bluuebunny/crossref_metadata_2025 huggingface dataset:
RDNA-07. INCREASING EXTENT OF ABLATION – A SENOLYTIC APPROACH TO PROMOTE APOPTOSIS OF LATENT GLIOBLASTOMA FOLLOWING CHEMORADIATION
Authors: Rahman Masum , Olson Ian , Tang Zhi , Rajani Karishma , Carlstrom Lucas , Burns Terry
Published: November 2019

BACKGROUND

Despite best current therapies, median survival for glioblastoma remains little more than a year. There remains an urgent need for improved treatment strategies. Current therapies, including radiation and temozolomide, are known to induce senescence in tumor cells. Advances in aging research have identified drugs with “senolytic” properties to kill senescent cells. This work tests the hypothesis that induction of senescence pathways following radiation can provide a window of opportunity to eliminate residual glioblastoma cells using drugs that block senescent cell-associated pathways (SCAPs).

METHODS

Human glioblastoma cells were radiated with 10, 15, or 20 Gy and maintained in culture for 3 to 4 weeks to facilitate maturation of a senescent phenotype. Given existence of multiple SCAPs, we evaluated the IC50 for several senolytic candidates including Dasatinib, Quercetin, Fisetin, AMG-232, Onalespib, A1331852, and Navitoclax in radiated vs non-radiated cells.

RESULTS

Among these, the Bcl-XL inhibitors A1331852 and Navitoclax both selectively killed multiple lines of radiated, senescent tumor cells at lower concentrations as compared to unirradiated, non-senescent tumor cells. Across multiple GBM cell line, the average IC50 for senescent cells was 12.88 nM (95%CI= 9.068–18.58 nM), as compared to the IC50 of non-senescent cells of 103.2 nM (95%CI= 74.24–143.9 nM; p< 0.005). Such differential sensitivity to Bcl-XL inhibition after radiation was not observed in the non-GBM control cells evaluated to date.

CONCLUSION

Our findings suggest that blocking the anti-apoptotic pathway Bcl-XL in GBM cells rendered at least transiently senescent following radiation may provide an avenue to selectively ablate residual glioblastoma cells following radiation. Our data provide proof of principle that senolytic therapy may represent a previously untapped window of opportunity to increase extent of tumor ablation following completion of standard cytotoxic therapies.
RDNA-10. TTFIELDS TREATMENT PLANNING FOR TARGETING MULTIPLE LESIONS SPREAD THROUGHOUT THE BRAIN
Authors: Naveh Ariel , Yesharim Ofir , Bomzon Ze’ev
Published: November 2019

Tumor Treating Fields (TTFields) are approved for the treatment of Glioblastoma Multiforme (GBM) in supratentorium. When treating GBM in the suprtaentorial brain, TTFields are delivered using 2 pairs of transducer arrays positioned in close proximity to the tumor. This results in an increased TTFields dose in the affected tumor region, whilst reducing the dose in other regions, particularly the infratentorium. Brain metastases, occur in 10 to 30 percent of adults with cancer, and can occur throughout the brain, including in infratentorial regions. Therefore, when using TTFields to treat brain metastases, it is desirable to deliver TTFields at therapeutic intensities to the entire brain or to the infratentorium depending on the location of the lesions. We performed computational studies to identify array layouts for delivering TTFields at therapeutic intensities to the infratentorium and to the entire brain. The computer simulations utilized a realistic computerized head model of a 40+ years old human male prepared in-house. TTFields could be delivered effectively to the infratentorium using a layout in which a pair of arrays was placed on the lateral aspects of the neck below the ears, and the second pair on the upper head and lower neck yielded field intensities above 1 V/cm in the infratentorial brain. Other layouts in which one pair of arrays was placed on the right temple and left scapula, and the second pair placed on the left temple and right scapula yielded a uniform intensity distribution within the entire brain. This layout could be useful for treating multiple lesion spread in both the infratentorial and supratentorial regions. This study suggests that careful treatment planning could be used to optimize TTFields treatment targeting multiple lesions spread throughout the brain.
RDNA-11. LOW MITOCHONDRIAL DNA CONTENT INDUCES TREATMENT RESISTANCE AND CONFERS POOR PROGNOSIS IN GLIOBLASTOMA
Authors: Sravya Palavalasa , Nimbalkar Vidya , Kanuri Nandaki , Sugur Harsha , Rao Shilpa , Somanna Sampath , Kondaiah Paturu , Arimappamagan Arivazhagan , Santosh Vani
Published: November 2019

BACKGROUND

Investigation of mitochondrial DNA (mtDNA) content in glioblastoma has gathered speed in recent years. Our study focusses on the effect of mtDNA content depletion on treatment response in glioblastoma.

MATERIALS AND METHODS

The study consists of a survival cohort (n=130), a recurrent cohort (32 pairs) and 35 non neoplastic control brain tissues. Malignant glioma cell lines, U87 and LN229 were utilized for radiation biology experiments. Patient tumor tissue was molecularly characterized for IDH, ATRX and TERT promoter mutations, MGMT promoter methylation and EGFR amplification using established methods. Relative quantification of mtDNA content was performed using quantitative real time PCR. Ethidium bromide was used to deplete mtDNA in U87 and LN229 cells. Clonogenic assay and MTT assay were performed to assess sensitivity to radiation and chemotherapy.

