tbuckley/cabot-search huggingface dataset:
HOUT-06. PATTERN OF LOW FIELD INTENSITY RECURRENCE IN HIGH-GRADE GLIOMAS FOLLOWING TUMOR TREATMENT FIELD THERAPY
Authors: Robert Briggs, Edward Pan, Josie Sewell, Karen Fink, Adam Smitherman, Andrew Conner, Collin Walsh, Michael Sughrue, John Villano, James Battiste
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is an aggressive neoplasm that continues to show recurrence despite recent advances in therapy. Tumor Treating Fields (TTFields) is a non-invasive, regional antimitotic treatment modality, delivering low-intensity (1–3 V/cm), intermediate-frequency (100–300 kHz), alternating electric fields to tumors via transducer arrays placed on the scalp of GBM patients. TTFields disrupts cell division processes in cancer cells. However, some mechanisms of escape have been described, in particular, out-of-field tumor recurrence. The brainstem dose not receive high intensity electric field stimulation during TTFields therapy, and represents one possible region of tumor recurrence following treatment. Six cases were identified via retrospective chart review from multiple providers that have experience with prescribing and planning treatment with TTFields. Clinical and radiographic reviews were performed after de-identification of patient records. Cases were compared according to demographics, tumor location and region of recurrence. The median patient age at diagnosis was 62 years (Range: 10–69) with 3/6 patients being male and 3/6 patients being female. Tumors were initially located in the frontal (3/6), parietal (2/6), and temporal lobes (1/6). Three patients received TTFields therapy at initial diagnosis in combination with surgery and chemoradiation, while the remaining patients received TTFields therapy at initial recurrence in conjunction with bevacizumab. Following TTFields treatment, tumors recurred predominantly in the pons (1/6), left cerebellar peduncles (3/6), and right cerebellar peduncles (2/6). The average time to brainstem recurrence following TTFields therapy was 152 days (Range: 49–228). Treatment options for patients with GBM are limited, however TTFields has been shown to improve overall survival when combined with temozolomide. TTFields can only be delivered in therapeutic intensities to the supratentorial brain. Brainstem recurrence may occur as field intensity in the brainstem is sub-therapeutic. Further investigation is warranted to determine optimal treatment for brainstem recurrences for patients receiving TTFields therapy.
Clinical Utility of Reinterpreting Previously Reported Genomic Epilepsy Test Results for Pediatric Patients
Authors: Jeffrey A. SoRelle, Drew M. Thodeson, Susan Arnold, Garrett Gotway, Jason Y. Park
Journal: JAMA Pediatrics (2018)

Clinical genomic tests that examine the DNA sequence of large numbers of genes are commonly used in the diagnosis and management of epilepsy in pediatric patients. The permanence of genomic test result interpretations is not known.To investigate the value of reinterpreting previously reported genomic test results.This study retrospectively reviewed and reinterpreted genomic test results from July 1, 2012, to August 31, 2015, for pediatric patients who previously underwent genomic epilepsy testing at a single tertiary care pediatric health care facility. Reinterpretation of previously reported variants was conducted in May 2017.Patient reports from clinical genomic epilepsy tests were reviewed, and all reported genetic variants were reinterpreted using 2015 consensus standards and guidelines for interpreting hereditary genetic variants. Three classification tiers were used in the reinterpretation: pathogenic or likely pathogenic variant, variant of uncertain significance (VUS), or benign or likely benign variant.A total of 309 patients had genomic epilepsy tests performed (mean [SD] age, 5.6 [0.8] years; 163 [52.8%] male), and 185 patients had a genetic variant reported. The reported variants resulted in 61 patients with and 124 patients without a genetic diagnosis (VUS variants only). On reinterpretation of all reported variants, 67 of the 185 patients (36.2%) had a change in variant classification. Of the 67 patients with a genetic variant change in interpretation, 21 (31.3%) experienced a change in diagnosis. During the 5 years of the study, 19 of 61 patients (31.1%) with a genetic diagnosis and 48 of 124 patients (38.7%) with undiagnosed conditions (VUS only) had their results reclassified. Review of genomic reports issued during the final 2 years of the study identified reclassification of variants in 4 of 16 patients (25.0%) with a pathogenic or likely pathogenic variant and 11 of 41 patients (26.8%) with a VUS.The identified high rate of reinterpretation in this study suggests that interpretation of genomic test results has rapidly evolved during the past 5 years. These findings suggest that reinterpretation of genomic test results should be performed at least every 2 years.
