospital between March 2017 to January 2019 were enrolled in this study. After automatic setup with infrared markers, Exactrac Xray image guide system was applied to obtain the image of bilateral oblique intersection field, which were then registered with the field image digitally reconstructed with planning system, so as to obtain the translational errors in LAT (X), LNG (Y), VRT (Z) directions and the corresponding rotational errors.

RESULTS

After the positioning with Exactrac Xray image guide system and sixdimensional couch, the translational errors of all 37 patients in LAT, LNG, VRT directions were (0.26±0.13), (0.17±0.13), (0.15±0.11) mm, respectively, and the corresponding rotational errors were 0.21°±0.15°, 0.18°±0.15°, 0.18°±0.14°, respectively. The space vector error was (0.32±0.16) mm; translational errors were all less than 0.5 mm; rotational errors were all less than 0.5°. All of these errors were less than specified values and in accordance with the requirements of SRS.

CONCLUSION

Using Exactrac Xray image guide system and sixdimensional couch can remarkably improve the accuracy of SRS for intracranial neural tumors in patients aged 314 years. Exactrac Xray image guide system is worthy of application in the clinic.
RTHP-20. MULTI-INSTITUTIONAL ANALYSIS OF HIGH-RISK WHO GRADE II OLIGODENDROGLIOMA TREATED WITH ADJUVANT RADIOTHERAPY PLUS TEMOZOLOMIDE (TMZ) VERSUS PROCARBAZINE, LOMUSTINE, AND VINCRISTINE (PCV)
Authors: Tom Martin , Routman David , Laack Nadia , Frechette Kelsey , Park Deborah , (Auston) Wei Wei , Leyrer Marc , Peereboom David , Ahluwalia Manmeet , Chao Samuel , Suh John , Murphy Erin
Published: November 2019

PURPOSE

To compare outcomes of adults with high-risk grade II oligodendroglioma treated with adjuvant radiotherapy plus adjunctive TMZ versus PCV.

METHODS

We queried a multi-institutional database from the Cleveland Clinic and Mayo Clinic of 158 adults with WHO grade II glioma who were high-risk (age > 40 and/or subtotal-resection [STR]) and underwent adjuvant chemoradiation (TMZ or PCV) between 1997–2017. We included patients with oligodendroglioma by 1p/19q-codeletion or traditional histopathology. Fisher’s exact test was used to associate factors with chemotherapy group. The log-rank test was used to compare OS and PFS by chemotherapy group and clinical characteristics.

RESULTS

52 patients were included with a median follow-up of 44 months (range, 3–259). Median age was 44 (range, 22–73), 49 (94%) underwent STR, and 28 (54%) were male. Presenting symptoms were seizure in 35 (67%) patients, sensory in 14 (27%), and motor in 8 (15%). Oligodendroglioma classification was by 1p/19q-codeletion in 27 (52%) and traditional histopathology in 25 (48%) patients. Median radiation dose was 54 Gy (range, 45–60). Chemotherapy was TMZ in 34 (65%) patients and PCV in 18 (35%). Patients who were older (P=0.003), lacked seizures (P=0.03), or had motor symptoms (P=0.04) were more likely to receive TMZ. Median OS was 223 months (95% CI, 181-not estimable) and median PFS was 118 months (95% CI, 69–223). Treatment with TMZ versus PCV was not associated with OS (median 186 vs. 223 months, respectively; P=0.71) or PFS (median 110 vs. 131 months, respectively; P=0.19). Age >40 (P=0.009) and motor symptoms (P=0.027) were associated with adverse OS. Presence of motor symptoms was associated with worse PFS (P=0.008).

CONCLUSION

There was no statistically significant difference in OS or PFS between adjunctive TMZ versus PCV for adult high-risk grade II oligodendroglioma. A larger cohort with longer follow-up will provide additional insight.
RBTT-03. USE OF VIRTUAL REALITY ENVIRONMENTS TO IMPROVE SELF-REPORTED DISTRESS, MOOD DISTURBANCE AND OVERALL SYMPTOM BURDEN USING CORRELATIVE STRESS BIOMARKERS IN PRIMARY BRAIN TUMOR (PBT) PATIENTS
Authors: King Amanda , Leggiero Nicole , Acquaye Alvina , Vera Elizabeth , Crandon Sonja , Gilbert Mark , Armstrong Terri
Published: November 2019

Approximately 20% of PBT patients experience moderate-severe distress at the time of neuroimaging & diagnostic evaluation, which can adversely impact their psychological health and ability to tolerate oncologic therapies. Virtual reality (VR) technology is increasingly being utilized in clinical populations with demonstrated improvement in self-reported pain, anxiety, and distress, though little is known about the biological pathways involved. We hypothesize that VR can improve distress through a combination of distraction and promotion of the relaxation response, both of which could blunt activity of physiological stress pathways. The purpose of this study is to assess the effect of VR breathing and relaxation scenarios on self-reported acute and long-term distress incorporating correlative stress biomarkers, as well as assessing long-term effects on mood disturbance and overall symptom burden. This is a phase 2 experimental pre-post design with a sample size of 100 PBT patients, stratified into low and high distress groups. Self-reported measures include the Distress Thermometer, PROMIS Anxiety and Depression Short Forms, and the MD Anderson Symptom Inventory Brain Tumor instrument. Correlative stress biomarkers include salivary cortisol and dehydroepiandrosterone-sulfate (DHEA-S), representing hypothalamic-pituitary-adrenal (HPA) axis activity, and salivary alpha amylase (sAA) and heart rate, representing activity of the sympathetic-adrenal-medullary (SAM) system. Baseline and post-intervention assessments will be taken surrounding a 5 to 10 minute VR experience in clinic, with repeat assessments 1 week later and at the next clinic appointment. Anticipated outcomes include a decrease in self-reported acute and remote distress with correlative decrease in stress biomarkers, as well as improvement of mood disturbance and overall symptom burden. VR has the potential to help PBT patients improve self-management of their psychological symptoms, potentially enhancing their tolerance of oncologic therapies and overall quality of life. Additionally, the benefits of this intervention may have broad applicability to other cancer patient populations.
RBTT-11. NRG ONCOLOGY NRG-BN006: A PHASE II/III RANDOMIZED, OPEN-LABEL STUDY OF TOCA 511 AND TOCA FC WITH STANDARD OF CARE COMPARED TO STANDARD OF CARE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Ahluwalia Manmeet , Pugh Stephanie , Ellingson Benjamin , Kotecha Rupesh , Cloughesy Timothy , Vogelbaum Michael , Aldape Kenneth , Cui Yunfeng , Armstrong Terri , Mehta Minesh
Published: November 2019

