tbuckley/cabot-search huggingface dataset:
CMET-47. PRECLINICAL VALIDATION OF NOVEL THERAPEUTICS TARGETING A BMIC POPULATION IN HUMAN BRAIN METASTASES
Authors: Mohini Singh, Chitra Venugopal, Tomas Tokar, Nicole McFarlane, David Bakhshinyan, Maleeha Qazi, Parvez Vora, Naresh Murty, Igor Jurisica, Sheila Singh
Journal: Neuro-Oncology (2017)

Brain Metastases (BM) are the most common neoplasm to affect the adult central nervous system, occurring at a rate 10 times greater than that of primary brain cancers. Despite the prevalence and severe lethality of BM, therapeutic strategies remain limited. Advancements in in vivo modelling of metastasis presents a useful platform to aid in the advance and screening of novel targeting therapeutics, though currently few models exist that properly recapitulate the clinical progression of brain metastasis. Utilizing primary patient samples of BMs, we have characterized a subpopulation of CSC-like cells, termed brain metastasis-initiating cells (BMICs), which are responsible for initiating BMs. Through injections of BMICs isolated from lung BMs into NOD-SCID mice, we have generated a novel patient-derived xeno-transplantation (PDXT) model of BM that allows for interrogation of each phase of the metastatic process from lung to brain. We then expanded our model to incorporate BMICs derived from breast and melanoma BMs. BMICs were harvested from primary sites and corresponding BMs, and RNA submitted for sequencing to identify metastatic and tissue-specific gene signatures. BMICs were found to possess a unique genomic profile as compared to BMICs isolated from full primary tumors and complete macro-metastases, exhibiting dysregulated expression in over 13,000 genes, including those involved in stem cell, epithelial-to-mesenchymal transition, and quiescence properties. In silico analysis was used to generate a list of therapeutics targeting this unique BMIC population. In vitro and in vivo screening has identified a subset of compounds with no previously known efficacy in cancer treatment that inhibits BMIC growth and metastasis. Ultimately, we aim to transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.
Tropical cyclones and public health: how climate change is driving increasingly extreme weather—an essay by Fintan Hughes, Jack Hodkinson, and Hugh Montgomery
Authors: Fintan Hughes, Jack Hodkinson, Hugh Montgomery
Journal: BMJ (2017)

Doctors must advocate for less use of fossil fuel, write <b>Fintan Hughes</b>, <b>Jack Hodkinson</b>, and <b>Hugh Montgomery</b>, if the harms to public health seen in this year’s hurricane season are not to become more regular occurrences
RTHP-32. PHASE II STUDY OF HYPO-FRACTIONATED ACCELERATED RADIOTHERAPY WITH CONCURRENT AND MAINTENANCE TEMOZOLOMIDE IN NEWLY DIAGNOSED GLIOBLASTOMA: COMPLIANCE AND EARLY CLINICAL OUTCOME (HyART)
Authors: Supriya Mallick, Kunhi parambath Haresh, Subhash Gupta, Dayanand Sharma, Pramod Julka, Goura Kishor Rath
Journal: Neuro-Oncology (2017)

To compare hypo-fractionated (HyRT) with conventional fractionated radiotherapy (CRT) for good prognosis newly diagnosed patients with glioblastoma (GBM). HyART, a Phase II trial randomly assigned newly diagnosed GBM patients 1:1 by computer generated randomization chart to HyRT and CRT. Patients of 16 - 65 years, Karnofsky performance score ≥70 and maximal safe surgical resection were randomized. SPSS v16. was used for all statistical analysis. 83 patients randomized, 77 were evaluable. Median age 45 years (Range: 16-65). Male: Female ratio was 2:1. 20(25.9%) patients had seizure at presentation. Median symptom duration was 2 months (1 day-72 months). 49 patients had GTR. Only two patients required hospitalization for features of raised intracranial pressure during radiation and two required long duration steroid after RT in the HyRT arm. Three patients in HyRT arm grade III thrombocytopenia during maintenance phase. At a median follow up of 9 months 31 experienced disease progression. However, none of the patient has a documented radio necrosis as of now. Median PFS was 13.1 months (95% CI: 11.7-14.5 months). Median PFS was significantly better for GTR than STR (14.1 vs 9.6 months; p=0.004). Patients operated at high volume center have better PFS (14.1 vs 9.6 months). Median PFS was better but not significant for IDH mutated patients (16.3 vs 13.1 months). A delay in initiation of RT by more than 6 weeks conferred worse PFS (9.9 vs 14.2 months; p=0.022). There was no difference in PFS for patients treated with HyRT vs CRT. Estimated median OS was 29.6 months (95% CI: 19.1-40.1 months). HyRT appears to be well tolerated with no treatment interruption and equivalent survival compared to CRT.