Quantitative lymph node burden as a ‘very-high-risk’ factor identifying head and neck cancer patients benefiting from postoperative chemoradiation
Authors: Z.S. Zumsteg, M. Luu, S. Kim, M. Tighiouart, A. Mita, K.S. Scher, D.J. Lu, S.L. Shiao, J. Mallen-St. Clair, A.S. Ho
Journal: Annals of Oncology (2018)

BackgroundAdjuvant chemoradiation (CRT) is standard for head and neck squamous cell carcinoma (HNSCC) patients with positive margins or extranodal extension (ENE) following surgery. However, emerging evidence suggests the number of positive lymph nodes (LNs) is the dominant determinant of survival in non-oropharyngeal HNSCC and thus may better identify those benefiting from treatment intensification.Patients and methodsPatients from the National Cancer Database diagnosed with non-oropharyngeal HNSCC (oral cavity, larynx, hypopharynx) between 2004 and 2014 and undergoing surgical resection, neck dissection, and postoperative radiotherapy (RT) were included. Multivariable regression with first-order interaction terms was used to model the interaction between postoperative CRT and continuous number of positive LNs with respect to overall survival.ResultsIn total, 7144 patients met inclusion criteria. In multivariable analysis, increasing number of positive LNs was associated with both increasing mortality (P < 0.001) and increasing benefit from postoperative CRT versus RT alone (interaction P < 0.001). While there was no benefit from postoperative CRT in patients with 0–2 LN+ [hazard ratio (HR) 0.96, 95% confidence interval (CI) 0.86–1.07, P = 0.47], increased benefit was seen in those with 3–5 LN+ (HR 0.84, 95% CI 0.70–1.00, P = 0.05) and those with ≥6 LN+ (HR 0.65, 95% CI 0.51–0.82, P < 0.001) in multivariable models. By contrast, margin status and ENE did not reliably identify patients benefitting from postoperative CRT based on statistical tests of interaction. Even in patients with ENE, positive margins, or both, only those with ≥6 LN+ had improved survival with postoperative CRT.ConclusionIncreasing metastatic nodal burden was associated with increased benefit from CRT compared with RT alone, surpassing conventional high-risk factors in identifying patients benefiting from CRT. Stratification by metastatic LN number may characterize a very-high-risk patient cohort best suited for treatment intensification.
