tbuckley/cabot-search huggingface dataset:
TRTH-10. PEDIATRIC PHASE 1/1B STUDY OF ENTRECTINIB IN PATIENTS WITH PRIMARY BRAIN TUMORS, NEUROBLASTOMA, AND NTRK, ROS1, OR ALK FUSIONS
Authors: Sunitha Rangaraju, Gang Li, Jason Christiansen, Zachary Hornby, Pratik Multani, Vanessa Esquibel, Edna Chow Maneval
Journal: Neuro-Oncology (2017)

The STARTRK-NG (Studies of Tumor Alterations Responsive to Targeting Receptor Kinases - Next Generation) trial is a Phase 1/1b study of entrectinib in pediatric patients with cancer, including primary brain tumors, neuroblastoma, and other non-neuroblastoma, extracranial solid tumors harboring NTRK, ROS1, or ALK gene fusions (NCT02650401). Entrectinib is a potent oral, CNS-penetrant, inhibitor of the tyrosine kinases TRKA/B/C (encoded by the genes NTRK1/2/3, respectively), ROS1, and ALK with IC50s < 2 nM (biochemical kinase assay). Overall, gene fusions are rare in the cancer population (<3%); however, they have been seen in over 40 solid tumor histologies, including non-small cell lung cancer, salivary gland cancers, soft tissue sarcomas and glioneuronal tumors. A survey of two pediatric cancer databases, St. Jude pediatric cancer database (PeCan; total n=1,604) and the University of Michigan database (Peds-MiOncoSeq; total n=91), identified malignancies with gene fusions in all three NTRK genes, including infantile fibrosarcoma, juvenile breast cancer, mesoblastic nephroma, intrinsic pontine gliomas, acute leukemias and anaplastic lymphoma. Previously, we reported an objective response rate of 79% was seen in 24 tyrosine kinase inhibitor-naïve patients with solid tumors harboring NTRK, ROS1, or ALK gene fusions, who were treated at doses consistent with the RP2D (Drilon et al, AACR 2016). The most common (>10% incidence) treatment-related adverse events have been fatigue/asthenia, dysgeusia, paresthesia, nausea, myalgia, diarrhea, dizziness, arthralgia, vomiting, and constipation; importantly, there has been no evidence of cumulative toxicity. In addition, we have treated a 20-month-old boy presenting with infantile fibrosarcoma metastatic to the brain, which harbored an ETV6-NTRK3 fusion. Tumor restaging following 1 month of therapy showed a significant tumor regression of CNS metastases accompanied by significant clinical improvement. Together, these data provide compelling evidence to identify pediatric patients harboring NTRK, ROS1, or ALK fusions for enrollment in the STARTRK-NG trial.
MEDU-23. UPREGULATED I2PP2A ACTIVATES PI3K PATHWAY AND PROMOTES TUMOR CELL SURVIVAL OF SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Yun Wei, Anna Kenney
Journal: Neuro-Oncology (2017)

Medulloblastoma is the most common solid brain malignancy of childhood. Approximately 30% of human medulloblastomas show aberrant Sonic Hedgehog (Shh) pathway activity. Current treatment strategies comprise surgery, radiation and chemotherapy, which generate side effects that severely impact survivors’ quality of life, and tumor recurrence is typically fatal. The PI3 kinase pathway plays critical roles in medulloblastoma tumor-repopulating cell survival, as shown in recent patient sample research. This pathway can be inhibited by activity of the tumor suppressor protein phosphatase 2A (PP2A). Using NeuroD2-SmoA1 mouse model which faithfully recapitulates human Shh MB, I’ve confirmed that the protein levels of p-AKT, downstream effector of PI3 kinase pathway, along with p-ERK, downstream of MAPK pathway, increase 24 hours after irradiation on SmoA1 mice. This leads me to the question whether the negative regulator of p-ERK and p-AKT, PP2A, has been suppressed in Shh MB. Among three endogenous inhibitors of PP2A, designated as CIP2A (cancerous inhibitor of PP2A), I1PP2A and I2PP2A (inhibitor 1 and inhibitor 2 of PP2A, respectively), I found that protein level of I2PP2A but not the other two is markedly elevated in mouse medulloblastomas compared with neighboring normal cerebellum. However, the mRNA level of I2PP2A in SmoA1 mice or patient samples did not show significant difference in Shh MB compared to control group. In primary cultures of mouse SmaA1 medulloblastoma cells, lentiviral knockdown and a peptide inhibitor of I2PP2A reactivated PP2A C and decreased the PI3K and MAPK pathway activity, indicated by reduced downstream p-Akt and p-ERK in Shh medulloblastoma. Employing SmoA1 tumor allograft model, I’m also testing whether I2PP2A knockdown can inhibit SmoA1 tumor growth in vivo and prolong the host survival. I hope to extrapolate this research into a novel therapy design targeting I2PP2A:PI3K interactions in SHH or even other subtypes of medulloblastoma.
Identification of new biomarkers in ovarian cancer using biotin-label-based antibody arrays
Authors: Steven (Ruochun) Huang, Jean (Qing) Yang, Rani Huang
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

