tbuckley/cabot-search huggingface dataset:
CTNI-39. PHASE 1B CLINICAL TRIAL OF OKN-007 IN RECURRENT MALIGNANT GLIOMA
Authors: James Battiste, Alexandra Ikeguchi, Sukyung Woo, Satish Sharan, Yan Zhao, Andrew Cohoon, Sarah Sung, Deborah Wright, April Teague, Randy Jensen, Eun Ha Kim, Won Yang, Rheal Towner
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The nitrone compound OKN-007 is a novel anti-cancer agent. In glioblastoma xenografts, OKN-007 reduces cell proliferation and angiogenesis, and increases apoptosis. Here we report on the safety, efficacy, and pharmacokinetics (PK) of OKN-007 in adults with recurrent glioma. METHODS NCT01672463 is a phase 1b trial of OKN-007 in adults with recurrent gliomas previously treated with standard therapy. OKN-007 was administered by IV. The study comprised a 3 + 3 dose escalation design followed by an expansion cohort at the maximum tolerated dose (MTD). The dose escalation drug levels were 20 (n = 3), 40 (n = 3), and 60 mg/kg (n = 3), treating on a schedule of thrice weekly for 4 weeks, then twice weekly for 4 weeks, then once weekly until progression. Drug PK was determined in the dose escalation cohorts. The expansion cohort was treated with 60 mg/kg thrice weekly for 12 weeks, then twice weekly for 12 weeks, then once weekly until progression (n = 6). Kaplan-Meier analysis was used to determine progression-free (PFS) and overall survival (OS). RESULTS Median age was 51 years (range, 25–62). No dose-limiting toxicities were observed. The expansion dose was 60 mg/kg. Of 123 adverse events (AEs), 34 were deemed probably (1.6%) or possibly (26%) treatment-emergent (TEAE). The most commonly-occurring TEAEs were fatigue (4.1%) and headache (3.3%). Grade 3 TEAEs included headache, urinary tract infection, and increased prothrombin time (0.8% each). Two grade 1 AEs, hypokalemia and dizziness, were considered probably attributable to OKN-007. In patients receiving 60 mg OKN-007/kg, median PFS was 1.4 months and OS was 21 months (log rank p = 0.08 for comparison across doses). Systemic PK exposure was dose proportional. The average half-life of OKN-007 is 2.8 hours. CONCLUSIONS OKN-007 appears safe and, compared to standard therapy, may prolong OS in recurrent glioma.
GCT-74. RETROSPECTIVE LITERATURE REVIEW OF CENTRAL NERVOUS SYSTEM (CNS) GERM CELL TUMORS (GCTs) IN PATIENTS WITH DOWN SYNDROME (DS)
Authors: Micah K Harris, Margaret Lamb, Joseph R Stanek, Jonathan L Finlay, Mohamed S AbdelBaki
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND A standard-of-care has not been established for the management of DS patients who develop primary CNS GCTs – the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS A review of the English-language medical literature between 1960 and 2020 was conducted. RESULTS Thirty-one cases of CNS GCTs in DS patients (median nine-years-old; 21 males) were reported; the majority (23/31) originated from East Asia. Twelve had germinomas (39%), 12 had non-germinomatous germ cell tumors (NGGCTs) (39%), and seven had teratomas (22%). Four patients (13%) died from tumor progression (one germinoma versus three teratoma). Seven patients (23%) died from treatment-related complications (four germinoma versus three NGGCT). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT) only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 58.1% for all patients, 52.5% for germinoma, 64.8% for NGGCT, and 60% for teratoma. Three-year OS for patients who received RT or chemotherapy was 63.6% and 59.6% respectively. Twenty patients (65%) remain alive (seven germinoma versus nine NGCCT versus four teratoma). Ten patients (32%) experienced serious treatment-related complications (five germinoma versus five NGGCT). CONCLUSIONS Patients with DS and CNS GCTs are at an increased risk of treatment-related complications. Therefore, a different therapeutic approach may need to be considered for this patient population in order to mitigate the treatment-related complications and long-term neurocognitive sequelae.