RESULTS

mtDNA content was lower in glioblastoma than in controls. Lower range of mtDNA copy number was associated with poor overall survival (p=0.033) and with markers of tumor aggressiveness like wild type IDH (p=0.02), unmethylated MGMT promoter, amplified EFGR and mutated TERT promoter. Out of 32 recurrent GBM patients, only 19 had received radiation treatment (RT) between the two surgeries and in these patients, mtDNA content was significantly higher in the recurrent tumor when compared to the primary tumor(p=0.01). U87 and LN229 cells showed a higher mtDNA copy number post irradiation (p=0.002). mtDNA depleted U87 and LN229 cells showed higher survival fraction post radiation exposure when compared to parent lines. The IC50 of TMZ was also higher for mtDNA depleted U87 and LN229 cells.

CONCLUSION

Low mtDNA content is associated with poor survival and aggressive tumor markers in glioblastoma. Lowering the mtDNA content in GBM cells induces radiation resistance as well as resistance to chemotherapy. Irradiation leads to increase in mitochondrial DNA content in both patient samples as well as malignant glioma cell lines.
RDNA-13. DOSE RESPONSE CURVE FOR RADIATION-INDUCED HYPERSOMNOLENCE (RIH) IN A MOUSE MODEL OF CRANIAL RADIATION: BEHAVIORAL ANALYSIS OF SLEEP AND ACTIVITY
Authors: Young Demarrius , Dee Smart Dee , King Amanda , Gilbert Mark , Armstrong Terri , Shuboni-Mulligan Dorela
Published: November 2019

BACKGROUND

Radiation therapy is the standard of care for both primary and secondary brain tumors. The majority of patients experience radiation induced hypersomnia (RIH) to varying extents which may impact life quality and treatment tolerance. Previously, we demonstrated that risk is enhanced by presence of select clock gene polymorphisms. The purpose of this study is to establish a mouse model of RIH to test dose effects of cranial irradiation on behavioral sleep and activity prior to introducing tumor in transgenic mice.

METHODS

Twenty-four non-tumor bearing C57BL/6 mice received whole brain radiation at one of 4 doses (sham, 2Gy, 5Gy, and 15Gy) using a single fraction. Behavior, total activity (distance) and sleep quantity (seconds) were monitored using Phenotyper cages and Ethovision Software with data collected at baseline (10 days) and post-radiation (11 days); percentage of activity was calculated as post-radiation/baseline activity. Blood and tissue samples were collected.

RESULTS

Baseline activity was not significantly different between groups (F(3.23) = 0.649, p=0.593). Shams and 2Gy mice were not affected by the procedure and activity levels were unchanged, 99.76±1.3% and 103.3±3.5%, respectively. The higher doses, 5Gy and 15Gy, had suppression of general activity compared to baseline with 90.8±2.7% and 88.9±1.3%, respectively. Between the two groups, suppression of activity started after 2 days in 15Gy and 5 days in 5Gy mice. Across three days (8–10), 5Gy and 15Gy (19,872±577sec) had more sleep during their active phase (t=2.27, p=0.03) than sham or 2Gy (17,618±803sec).

CONCLUSION

Activity and sleep are affected by cranial irradiation in our RIH mouse model in dose dependent manner. This model closely resembles the effects seen in patients and provides a critical tool for interrogating the physiological drivers of RIH. In future studies, we will examine other behaviors and the association between circadian gene variants and RIH susceptibility as previously reported in patients.
RTHP-05. CONTRIBUTION OF ATM MUTATION TO THE IMPROVED RADIO-SENSITIVITY: RETROSPECTIVE ANALYSIS USING NEXT-GENERATION SEQUENCING DATA
Authors: In Yoon Hong , Kim Nalee , Hoon Kim Se , Hyung Moon Ju , Kang Seok-Gu , Suh Chang-Ok , Hee Chang Jong
Published: November 2019

PURPOSE/OBJECTIVES

To identify the association of somatic ATM mutation (mATM) with improved radiotherapy sensitivity, we retrospectively reviewed the next-generation sequencing (NGS) data from high grade glioma patients.

MATERIALS/METHODS

This analysis includes 48 consecutive individuals diagnosed with high grade glioma (diffuse astrocytoma IDH-wild type n=2, anaplastic astrocytoma n=18, and glioblastoma n=28) between June 2017 and October 2018. Patients who underwent subtotal (n=30, 62.5%), partial (n=17, 35.4%) removal or biopsy (n=1, 2.1%) were included in this analysis for interpreting radio-sensitivity of residual tumor. We investigated mATM by NGS of FFPE specimens with a TruSight Tumor 170 (TST-170) cancer panel.

RESULTS

Among 48 samples, mATM was detected in 17% of cases (n=8). There was no significant difference in patient or tumor characteristics. Among mATM patients, there were 5 patients with glioblastoma and 3 patients with anaplastic astrocytoma IDH-wildtype. Most mutation was missense mutation (n=7, 88%). Median variant allele frequency was 44.7% (Interquartile range, IQR, 10.5–59.9%). Median follow-up duration after radiotherapy was 11.4 (IQR, 8.0–15.8) months. Radiation-related change was observed in 34 patients (71%). Tumors with mATM were related to higher frequency of radiation-related change at 6 months than tumors without mATM, respectively (88% and 64%, p = 0.016). Cases with mATM exhibited significantly 1-year progression free survival (PFS, 100% vs. 54%, p = 0.036). On subgroup of IDH WT (n=39) known as poor prognostic molecular marker, patients with mATM showed significantly higher PFS than patients without mATM (p=0.016, 1yr PFS 100% vs 43%). On subgroup with sub-ventricular zone involvement (n=38) representative of aggressiveness, PFS of patients with mATM was significantly higher than others (p=0.026, 1yr PFS 100% vs 43.9%).

