tbuckley/cabot-search huggingface dataset:
Paucigranulocytic asthma: Uncoupling of airway obstruction from inflammation
Authors: Omar Tliba, Reynold A Panettieri
Journal: Journal of Allergy and Clinical Immunology (2018)

Among patients with asthma, heterogeneity exists regarding the pattern of airway inflammation and response to treatment, prompting the necessity of recognizing specific phenotypes. Based on the analysis of inflammatory cell counts in induced sputum, asthmatic patients can be classified into 4 unique phenotypes: eosinophilic asthma, neutrophilic asthma, mixed granulocytic asthma, and paucigranulocytic asthma (PGA). PGA is an asthma phenotype with no evidence of increased numbers of eosinophils or neutrophils in sputum or blood and in which anti-inflammatory therapies are ineffective at controlling symptoms. Although underinvestigated, PGA is the most common asthma phenotype in patients with stable asthma. However, PGA is sometimes underestimated because of the exclusive reliance on induced sputum cell counts, which are variable among cohorts of studies, prompting the necessity of developing improved biomarkers. Importantly, investigators have reported that inhaled corticosteroids had a limited effect on airway inflammatory markers in patients with PGA and therefore defining PGA as a potentially "steroid-insensitive" phenotype that requires exploration of alternative therapies. PGA manifests as an uncoupling of airway obstruction from airway inflammation that can be driven by structural changes within the airways, such as airway smooth muscle tissue hypertrophy. Animal models provide evidence that processes evoking airway hyperresponsiveness and airway smooth muscle thickening occur independent from inflammation and might be a consequence of a loss of negative homeostatic processes. Collectively, further understanding of PGA with a focus on the characterization, prevalence, clinical significance, and pathobiology derived from animal studies will likely provide precision therapies that will improve PGA clinical outcomes.
Immunohistochemical study of KRAS, NRAS, BRAF and MSI phenotype in small bowel adenocarcinoma
Authors: V. Michalaki, G. Frangulidis, A. Poydorou, T. Theodosopoulos, A. Vezakis, N. Dafnios, M. Frangou, E. Karvouni, C. Papadimitriou
Journal: Annals of Oncology (2018)

Introduction: Small-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) The aim of this study was to perform a comprehensive immunohistochemical analysis of KRAS, NRAS, V600E BRAF mutations and microsatellite instability using a cohort of surgically resected cases in our institution. Methods: A total of 17 patients (10 males and 7 females; mean age, 56.2 years old; range, 45 75 years old) received chemotherapy due to non curative tumor resection, unresectable tumor or post operative recurrence. Twelve patents received fluoropyrimidine and oxaliplatin based first line chemotherapy. Molecular targeted agents were administered to 15 patients, for whom it was their first or second line therapy. Results: KRAS mutations were found in 7 cases (41%), out of which 5 (29%) were in exons 12/13. BRAFV600E mutation was observed in 1/17 pt. Microsatellite instability was identified in 3/17pt (MSI; 18%), mainly related to a loss of expression of MLH1 protein. Univariate analysis revealed a PS of 0 (P = 0.0226) and treatment with platinum-based chemotherapy (P = 0.0047) were significant factors for an improved prognosis. Among the 12 patients who received oxaliplatin-based chemotherapy as a first-line chemotherapy, a PS of 0 (P = 0.0255) and treatment with anti-EGFR agents (P = 0.0127) were significant positive prognostic factors. Toxicities due to the molecular targeted agents were not experienced. The median overall survival time was 14.3 months (range, 3-52 months), the median DFS was 14.2 months and the median OS was 32 months. Conclusion: To date, there is no standard chemotherapy regimen for advanced SBAs and little is known about their molecular characteristics. The results of the present study indicate that oxaliplatin based chemotherapy containing molecular targeted agents is a well-tolerated and effective treatment option for SBA. A better understanding of disease biology may help to identify therapeutic targets and advance precision medicine.
Targeting adenosine for cancer immunotherapy
Authors: Robert D. Leone, Leisha A. Emens
Journal: Journal for ImmunoTherapy of Cancer (2018)