RONC-26. A CASE OF RADIATION NECROSIS OF THE CEREBELLUM 16 YEARS AFTER CHEMORADIOTHERAPY FOR MEDULLOBLASTOMA
Authors: Mayuko Miyata, Masahiro Nonaka, Akio Asai
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND If new lesions are observed during follow-up of the malignant tumor after treatment, it is difficult to distinguish whether the tumor is a recurrent lesion, secondary cancer, or radiation necrosis of the brain. We have encountered a patient with symptomatic radiation necrosis of the cerebellum 16 years after treatment of medulloblastoma. CASE PRESENTATION: A 24-year-old man who had received a tumor resection and chemoradiotherapy for cerebellar medulloblastoma at the age of 8 presented with dizziness. For the past 16 years, there was no recurrence of the tumor. He subsequently underwent MRI scan, and T1-Gd image showed enhanced lesion in the right cerebellar peduncle. Cerebrospinal fluid cytology analysis was negative for tumor. We suspected tumor reccurence or secondary cancer, and performed lesion biopsy. The result of the pathological examination was radiation necrosis of the cerebellum. DISCUSSION: The interval of radiation necrosis of the brain and radiotherapy can vary from months to more than 10 years. So, whenever a new lesion is identified, radiation brain necrosis must be envisioned. According to guidelines in Japan, there is no absolute examination for discriminating tumor recurrence from radiation brain necrosis and diagnosis by biopsy may be required. CONCLUSION We experienced a case of symptomatic radiation necrosis of the cerebellum 16 years after treatment. In patients showing new lesion after long periods of time, the possibility of radiation necrosis to be considered.
TMOD-37. IN VIVO COMPRESSION AND IMAGING FOR CAUSAL STUDIES OF MECHANICAL FORCES IN THE BRAIN
Authors: Meenal Datta, Hadi Nia, Giorgio Seano, Sylvie Roberge, Peigen Huang, Lance Munn, Rakesh Jain
Journal: Neuro-Oncology (2020)

Abstract Clinicians have long observed the effects of abnormal mechanical forces – edema (fluid pressure) in particular – in brain tumors and the surrounding normal brain tissue. However, it was not previously possible to dissect the direct effects of solid stress (i.e., “mass effect”), a mechanopathology resulting from solid components of the tumor tissue, on the brain from the biological and physiological adverse effects exerted by cancer cells. We recently developed for the first time an in vivo compression device that allows for causal and mechanistic studies that delineate the solid mechanical forces of a tumor growing in the brain from its biological effects. The brain poses a unique anatomical consideration of abnormal mechanical forces due to its physical confinement by the skull. We adapted standard transparent cranial windows normally used for intravital imaging studies in mice to include a tunable screw for controlled and acute or chronic compression and decompression in the brain. This compressive cranial window allows for longitudinal imaging of the surrounding brain tissue (cortex or cerebellum) over time (weeks or months) as the screw is lowered further into the brain tissue to recapitulate tumor growth-induced solid stress. Using this device, we have demonstrated that solid stress is causally linked to vascular and neurological dysfunction in the brain. We have also been able to utilize this preclinical system to screen for effective therapeutic interventions to reduce solid stress-induced neuronal death and improve neurological function. Beyond cancer, this technique can be used to study a variety of diseases or disorders that present with abnormal solid masses in the brain, including cysts and benign growths. Thus, mechanistic studies enabled by the compressive cranial window can elucidate the role of mechanics in brain tumor progression, and reveal novel targets for treatment.
EXTH-08. MINIPIG MODELS OF NEUROFIBROMATOSIS TYPE 1 FOR THERAPEUTIC DEVELOPMENT
Authors: Adrienne Watson, Sara Osum, Mandy Taisto, Barbara Tschida, Dylan Duerre, Christopher Moertel, Mark Kirstein, David Largaespada, Eunice Oribamise
Journal: Neuro-Oncology (2020)

Abstract Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in the neurofibromin 1 (NF1) gene. NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. Using gene-editing technology, we have developed a minipig model of NF1 that exhibits clinical hallmarks of the disease, including café au lait macules, neurofibromas, and optic pathway glioma. We have conducted pharmacological studies in our NF1 minipigs to assess the pharmacokinetic and pharmacodynamic properties of MEK inhibitors for NF1. We have demonstrated that oral administration of several MEK inhibitors results in clinically relevant plasma concentrations and consequent inhibition of Ras signaling in immune cells, and certain MEK inhibitors can cross the blood brain barrier and have a pharmacodynamic effect, suggesting that they may be effective in treating NF1-associated brain tumors. Because over 20% of NF1 patients harbor NF1 nonsense mutations, we are assessing safety and efficacy of nonsense mutation suppressors that may be effective in treating NF1. We evaluated six drugs known to induce nonsense mutation suppression in several primary cell types isolated from NF1 minipigs and show that several of these drugs have the propensity to induce the production of full length neurofibromin protein, leading to a subsequent reduction in MAPK signaling. Information acquired from this NF1 minipig preclinical model will be leveraged towards initiating a clinical trial in NF1 patients. The NF1 minipig provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1 therapies.