CONCLUSIONS

Our results demonstrated that mATM is involved in radio-sensitivity with immediate radiologic change after radiation therapy followed by favorable radiologic response and clinical outcome beyond the aggressive nature of high grade glioma.
RTHP-12. NATIONWIDE DISTRIBUTION OF LINEAR ACCELERATOR VERSUS GAMMA KNIFE STEREOTACTIC RADIOSURGERY UTILIZATION FOR METASTATIC BRAIN DISEASE IN ACADEMIC VERSUS COMMUNITY HOSPITALS
Authors: McClelland III Shearwood , Degnin Catherine , Chen Yiyi , Watson Gordon , Jaboin Jerry
Published: November 2019

INTRODUCTION

Single-fraction stereotactic radiosurgery (SRS) is often the preferred treatment modality for metastatic brain disease, particularly when patients have a small enough volume of disease to preclude whole brain radiation therapy and its associated permanent cognitive morbidity. The two predominant SRS treatment modalities are Gamma Knife and linear accelerator (LINAC). The recent impact of SRS modality in academic versus community hospital settings in the United States (US) since the 2013 implementation of the American Tax Payer Relief Act (ATRA) has yet to be examined.

METHODS

Brain metastases patients from non-small cell lung cancer (NSCLC) throughout the United States having undergone SRS were identified using the 2010–2016 National Cancer Data Base (NCDB). SRS utilization in academic versus community (non-academic) hospitals was identified and assessed.

RESULTS

Of the 4,012 SRS patients examined, the majority (64%) were treated at academic hospitals. Beginning in 2014, LINAC SRS rapidly increased in popularity compared to GKRS, reversing an annual decline in utilization originating from 2011. The 63% LINAC composition of SRS cases at non-academic centers in 2016 was an all-time high, a 12% increase from a year earlier. This was markedly different than SRS utilization at academic hospitals, where despite a steady increase in LINAC SRS since 2013, GKRS remained the predominant SRS modality, comprising 73% of cases in 2016.

CONCLUSIONS

The implementation of LINAC over Gamma Knife SRS in the non-academic hospital setting has markedly increased in the timespan since ATRA implementation, comprising more than 60% of SRS cases compared to only 27% of academic hospital SRS cases in 2016. These findings indicate that without the substantially increased Medicare reimbursement advantage formerly associated with Gamma Knife compared to LINAC prior to ATRA, the non-academic setting may be more sensitive than academic centers to conditions optimizing reimbursement.
RTHP-13. EFFICACY OF FRACTIONATED GAMMA KNIFE RADIOSURGERY FOR ORBITAL CAVERNOUS HEMANGIOMA: 10-YEAR EXPERIENCE AT A SINGLE INSTITUTION
Authors: Hwan Kim Kyung , Kim Seon-Hwan , Lee Jung-Il , Kong Doo-Sik , Jun Seol Ho , Nam Do-Hyun
Published: November 2019

This study aimed to evaluate the efficacy and safety of fractionated gamma knife radiosurgery (GKS) for the treatment of orbital cavernous hemangioma (OCH).

METHODS

From January 2007 to June 2018, 34 patients who underwent fractionated GKS (median 20 Gy in 4 fractions) for OCH at a single tertiary institution were reviewed. Ophthalmic evaluations including exophthalmometry, best corrected visual acuity with the Snellen chart and Humphrey visual field were investigated. Changes in lesion volume were also analyzed.

RESULTS

The median age was 43 years (range, 10–67 years) and 18 patients were male (53%). The median clinical follow-up time was 42 months (range, 12–132 months). The most common presenting symptom was proptosis followed by visual impairment. Proptosis improved in all 27 patients. The mean value of proptosis was reduced from 2.9 mm to 1.1 mm (P < 0.001). Of 15 patients who showed decreased visual acuity preoperatively, 12 patients (80%) had improved in vision. Preoperative visual field defects were evident in 17 patients and resolved in 15 patients (88%) after treatment. The median tumor volume at the time of GKS was 2.2 cm3 (range, 0.2–8.5 cm3). Tumor shrinkage was observed in all patients and the mean volume reduction rate was 64%. No patient experienced GKS-related ocular morbidity, though two transient GKS-related adverse events (6%) were observed.

CONCLUSION

Fractionated GKS is an effective and safe option for the treatment of OCH, with significant reduction in tumor volume and improvement of ophthalmic outcomes.
RTHP-18. PROSPECTIVE PHASE II RANDOMIZED TRIAL COMPARING PROTON THERAPY VS. PHOTON IMRT FOR NEWLY DIAGNOSED GBM: SECONDARY ANALYSIS COMPARISON OF GENDER AND NEUTROPHIL-LYMPHOCYTE RATIO (NLR) IN GBM OUTCOMES
Authors: Randall James , Al Feghali Karine , Wefel Jeffrey , Grosshans David , Dibaj Seyedeh , Milton Denai , McAvoy Sarah , Li Jing , McGovern Susan , McAleer Mary , Ghia Amol , Paulino Arnold , Sulman Erik , Penas-Prado Marta , Wang Jihong , DeGroot John , Heimberger Amy , Armstrong Terri , Gilbert Mark , Mahajan Anita , Brown Paul , Chung Caroline
Published: November 2019

BACKGROUND

While glioblastoma (GBM) is more prevalent in males, studies show that females with GBM tend to have longer overall survival (OS) than males. Pretreatment neutrophil to lymphocyte ratio (NLR) has also proven to be prognostic in GBM, with lower NLR having favorable outcomes. This secondary analysis of a prospective randomized trial of proton vs. photon intensity modulated radiotherapy aims to explore the interaction of gender and NLR on GBM outcomes.