Immune checkpoint antagonists (CTLA-4 and PD-1/PD-L1) and CAR T-cell therapies generate unparalleled durable responses in several cancers and have firmly established immunotherapy as a new pillar of cancer therapy. To extend the impact of immunotherapy to more patients and a broader range of cancers, targeting additional mechanisms of tumor immune evasion will be critical. Adenosine signaling has emerged as a key metabolic pathway that regulates tumor immunity. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment. Hypoxia, high cell turnover, and expression of CD39 and CD73 are important factors in adenosine production. Adenosine signaling through the A2a receptor expressed on immune cells potently dampens immune responses in inflamed tissues. In this article, we will describe the role of adenosine signaling in regulating tumor immunity, highlighting potential therapeutic targets in the pathway. We will also review preclinical data for each target and provide an update of current clinical activity within the field. Together, current data suggest that rational combination immunotherapy strategies that incorporate inhibitors of the hypoxia-CD39-CD73-A2aR pathway have great promise for further improving clinical outcomes in cancer patients.
Platelet Signaling and Disease: Targeted Therapy for Thrombosis and Other Related Diseases
Authors: Jennifer Yeung, Wenjie Li, Michael Holinstat
Journal: Pharmacological Reviews (2018)

Platelets are essential for clotting in the blood and maintenance of normal hemostasis. Under pathologic conditions such as atherosclerosis, vascular injury often results in hyperactive platelet activation, resulting in occlusive thrombus formation, myocardial infarction, and stroke. Recent work in the field has elucidated a number of platelet functions unique from that of maintaining hemostasis, including regulation of tumor growth and metastasis, inflammation, infection, and immune response. Traditional therapeutic targets for inhibiting platelet activation have primarily been limited to cyclooxygenase-1, integrin <i>α</i><sub>IIb</sub><i>β</i><sub>3</sub>, and the P2Y<sub>12</sub> receptor. Recently identified signaling pathways regulating platelet function have made it possible to develop novel approaches for pharmacological intervention in the blood to limit platelet reactivity. In this review, we cover the newly discovered roles for platelets as well as their role in hemostasis and thrombosis. These new roles for platelets lend importance to the development of new therapies targeted to the platelet. Additionally, we highlight the promising receptor and enzymatic targets that may further decrease platelet activation and help to address the myriad of pathologic conditions now known to involve platelets without significant effects on hemostasis.
A randomized clinical trial of apatinib on an intermittent versus continuous dosing schedule in combination with docetaxel for advanced gastric cancer in second-line setting - Trial in progress
Authors: Y. He, Y. Yan, L. Ke, X. Hu, S. Wu, J. Niu, H. Li, H. Xu, H. Luo, L. Cao, W. Chen, C. Ji, Y. Sun, G. Wang, T. Xu, B. Hu
Journal: Annals of Oncology (2018)

Introduction: Apatinib, a small molecule oral tyrosine kinase inhibitor (TKI) that mainly targets vascular endothelial growth factor receptor-2, has been approved in the treatment of advanced gastric cancer in China. Whereas, many patients treated with apatinib experienced toxicity necessitating dose reduction. Maintaining adequate dosing and drug levels are essential for optimizing clinical efficacy. Thus, it is urgently needed to explore optimal dosing strategy of apatinib treatment in advanced gastric cancer. Other small molecule TKIs such as sunitinib [J Clin Oncol, 27 (22): 3584-3590], sorafenib [Future Oncol, 13(8): 679-693] and anlotinib [J Hematol Oncol, 9(1): 105] have demonstrated efficacy and acceptable tolerability in advanced cancers via an intermittent dosing schedule. The current study was conducted to compare the efficacy and safety of intermittent (5days on/2 days off schedule) vs continuous apatinib therapy in combination with docetaxel as second-line treatment for advanced gastric cancer. Methods: This study is designed as an open-label, randomized clinical trial. To enroll, patients are required to have pathologically or histologically confirmed advanced gastric cancer and have experienced treatment failure with first-line chemotherapy. Other inclusion criteria include ≥18 years; Eastern Cooperative Oncology Group performance status of 0-2; life expectancy more than 3 months. Eligible patients are randomized to the treatment arms in a ratio of 1:1. In intermittent dose schedule, patients receive oral apatinib 500 mg/d for 5 days followed by 2 days off treatment. In continuous dose arm, patients received oral apatinib 500 mg/d as a continuous daily dosing. Docetaxel 60 mg/m2 is administered intravenously to patients on day 1 in a 21-day cycle in both groups. Treatment is continued until disease progression, intolerable toxicity or withdraw of consent. The primary outcome is progression free survival. The secondary outcomes include objective response rate, disease control rate, overall survival, quality of life and safety. Tumor response is assessed according to Response Evaluation Criteria in Solid Tumors guideline version 1.1. The incidence and severity of adverse events are defined by the Common Terminology Criteria for Adverse events version 4.0. Approximately 60 patients will be enrolled, with 30 subjects in each arm. Enrollment opened on September, 2017. As the cutoff date of February 27 2018, 19 patients were enrolled: 11 patients in the intermittent dose arm and 8 patients in the continuous dose arm. Clinical trial information: NCT03334591.
MBCL-27. RESPONSE OF RECURRENT MALIGNANT CHILDHOOD CNS TUMORS TO A MEMMAT BASED METRONOMIC ANTIANGIOGENIC COMBINATION THERAPY VARIES DEPENDENT ON TUMOR TYPE: EXPERIENCE IN 71 PATIENTS
Authors: Irene Slavc, Andreas Peyrl, Monika Chocholous, Dominik Reisinger, Lisa Mayr, Amedeo Azizi, Karin Dieckmann, Christine Haberler, Thomas Czech
Journal: Neuro-Oncology (2018)