EPEN-36. THE TREATMENT OUTCOME OF PAEDIATRIC SUPRATENTORIAL C11ORF95-RELA FUSED EPENDYMOMA: A COMBINED REPORT FROM E-HIT SERIES AND AUSTRALIAN NEW ZEALAND CHILDREN’S HAEMATOLOGY/ONCOLOGY GROUP
Authors: Chia Huan Ng, Denise Obrecht, Molly Buntine, Olivia Wells, Martin A Campbell, Kanika Bhatia, Michael Sullivan, Molly Williams, Dong Anh Khuong Quang, Kathryn Kinross, Christine White, Elizabeth Algar, Hendrik Witt, Ulrich Schuller, Martin Mynarek, Torsten Pietsch, Nicolas U Gerber, Martin Benesch, Monika Warmuth-Metz, Rolf Kortmann, Brigitte Bison, Michael D Taylor, Vijay Ramaswamy, Stefan Rutkowski, Stefan M Pfister, David T W Jones, Nicholas G Gottardo, Katja Von Hoff, Kristian W Pajtler, Jordan R Hansford
Journal: Neuro-Oncology (2020)

Abstract AIM Advances in molecular classification of paediatric ependymoma have been pivotal in improving risk stratification and understanding of this disease. C11orf95-RELA fused supratentorial ependymoma (ST-EPN) have been reported to have a poor outcome, with 10-year overall survival (OS) of 49% and progression free survival (PFS) of 19%. A cohort of patients from multiple international institutions with molecularly confirmed C11orf95-RELA fused ST-EPN were reviewed to assess their disease behaviour. METHOD: We reviewed patients with molecularly determined C11orf95-RELA supratentorial ependymoma diagnosed between 1999 – 2019. Demographic information, extent of surgical resection, use of radiotherapy and/or chemotherapy, disease recurrence, treatment at recurrence and clinical outcome data was collected. PFS and OS of all patients were estimated using Kaplan-Meier method. RESULTS A total of 76 ST-EPN patients with C11orf95-RELA fusion were identified (median age: 7 years3 months, range: 5 months – 18 years7 months). 58 patients (76.3%) had complete surgical resection. 70 patients(92.1%) received radiotherapy. 55 patients(72.3%) received chemotherapy. The 10-year OS of C11orf95-RELA fused ST-EPN was 72.4% and PFS was 63.8%. In contrast, ST-EPN at a single institution with unconfirmed molecular status had an OS of 61.1% and PFS of 34.9%. CONCLUSION Detailed molecular analysis identified distinct subgroups of patients with ST-EPN. Patients from this cohort with C11orf95-RELA methylation profiles had a significantly higher OS compared to previous reports and those with unconfirmed fusion status, emphasising the critical importance of complete molecular profiling to assist in treatment decision making. Complete molecular analysis in future prospective cohorts is essential for accurate risk stratification and treatment selection.
Persistent Lymphocytopenia Does Not Increase Nosocomial Infection Risk in the ICU
Authors: Meri R. J. Varkila, Louise Marrec, Thomas Daix, Imo E. Hoefer, Saskia Haitjema, Marc J. M. Bonten, Olaf L. Cremer
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Background: Lymphocytopenia is frequent in critically ill patients and has been associated with an increased risk of nosocomial infections and death in the ICU. Immunotherapies to promote recovery of lymphocyte counts have therefore been proposed. However, it is unknown if lymphocytopenia is a direct cause of ICU-acquired infections and death, or merely a marker of disease severity. We set out to study the prevalence, temporal evolution, and clinical correlates of lymphocytopenia in ICU patients, and estimate the attributable risk of lymphocytopenia in ICU-acquired infections.
Methods: We assessed the association between persistent lymphocytopenia (absolute lymphocyte counts <1x10^9/L on day 4) and ICU-acquired infections using multivariable competing risk Cox-regression analyses. 
Results: Among 2302 patients admitted to a Dutch tertiary ICU having sepsis, trauma, or major surgery between 2011 and 2018, persistent lymphocytopenia was observed in 980 (42.6%) subjects. Lymphocyte counts remained relatively stable during early ICU admission, and the median duration of lymphocytopenia was 3 (IQR 1-6) days among exposed patients. ICU-acquired infections occurred in 239 (18.1%) patients without and 214 (21.8%) patients with persistent lymphocytopenia (p=0.03). However, in multivariable survival analysis persistent lymphocytopenia was not associated with infection occurrence, either directly (adjusted cause-specific HR 1.08, 95% CI, 0.90-1.31) or indirectly (subdistribution HR 1.09, 95% CI, 0.91-1.32). Sensitivity analyses did not alter these findings.