METHODS

Analysis was performed on the full patient population. Kaplan-Meier methods estimated OS with censoring at last follow-up for those who were alive. Univariate (UVA) and multivariate (MVA)Cox proportional hazards models assessed predictors of OS.

RESULTS

Of 90 patients, 77 were included (43 males; 34 females) with median age of 52 years (range: 26–82 years). Median OS was longer for females than males (30.7 vs 18.2 months, p=0.004). On UVA, patients with NLR below median value (NLR= 3.1) tended to have longer OS than those above median, though not meeting statistical significance (23.1 vs. 17.9 months, p=0.051). Difference in OS was statistically significant in females (OS 36.4 months NLR >median vs. 16.7 months NLR< median, p=0.002), but not in males (OS 17.8 months NLR >median vs. 19.1 NLR< median, p=0.95). MVA analysis was consistent, with female gender predicting reduced hazard ratio (HR) (0.28, p=0.034) and females with below median NLR showing a reduced HR over those with above median (0.28, p=0.005). Again, males did not benefit (HR 0.90, p=0.77).

CONCLUSION

Consistent with prior publications, females and all patients with lower pre-treatment NLR with newly diagnosed GBM had longer OS. However, combining these two factors revealed that the benefits from lower pre-treatment NLR were conferred only in females with no impact on males. This different impact of NLR between genders may suggest innate immune differences in gender during response to malignancy.
RTHP-33. A SINGLE INSTITUTION RETROSPECTIVE ANALYSIS ON SURVIVAL BASED ON TREATMENT PARADIGMS FOR PATIENTS WITH ANAPLASTIC OLIGODENDROGLIOMA
Authors: Young Jacob , Zhang Yalan , Molinaro Annette , Taylor Jennie , Clarke Jennifer , Prados Michael , Chang Susan , Berger Mitchel , Butowski Nicholas , Ann Oberheim-Bush Nancy
Published: November 2019

Anaplastic oligodendrogliomas are a type of high grade glioma defined molecularly by the 1p19q co-deletion. Currently, there is no curative therapy, and some studies have estimated median survival is estimated to be approximately 5 years. Current standard of care includes surgical resection followed by radiation and chemotherapy. However, the benefit of up-front radiation with chemotherapy compared to chemotherapy alone following surgical resection has not been shown in a randomized control trial. Given the long-term cognitive consequences of radiation therapy and the high percentage of patients who lives beyond 15 years with AO, there is an effort to balance longevity with radiation toxicity. As such we performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years. 159 patients were identified as diagnosed with an anaplastic oligodendroglioma between 1996–2016. Of those, 57 patients were found to have anaplastic olidodendroglioma at original diagnosis and had long term follow-up. Sixty-six percent of patients were between the ages of 30–50 and mean KPS was 87.3. At the time of analysis, 33% of patients had died. In this cohort, 60% of patients were initially treated with radiation and chemotherapy (either temozolomide or CCNU) at diagnosis and 40% were treated with chemotherapy alone. Median overall survival for the entire cohort was 142 months. The related risk of progression in the upfront chemotherapy only group is approximately 5.87 times higher than the patients who received radiation and chemotherapy (Hazard ratio=5.87, 1.92–17.90, p=0.002). However, there was no significant difference in overall survival in patients treated with upfront chemotherapy compared to patients treated upfront with chemotherapy and radiation (p=0.14). On univariate analysis, there was no association between age, KPS, EOR, or upfront vs. delayed radiation and survival. As such initial treatment with chemotherapy alone may be an option for some patients with anaplastic oligodendroglioma.
RARE-33. LEPTOMENINGEAL DISEASE IN PATIENTS WITH MIDLINE GLIOMAS HARBORING HISTONE H3 K27M MUTATIONS
Authors: Eduardo Silva Correia Carlos , Pentsova Elena , Lin Andrew , Miller Alexandra
Published: November 2019

INTRODUCTION

The 2016 WHO classification describes a specific subtype of midline gliomas harboring histone 3 (H3) K27M mutations which compromise 15–40% of gliomas in children and young adults. Since we began to perform molecular profiling at Memorial Sloan Kettering Cancer Center (MSKCC) we have observed an increased prevalence of leptomeningeal disease (LMD) in this population. However, the true incidence and the clinical behavior of this group has not been well-defined.

METHODS

This is a retrospective study of patients with H3K27M/I diffuse midline gliomas at MSKCC from 01/2012 to 01/2019. Mutations were identified through next-generation sequencing (NGS).

RESULTS

We identified 24 patients. Median age was 21 (6–70) and 13 were male. Thirteen tumors were in the thalamus, 6 in the brainstem, 4 in the spinal cord, and 1 in the pineal region. H3K27M mutations were detected by NGS from tumor tissue in 21 patients, from cerebral spinal fluid (CSF) circulating tumor DNA (ctDNA) in 2 and from tissue and CSF ctDNA in one. LMD was diagnosed in 17/24 (71%) patients radiographically. Of these, 8 underwent LP: CSF cytology was positive in 2/8 and CSF ctDNA was detected in 3/3. All patients received RT and one or more lines of chemotherapy. At analysis, thirteen patients remain alive. Median time to last follow up for all patients was 14.2 months. Median time from diagnosis to LMD was 13.2 months (0–45.1), with median OS of 6.5 months (0.3–27) after diagnosis of LMD.