Patients with recurrent malignant CNS tumors have a poor prognosis irrespective of salvage therapy applied. We used a metronomic antiangiogenic combination therapy and report on the response of individual tumor types to this approach. Since 2006, 81 patients with various recurrent malignant brain tumors started treatment with an antiangiogenic multidrug-regimen at the Medical University of Vienna. Therapy consisted of daily oral thalidomide, fenofibrate, celecoxib, and 21-day cycles of low dose oral etoposide alternating with cyclophosphamide augmented with IV bevacizumab and intraventricular therapy (etoposide and liposomal cytarabine). Excluding the 10 patients with recurrent medulloblastoma treated in the formal international protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290), 71 patients were treated according to the same strategy "off trial". Diagnoses were medulloblastoma (n=20), atypical teratoid rhabdoid tumor (ATRT) (n=11), ependymoma (n=9), high grade glioma/diffuse intrinsic pontine glioma (HGG/DIPG) (n=9), and various other entities in the remaining patients. As of the end of 2017, 3-year and 5-year OS for the 20 patients with recurrent medulloblastoma was 64.2 ± 10.9% and for the 11 patients with recurrent ATRT 45.7 ± 16.6% and 30.5 ± 16.7%, respectively. Remission could be maintained after discontinuation of treatment in a certain percentage of patients with medulloblastoma, ATRT and ependymoma. Patients with HGG and DIPG did not respond to this approach. The proposed antiangiogenic regimen seems most promising in medulloblastoma and ATRT and possibly also ependymoma. In a number of other tumor entities time to progression could be prolonged while maintaining good quality of life.
EPEN-31. SUBGROUP SPECIFIC LONG-TERM SURVIVAL AND NEUROCOGNITIVE OUTCOMES IN POSTERIOR FOSSA EPENDYMOMA (PFE)
Authors: Michal Zapotocky, Kiran Beera, Jenny Adamski, Sharon Guger, Laura Janzen, Normand Laperierre, Ute Bartels, Cynthia Hawkins, Michael Taylor, Eric Bouffet, Donald Mabbott, Vijay Ramaswamy
Journal: Neuro-Oncology (2018)

PFE comprises two groups, EPN_PFA and EPN_PFB with stark differences in outcome. However, the long-term outcomes of PFA ependymoma and the pattern of relapse have not been fully described. We aimed to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped PFE over three decades. Seventy-three PFE were identified, of which 89% were PFA. There were no relapses amongst PFB. Ten-year PFS of PFA was poor at 37 +/- 7%. Analysis of consecutive 10-year epochs revealed significant improvement in PFS/OS over time (2005–2014 compared to 1985–1994 and 1995–2004). This pertains to the GTR rate increased from 35% to 77% and use of upfront radiation increased from 65% to 96% over the observed period and confirmed in a multivariable model. The pattern of relapse changed over time, related to GTR PFA relapsing with metastasis. Analysis of longitudinal neuropsychological outcomes in a mixed linear model shows continuous declines in IQ over time with upfront conformal radiation, which are particularly pronounced in infants under the age of 3 (FSIQ -1.33 points/year). Data from a molecularly informed large prospective cohort of PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiation. However for the first time in a subgrouped cohort, we show that this approach results in reduced neurocognitive outcomes over time. Our data suggest that all children with EPN_PFA should receive upfront radiation and be concomitantly prioritized for early neuropsychological testing and intervention.
EPEN-30. HISTONE H3 LYSINE 4 TRIMETHYLATION IS A POTENTIAL TARGET TO IMPROVE CHEMOTHERAPEUTIC EFFICACY FOR PEDIATRIC PRIMARY EPENDYMOMAS
Authors: Guifa XI, Yuping Li, Lindsey Hoffman, Rintaro Hashizume, Rebecca Lewis, Gordan Gravohac, Nitin Wadhwani, Gavin Rice, Chunfa Jie, Bemjamin Best, Amanda Saratisis, Tord Alden, Robin Bowman, Arthur DiPatri, Barbara Mania-Farnell, Marcelo Soares, Charles James, Nick Foreman, Tadanori Tomita
Journal: Neuro-Oncology (2018)