Abstract 23073: Cardiovascular Efficacy of PCSK9 Inhibition Among 1,578 Patients With Familial Hypercholesterolemia: The SPIRE Clinical Trials FH Analysis
Authors: Paul M Ridker
Journal: Circulation (2017)

Background: Familial hypercholesterolemia (FH) is a genetic disorder with elevations of low-density lipoprotein cholesterol (LDLC) and premature atherosclerotic events. Therapeutic monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are indicated for the reduction of LDLC in patients with FH, but placebo-controlled outcome data for FH patients are not available. Objective: To estimate the efficacy of PCSK9 inhibition with bococizumab on future cardiovascular events among FH and non-FH patients enrolled in the four 1-year SPIRE Lipid Lowering trials or in the two cardiovascular outcomes trials (SPIRE-1 and SPIRE-2). Design, Setting, and Participants: Six multinational, randomized, placebo-controlled trials inclusive of 1,578 patients with FH (molecular analysis or Simon Broome criteria) and 15,959 patients without FH and levels of LDLC ≥100 mg/dL or non-HDLC ≥130 mg/dL at trial entry. Intervention: Bococizumab 150 mg SC every 2 weeks or matching placebo. The median follow-up period was 49 weeks. Main Outcomes and Measures: Incident major adverse cardiovascular events (MACE) including nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Results: Among FH patients, MACE occurred in 18 allocated to bococizumab and 22 to placebo (hazard ratio [HR]=0.83; 95% confidence interval [CI] 0.44-1.54, P=0.55). In the subgroup of 620 FH patients with LDLC ≥160 mg/dL, MACE occurred in 9 allocated to bococizumab and 13 to placebo (HR=0.74; 95% CI 0.31-1.75, P=0.49). For the 1,065 FH patients specifically enrolled in SPIRE-1 or SPIRE-2, MACE occurred in 11 allocated to bococizumab and 18 allocated to placebo (HR=0.64, 95% CI 0.30-1.35, P=0.24). These effect estimates are similar in magnitude to that observed in the 15,959 patients without FH (HR=0.79, 95% CI 0.64-0.97, P=0.023). Conclusions and Relevance: Statin-treated FH patients given the PCSK9 inhibitor bococizumab have a similar magnitude of risk reduction for hard cardiovascular events as do patients without FH. These data have importance for clinical practice and guidelines for cardiovascular disease prevention. Trial Registration: ClinicalTrials.gov: NCT01968954, NCT01968967, NCT02100514, NCT01968980, NCT01975376, NCT01975389
Role of Donor Clonal Hematopoiesis in Allogeneic Hematopoietic Stem-Cell Transplantation
Authors: Mareike Frick, Willy Chan, Christopher Maximilian Arends, Raphael Hablesreiter, Adriane Halik, Michael Heuser, David Michonneau, Olga Blau, Kaja Hoyer, Friederike Christen, Joel Galan-Sousa, Daniel Noerenberg, Verena Wais, Michael Stadler, Kenichi Yoshida, Johannes Schetelig, Esther Schuler, Felicitas Thol, Emmanuelle Clappier, Maximilian Christopeit, Francis Ayuk, Martin Bornhäuser, Igor Wolfgang Blau, Seishi Ogawa, Tomasz Zemojtel, Armin Gerbitz, Eva M. Wagner, Bernd M. Spriewald, Hubert Schrezenmeier, Florian Kuchenbauer, Guido Kobbe, Markus Wiesneth, Michael Koldehoff, Gérard Socié, Nicolaus Kroeger, Lars Bullinger, Christian Thiede, Frederik Damm
Journal: Journal of Clinical Oncology (2018)

Clonal hematopoiesis of indeterminate potential (CHIP) occurs in the blood of approximately 20% of older persons. CHIP is linked to an increased risk of hematologic malignancies and of all-cause mortality; thus, the eligibility of stem-cell donors with CHIP is questionable. We comprehensively investigated how donor CHIP affects outcome of allogeneic hematopoietic stem-cell transplantation (HSCT).We collected blood samples from 500 healthy, related HSCT donors (age ≥ 55 years) at the time of stem-cell donation for targeted sequencing with a 66-gene panel. The effect of donor CHIP was assessed on recipient outcomes, including graft-versus-host disease (GVHD), cumulative incidence of relapse/progression (CIR/P), and overall survival (OS).A total of 92 clonal mutations with a median variant allele frequency of 5.9% were identified in 80 (16.0%) of 500 donors. CHIP prevalence was higher in donors related to patients with myeloid compared with lymphoid malignancies (19.2% v 6.3%; P ≤ .001). In recipients allografted with donor CHIP, we found a high cumulative incidence of chronic GVHD (cGVHD; hazard ratio [HR], 1.73; 95% CI, 1.21 to 2.49; P = .003) and lower CIR/P (univariate: HR, 0.62; 95% CI, 0.40 to 0.97; P = .027; multivariate: HR, 0.63; 95% CI, 0.41 to 0.98; P = .042) but no effect on nonrelapse mortality. Serial quantification of 25 mutations showed engraftment of 24 of 25 clones and disproportionate expansion in half of them. Donor-cell leukemia was observed in two recipients. OS was not affected by donor CHIP status (HR, 0.88; 95% CI, 0.65 to 1.321; P = .434).Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster cGVHD development and reduce relapse/progression risk.