CONCLUSION

Our study showed that more than two-thirds of the patients with H3 K27M diffuse midline developed LMD. Neuroaxis imaging should be performed in conjunction with CSF studies to diagnose LMD. Besides, CSF ctDNA represents an important tool to identify molecular profile of tumors when biopsy is not feasible or limited for the analysis.
RARE-35. MRI FINDINGS AT PROGRESSION IN ADULT PATIENTS WITH MEDULLOBLASTOMA
Authors: Cordova Christine , Vera Elizabeth , Aboud Orwa , Antony Ramya , Boris Lisa , Bryla Christine , Burton Eric , Crandon Sonja , Leggiero Nicole , Reyes Jennifer , Siegel Christine , Theeler Brett , Vyas Yamini , Wall Kathleen , Wu Jing , Gilbert Mark , Armstrong Terri , Penas-Prado Marta
Published: November 2019

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.
RARE-45. ACTIVITY OF LAROTRECTINIB IN TRK FUSION CANCER PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM TUMORS
Authors: Doz Francois , Geoerger Birgit , DuBois Steven G , Grilley-Olson Juneko E , van Tilburg Cornelis M , Italiano Antoine , Lissat Andrej , Jin Kang Hyoung , Tahara Makoto , Boni Valentina , Perreault Sebastien , Capra Michael , Nanda Shivani , Brega Nicoletta , Holynskyj Ariadna , Ziegler David S , Hong David S , Hyman David M , Drilon Alexander
Published: November 2019

BACKGROUND

TRK fusions are oncogenic drivers of a variety of tumors, many of which can involve the central nervous system (CNS). Larotrectinib is a selective TRK inhibitor FDA-approved for the treatment of TRK fusion cancers (Drilon et al., NEJM 2018). Here we report on the clinical activity of larotrectinib in an expanded set of TRK fusion-positive primary CNS tumors.

METHODS

Patients with primary CNS tumors harboring a TRK fusion treated with larotrectinib on two clinical trials (NCT02637687 and NCT02576431) were identified by local molecular testing. Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was investigator assessed (RANO). Data cutoff: February 19, 2019.

RESULTS

18 patients with various histological types of glial tumors (11 high-grade, 4 low-grade, 3 unknown) were identified. The patients had gene fusions involving NTRK2 (n=13), NTRK1 (n=2) and NTRK3 (n=2); one was not determined. Median age was 10 years (range 1–79); 14 patients were pediatric (< 18). In 14 evaluable patients, the objective response rate was 36% (2 CR, 3 PR), with responses seen in high- and low-grade disease and across histologies. Nine patients had SD. The 24-week disease control rate was 71%. The duration of treatment ranged from 0.03+ to 16.6+ months. One patient (3.7 years old) with glioblastoma progressed after 5.5 months on larotrectinib. Sequencing revealed a solvent front mutation and the patient was subsequently enrolled in compassionate use protocol for BAY2731954 (formerly known as LOXO-195).

CONCLUSION

Larotrectinib is active in patients with TRK fusion cancer with intracranial disease. Confirmed responses and durable disease control were seen in primary CNS tumors of various grades and histologies. These results further support expanded testing for NTRK gene fusions in patients with primary CNS tumors.
RARE-55. RIT1 MUTATION ASSOCIATED WITH SPINAL NEUROFIBROMATOSIS
Authors: Anderson Mark , Shaikh Nawal , Long Eugene , Maher Joseph
Published: November 2019

Neurofibromatosis type 1 is defined clinically and molecularly by the presence of a mutation in neurofibromin, resulting in typical cutaneous, peripheral nerve and nerve root neurofibromas through the changes in regulation of the RAS pathway. A 33-year-old right-handed African-American female presented with a complaint of back pain, radiating down the legs and arms worsening over several years. On physical exam, the patient had no cutaneous neurofibromas, café-au-lait spots, or axillary freckling. MRI spine revealed diffuse symmetric fusiform nerve sheath tumors throughout the cervical, thoracic, and lumbar spine favored to represent neurofibromatosis. Genetics evaluation with pedigree revealed no family history of genetic disorders. Genetic testing was positive solely for a c.293A >G transition in exon 5 of the RIT1 gene, previously reported as a cause of the RASopathy Noonan syndrome, type-8. RASopathies are conditions caused by mutations in the proteins of the RAS-MAPK pathway. Noonan Syndrome can present with some combination of abnormalities of the ears, webbing of the neck, developmental delay, and cardiac abnormalities. This patient was without external phenotypic characteristics of Noonan Syndrome, yet was found to have a mutation in this pathway. RIT1 mutation has been previously described rarely with glioma development. Alternate mutations in the RAS-MAPK pathway should be considered in the differential for patients with spinal neurofibromatosis when typical neurofibromatosis mutations are absent.
STEM-08. GENE THERAPY USING IL-24-EXPRESSING UMBILICAL CORD-DERIVED MESENCHYMAL STEM CELLS AGAINST GLIOMA
Authors: Fan Shaochen , Gao Yilu
Published: November 2019