The standard of care (SOC) in newly diagnosed glioblastoma (nGBM) includes resection and chemoradiotherapy. With a median overall survival (OS) of only 16–18 months for well-selected patients in clinical trials, better therapeutic options are needed. Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC (extended-release 5- fluorocytosine,5-FC) into 5-fluorouracil. Preclinical evidence demonstrates that Toca 511 & 5-FC kill cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to durable antitumor immune responses. Three phase (P) 1 studies in patients with recurrent high grade glioma have demonstrated tolerable safety profile and encouraging efficacy. NRG-BN006 is a randomized P2/3 trial of Toca 511 & Toca FC with SOC versus SOC for patients with nGBM. Optune use is allowed on the SOC arm, but not on the experimental arm. Patients will be stratified by age and KPS score for 1:1 randomization. The primary endpoint is progression-free survival for P2 and OS for P3. The secondary endpoints include objective response rate in patients with measurable disease and safety. Key inclusion criteria include presumptive diagnosis of glioblastoma with anticipated 80% resection, unifocal tumor, and KPS≥70. Immune monitoring and molecular profiling will be performed. P2 has 90% power to detect a hazard ratio (HR)=0.67 in 250 nGBM patients. P3 has 85% power to detect a HR=0.75 in 720 nGBM patients. Since patients are enrolled prior to surgery and confirmatory diagnosis of GBM, approximately 900 patients will be enrolled, and two interim analyses are planned for OS. In addition, two interim safety analyses will be conducted for the experimental treatment, with the first 15 and 30 eligible and analyzable patients randomized to the experimental arm. NRG-BN006 is anticipated to start enrollment in Q4 2019. Supported by grants U10CA180868, U10CA180822 from NCI and Tocagen.
RARE-10. IMPROVING CARE FOR ADULT PATIENTS WITH RARE CNS TUMORS: THE NATIONAL CANCER INSTITUTE-COMPREHENSIVE ONCOLOGY NETWORK EVALUATING RARE CNS TUMORS (NCI-CONNECT) PROGRAM AND CLINIC
Authors: Siegel Christine , Raygada Margarita , Acquaye Alvina , Stearn Sylvia , Wall Kathleen , Crandon Sonja , Stevens-Brown Kristen , Wu Jing , Vera Liz , Theeler Brett , Reyes Jennifer , Leggiero Nicole , Cordova Christine , Bryla Christine , Burton Eric , Boris Lisa , Antony Ramya , Ani Tracy , Aboud Orwa , Armstrong Terri , Gilbert Mark , Penas-Prado Marta
Published: November 2019

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.
RARE-13. CHARACTERISTICS AND TREATMENT PATTERNS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 (NF1) AND PLEXIFORM NEUROFIBROMAS (PN): A CROSS-SECTIONAL ANALYSIS OF CHILDREN’S TUMOR FOUNDATION (CTF) REGISTRY DATA
Authors: He Jinghua , Anne Pinto Cathy , Yang Xiaoqin , Diede Scott , Deitz Anne
Published: November 2019

BACKGROUND

NF1-related PN can cause substantial morbidity, with no currently approved drug treatment available for PN treatment. Although surgery is the standard of care, complete resection of PN is often difficult due to encasement of vital structures and invasive and extensive PN growth. With limited real-world data among children with NF1-related PN, the study objectives were to describe the demographic, clinical characteristics, and treatment of these children.

METHODS

A cross-sectional analysis of existing CTF web-based, patient-entered, registry data collected between 2012–2018 was conducted. To be included in analysis, patients had to complete at least one registry survey, and be ≤ 19 years of age at the time of first survey completion, with patient- or parent/ guardian reported diagnosis of NF1 and at least 1 PN. Descriptive statistical analysis was conducted on data collected from the first survey for each patient, to describe patient characteristics and treatment patterns. Results were stratified by region (US, ex-US).

RESULTS

The sample included 943 pediatric patients (n=750 US, n=193 ex-US). The majority (85.9%) were less than 5 years of age at NF1 diagnosis (US: 87.6%; ex-US: 79.3%). Approximately half were male, and half reported more than 1 PN. The most common PN site include head (15.1%) and neck (12.6%). More than half of patients received no treatment (53.1%) for their PN. The most common treatments reported for PN were surgery (27.0%) and chemotherapy or drug therapy (10.0%). These results were generally consistent across regions. A malignant peripheral nerve sheath tumor (MPNST) and optic glioma (OG) were diagnosed in 21 (2.2%) and 308 (32.7%) patients, respectively; a large proportion of OG patients remained untreated (57.5%). Too few ex-US patients were available for detailed regional analysis.