Ependymomas are the third most common form of brain tumors in children. These tumors are resistant to chemotherapy and despite genomic sequencing, there is a lack of effective molecular treatment targets. Efficient treatment targets need to be identified. Increasing evidence shows epigenetic alterations including posttranslational histone modifications (PTMs), associated with malignancy, chemotherapeutic resistance and prognosis in pediatric ependymomas. In this study we examined histone PTMs in ependymomas and identified potential targets to improve chemotherapeutic efficacy. Global levels of trimethylation at lysine 4 on histone H3 (H3K4me3), detected with immunohistochemistry and western blots, positively correlated with malignancy in pediatric primary ependymomas. Micro-array analysis of 22 pediatric ependymomoas identified upregulated candidate drug resistance genes. Promoter H3K4me3 occupancy was examined for two of these genes, CCND1 and ERBB2. Chromatin-immunoprecipitation with H3K4me3 coupled with real-time PCR, showed higher levels of H3K4me3 at these genes in grade III tumors, in comparison to grade II ones. When H3K4me3 levels were reduced in primary cultured ependymoma cells in vitro, cell response to chemotherapy increased. In summary, these results indicate that H3K4me3 levels are high at promoters of genes which confer chemotherapeutic resistance. Consequently, a novel treatment regimen which targets H3K4me3 in combination with traditional protocols may increase chemotherapeutic efficacy and improve prognosis for children who present with ependymoma.
Abstract 16398: Effect of CETP Inhibition With Anacetrapib on VLDL Triglyceride and Plasma ApoC-II, ApoC-III and ApoE Metabolism
Authors: John S Millar, Michael E Lassman, Marianna Pavlyha, Colleen Ngai, Nelson Fontanez, Rajasekhar Ramakrishnan, Patricia Jumes, Richard Dunbar, Emile M deGoma, Amanda L Baer, Wahida Karmally, Daniel S Donovan, Hashmi Rafeek, Amy O Johnson-Levonas, John Wagner, Stephen Holleran, Yang Liu, Soumia Aoujil, Taylor Standiford, David E Gutstein, Henry N Ginsberg, Daniel J Rader, Gissette Reyes-Soffer
Journal: Circulation (2016)

Background:  CETP inhibition with anacetrapib reduces triglyceride (TG) and cholesteryl ester transfer among lipoproteins and increases very low density lipoprotein (VLDL) apolipoprotein B (apoB) clearance. This study reports the effects of anacetrapib on VLDL-TG, apoC-II, apoC-III and apoE metabolism.   Methods:  Mildly hypercholesterolemic subjects were randomized to background placebo (N=10) or atorvastatin 20 mg (N=29) for 4 weeks, followed by addition of anacetrapib 100 mg for another 8-weeks. Subjects underwent stable isotope kinetic studies to determine fractional catabolic rates (FCR) and production rates (PR) of VLDL-TG, apoC-II, C-III and E.   Results:  Anacetrapib reduced the circulating VLDL-TG pool by 14% (p=.006) in subjects on atorvastatin due to an increase in FCR (29%; p=.002) without changing plasma TG. VLDL-TG pool size did not change in the anacetrapib monotherapy group; although FCR increased by 40% (p=.11), these changes were offset by a 39% increase in PR (p=.01), which was not observed in the atorvastatin plus anacetrapib group. Anacetrapib increased plasma apoE (with a trend towards increased PR; p=.10) and increased plasma apoC-II (with a trend towards decreased FCR; p=.08). Anacetrapib also increased plasma apoC-III and tended to increase PR (p=.07) and decrease FCR (p=.08); these changes could be due an increased association of apoCIII with HDL particles.   Conclusion:  Anacetrapib increases VLDL-TG FCR, possibly through effects mediated by apoE and apoC-II. In subjects on atorvastatin background, this was associated with reduced circulating VLDL-TG. In anacetrapib monotherapy subjects, there were no changes in VLDL-TG due to competing mechanisms of FCR and PR.
Abstract 14630: Hydrogen Gas Inhalation Improves Survival in Rats With Lethal Hemorrhagic Shock Resuscitated With Saline
Authors: Tadashi Matsuoka, Masaru Suzuki, Motoaki Sano, Kei Hayashida, Tomoyoshi Tamura, Keiichi Fukuda, Junichi Sasaki
Journal: Circulation (2016)