STEM-38. SOX2 ACTIVATES THE EXPRESSION OF ONCO-miR-486-5p
Authors: Hernando Lopez-Bertoni, Nicole Michelson, Ivan Kotchetkov, Yunqing Li, John Laterra
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM) and other solid malignancies are heterogeneous and contain subpopulations of tumor cells that exhibit stem-like features. These cancer stem cells (SCs) have the ability to self-renew and efficiently propagate tumor growth, and are thought to be a critical component of resistance to therapy. Recent findings from the Laterra lab point to a de-differentiation mechanism in which reprogramming transcription factors Oct4 and Sox2 drive non-SCs to express the stem-like phenotype in glioblastoma, in part by differentially regulating subsets of microRNAs (miRNAs). Currently, the molecular mechanisms by which reprogramming transcription factors and miRNAs coordinate SC tumor-propagating capacity are unclear. One commonly overlooked feature of reprogramming transcription factors (TFs) is their ability to inhibit gene transcription by acting on various downstream effectors. We postulate that these TFs drive tumorigenesis in part by activating miRNAs that target repressors of cell stemness and tumor propagating potential. In this study, we identify miR-486-5p as a Sox2-induced miRNA that regulates GBM SC self-renewal, through its inhibition of the tumor suppressor genes PTEN and FoxO1. Using established glioma cell lines and patient-derived neurospheres as models of GBM, we show that miR-486-5p associates with the GBM SC phenotype and is directly induced by Sox2. Forced expression of miR-486-5p in vitro enhances the self-renewal capacity of GBM neurospheres and inhibition of endogenous miR-486-5p leads to cell death, concomitant with the activation of the miR-486-5p targets PTEN and FoxO1. These results suggest that Sox2 regulates the survival of GBM stem cells, in part by activating miR-486-5p and repressing tumor suppressor genes, thereby preventing apoptosis of glioblastoma cells. The Sox2:miR-486-5p axis offers a new target for therapies aiming to deplete GBM of its stem-like subset of cells responsible for malignancy and poor prognoses.
ACTR-58. PHASE III TRIAL OF CCNU/TEMOZOLOMIDE (TMZ) COMBINATION THERAPY VS. STANDARD TMZ THERAPY FOR NEWLY DIAGNOSED MGMT-METHYLATED GLIOBLASTOMA PATIENTS: THE CeTeg/NOA-09 trial
Authors: Ulrich Herrlinger, Theophilos Tzaridis, Frederic Mack, Joachim Steinbach, Uwe Schlegel, Michael Sabel, Peter Hau, Rolf-Dieter Kortman, Dietmar Krex, Oliver Grauer, Roland Goldbrunner, Oliver Schnell, Oliver Baehr, Martin Uhl, Ghazaleh Tabatabai, Florian Ringel, Friederike Schmidt-Graf, Stefanie Brehmer, Astrid Weyerbrock, Lars Bullinger, Peter Vajkoczy, Hartmut Vatter, Niklas Schäfer, Sied Kebir, Johannes Weller, Walter Stummer, Matthias Simon, Vera Keil, Michael Nelles, Rolf Fimmers, Torsten Pietsch, Elke Hattingen, Christoph Coch, Martin Glas
Journal: Neuro-Oncology (2017)

There is an urgent need for more effective therapies in glioblastoma (GBM). Data from the single arm UKT-03 trial (Glas et al., J Clin Oncol 27, 1257, 2009) suggested that combined lomustine/temozolomide (CCNU/TMZ) therapy might have superior activity in MGMT-methylated GBM. The phase III CeTeG/NOA-09 trial was set up to test this hypothesis in a randomized setting. Patients with MGMT-methylated GBM were randomized (1:1) for standard therapy with daily TMZ (75 mg/m2) during local radiotherapy (RT, 30 x 2 Gy) followed by 6 courses