CONCLUSIONS

This study demonstrated that a large proportion of children diagnosed with NF1-related PN remain untreated, highlighting a substantial unmet need.
RARE-15. OUTCOMES OF TREATMENT OF GLIOMAS IN PATIENTS WITH NEUROFIBROMATOSIS TYPE I TREATED WITH RADIATION THERAPY
Authors: Son Jessica , Sloan Lindsey , O Blakeley Jaishri , Slobogean Bronwyn , Kleinberg Lawrence
Published: November 2019

INTRODUCTION

Neurofibromatosis type 1 (NF1) is a rare tumor suppressor syndrome that predisposes to nervous system tumors. The optimal treatment of gliomas in adults with NF1 is uncertain. Specifically, little is known about the effectiveness or toxicity of radiation therapy (RT) in this population although it is standard of care for progressive low grade glioma (LGG) or high grade glioma (HGG) in general. We evaluated the tolerability of RT and time to progression (TTP) after completion of RT in people with NF1 diagnosed with glioma in adulthood.

METHODS

Charts were reviewed for patients with a confirmed NF1 syndrome, LGG or HGG, > 18 years old, receiving RT and followed at Johns Hopkins University between 2009–2019. Secondary outcomes were overall survival (OS) from diagnosis and RT associated toxicity. Progression was defined radiographically; toxicity was graded by CTCAE.

RESULTS

Eight people (6 males) with median age of 36.5 years (range, 20–63) received RT at median of 56.7Gy either at the time of diagnosis (N=4) or at recurrence (N=4). Three patients (37.5%) had LGG; five (62.5%) had HGG. Tumor locations were brainstem (6) and temporal lobe (2). All patients received concurrent chemotherapy with RT; temozolomide (7) or bevacizumab (1). At median follow-up of 28.3 months (0.9–90.2) from RT completion, 5/8 patients had progression. Of those who progressed, median TTP was 12.7 months (2.5–26.6). The longest period of disease control was 28.9 months. One and two-year OS rates were 87% and 32%, respectively. RT associated toxicities were within the expected range.

CONCLUSIONS

Overall disease control after RT was variable, with some examples of extraordinary duration of disease control, and RT toxicities were within expected range. Collaborative efforts to examine a larger cohort of adults with NF1 associated gliomas are needed to define optimal care, but these observations suggest RT is a feasible modality.
RARE-16. A NOVEL RADIOMICS MODEL DIFFERENTIATING CHORDOMA AND CHONDROSARCOMA
Authors: Yamazawa Erika , Takahashi Satoshi , Tanaka Shota , Takahashi Wataru , Nakamoto Takahiro , Takayanagi Shunsaku , Kitagawa Yosuke , Hana Taijun , Koike Tsukasa , Kushihara Yoshihiro , Shin Masahiro , Saito Nobuhito
Published: November 2019

BACKGROUND

Chordoma and chondrosarcoma account for the majority of skull base tumors affecting the petroclival region. Chondrosarcoma has better prognosis than chordoma; heavy particle therapy is often indicated for residual/recurrent chordoma. Preoperative, precise diagnosis of the tumor would be desirable, as it can potentially impact on the choice of a surgical approach and the aggressiveness of surgery.

METHODS

We conducted a radiomics study to create a machine learning model distinguishing chondrosarcoma from chordoma. We collected DICOM T2-weighted images and T1-weighted images with gadolinium (GdT1) enhancement in the consective patients of chordoma or chondrosarcoma who underwent surgery at The University of Tokyo Hospital from September of 2012 to January of 2019. We selected patients with uniform MRI images. VOI (volume of interest) was set using Monaco (https://www.elekta.com/software-solutions/treatment-management/external-beam-planning/monaco.html). Not only sematic features but also agnostic features were calculated. The original images and 8 wavelet transformed images were calculated for texture agnostic features such as Gray-Level Co-occurrence Matrix (GLCM). Features were selected by recursive feature elimination (RFE). The final model evaluation was performed by average area under the curve (AUC).

RESULTS

The study population included 17 chordomas and 22 chondrosarcomas in a total of 39 patients. 476 features were obtained per image sequence. The number of features per case was 476 × 2 = 952 The most accurate machine learning model was created using the extracted three features from only T2. The best AUC was 0.77 ± 0.11 in logistic regression (dataset was divided randomly into halves, average value of AUC calculated six times).

CONCLUSIONS

This novel machine learning model can differentiate chordoma and chondrosarcoma reasonably well. A validation study with a larger number of patients is warranted.
RARE-18. CLINICAL EXPERIENCE OF DABRAFENIB IN COMBINATION WITH TRAMETINIB TREATMENT FOR ANAPLASTIC PXA CASES
Authors: Maruyama Takashi , Muragaki Yoshihiro , Tsuzuki Syunsuke
Published: November 2019