Objectives:  Hemorrhagic shock is a life-threatening condition. In addition to conventional treatments such as hemostasis and fluid resuscitation, further investigations are warranted to develop more effective treatments. We investigated the effectiveness of hydrogen (H2) gas inhalation in a fixed-pressure model of hemorrhagic shock in rats.   Methods:  Hemorrhagic shock is induced by withdrawing blood from the left carotid artery until the mean arterial pressure (MAP) reaches 30~35 mmHg. Blood pressure is then maintained at this value either by further blood withdrawal or reinfusion of collected blood. Sixty minutes after shock induction, rats were resuscitated over a period of 15 minutes with a volume of saline, four times that of the shed blood. Inhalation of H2 gas (1.3% H2, 21% O2 and 77.7% N2, n=10) or control gas (21% O2 and 79% N2, n=10) was commenced at the beginning of the shock induction period, and continued for 2 hours after resuscitation.   Results:  (1) The H2 group shed more blood than controls to maintain hemorrhagic shock (2.76 ± 0.35 ml/100g vs 2.42 ± 0.39 ml/100g; p=0.058).  (2) After resuscitation, the MAP in the H2 group reached a significantly higher level than in the control group [92.5 vs 71.0 mmHg (30 min), 103.0 vs 79.1 mmHg (60 min); 102.0 vs 70.4 mmHg (90min); 92.4 vs 63.1 mmHg (120min), p  (3) The survival rate at 6 hours after resuscitation was significantly higher in the H2 group than in the control group (80% vs. 30%, p  (4) H2 gas inhalation did not affect blood gases (pH, lactate, HCO3, base excess, PaO2, PaCO2, Hb, Hct) or blood chemistry (Na, K) before, or 6 hours after, fluid resuscitation.   Conclusions:  It is well accepted that survival time is prolonged by resuscitation with blood compared to saline. However, blood transfusions are not performed immediately at the site of an emergency. We have demonstrated that inhalation of H2 gas, commenced upon excessive bleeding, prolonged survival in rats resuscitated with saline alone after suffering a lethal hemorrhagic shock.
MBRS-26. WHOLE EXOME SEQUENCING OF CIRCULATING TUMOR DNA EXTRACTED FROM THE CEREBROSPINAL FLUID ALLOWS A PANGENOMIC CHARACTERISTISATION OF THE PRIMARY TUMOR
Authors: Mathieu Chicard, Valérie Combaret, Adrien Danzon, Nathalie Clément, Julien Masliah-Planchon, Mylène Bohec, Sylvain Baulande, Célio Pouponnot, Didier Frappaz, François Doz, Olivier Delattre, Gudrun Schleiermacher, Franck Bourdeaut
Journal: Neuro-Oncology (2018)

Liquid biopsies are revolutionary tools to detect tumour-specific genetic alterations in body fluids. Here, we assess whether the circulating tumor DNA (ctDNA) in Cerebral Spinal Fluid (CSF) could be used for tumor genetic profiling of Medulloblastomas (MB). We extracted the ctDNA of 4-5 CSF droplets after lumbar puncture from patients with Medulloblastoma (12), or ETMR (1). ctDNA (quantity mean 30ng; range 8-177ng) and matched genomic DNA from primary tumors were sequenced by Whole Exome Sequencing (WES) (Illumina 100PE) using Nimblegen Medexome Capture. SNVs/mutations were called using GATK-UnifiedGenotyper, GATK-HaplotypeCaller and Samtools, and filtered on constitutional DNA from public databases. Copy Number profiles were generated with CNVkits. 10/13 cfDNA WES yielded satisfactory depth (>10x). A mean of 466 (range 93-945) SNVs were detected in the primary tumor and 474 (range 18-922) in the CSF. A mean of 416 (range 18-872) commons SNVs were observed between the cfDNA and the primary tumor, comprising classical Medulloblastoma genes such as SMO or MLL2. Interestingly, several SNVs were observed either in the tumor only (mean 50; range 3-115) or in CSF only (mean 58; range 0-148) suggesting a clonal heterogeneity. For 5 cases, Copy Number profiles were also available, allowing the detection of MYCN amplification in 1 MB or 19q13 miRNA cluster amplification in the ETMR.