of TMZ (150–200 mg/m2/day for 5 days q4w) or experimental therapy with CCNU/TMZ in addition to local RT. Six 6-week courses of CCNU/TMZ (CCNU 100 mg/m2 d1, TMZ 100 mg/m2 d2-6) were applied with the first course starting on the first day of RT while continuous concomitant TMZ was not applied. The TMZ dose was adapted in further courses. The primary endpoint was overall survival (OS) in the modified intention-to-treat (mITT) population of patients who had received at least one dose of study medication. For confirmatory analysis, differences in OS were analyzed using the logrank test stratified for center and recursive partitioning analysis group. The trial randomized 141 patients; 129 patients (63 TMZ, 66 CCNU/TMZ) belonged to the mITT population. OS was superior in the CCNU/TMZ arm as compared to the TMZ arm (p=0.049). Significant OS differences were also found in the as-randomized population (p=0.043) and in the subgroup of 103 patients with an IDHwt GBM (p=0.039). In the mITT population, median OS was prolonged from 31.4 months (95%CI 27.0–44.8 months) with TMZ to 37.9 months (95% CI 29.2–51.4 months) with CCNU/TMZ (hazard ratio for death 0.60, 95% CI 0.35–1.03, p=0.064). In summary, CCNU/TMZ combination chemotherapy showed improved efficacy as compared to TMZ standard therapy in patients with newly diagnosed MGMT promotor-methylated GBM.
ACTR-19. A PHASE 2 STUDY OF TUMOR TREATING FIELDS AND BEVACIZUMAB IN RECURRENT OR PROGRESSIVE MENINGIOMA
Authors: Priya Kumthekar, Timothy Kruser, Sean Sachdev, Jeffrey Raizer, Sean Grimm, Karan Dixit
Journal: Neuro-Oncology (2017)

Meningioma is the most common primary brain tumor with a prevalence of ~170,000 in the United States. For patients with WHO grade II meningioma, the two- and five-year overall survival was 93% and 73%, respectively. Patients with malignant meningioma (grade III) had significantly worse outcomes, with two-year and five-year overall survival rates of 57% and 42%. The recurrence rate remains high and for grade 3 meningioma overall survival is as low as 3 years after diagnosis. The current treatment for high grade and recurrent meningioma includes maximal safe surgical resection and radiation. Tumor treating fields (TTFields) and Bevacizumab (BEV) have been reported to show activity in recurrent and high-grade meningioma. This Phase 2 Simon two-staged, non-randomized, open-label, phase II, single arm clinical trial [NCT02847559] will investigate the combination of TTFields and BEV in recurrent or progressive meningioma. The primary endpoint is progression free survival (PFS) at 6 months (PFS-6). Secondary endpoints will include overall survival (OS); Tumor Response Rate (TRR), Objective Response Rate (ORR); and Quality of Life (QOL) using FACT-Br questionnaire. Patients (N=27) will receive BEV IV over 30–90 minutes on days 1 and 15 of courses 1–4. Beginning on day 1 of course 5, patients may choose to receive bevacizumab IV every 3 weeks or remain on the every 2-week schedule. Patients will receive TTFields 200KHZ daily via the Optune device for over 18 hours. This study is powered to detect a true PFS-6 rate of 20% with 80% probability (80% power) and to detect a true PFS-6 rate of 5% with 90% probability (alpha=0.10). We planned for 27 patients in total to have 24 evaluable patients. For patients who are unable to obtain commercial BEV, the study has been amended to include a monotherapy arm of TTFields alone to increase the pool of eligible patients.