Anaplastic PXA is classed as grade III tumor because of its aggressive behavior in 2016 WHO classification. Typical treatment of PXA is gross total resection followed by radiotherapy and cytotoxic chemotherapy at recurrence. Despite aggressive behavior of anaplastic PXA, there is some evidence for the use of BRAF inhibitors in BRAF V600 mutant PXA. We report two cases of successful treatment with BRAF-MEK inhibitor combination therapy (dabrafenib plus trametinib). A 19 year-old man initially diagnosed as PXA for rt temporal tumor. Subtotal removal and following 30Gy radiation was performed. After eight years, the recurrent tumor was removed subtotally and diagnosed as anaplastic PXA. Residual tumor and distant metastasis region were completely disappeared by Dabrafenib-Trametinib therapy. Tumor was diagnosed as BRAF V600 mutant and TERT wt. A 30 year-old female initially diagnosed as PXA for rt temporal cystic tumor. She was treated with subtotal removal followed by stereotactic radiosurgery. Instead of Gd-total removal, tumor recurred six times. Chemotherapy with alkyl-agent did not respond. Tumor at first surgery was diagnosed as grade II PXA. Tissues collected after SRS showed malignant feature and diagnosed as anaplastic PXA. All five specimens showed BRAF V600 mutation and additional TERT mutation was confirmed after SRS treatment. She showed paraparesis because of thoracic metastases then Dabrafenib-Trametinib therapy was started. Thoracic tumor showed PR and no remarkable recurrence in intracranial region for more than eight months, so far. BRAF and MEK inhibitor combination treatment are thought to have potential for BRAF V600 mutant NSCLC and melanoma. Anaplastic PXA with BRAF V600 mutation could be another target for the treatment.
RARE-21. CLINICAL CHARACTERISTICS OF GLIOSARCOMA AND OUTCOME FROM STANDARDIZED TREATMENT RELATIVE TO CONVENTIONAL GLIOBLASTOMA
Authors: Frandsen Simone , Broholm Helle , Larsen Vibeke A , Grunnet Kirsten , Møller Søren , Skovgaard Poulsen Hans , Regner Michaelsen Signe
Published: November 2019

INTRODUCTION

Gliosarcoma (GS) is a rare histopathologic variant of glioblastoma (GBM) characterized by a biphasic growth pattern consisting of both glial and sarcomatous components. Reports regarding its relative prognosis compared to conventional GBM are conflicting and although GS is treated as conventional GBM, supporting evidence is lacking. The aim of this study was to characterize demographic trends, clinical outcomes and prognostic variables of GS patients receiving standardized therapy and compare these to conventional GBM.

METHODS

680 GBM patients, treated with maximal safe resection followed by Stupp’s regimen (radiotherapy with concomitant and adjuvant temozolomide) at a single institution, were retrospective reevaluated by reviewing histopathological records and tumor tissue for identification of GS patients. Clinicohistopathological characteristics obtained via assessment of medical records and imaging analysis were compared between the GS and GBM cohorts. Kaplan-Meier survival estimates were compared with log-rank testing, while cox-regression modeling tested for prognostic factors in GS patients.

RESULTS

The cohort revealed 26 primary gliosarcoma (PGS) patients (3.8 %) and 7 secondary gliosarcoma (SGS) patients (1.0 %). Compared to conventional GBM tumors, PGS tumors were significantly more often located in the temporal lobe (53.8 %, p = 0.006) and MGMT-unmethylated (73.9 %, p = 0.009). No significant differences were found between PGS and conventional GBM in progression-free-survival (6.8 and 7.6 months respectively, p = 0.105) and in overall survival (13.4 and 15.7 months respectively, p = 0.201). Also, survival from recurrence was not significant different between PGS, SGS and GBM (5.8, 8.6 and 7.4 months respectively, p = 0.694). MGMT status was the only factor prognostic for PGS survival (p = 0.022).

CONCLUSION

Despite tumor difference between GS and GBM, the patients present similar survival outcome from standardized treatment. This support continues practice of radiation and temozolomide for GS patients.
RARE-24. GROWTH PATTERN ANALYSES OF HEMANGIOBLASTOMA IN SPORADIC AND VHL CASES
Authors: Takami Hirokazu , Burns Terry , Parney Ian
Published: November 2019

Central nervous system hemangioblastoma (CNS HGB) is a rare neoplasm. Sporadic and von-Hippel Lindau (VHL)-associated forms exist. Predicting tumor growth is difficult, making the indication for intervention challenging. A retrospective analysis of consecutive, neurosurgically managed CNS HGB at Mayo Clinic spanning 1988–2018 was performed to clarify their characteristics. 117 sporadic and 67 VHL HGBs were reviewed. 9 sporadic lesions (8 cases) and 80 VHL lesions (35 cases) had tumor size data at ≥4 follow-up time-points beyond 1 year. The median follow-up was 8.0 years. No statistical difference existed between sporadic and VHL lesions regarding growth speed or growth latency (period of time without growth). Symptomatic lesions showed faster growth than asymptomatic lesions (2.79 vs 0.59 cm3/month, p=0.005). Solid and cystic portions often showed different growth patterns in cases harboring both (66.7%). Cyst growth was faster than solid portions (1.22 vs 1.05cm3/month, p=0.009) and growth latency was longer in the latter (15.2 vs 18.5%, p=0.25). Lesions’ growth were classified as linear (7), exponential (49), cubic (regressed to cubic function curve, 7), saltatory (19) and no-growth (7) patterns. Growth latency often existed in growing lesions (27-out-of-64 linear/exponential/cubic lesions, 57.8%), being average 8.3% of follow-up time. Contrarily, although saltatory lesions grew slower than exponential lesions (p=0.03), their overall growth speed was comparable to linear/cubic lesions (0.67cm3/month), and 9-out-of-19 showed growth surges at their ends. Growth speed at each follow-up roughly depended on the tumor size in cubic regression (R2=0.52). However, whereas total 18/821 time-point lesions showed rapid growth (≥1cm3/m, 2.2%), relatively small lesions (≤2cm3) also occasionally showed rapid growth (5/687, 0.73%). Not all large (>5cm3) lesions grew rapidly (8/62, 12.9%). These results revealed while symptomatic/large/cystic lesions tend to grow more rapidly, HGB behavior is difficult to predict, which stresses the importance of careful follow-up.
RARE-30. PEDIATRIC GLIOBLASTOMA IN THE POST-TEMOZOLOMIDE ERA: OUTCOMES AND CHARACTERISTICS
Authors: Chandra Ankush , Oh Taemin , Wadhwa Harsh , Shah Sumedh , Gupta Nalin , McDermott Mike , Berger Mitchel , Aghi Manish
Published: November 2019

INTRODUCTION

Glioblastoma (GBM) is the most common brain tumor, however, is a rare occurrence in children and is poorly characterized. We evaluated the characteristics and outcomes of pediatric GBM (pGBM).