Conclusion: Persistent lymphocytopenia was not associated with a higher incidence rate of nosocomial infections in critically ill patients. This challenges the rationale for using absolute lymphocyte counts as a therapeutic target to prevent ICU-acquired infections.
CTNI-52. PHASE II STUDY OF EVEROLIMUS (AFINITOR®) FOR CHILDREN WITH RECURRENT OR PROGRESSIVE EPENDYMOMA
Authors: Daniel Bowers, Matthias Karajannis, Sharon Gardner, Jack Su, Patricia Baxter, Sonia Partap, Laura Klesse
Journal: Neuro-Oncology (2020)

Abstract Preclinical studies suggested that the mTOR signaling pathway could be a potential therapeutic target in childhood ependymomas. As a result, a phase II clinical trial (ClinicalTrials.gov identifier: NCT02155920) of single-agent everolimus was performed to test the hypothesis that inhibition of the mTOR pathway would result in tumor responses for children with recurrent and/or progressive ependymoma. Eleven patients [sex: 4 females (36.4%); median age: 8 years (range: 2 – 15 years); race: 9 white and 2 other; prior therapies: median 6 (range: 3 – 9)] were enrolled on the study. The primary tumor location for 10 participants was the posterior fossa; the primary location of the remaining tumor was the cervical spine. All patients were treated with oral everolimus 4.5 mg/m2/day (each cycle = 28 days) that was titrated to achieve serum trough levels of 5 – 15 ng/mL. Overall, everolimus was well tolerated; adverse events were grade 1 – 2 and consistent with its previously established safety profile in children. No objective tumor responses were observed. All patients discontinued therapy due to tumor progression after a median of 2 cycles of therapy (1 cycle = 2; 2 cycles = 6; 3, 4, and 8 cycles = 1 each). This study does not support the use of everolimus for children with recurrent or progressive ependymoma.
Prospective Observational Study Revealing Early Pulmonary Function Changes Associated With Brigatinib Initiation
Authors: Terry L. Ng, Amber Johnson, Raphael A. Nemenoff, Elena Hsieh, Andrea Abeyta Osypuk, Adrie van Bokhoven, Howard Li, D. Ross Camidge, Erin L. Schenk
Journal: Journal of Thoracic Oncology (2020)
TBIO-17. INTEGRATIVE ANALYSES OF BRAFv600e MUTATED GLIOMAS: FROM MOLECULAR BIOLOGY TO RADIOLOGY AND TREATMENTS
Authors: Benoit Lhermitte, Eric Guerin, Elisa Ruhland, Consuelo Sebastia, Agathe Chammas, Quentin Fuchs, Caroline Bund, Izzie Jacques Namer, Monique Dontenwill, Natacha Entz-Werle
Journal: Neuro-Oncology (2020)

Abstract BRAFv600e mutation is encountered mostly in low-grade pediatric gliomas (LGG) and epileptogenic glioneuronal tumors, such as gangliogliomas (GG). Less frequently this mutation is present in high-grade glial (HGG) or glioneuronal tumors. Recent publications were highlighting BRAF mutation and CDKN2A deletion, as independent prognostic factors linked to a worst outcome in LGGs. We studied retrospectively a monocentric cohort of 12 LGGs (9 GG and 3 pilocytic astrocytomas) and 9 HGG (5 “de novo” tumors and 4 with a long past of LGG evolution) with BRAFv600e positivity. The patients were aged from 1 to 47 years. LGGs were under 20 years and only 3 patients with HGGs had less than 18 years. We focused on extended tumors’ biology assessment by DNA single-cell analyses, RNAsequencing, NGS, metabolomics, radiology (MRI, PET-scanning and spectroscopy) and correlated them to tumor’s data. One LGG had a CDKN2A deletion. Six had a complete surgical resection, 2 had a minimal residue and 4 had chemotherapies after partial surgery and relapsed. All HGGs had a surgical resection followed by chemotherapy and radiotherapy and additional CDKN2A deletion. Two pediatric HGGs relapsed rapidly. Only one benefited positively from targeted therapy. Specific radiological and spectroscopic signs were linked to the BRAF mutation itself and those different groups (LGGs, HGGs and LGGs with long term evolution of HGG), where specific molecular pathways and metabolomic profiles are associated. Currently, we are going further in the correlations to be able to predict in LGG their potential long-term evolution, where MAPK pathway modulations might be involved.