INNV-17. TUMOUR TREATING FIELDS: ACCEPTABLE TO A UK POPULATION?
Authors: Andrew Brodbelt, Matthew Williams, Antonia Thorpe, Samantha Mills, Stephen Price, Elvira Lekka, Colin Watts, Charles Davis, Michael Jenkinson
Journal: Neuro-Oncology (2018)

Tumour treating fields (TTFields) are an innovative anticancer treatment that uses alternating electrical fields to disrupt cell division. In a randomized controlled trial, TTFields significantly improved newly diagnosed Glioblastoma patient survival. The device may be thought to be taxing for patients, with almost constant electrode application and battery use. Methods were explored to reduce cost and examine acceptance. Three United Kingdom (UK) centres were offered support for trialing the treatment. Patients with proven MGMT unmethylated glioblastoma, had completed radical chemoradiotherapy, had a performance score > 70, and had social support (for placing the electrodes), where approached. Monthly assessments of compliance and quality of life (QOL) (EORTC BN 20), and quarterly MRIs and tolerability questionnaires were completed. Oncologists in one centre declined to support any use of the device. 8 patients were approached in the other two centres, 5 accepted, and 1 further patient had treatment started elsewhere. A UK politician developed glioblastoma, used the device, and this was followed by positive press reports. Clinicians were trained in the use and interface with the equipment. All patients tolerated the treatment and used for 85% or more. The reason for patient refusal was monthly travelling for compliance checks. Adverse comments related to the mobile battery weight. Two patients had skin irritation, and two found that showering was affected. Four patients have progressed, but maintained stable QOL scores. Two patients have died. TTFields is well tolerated but requires patient dedication to use the device for at least 18 hours per day and in our pilot access study was acceptable to a UK population. Recent positive press support aided recruitment. A significant reduction in cost is required to allow routine UK use.
Corrigendum re “Neoadjuvant Short-term Intensive Intravesical Mitomycin C Regimen Compared with Weekly Schedule for Low-grade Recurrent Non–muscle-invasive Bladder Cancer: Preliminary Results of a Randomised Phase 2 Study” [Eur Urol 2012;62:797–802]
Authors: Renzo Colombo, Lorenzo Rocchini, Nazareno Suardi, Fabio Benigni, Giorgia Colciago, Arianna Bettiga, Federico Pellucchi, Carmen Maccagnano, Alberto Briganti, Andrea Salonia, Patrizio Rigatti, Francesco Montorsi
Journal: European Urology (2018)
CADD-17. CT-179: AN INHIBITOR OF THE OLIG2 TRANSCRIPTION FACTOR WITH POTENT ANTI-TUMOUR ACTIVITY IN BRAIN CANCER
Authors: Terrance Johns
Journal: Neuro-Oncology (2018)

High Grade Glioma (HGG) is incurable and has a median survival of less than 5% at five years, highlighting a desperate need for new therapeutic strategies. OLIG2 is a basic helix-loop-helix (bHLH) transcription factor that is expressed in neural progenitor cells during embryonic development where it sustains their replication-competent state and regulates their oligodendrocyte and motor neuron multi-lineage potential. In HGG, OLIG2 is re-expressed at high levels and drives an oncogenic program that leads to dysregulation of the cell cycle and subsequent gliomagenesis. This central role for OLIG2 in HGG initiation and growth, along with its low expression in normal tissues, identifies OLIG2 as a target for HGG therapy. We report the characterisation of an orally bioavailable small-molecule OLIG2 inhibitor, CT-179, the first bHLH transcription factor targeting drug developed for the treatment of cancer. The drug is well tolerated and easily penetrates the blood brain barrier, where it reduces brain tumour burden in orthotopic mouse and zebrafish avatar models. Mechanistically, CT-179 displayed nanomolar anti-proliferative activity and induced significant apoptosis mediated through disruption of the cell cycle that resulted in mitotic catastrophe at prometaphase. CT-179 showed enhanced anti-tumour activity in mouse models of HGG when used in combination with standard of care radiotherapy and temozolomide. These studies demonstrate that the pharmacological inhibition of OLIG2 is an effective treatment strategy for HGG that warrants rapid translation into the clinic.