METHODS

Retrospective analysis of pediatric (age< 18) patients diagnosed with GBM undergoing first glioblastoma resection at our brain tumor center (2005- 2016).

RESULTS

From 1457 GBM patients, we identified twenty-four (1.65%) pGBMs (Median Age=9 years, Females=45.8%). Median overall survival (OS) was 32.1 months, while the median progression-free survival was 11.5 months. The commonest symptoms at presentation were headaches (54.2%,n=13) and motor symptoms (50%,n=12). Mean tumor diameter was 4.5 cm and 25% of the cohort underwent gross total resection (GTR) of their tumor. Univariate analysis revealed median OS significantly associated with tumor extent of resection (GTR=56.4 months; STR/Biopsy=13.7 months, p=0.001), age at surgery (>10 years=43.9 months, < 10 years= 17.2 months, p=0.01), tumor size (> 4cm= 9.1 months, < 4cm=56.9 months, p=0.01),motor symptoms at presentation (present=14.9 months, absent=41.04 months, p=0.02) and infratentorial tumors (infratentorial=17.4 vs supratentorial=53.4 months, p=0.02). Multivariate analysis revealed GTR (HR 0.2[95% CI 0.07–0.72]; p=0.03), Age >10 years (HR 0.6[95% CI 0.02–0.64]; p=0.002), tumor >4 cm (HR 2.89[95% CI 1.88–4.11]; p=0.001) and EGFR amplification (HR 3.48[95% CI 0.82–17.4]; p=0.005) to be independent predictors of OS. Comparing patients under and over 10 years, we found that older patients had smaller tumors at presentation (4.9 vs 3.6 cms, p=0.03), greater rates of preoperative temozolomide (n=1,7.7% vs n=6, 54.5%) and bevacizumab (n=1,7.7% vs n=4, 36.4%) treatment, and lower rates of EGFR amplification (66.7% vs 11.1%) that could explain survival disparities between groups.

CONCLUSION

Motor symptoms, larger tumors at presentation and tumor EGFR amplification may be indictive of poorer outcomes in pGBM. However, maximal tumor resection, aggressive chemoradiation and tumor presentation at age >10 years may confer better prognosis in these patients.
RARE-31. TREATMENT OUTCOME OF CHILDREN WITH PLEOMORPHIC XANTHOASTROCYTOMA: RETROSPECTIVE ANALYSIS – A SINGLE INSTITUTION EXPERIENCE
Authors: Maher Ossama , Niazi Toba , Khatib Ziad , Ragheb John
Published: November 2019

BACKGROUND

Pleomorphic xanthoastrocytoma (PXA) and anaplastic pleomorphic xanthoastrocytoma (APXA) are two types of rare astrocytomas in pediatrics. There is limited literature reporting their outcomes.

METHODS

A retrospective analysis of pediatric patients with diagnosis of PXA and APXA treated at Nicklaus Children’s Hospital was conducted using descriptive measures.

RESULTS

A chart review of patients with brain tumors from 2001 to 2019 revealed that 13 patients (median age 6 years, range 2–17 years) were diagnosed with non-metastatic PXA (n=12) and APXA (n=1). Six patients (46%) were male. Clinical presentation included seizures (n=8), headaches (n=2) cranial nerve palsies (n=2). Diagnostic imaging showed tumor in the temporal lobe (n=5), parietal lobe (n=2), temporoparietal lobe (n=2), frontal lobe (n=1), occipital lobe (n=1), others (n=2). BRAF V600E mutation were identified in three of five analyzed tumors including PXA (n=4) and APXA (n=1). Surgical intervention consisted of gross total resection (n=8) and near/subtotal resection (n=5). Ten patients (76%) required a second surgery (median 2; range 1–4) due to local recurrence. The median time to recurrence was 3 years (range 6 months - 7 years). Three patients (23%) had malignant transformation of PXA, which occurred three to eight years from the initial surgery; one of them also had extensive spinal metastasis. Focal radiation was given to six patients (46%) due to multiple recurrence (n=2), malignant transformation (n=3), APXA (n=1). At a median follow up of 8 years (range 3 to 20 years), eight patients remain alive, three patients had lost to follow up, two patients died from progressive disease. Long-term sequelae varied as follows; seizures (n=5), motor weakness (n=4), cranial nerve palsies (n=2), and learning disability (n=1).

CONCLUSION

PXA is associated with high local recurrence rate and uncommonly malignant transformation to APXA in pediatrics, which requires close follow-up due to unpredictable biological behavior of these tumors.
RARE-34. TUMOR IMMUNITY AND EXTRACRANIAL METASTASES, AND MECHANISM OF PD-L1 EXPRESSION IN INTRACRANIAL SOLITARY FIBROUS TUMOR/HEMANGIOPERICYTOMA
Authors: Kamamoto Dai , Ohara Kentaro , Kitamura Yohei , Yoshida Kazunari , Sasaki Hikaru
Published: November 2019