RARE-15. PROGNOSTIC FACTORS, TREATMENT AND OUTCOME IN PATIENTS WITH INTRACRANIAL HEMANGIOBLASTOMA: A STUDY OF 3449 PATIENTS FROM THE NATIONAL CANCER DATA BASE
Authors: Harrison Bai, Yuqian Huang, Lilian Chan, Xuejun Li, Weihua Liao, Ya Cao, Giogos Karakousis, Raymond Huang, Bo Xiao, Paul Zhang, Li Yang
Journal: Neuro-Oncology (2017)

Current literature on intracranial hemangioblastoma is limited to case reports or small case series. There is no treatment guideline. Intracranial hemangioblastoma patients were identified using the US National Cancer Data Base from 2004-2013. Univariable followed by multivariable Cox proportional hazard regression was used to identify predictors of overall survival (OS). Subgroup analyses based on age, tumor location, and receipt of adjuvant radiotherapy (RT) were performed. 3449 patients were included. The survival rate at 10 years was 73%. On multivariable analysis, independent predictors of shorter OS included age≥40 (HR, 3.155; 95% CI, 2.241-4.441;p<0.001), Charlson-Deyo score of 1 or 2 (HR, 1.833; 95% CI, 1.427-2.353;p<0.001), tumor location in brainstem (HR, 1.806; 95% CI, 1.169-2.790; p=0.008), no surgery (HR, 2.207; 95% CI, 1.460-3.337;p<0.001), and receipt of RT (HR, 1.639;95% CI, 1.131-2.375;p=0.009). Gross total resection (GTR) was associated with longer OS when compared to subtotal resection (STR)/biopsy in patients with cerebellar (HR, 0.566;95% CI, 0.321-0.997;p=0.049) but not brainstem tumors. Among patients <40 years, tumors tended to be larger, multifocal and located in the brainstem. Additionally, black/Asian race and brainstem location predicted shorter OS, while receipt of surgery and extent of resection were not associated with OS. Among patients who underwent STR/biopsy, there was no difference in OS between receipt of RT and no RT (log-rank p=0.349), after propensity score matching on age, gender and Charlson-Deyo score. GTR remained the optimal treatment for cerebellar hemangioblastoma. Brainstem tumors had worse outcome when compared to cerebellar tumors. Younger patients (age <40), more likely to have multifocal or brainstem tumors, may not benefit long-term from surgery and/or GTR. Adjuvant RT did not provide any survival benefits. Racial disparities in survival outcome were identified.
P1.02-028 Pathways Involved in Early Stage Lung Cancers
Authors: V. Haakensen, S. Nygårad, V. Nygaard, L. Jørgensen, S. Solberg, E. Hovig, O.T. Brustugun, O.C. Lingjærde, Å. Helland
Journal: Journal of Thoracic Oncology (2017)
ACTR-49. THE EFFECT OF TUMOR TREATING FIELDS IN WHO GRADE 2 AND 3 GLIOMAS
Authors: Jessica Bloomfield, Nicholas Blondin
Journal: Neuro-Oncology (2017)

Analyze the effects of alternating electrical field therapy (also known as tumor treating fields, or TTFields) on WHO grade 2–3 gliomas. Malignant gliomas in adults comprise an incurable brain cancer with variable prognosis, depending on WHO grade and other molecular characteristics. Current treatment strategies include surgery, radiation, and/or chemotherapy, but these all carry their own risks and are not curative. TTFields therapy has been FDA approved in glioblastoma (WHO grade 4) but little research has been done to determine their effectiveness in WHO grade 2–3 gliomas. This is a case study of 6 patients diagnosed with WHO grade 2 or 3 glioma and 12 patients with glioblastoma treated with TTFields therapy in addition to standard of care treatment. Qualitative measures and outcome variables include pathology at diagnosis, treatment before TTFields therapy, length of time on TTFields therapy, concurrent therapy, radiographic and clinical evidence of treatment, compliance data, and reasons for discontinuation. These factors were compared between the two groups to investigate trends to inform more rigorous future studies of efficacy in the WHO grade 2 and 3 glioma population. All patients with glioblastoma started TTFields therapy due to increased symptoms and/or tumor size despite traditional chemo-radiation treatment. However, those with grade 2 or 3 gliomas started TTFields due to the diffuse nature of the disease and its inoperability. Based on radiographic evidence, 4/6 patients with grade 2 and 3 glioma demonstrated either stable disease or improvement with the use of TTFields, even with some compliance rates as low as 60% (average 84%). The main reasons for discontinuation in both groups were tumor progression, device-related side effects, or non-compliance. TTFields treatments show promise as an alternative or adjunct treatment to traditional chemotherapy or radiation in patients with grade 2–3 gliomas.