Pycnogenol® inhibits growth of ovarian cancer cells in vitro.
Authors: Amber R. Buz’zard, Benjamin H. Lau
Journal: Cancer Research (2004)

3140  Ovarian cancer is the sixth most commonly occurring cancer in women. Symptoms are often vague and easily confused with other disorders, resulting in advanced stage detection in more than two-thirds of cases. Which is why it accounts for more deaths than any other cancers of the female reproductive system. Chemoprevention is regarded as an efficient strategy to prevent cancer. The most useful cancer chemopreventive compounds will have minimal long-term toxicity, while significantly reducing cancer incidence, delaying cancer onset or preventing cancer progression. Pycnogenol® (Pyc) is a proprietary mixture of water-soluble bioflavonoids extracted from the bark of French maritime pine (Pinus pinaster Aiton). Recently, Pyc has been shown to selectively induce apoptosis in breast cancer cells in vitro. The purpose of this study was to determine the ability of Pyc to inhibit the growth of ovarian cancer cells in vitro. Human cell lines ML5TA (benign cystadenoma), TOV-21G (malignant adenocarcinoma) and PA-1 (malignant teratocarcinoma) were incubated with 5, 10, 20, 40, 60, 80, 100, 120, 140 or 160 μg/ml Pyc for 24 hours. Cells were then processed for MTT assay or DAPI staining. MTT: MTT solution was added to each well and incubated for 4hr. DMSO was added to dissolve the crystals and the absorbance was read. A decrease in absorbance indicates a loss in cell viability. DAPI: Cells were harvested, incubated with DAPI and viewed microscopically for evidence of apoptosis. Apoptosis is detectable by morphology, chromatin condensation, nuclear DNA fragmentation, DNA strand breakage or apoptotic bodies. DAPI is a DNA-binding fluorescent dye used to visualize DNA fragmentation. Results of MTT assays showed a slight dose-dependent increase in cell viability for the benign ML5TA cells. Pyc decreased cell viability of the malignant TOV-21G and PA-1 cells. The most astonishing was that a dose as low as 20 μg/ml Pyc decreased PA-1 viability. Apoptosis, as detected by DAPI staining, was significantly higher for PA-1 cells than for the others. Nine out of ten treatments were significantly different for the PA-1 treated cells, whereas six out of ten ML5TA treatments and five out of ten TOV-21G treatments were significantly different in comparison to their respective controls. (p
PDTM-27. EPIGENETIC LOSS OF BAI1 EXPRESSION IN CEREBELLAR GRANULE NEURON PRECURSORS INACTIVATES THE p53 TUMOR SUPPRESSOR AND FACILITATES MEDULLOBLASTOMA FORMATION IN THE CEREBELLUM
Authors: Dan Zhu, Satoru Osuka, Zhaobin Zhang, Zachery Reichert, Yonehiro Kanemura, Ryo Nishikawa, William G. Nelson, Jeffrey J. Olson, Erwin G Van Meir
Journal: Neuro-Oncology (2018)

Adhesion G-protein coupled receptors (ADGRs) are transmembrane proteins involved in cell-cell/matrix interactions. We show ADGRB1 gene, which encodes Brain-specific angiogenesis inhibitor 1 (BAI1), is epigenetically silenced in human medulloblastomas through a methyl-CpG binding protein 2 (MBD2)-dependent mechanism. Knockout of Adgrb1 in mice augments proliferation of cerebellar granule neuron precursors (GNPs), and increases medulloblastoma penetrance and accelerated death in Ptch1+/- mice. BAI1 prevents Mdm2-mediated p53 polyubiquitination, and its loss substantially reduces p53 levels. Reactivation