Intracranial solitary fibrous tumor (SFT) /hemangiopericytoma (HPC) are rare, however, these tumors are often associated with aggressive clinical course with recurrence and/or extracranial metastasis. PD-1, PD-L1 play important roles as immune-checkpoint mediators within tumor microenvironment, and the antibodies to these molecules are now approved for the treatment of various kinds of cancers. Some mechanisms of activation of PD-L1 are reported, including cytokines or chemokines from immune cells in tumor microenvironment, and genetic mutations such as translocation, or amplification. We have investigated the expression of PD-1, PD-L1, and tumor infiltrating lymphocytes (TIL) in 16 cases of SFT/HPC by immunohistochemistry. Kaplan-Meier method and log-rank/Wilcoxon tests were used to analyze the relationship between their expression with overall survival (OS), progression free survival (PFS), metastasis free survival (MFS), and time to treatment failure (TTF; metastasis or death). Additionally, we have analyzed amplification of PD-L1 gene by FISH, translocation between promotor region of CIITA and PD-L1 by PCR, and mutation in 3’-UTR by immunohistochemistry with antibody recognizes C-terminus (clone; SP-142) of PD-L1. PD-L1 was expressed in most of tumor cells. The intensity of PD-L1 expression was negatively associated with MFS (p=0.04), and diffuse pattern of PD-L1 expression showed trends towards shorter TTF compared with partial expression (p=0.08). Notably, with the combination analysis of PD-L1 and CD8(+) TIL, the diffuse PD-L1 expression with less CD8(+) was significantly associated with shorter TTF (p=0.005). However, there was no significant relevance between the expression of those immune-checkpoint molecules and OS or PFS. Although neither amplification of PD-L1 gene, 9p24.1, nor translocation between CITTA and PD-L1 were observed, difference in immunohistochemistry with two different anti-bodies was observed. In intracranial SFTs/HPCs, tumor immunity mechanism associated with PD-1/PD-L1 may play an important role in their extracranial metastases, and mutation in 3’-UTR may be a cause of PD-L1 activation in SFT/HPC.
RARE-38. CNS LYMPHOMA INVOLVING HYPOTHALAMIC-PITUITARY AXIS
Authors: Shin Dong-Won , Jun Yoo Hee , Hoon Kim Jeong
Published: November 2019

BACKGROUND

It is rare for CNS lymphoma which involves the hypothalamic-pituitary axis. It could result in misdiagnoses such as pituitary adenoma, craniopharyngioma, or glioma. We report clinical findings of eight cases of either primary or secondary lymphoma involving the hypothalamic-pituitary axis(H-P axis).

METHODS

We retrospectively reviewed 488 patients who were diagnosed as CNS lymphoma from 2000 to 2017 in our institute. There were eight patients (8/488, 1.6%) who had H-P axis involvement in radiographic findings while six patients received chemotherapy. We analyzed patient characteristics, pathologies, clinical features, laboratory findings, imaging, and treatment outcome.

RESULTS

The mean age was 48-year-old (range 18~80) and male to female ratio was 5:3. We performed endonasal TSA for four patients, endoscopic biopsy for two patients, and stereotactic biopsy for two patients. There were six patients of diffuse large B-cell lymphoma and two patients of MALT lymphoma. Seven patients were PCNSL and one patient was metastasized lymphoma. All patients had hormone imbalance whereas three patients had visual disturbance and one patient had diabetes insipidus. Initial serum LDH was 337±167IU/L(range 169~567 except one patient). MRI finding was different from the usual pattern which was low SI in T1 and high SI with perilesional edema in T2, on the other hands, our patients group revealed that five patients(62.5%) had iso SI in both T1 and T2, and only two patients(25%) showed perilesional edema in T2. Median OS and PFS of six patients who received chemotherapy were 34.8 months(range 0.9~93.7) and 33.0 months(range 0.9~93.4), respectively. Two patients(25%) died in 26 days and 51 days after diagnosis because of pneumonia and cardiac arrest, respectively. And one patient lost to follow up after diagnosis.

CONCLUSION

CNS lymphoma involving H-P axis is rare, however, we need to understand its unique characteristic.
RARE-41. GLIOBLASTOMA MULTIFORME AND OTHER CNS TUMORS IN HEREDITARY MISMATCH REPAIR DEFICIENCIES
Authors: Dishion Evan , Korson Clayton , Groh Darren
Published: November 2019

BACKGROUND

Lynch syndrome (LS) and constitutional mismatch repair deficiency syndrome (CMMRD) are caused by germline mutations in mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2. LS patients have an inherited mono-allelic MMR defect, whereas CMMRD patients have a bi-allelic defect. MMR is critical to maintaining genomic integrity during DNA replication and these germline defects are known to produce microsatellite instability (MSI). Both LS and CMMRD have reported cases of increased primary brain cancer, namely glioblastoma multiforme (GBM). Given the shared pathophysiology of these syndromes, the large number of cases and registry studies published, and recent treatments of CNS tumors in CMMRD, a literature review has been conducted. OBJECTIVES: Review the pathophysiology of germline MMR deficiency and how it relates to brain tumor formation. Review the risk of developing primary CNS tumors with various MMR defects. Review the current management of CNS tumors in LS and CMMRD.

METHODS

Literature review of the most recent understanding of pathophysiology, all literature on CNS tumors in LS and CMMRD, and the current management of GBM including recent literature on CMMRD.