MA 19.02 Tremelimumab plus Durvalumab in First- or Second-Line Mesothelioma Patients: Final Analysis of the NIBIT-MESO-1 Study
Authors: L. Calabro, A. Morra, D. Giannarelli, G. Amato, E. Bertocci, A. D'Incecco, R. Danielli, L. Brilli, F. Giannini, M. Altomonte, A.M. Di Giacomo, M. Maio
Journal: Journal of Thoracic Oncology (2017)
P3.16-028 Necrosis Is a Predictor of Recurrence in Patients with Small Lung Adenocarcinoma ≦2cm
Authors: Y. Terada, J. Nitadori, S. Morita, T. Takahashi, T. Yotsumoto, Y. Sawai, T. Karasaki, K. Kitano, K. Nagayama, M. Anraku, M. Sato, A. Ushiku, M. Fukayama, J. Nakajima
Journal: Journal of Thoracic Oncology (2017)
CSIG-32. ACTIVATED Trk/Met PATHWAY IS A NOVEL RESISTANCE MECHANISM FOR CDK4/6 INHIBITORS THAT CAN BE TARGETED WITH A SPECIFIC SMALL MOLECULE INHIBITOR
Authors: Inan Olmez, Benjamin Purow
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is among the deadliest malignancies, with an extremely poor prognosis. Clinical trials with single agents have largely proven disappointing largely due to tumor heterogeneity and cancer stem cell plasticity. Often times, single agent treatments induce cancer stem cell reprogramming—driving specific resistance mechanisms in a way that cancer cells become addicted to particular pathways. Thus, identification of treatment-induced pathways can offer significant opportunity for designing more effective combinatorial drug therapies. Based on this rationale, we performed an ELISA-based high throughput screening of glioma stem cells (GSC) for various phosphorylated receptor tyrosine kinases (RTKs) and found that treatment with a CDK4/6 inhibitor, abemaciclib, significantly induced Trk/Met pathway activation. Confirmatory immunoblot revealed that while the parental cells had almost no Trk/Met activity, 12h abemaciclib treatment significantly induced phosphorylation of Trk/Met. A specific Trk/Met/VEGFR inhibitor, altiratinib, has recently been tested against GBM in a preclinical model with modest effect. Based on our ELISA findings, we studied the combination of abemaciclib and altiratinib on several GSC lines. While individual drugs exhibited modest cytotoxicity, the combined treatment induced extreme cell death. Compared to altiratinib, specific Trk or Met inhibitors and siRNAs resulted in significantly less cytotoxicity when combined with abemaciclib. Mechanistically, the combined treatment triggered significant apoptosis and autophagy leading to enhanced cytotoxicity. Both abemaciclib and altiratinib have been shown to cross the BBB efficiently signifying that the combined therapy can be effectively used against GBM. Our results indicate that the combination of abemaciclib and aitoratinib is a viable therapeutic option against GBM and further studies will determine whether this novel combination can be tested in clinical trials.