QOLP-18. A CALL TO ACTION: DEATH ANXIETY IN NEURO-ONCOLOGY
Authors: Ashlee Loughan, Mariya Husain, Kelcie Willis, Sarah Braun, Julia Brechbiel, Farah Aslanzadeh, Laurel Kovalchick
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Patients with primary brain tumors (PBT) are at increased risk for psychological distress given the certainty of tumor progression, lack of curative treatments, and poor prognoses. A specific type of distress, death anxiety, was recently identified as an area of concern among neuro-oncology patients. However, researchers have yet to fully examine the prevalence or risk-factors of death anxiety in this population, and, importantly, what evidence-based treatments may be available to alleviate symptoms. METHODS Adult PBT patients (N=81) completed validated questionnaires on symptoms of death anxiety, generalized anxiety, and depression. Item-level frequencies were run to determine prevalence rates. Analyses were then conducted (t-tests, ANOVAs, Pearson correlations, regressions) to determine whether certain demographic, disease-related variables, and/or symptoms of psychological distress put patients at higher risk for death anxiety. Literature on evidence-based treatment options was also reviewed. RESULTS Over half (50-64%) of our sample endorsed items related to fear of death, distressing thoughts about death, and fear of the future, with 35% scoring above the cut-off for death anxiety. Predictors of death anxiety included generalized anxiety symptoms, bilateral or right hemisphere tumor, and female gender (r2=0.367; F(3,77)=16.488, p&amp;lt; .05). Younger age, lower grade tumors, and heightened depressive symptoms were associated with higher death anxiety (p&amp;lt; .05). While interventions to reduce distress in advanced cancer populations are available, most have purposely excluded neurological cancers, thus limiting their generalizability in neuro-oncology. CONCLUSION The proportion of PBT patients who endorsed death anxiety aligns with other advanced cancer populations. However, item-level analysis suggests heightened concern in neuro-oncology and a need for targeted intervention. Moreover, specific demographic, disease-related, and psychological distress variables put certain PBT patients at increased risk. These findings highlight the need for routine screenings and monitoring, as well as inclusion of neuro-oncology patients in evidenced-based treatment trials for reducing distress, specifically death anxiety.
RARE-02.RE-IRRADIATION FOR RECURRENT CRANIOPHARYNGIOMA
Authors: Sarah Foran, Normand Laperriere, Kim Edelstein, Laura Janzen, Vijay Ramaswamy, David Shultz, Fred Gentili, Eric Bouffet, Derek Tsang
Journal: Neuro-Oncology (2020)

Abstract PURPOSE Patients with recurrent craniopharyngioma after radiotherapy (RT) have few treatment options. At our institution, re-irradiation has been offered to selected individuals with recurrent craniopharyngioma not suitable for further surgery, intracystic therapy or targeted agents. METHODS A retrospective study was performed of patients with craniopharyngioma treated with two courses of fractionated RT. First RT (RT1) prescriptions ranged from 50–54 Gy in 25–30 fractions; re-irradiation (RT2) prescriptions were 54 Gy in 30 fractions with full, in-field overlap of dose. The maximum dose to organs-at-risk (brainstem, optic structures) were maintained at or below the prescription dose. There was no cumulative dose limit to any structure. RESULTS We identified four patients. Median RT1-to-RT2 interval was 5.8 years (range, 4.7–20.4). Cumulative maximum doses to optic chiasma and nerves were &amp;gt;100 Gy in all four patients. With a median follow-up of 33 months after RT2, three patients had disease control and are alive at 9, 23 and 42 months from RT2; one patient developed progressive disease and died 33 months after RT2. In three evaluable patients, vision remained stable or improved after RT2; the remaining one patient had no light perception prior to re-irradiation. Two patients had neuropsychological testing before and after RT2; neurocognitive domains were generally stable in one patient but working memory declined in the second patient. CONCLUSIONS Despite exceeding usual tolerances for optic chiasm and nerves, visual outcomes were stable in all living patients. Re-irradiation should be discussed as a treatment option for patients with recurrent craniopharyngioma but without other therapeutic options.
The Discovery of Hepatitis C — The 2020 Nobel Prize in Physiology or Medicine
Authors: Jay H. Hoofnagle, Stephen M. Feinstone
Journal: New England Journal of Medicine (2020)

Interview with Dr. Jay Hoofnagle on the discovery of hepatitis C and progress in preventing and treating chronic infection. (14:28)Download The discovery of HCV was a major milestone in 20th-century medicine, and the 2020 Nobel awardees represent three critical periods of research on this important virus. Their discovery led to elimination of post-transfusion hepatitis and a means to cure hepatitis C.