RESULTS

The lifetime risk of developing a primary malignant brain tumor or other CNS tumor in the United States has been calculated at 0.62%. Based on registry data, current estimates of the lifetime risk of developing a primary CNS tumor in LS is between 1–8.7%. Of the 146 genetically confirmed cases of CMMRD, 58 cases of high-grade gliomas were identified (including GBM). Most patients with CMMRD carry homozygous germline mutations in PMS2 (approximately 60%). Although primary CNS tumors appears to be a less common extra-colonic manifestation in LS, it is relatively common amongst CMMRD patients. Acknowledgement: Henry Lynch
RARE-48. GROWING KNOWLEDGE AND EMERGING QUESTIONS RELATED TO POT-1 GERMLINE MUTATIONS AND ASSOCIATED MALIGNANCIES: A CASE REPORT
Authors: Ruiz Amber , Eastman Boryana , Halasz Lia , Jarvik Gail , Brown Lauren , Graber Jerome
Published: November 2019

Protection of telomeres 1 (POT1) is a member of a family of genes responsible for maintenance of telomere integrity. Germline mutations of the POT1 gene have been associated with tumorigenesis of multiple tissue types, conferring an increased risk of development of malignancies such as melanoma, chronic lymphocytic leukemia, gliomas, and cardiac sarcomas. We present the case of a 28 year old male who first presented at the age of 15 with personality changes. Several years later, he was found to have a left frontal, IDH mutated, WHO grade III anaplastic astrocytoma. Following successful treatment with gross total resection, radiation therapy, and adjuvant chemotherapy, the patient represented with an MRI showing enhancement concerning for osteomyelitis and possible tumor recurrence. Pathology of the dura was consistent with myxofibrosarcoma. Staging PET scan at that time revealed multiple hypermetabolic lung lesions found to be Lanagerhans cell histiocytosis. Given the patient’s complex oncological history, genetic testing was performed. He was found to carry a heterozygous mutation of the POT1 gene. This case raises the suspicion for a broader POT1-associated cancer predisposition than previously described in the literature. Moreover, this prompts further questioning of an association between POT1 mutations and IDH status in related gliomas. Patients with POT1 mutations might also be at increased risk of secondary malignancies after radiation exposure, which may require closer observation after treatment.
STEM-01. CHARACTERIZATION OF ORTHOTOPIC GLIOBLASTOMA MODEL FOR THE GENE-AND CELL THERAPY
Authors: Han Ji-Hun , Chang Da-Young , Lee Young-Joon , Suh-Kim Haeyoung , Kim Sung-Soo
Published: November 2019

Intrinsic heterogeneous and infiltrative nature of glioblastoma cells to the adjacent normal brain parenchyma are the main obstacles to the treatment of glioblastoma multiforme (GBM). The infiltrative nature of GBM increases following various treatments, which often leads to tumor recurrence. U87 cell line, a commonly used as a GBM cell line till recently, has appeared inappropriate for GBM model. Thus, we established an orthotopic GBM model using another cell line, LN229. Here, we discuss the infiltrative nature of LN229 in the mouse brain and their interaction with adjacent brain microenvironment. We also show that the LN229-driven brain tumor model is appropriate for the study of mesenchymal stem cell-mediated gene therapy using deliver a bacterial suicide gene, cytosine deaminase (CD).
STEM-03. CONSUMPTION OF A HIGH-FAT DIET INHIBITS THE TUMOR SUPPRESSIVE ACTIVITY OF HYDROGEN SULFIDE, DRIVING CANCER STEM CELL ENRICHMENT AND DISEASE AGGRESSION IN GLIOBLASTOMA
Authors: Silver Daniel , Roversi Gustavo , Bithi Nazmin , Troike Katie , Neumann Chase , Mark Brown J , Hine Christopher , Lathia Justin
Published: November 2019

Glioblastoma (GBM) remains among the deadliest of human malignancies. Effective disease management is lacking due in part to the emergence of the cancer stem cell (CSC) phenotype. The tumor cell extrinsic, environmental, and lifestyle factors that result in CSC enrichment are not well understood. Alongside other pathological features, the CSC state endows populations of tumor cells with a fluid metabolic profile that enables utilization of multiple nutrition sources. Therefore, to test the impact of diet on CSC enrichment, we interrogated disease progression in tumor-bearing mice fed either a high-fat diet (HFD), similar to the Western Pattern diet or a control low-fat diet. Compared to controls, HFD-consumption resulted in the presentation of a hyper-aggressive disease phenotype with truncated survival and tumors markedly enriched in tumor-initiating SOX2+ CSCs. To understand the underlying mechanism driving this finding, we examined tumors for the diet-regulated metabolite hydrogen sulfide (H2S). H2S is an endogenously produced bio-active gasotransmitter similar to nitric oxide. It functions principally through protein S-sulfhydration to regulate a variety of cellular programs including mitochondrial function, stress signaling and metabolism. While there is exceedingly limited information on H2S and GBM, its HFD-driven suppression has been reported in other organ systems. We discovered a significant reduction in H2S synthesis resulting from HFD-consumption in the brain of the mouse and a striking decrease in protein S-sulfhydration in human GBM tumor tissue when compared to non-cancerous control brain tissue. We demonstrated that chemical inhibition of H2S synthesis resulted in increased tumor cell viability whereas exposure to chemical H2S donors led to pronounced cell death of cultured mouse and human GBM cells. These data demonstrate for the first time, that H2S serves as a tumor suppressor for GBM. Moreover, the diet-driven suppression of H2S helps explain the hyper-aggressive in vivo phenotype that presents in response to HFD-consumption.
STEM-04. NICARDIPINE SENSITIZES APOPTOSIS OF GLIOMA STEM CELLS INDUCED BY TEMOZOLOMIDE THROUGH INHIBITING AUTOPHAGY
Authors: Dong Jun , Shi Jia
Published: November 2019

BACKGROUND

Glioma stem cells (GSCs) play an important role in tumor progression and recurrence. Currently, treatments of glioma are limited mainly due to strong tolerance of GSCs against conventional chemotherapeutic drugs such as temozolomide. Nicardipine, a calcium antagonist, is commonly used in the therapy of hypertension, which is recently repurposed in the comprehensive strategies against gliomas in our previous studies. Here, we explored the cytotoxic sensitization effect of nicardipine combining temozolomide and the underlying mechanisms.