Despite many advances have been made in treatment of gliomas, patients prognosis remains poor. Stem cell-based therapy has been thought to be a promising option for gliomas and many studies have reported that umbilical cord-derived mesenchymal stem cells (UC-MSCs) are ideal gene vectors for tumor gene therapy. Interleukin 24 (IL-24) is a pleiotropic immunoregulatory cytokine which has an apoptotic effect on many kinds of tumor cells and can inhibit the growth of tumors specifically without damaging normal cells. However, there are still some challenges in its clinical application, such as the half-life, toxicity caused by high-dose application, and so on. Therefore, we hypothesize that combination of gene transfer with stem cell transplantation could overcome the problems. In this study, we investigated UC-MSCs transduced with lentiviral vectors carrying IL-24 complementary DNA as a vehicle for the targeted delivery of IL-24 to local tumor sites. The engineered UC-MSCs selectively migrated to glioma cells and showed the antitumor effect in vitro and in vivo. The restrictive efficacy of these UC-MSCs was related to the inhibition of proliferation and induction of apoptosis in tumor cells. These findings indicate that UC-MSCs-based IL-24 gene therapy can obviously suppress the growth of glioma xenografts, thereby suggesting the potential for future therapeutic interventions in the treatment of gliomas. Keywords: Glioma, Gene therapy, Umbilical cord-derived mesenchymal stem cells (UC-MSCs), Interleukin 24 (IL-24)
STEM-17. LOW GRADE ASTROCYTOMA MUTATIONS COOPERATE TO DISRUPT SOX2 GENOMIC ARCHITECTURE AND BLOCK DIFFERENTIATION VIA PREVIOUSLY UNIDENTIFIED ENHANCER ELEMENTS
Authors: Bready Devin , Modrek Aram , Guerrera Adler , Frenster Joshua , Skok Jane , Placantonakis Dimitris
Published: November 2019

Neomorphic mutations in isocitrate dehydrogenase I (IDH1) result in the formation of the oncometabolite 2-hydroxyglutarate (2HG) in a significant subset of gliomas and other tumors including acute myeloid leukemias. Preclinical evidence suggests that gliomas harboring IDH1 mutations undergo widespread, long-lasting modifications to the epigenome that persist following inhibition of 2HG production. However, the exact mechanism underlying gliomagenesis remains unclear. To address difficulties in growing these tumors in culture, our group generated a model of low-grade astrocytoma in human neural stem cells (NSCs). This model, referred to as 3-Hit NSCs, suggested a block in differentiation potential underlies gliomagenesis at the cellular level. This block is rescued by restoration of expression of the transcription factor (sex determining region Y)-box 2 (SOX2), which is transcriptionally downregulated during IDH mutant gliomagenesis. We believe that these changes occur secondary to profound alterations in 3-dimensional chromatin organization around the SOX2 genomic locus. Our preliminary data suggest SOX2 expression in control NSCs depends on 3-dimensional association of its promoter to an uncharacterized, distal enhancer located 600 kb telomeric to the SOX2 gene. We believe this association is disrupted in 3-Hit NSCs due to eviction of chromatin organizer CTCF from its motifs in the SOX2 topologically associating domain (TAD). To test this hypothesis, we used CRISPR-Cas9 technology to excise CTCF motifs immediately upstream of the SOX2 promoter and in the region of the putative enhancer in control NSCs. Excision of such motifs significantly reduced SOX2 mRNA levels and impaired growth of control NSCs. We are currently working on characterizing this novel SOX2-enhancer interaction in native stem cells, as well as tumors that depend on SOX2 expression. This works aims to elucidate the core epigenetic mechanisms underlying IDH mutant gliomagenesis. Our findings will be used to improve therapy in IDH-mutant glioma.
STEM-21. INVESTIGATING DOT1L AS AN EPIGENETIC VULNERABILITY IN BRAIN TUMOR STEM CELLS
Authors: Bozek Danielle , MacLeod Graham , Hao Xiaoguang , Rajakulendran Nishani , Ahmadi Moloud , Dirks Peter , Angers Stephane , Luchman Artee , Weiss Sam
Published: November 2019

Glioblastoma (GBM), the most common and aggressive primary adult brain cancer, is thought to be driven by a small subpopulation of brain tumor stem cells (BTSCs). BTSCs exhibit shared properties with normal stem cells such as self-renewal and multilineage differentiation. These stem cell properties have been proposed to underlie GBM tumorigenicity, treatment evasion and contribute to tumor heterogeneity. To investigate the biology underlying the stem cell properties of GBM, we compared gene essentiality profiles for a panel of BTSCs, fetal neural stem cells and non-GBM cell lines using a CRISPR Cas9 knockout library. Interestingly, from these screens, we identified the histone methyltransferase disrupter of telomeric silencing-1-like (DOT1L) as an essential gene for the growth of BTSCs and fetal neural stem cells but not for non-GBM cell lines. DOT1L is the only known histone methyltransferase responsible for histone 3 lysine 79 methylation, an epigenetic mark associated with active gene transcription. The role of this epigenetic regulator in BTSCs was investigated in depth using EPZ-5676, a clinically relevant small molecule inhibitor. Short-term treatment with EPZ-5676 in BTSCs showed minimal effects on cell viability but led to striking morphological changes, increased neuronal and astrocytic differentiation and a reduction in self-renewal. Longer treatment periods with EPZ-5676 led to a decrease in BTSC proliferation and an increase in apoptosis. Furthermore, BTSCs pretreated with EPZ-5676 led to slowed orthotopic tumor growth and improved overall survival in a SCID mouse model. Overall, these findings suggest DOT1L epigenetically regulates GBM stem cell properties and tumor growth. We are further investigating the mechanisms underlying DOT1L regulation of gene expression in BTSCs with the goal of improving the field’s understanding of epigenetics and the therapeutic implications of targeting epigenetic processes in GBM.
ΔNp73/ETS2 complex drives glioblastoma pathogenesis— targeting downstream mediators by rebastinib prolongs survival in preclinical models of glioblastoma
Authors: Cam Maren , Charan Manish , Welker Alessandra M , Dravid Piyush , Studebaker Adam W , Leonard Jeffrey R , Pierson Christopher R , Nakano Ichiro , Beattie Christine E , Hwang Eugene I , Kambhampati Madhuri , Nazarian Javad , Finlay Jonathan L , Cam Hakan
Published: November 2019

Background

Glioblastoma (GBM) remains one of the least successfully treated cancers. It is essential to understand the basic biology of this lethal disease and investigate novel pharmacological targets to treat GBM. The aims of this study were to determine the biological consequences of elevated expression of ΔNp73, an N-terminal truncated isoform of TP73, and to evaluate targeting of its downstream mediators, the angiopoietin 1 (ANGPT1)/tunica interna endothelial cell kinase 2 (Tie2) axis, by using a highly potent, orally available small-molecule inhibitor (rebastinib) in GBM.