of BAI1/p53 signaling axis by targeting MBD2 pathway suppresses human medulloblastoma growth in orthotopic xenograft models. Our findings highlight the importance of BAI1 loss in medulloblastoma and demonstrate that epigenetic restoration of its expression with a new brain-permeable MBD2 inhibitor has therapeutic potential. Revealing BAI1 as a physiological tumor suppressor in medulloblastoma unveils a direct crosstalk between ADGRs and p53 signaling, and provides a causal relationship between ADGRs and cancer. The discovery of a novel upstream regulator of the p53 tumor suppressor is highly significant because of this pathway’s involvement in many cancers. Disruption of the BAI1/mdm2/p53 signaling axis through BAI1 silencing reveals a vulnerability in cancer, and offers an opportunity for therapeutic exploitation through epigenetic reactivation. We provide proof-of-principle that this can be achieved with a chemical scaffold targeting MBD2, and this lead molecule is actionable for translation into a first-in-class therapeutic intervention against medulloblastoma, and possibly other cancers (Zhu D et al, Cancer Cell, in press).
Simultaneously Elevated Fraction Of Exhaled Nitric Oxide And Blood Eosinophil Counts Relates To Recent Asthma Events
Authors: Ida Mogensen, Kjell Alving, J. A. Fonseca, T. Jacinto, Christer Janson, Andrei Malinovschi
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Simultaneously Elevated Fraction Of Exhaled Nitric Oxide And Blood Eosinophil Counts Relates To Recent Asthma Events
EXTH-44. TARGETING GLIOMA STEM CELLS WITH CAR-T IMMUNOTHERAPY IN XENOGRAFT ANIMAL MODELS
Authors: Mansour Gergi, Sudarshana Sengupta, Prakash Sampath, Sadhak Sengupta
Journal: Neuro-Oncology (2018)

Recurrent Glioblastoma (GBM) tumors often arise from glioma-initiating cells or glioma stem cells (GSCs). GSCs are usually resistant to the standard therapeutic regiment of radiation and chemotherapy and hence have been an attractive target for the development of immunotherapeutic strategies to treating recurrent GBMs. Chimeric antigen receptor expressing engineered T (CAR-T) cells are redirected to detect and destroy rare tumor cells that express specific tumor antigens. CAR-T cells have been successful in treating hematological cancers, and moderately effective in remission of primary GBM tumors, but not yet been successful in the immunotherapeutic targeting of GSCs or recurrent GBMs. In this study, we have treated two patient-derived GSCs and tumor cell line derived neurospheres, as well as GSC/neurosphere-derived secondary tumor cells with CAR-T cells that specifically target IL13Rα2 tumor antigens on GBMs. These GSCs and neurospheres were resistant to radiation and adjuvant chemotherapy but were successful in activating antigen-specific CAR-T cells- as observed by increased proliferation as well as secretion of cytokines. In vitro co-culture of CAR-T cells with GSCs, neurospheres, and secondary tumors resulted in the effective cytotoxic killing of tumor cells. In experimental animals bearing xenograft implantation of GSCs or redefined secondary tumor cells, tumors went into remission when treated with CAR-T cells, in comparison to treatment with T cells that did not express specific CAR molecule. Together, we conclude that CAR-T cell immunotherapy can be an effective approach to targeting GSCs and treating secondary or recurrent GBM tumors.