METHODS

Two human glioma stem cell lines were applied and treated with nicardipine, temozolomide, and combination of both, respectively. Cell viability was detected by CCK-8, cell apoptosis was analyzed by flow cytometry, and immunoblot was used to detect autophagic-releated proteins including p62, LC3 and mTOR. The mTOR agonists and inhibitors were applied to further evaluate whether nicardipine inhibits autophagy via mTOR pathway.

RESULTS

GSCs had strong tolerance against temozolomide while nicardipine could significantly inhibit the viaibility of GSCs and promote cell apoptosis when acting together with temozolomide, indicating that nicardipine could sensitize the toxicity of temozolomide. Furthermore, both temozolomide and nicardipine could inhibit autophagy, and the effects of nicardipine was more prominent, suggesting that nicardipine might enhance GSCs apoptosis induced by temozolomide through inhibiting autophagy. Further molecular studies showed that the cytotoxic sensitization effects of nicardipine was induced through activation of the phosphorylation level of mTOR, which was abolished with the treatment of rapamycin, a mTOR inhibitor.

CONCLUSION

Our results suggested that nicardipine could sensitize apoptosis of glioma stem cells induced by temozolomide through inhibiting autophagy, which was mediated by activation of mTOR activity.
STEM-09. INTRINSIC TUMOR PLASTICITY IN GLIOBLASTOMA ALLOWS FOR RECREATION OF STEM LIKE-STATES AND EFFICIENT TUMOR CELL ADAPTATION TO NEW MICROENVIRONMENTS
Authors: Golebiewska Anna , Dirkse Anne , Buder Thomas , Yabo Yahaya A , Muller Arnaud , Nazarov Petr V , Bjerkvig Rolf , Skupin Alexander , Poovathingal Suresh K , Herold-Mende Christel , Voss Anja , Deutsch Andreas , Niclou Simone
Published: November 2019

BACKGROUND

Cellular heterogeneity is a hallmark of numerous cancer types, including Glioblastoma (GBM). Cancer stem cells (CSC) have been accounted for the generation of phenotypic heterogeneity and tumor progression in GBM. Recent data, however, suggest that CSCs may not represent a stable entity and intrinsic plasticity plays a key role in tumor adaptation to changing microenvironments. The question arises whether CSCs are a defined subpopulation of GBM or whether they represent a cellular state that any cancer cell can adopt.

METHODS

We interrogated intra-tumoral phenotypic heterogeneity at the single cell transcriptomic and proteomic level in GBM biopsies, patient-derived stem-like cultures and orthotopic xenografts (PDOXs). Tumor cell subpopulations, classified based on their expression of four proposed stem cell markers (CD133, CD15, A2B5 and CD44), were FACS isolated and functionally characterized under various microenvironmental conditions. Mathematical Markov modelling was applied to calculate state transitions.

RESULTS

GBM patient biopsies, PDOXs and stem-like cell cultures displayed remarkable stem cell-associated intra-tumoral heterogeneity. However independent of marker expression, all analysed tumor subpopulations carried stem-cell properties and recreated phenotypic heterogeneity. Mathematical modeling revealed a different propensity in reforming heterogeneity over time, which was independent of the proliferation index but linked to in vivo tumorigenic potential. Although GBM subpopulations varied in their potential to adapt to new environments, all were able to reach a steady state microenvironment-specific equilibrium.

CONCLUSIONS

Our results suggest that phenotypic heterogeneity in GBM results from intrinsic plasticity allowing tumor cells to adapt to changing microenvironmental conditions. Cellular states are non-hierarchical, reversible and occur via stochastic state transitions, striving towards a microenvironment-instructed equilibrium. Our data provides evidence that CSCs do not represent a defined clonal entity, but rather a cellular state determined by environmental conditions, which has implications for the design of treatment strategies targeting CSC-like states.
STEM-23. METASTATIC BRAIN TUMOR IMAGING THROUGH TARGETED PEPTIDES ISOLATED VIA PHAGE DISPLAY BIOPANNING AGAINST BRAIN METASTASIS-INITIATING CELLS
Authors: Kim JongMyung , Liu James
Published: November 2019

To effectively target metastatic brain tumors (MBTs), the paradigm of initiating treatment against MBTs following detection on clinical imaging needs to be shifted to an understanding of the mechanisms that drive the formation and maintenance of brain metastasis-initiating cells (BMICs). Targeting this tumor sub-population, which may form as a result of activation of the epithelial-mesenchymal transition, may allow for more effective means of understanding and targeting brain metastases. In order to isolate BMICs, we have harvested cells from patient derived MBTs originating from lung cancer and cultured the cells using stem cell media conditions. We then performed in vitro and in vivo phage display biopanning to isolate 12-amino acid length peptides that specifically target BMICs. Several peptides were isolated from both in vitro and in vivo biopanning strategies. Of the peptides recovered, one peptide, LBM4, demonstrated specific binding to MBT cells over primary lung cancer cells in vitro through flow cytometry analysis and immunocytochemistry. Fluorescent tagged LBM4 intravenously injected into mice harboring intracranial brain metastases demonstrated peptide localization to the tumor within the intracranial cavity visualized with live animal imaging. Peptide imaging of tumor corresponded to MRI imaging confirming that the peptides could serve as an alternative to tumor imaging, with the potential for greater sensitivity resulting from the cellular targeting of MBTs. Our results demonstrate that we can use a combination of in vitro and in vivo phage display biopanning to isolate cell specific targeting peptides. MBT targeting peptides can potentially result in a shifting of the clinical treatment paradigm of brain metastases, through the development of more effective targeted therapeutics aimed at BMICs, as well as improving detection of MBT cells which may result in earlier tumor visualization, as well as delineation of tumor recurrence versus radiation effects.