Methods

ΔNp73 expression was assessed in glioma sphere cultures, xenograft glioblastoma tumors, and glioblastoma patients by western blot, quantitative reverse transcription PCR, and immunohistochemistry. Immunoprecipitation, chromatin immunoprecipitation (ChiP) and sequential ChIP were performed to determine the interaction between ΔNp73 and E26 transformation-specific (ETS) proto-oncogene 2 (ETS2) proteins. The oncogenic consequences of ΔNp73 expression in glioblastomas were examined by in vitro and in vivo experiments, including orthotopic zebrafish and mouse intracranial-injection models. Effects of rebastinib on growth of established tumors and survival were examined in an intracranial-injection mouse model.

Results

ΔNp73 upregulates both ANGPT1 and Tie2 transcriptionally through ETS conserved binding sites on the promoters by interacting with ETS2. Elevated expression of ΔNp73 promotes tumor progression by mediating angiogenesis and survival. Therapeutic targeting of downstream ΔNp73 signaling pathways by rebastinib inhibits growth of established tumors and extends survival in preclinical models of glioblastoma.

Conclusion

Aberrant expression of ΔNp73 in GBM promotes tumor progression through autocrine and paracrine signaling dependent on Tie2 activation by ANGPT1. Disruption of this signaling by rebastinib improves tumor response to treatment in glioblastoma.
The state of nutrition in medical education in the United States
Authors: Bassin Sandhya R , Al-Nimr Rima I , Allen Kathleen , Ogrinc Greg
Published: November 2019

Despite the significant impact diet has on health, there is minimal nutrition training for medical students. This review summarizes published nutrition learning experiences in US medical schools and makes recommendations accordingly. Of 902 articles, 29 met inclusion criteria, describing 30 learning experiences. Nutrition learning experiences were described as integrated curricula or courses (n = 10, 33%), sessions (n = 17, 57%), or electives (n = 3, 10%). There was heterogeneity in the teaching and assessment methods utilized. The most common was lecture (n = 21, 70%), often assessed through pre- and/or postsurveys (n = 19, 79%). Six studies (26%) provided experience outcomes through objective measures, such as exam or standardized patient experience scores, after the nutrition learning experience. This review revealed sparse and inconsistent data on nutrition learning experiences. However, based on the extant literature, medical schools should build formal nutrition objectives, identify faculty and physician leadership in nutrition education, utilize preexisting resources, and create nutrition learning experiences that can be applied to clinical practice.
Changes in the Fungal Marker β-D-Glucan After Antiretroviral Therapy and Association With Adiposity
Authors: Dirajlal-Fargo Sahera , Moser Carlee , Rodriguez Katherine , El-Kamari Vanessa , Funderburg Nicholas T , Bowman Emily , Brown Todd T , Hunt Peter W , Currier Judith , McComsey Grace A
Published: November 2019

Background

Bacterial translocation in HIV is associated with inflammation and metabolic complications; few data exist on the role of fungal translocation.

Methods

A5260s was a substudy of A5257, a prospective open label randomized trial in which treatment-naïve people with HIV (PWH) were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or raltegravir (RAL) over 96 weeks. Baseline was assessed, and changes in β-D-glucan (BDG) were assessed at weeks 4, 24, and 96. Wilcoxon rank-sum tests were used to compare distribution shifts in the changes from baseline between treatment arms and linear regression models to assess associations between BDG and measures of inflammation, body composition, and insulin resistance.

Results

Two hundred thirty-one participants were randomized; 90% were male, the median age was 36 years, HIV-1 RNA was 4.56 log10c/mL, and CD4 cell count was 338 cells/mm3. There was an overall increase in BDG over 96 weeks (1.57 mean fold-change; 95% confidence interval, 1.39 to 1.77) with no differences between arms. Twofold higher BDG levels at week 96 were associated with increases in trunk fat (8%) and total fat (7%) over 96 weeks (P ≤ .035). At week 4, BDG correlated with I-FABP, a marker of enterocyte damage, and zonulin, a marker of intestinal permeability (r = .19–.20; P < .01).