ATIM-29. A PHASE 1 STUDY OF PF-06840003, AN ORAL INDOLE 2,3-DIOXYGENASE 1 (IDO1) INHIBITOR IN PATIENTS WITH MALIGNANT GLIOMAS
Authors: David Reardon, Annick Desjardins, Olivier Rixe, Timothy Cloughesy, Shilpa Alekar, Erick Gamelin, Jason Williams, John Meissen, Carrie Taylor, Andrew Lassman
Journal: Neuro-Oncology (2017)

BACKGROUNDPF-06840003 is a highly selective and active IDO1 inhibitor, presumed to cross the blood brain barrier. IDO1, produced by cancer or immune cells, by affecting tryptophan catabolism, producing immunosuppressive metabolites such as kynurenine, inhibits proliferation of T cells, induces T cell anergy and apoptosis and promotes generation and activity of regulatory T cells and MDSCs. IDO1 is involved in malignant glioma immunosuppression, playing a key role in acquired resistance to PD-1/PD-L1 or CTLA-4 inhibition; their combination with IDO1 inhibition can lead to more efficacious antitumor immunity. Preclinical studies show high PF-06840003 CNS penetration and in the GL261 murine glioma model a synergistic effect in combination with PD-1/PD-L1 blockade, CTLA-4 inhibition, radiation therapy and temozolomide. This ongoing multi-center clinical trial aims to assess the safety, PK and PD activity of PF-06840003 in malignant glioma, confirm CNS penetration and verify its effectiveness in combination.
METB-04. METABOLIC EFFECTS OF A GLUTAMINASE INHIBITOR ON GLIOMA CELL LINES
Authors: Victor Ruiz Rodado, Alejandra Cavazos Saldana, Sriya Movva, Adrian Lita, Tyrone Dowdy, Mark R Gilbert, Mioara Larion
Journal: Neuro-Oncology (2017)

Recent investigations have reported that glioblastoma, the most aggressive type of glioma, exhibits glutamine addiction. Glutamine contributes to the TCA cycle through its conversion into glutamate which subsequently yields α-ketoglutarate. Moreover, the reaction involving glutaminase provides the cell a necessary glutamate source for the synthesis of additional amino acids such as proline, aspartate, etc., and further metabolites such as glutathione. Previous investigations revealed that glioma cell lines experience a decreased cell grow rate with glutaminase-inhibitor treatment. We postulated that IDH1-mutated tumors might be sensitive to glutaminase inhibitors given the carbon depletion caused by 2-hydroxyglutarate production that results from IDH mutations. IDH1 wild type and mutant glioma cell lines were treated with 1 µM glutaminase inhibitor (CB839) for 72 hrs. Subsequently, cells were quenched, cell media collected, and both polar and lipid metabolites extracted for analysis. We employed an untargeted NMR- and mass spectrometry-based metabolomics approach in order to investigate the metabolic consequences of this glutaminase inhibitor in both IDH1-mutated and wild-type glioma cell lines. With glutaminase inhibitor treatment there was a decrease in the growth rate of the cells that was more intense in the more aggressive glioma-derived cell lines, regardless of the IDH1 mutation status. Downstream metabolites arising from glutamate metabolism were most impacted by the treatment, mainly those which require glutamate as a synthetic precursor, (e.g. aspartate and glutathione). Our analysis reveals the metabolic changes caused by treatment-induced glutamine deficiency and the cellular metabolic response to the loss of this carbon source. The observed metabolic changes arising from glutaminase inhibition, and concomitant reduced levels of glutamate, slow the growth of glioma cells. These findings suggest that metabolic vulnerabilities caused by the metabolic switch of tumors due to enhanced energy requirements can be exploited to develop new treatments such as targeting glutamine metabolism.
Potential Visualization of Sorafenib-Induced Acidosis Using 11C-Acetate PET/CT in Patients With Hepatocellular Carcinoma
Authors: Seong Young Kwon, Dong-Yeon Kim, Jung-Joon Min, Woo Kyun Bae
Journal: Clinical Nuclear Medicine (2017)

C-acetate uptake could be increased in physiologic or inflammatory conditions without evidence of cancer. We report a hepatocellular carcinoma patient with sorafenib-induced metabolic acidosis, who showed increased hepatic uptake of C-acetate. C-acetate PET/CT might be a potentially useful surrogate marker to monitor these adverse effects via the changes in C-acetate uptake patterns from before to after drug withdrawal.