Conclusions

In treatment-naïve participants initiating antiretroviral therapy (ART) with TDF/FTC and either RAL or ATV/r, DRV/r, BDG, a marker of fungal translocation, increased similarly in all arms over 96 weeks. This may represent continued intestinal damage during ART and resulting fungal translocation. Higher BDG was associated with larger fat gains on ART.
X-ray emissions from magnetic polar regions of neutron stars
Authors: Inoue Hajime
Published: November 2019

Structures of X-ray emitting magnetic polar regions on neutron stars in X-ray pulsars are studied in the accretion rate range 1017 g s−1–1018 g s−1. It is shown that a thin but tall, radiation-energy-dominated, X-ray emitting polar cone appears at each of the polar regions. The height of the polar cone is several times as large as the neutron star radius. The energy gain due to the gravity of the neutron star in the polar cone exceeds the energy loss due to photon diffusion in the azimuthal direction of the cone, and a significant amount of energy is advected to the neutron star surface. Then, the radiation energy carried with the flow should become large enough for the radiation pressure to overcome the magnetic pressure at the bottom of the cone. As a result, the matter should expand in the tangential direction along the neutron star surface, dragging the magnetic lines of force, and form a mound-like structure. The advected energy to the bottom of the cone should finally be radiated away from the surface of the polar mound and the matter should be settled on the neutron star surface there. From such configurations, we can expect an X-ray spectrum composed of a multi-color blackbody spectrum from the polar cone region and a quasi-single blackbody spectrum from the polar mound region. These spectral properties agree with observations. A combination of a fairly sharp pencil beam and a broad fan beam is expected from the polar cone region, while a broad pencil beam is expected from the polar mound region. With these X-ray beam properties, basic patterns of pulse profiles of X-ray pulsars can be explained too.
Cow–calf performance, forage utilization, and economics of warm-season annual baleage in beef cattle winter feeding systems1
Authors: Panhans Mekenzie H , Mason Katie M , Mullenix Mary K , Prevatt Chris G , Moisá Sonia J , Muntifering Russell B
Published: November 2019

A 52-d winter feeding trial was conducted to determine animal performance, utilization, and economics of pearl millet (PM) baleage, sorghum × sudangrass (SS) baleage, and “Tifton 85” bermudagrass (B) hay for lactating beef cow–calf pairs. Cone (C) and open-shaped (O) rings were evaluated for potential to minimize forage wastage. The experiment was a completely randomized design with a 3 × 2 factorial arrangement of treatments for each forage type × hay ring (3 cow–calf pairs per treatment; 2 replications per treatment). Animal response measures included cow body weight (BW) change and body condition score (BCS) over the 52-d trial, initial and final calf BW, and cow milk production at the midpoint and end of the study. Forage nutritive value parameters evaluated for each forage type included ash, crude protein (CP), in vitro true digestibility (IVTD), neutral detergent fiber (NDF), acid detergent fiber, and acid detergent lignin (ADL). Forage wastage was estimated for each forage × ring treatment as the percentage of the bale weight remaining in feeding rings at the time of bale replacement. An economic evaluation of the relative costs associated with production and utilization of each forage type was calculated. There were no differences (P ≥ 0.10) in cow BW change or BCS change among forage types, between ring shapes, or an interaction observed for these response variables. Proportion of waste from PM and SS baleage was greater (P < 0.10) than for B hay, although there was no forage type × hay ring interaction or differences between O and C hay ring treatments for forage waste (P ≥ 0.10, respectively). Cow milk production and calf BW gain did not differ among forage type (P ≥ 0.10, respectively); however, beef calves in pens containing the O ring feeder weighed 6 kg more (P ≤ 0.05) than calves whose dams were fed using C rings. The economic analysis implies that it is more costly to feed warm-season annual forage baleage to cow–calf pairs than dry hay, largely due to greater costs of production, lack of difference in animal performance responses, and less utilization of baleage compared with feeding bermudagrass hay in this trial.
Road-safety recognition and network equilibrium with perceived route-choice sets
Authors: Li Mao-sheng , Huang He-lai
Published: November 2019

Safety is regarded as the second basic need in Maslow’s hierarchy of needs (1943), and safety recognition and circumvention behaviour in the route-choice decision-making process should therefore be accommodated in network-traffic equilibrium analysis frameworks. This paper proposes a framework by which crash frequency, forecasted using the safety-analysis method or compiled from historical data for intersections, is used to measure the safety consciousness of drivers. Drivers are then classified into different groups according to their acceptable-risk thresholds, and each group has its own route-choice set. Decision behaviour whereby drivers are willing to bear additional costs in order to circumvent travel risk is incorporated into the variational inequality model based on the user equilibrium in the perceived route-choice set (UE-PRCS), which is an extension of Wardrop’s first principle. The Frank–Wolfe algorithm, based on the convex combination method, is employed to obtain the solution. A small road network is used as a case study to illustrate the proposed framework, incorporating risk recognition and circumvention behaviour under different combinations of traffic demand and risk-sensitivity group ratio. The results show that the standard user equilibrium is a special case of the UE-PRCS, but that the UE traffic state is more common than the UE-PRCS under different parameters.
Cosmological evolution of semilocal string networks
Authors: Achúcarro A. , Avgoustidis A. , López-Eiguren A. , Martins C. J. A. P. , Urrestilla J.
Published: November 2019

Semilocal strings—a particular limit of electroweak strings—are an interesting example of a stable non-topological defect whose properties resemble those of their topological cousins, the Abrikosov–Nielsen–Olesen vortices. There is, however, one important difference: a network of semilocal strings will contain segments. These are ‘dumbbells’ whose ends behave almost like global monopoles that are strongly attracted to one another. While closed loops of string will eventually shrink and disappear, the segments can either shrink or grow, and a cosmological network of semilocal strings will reach a scaling regime. We discuss attempts to find a ‘thermodynamic’ description of the cosmological evolution and scaling of a network of semilocal strings, by analogy with well-known descriptions for cosmic strings and for monopoles. We propose a model for the time evolution of an overall length scale and typical velocity for the network as well as for its segments, and some supporting (preliminary) numerical evidence.

This article is part of a discussion meeting issue ‘Topological avatars of new physics’.