5170 

Early diagnosis of cancer, particularly ovarian cancer, can significantly increase survival and cure rates. Currently, no standardized screen exists to reliably detect ovarian cancer in its early stages. To address this problem, we have developed the first high density cytokine antibody array and used this technology to uncover the potential biomarkers of ovarian cancer. In this system, biological samples are labeled with biotin. The biotinylated proteins are then incubated with antibody chips. The presence of proteins captured by the antibody chip is detected using Alexa Fluor-labeled streptavidin. The signals, which are visualized by laser scanning, are normalized using positive, negative, and internal controls. Using this biotin-label-based antibody array technology, the expression levels of 507 human, 308 mouse, or 90 rat target proteins can be simultaneously detected, including cytokines, chemokines, adipokines, growth factors, angiogenic factors, proteases, soluble receptors, soluble adhesion molecules, and other proteins in cell culture supernatants or sera. Most proteins can be detected at pg/ml and ng/ml levels with a CV of less than 15%. Using human biotin-based antibody arrays, we screened the serum expression profiles of 507 proteins in ovarian cancer patients and normal subjects. Cluster analysis of these two groups revealed several proteins with significantly different expression patterns between ovarian cancer and normal state. Our results suggest that the biotin label-based antibody arrays which we have developed will have promising applications in cancer biomarker discovery.
Early prediction of efficacy of endocrine therapy in breast cancer (BC): Pilot study and validation with 18F fluoroestradiol (18F-FES) PET/CT.
Authors: Alessandra Gennari, Dino Amadori, Etienne Brain, Javier Cortes, Nadia Harbeck, Matteo Puntoni, Rachel Wuerstlein, Oriana Nanni, Eva Muñoz-Couselo, Giovanni Paganelli, Maribel Lopera Sierra, Federica Matteucci, Arnoldo Piccardo, Paolo Bruzzi
Journal: Journal of Clinical Oncology (2013)

TPS649 Background: Almost 70% of early BC are endocrine responsive, as defined by estrogen receptor (ER) expression; however roughly 30% of ER+ BC patients will relapse despite adjuvant ET. Moreover, 10 to 20% of BC metastases lose ER expression. The upfront administration of ET in ER+ women with MBC is recommended by major guidelines. However, the early identification of endocrine resistance might improve systemic treatment options, sparing unnecessary toxicities and inactive drugs. 18F-FES, an oestradiol analogue labeled with 18F, may allow to test the performance of ERs, by testing their in vivo linkage ability. In MBC, 18F-FES uptake has been proposed to be a better predictor of response to ET than ER expression itself. The aim of the ET-FES study is to validate the predictive value of 18F-FES uptake at PET/CT scan in metastatic ER+ patients. Methods: This is aphase II, multicentric european comparative study of first line ET vs CT in ER+ MBC with low 18F- FES uptake. The primary endpoint is disease control rate (DCR). Correlative studies include: 1. Optimization of 18F-FES production; 2. Association between gene alterations in ESR1/ESR2 genes and 18F- FES uptake; 3. Development of a predictive score of endocrine responsiveness based on 18F-FES SUV value and clinical and biological information. All patients with ER+ MBC candidate to first line ET will receive a 18F-FES CT/PET at baseline, in addition to standard staging. Patients with 18F-FES uptake (SUV) &gt; 2 will receive ET. Patients with 18F-FES SUV &lt; 2 will be randomized to ET until disease progression (control arm) or CT (single agents) until PD. A total of 220 patients with ER+ MBC will be enrolled. Of these, approximately 50% (n=110) will show a 18F-FES SUV &lt; 2 and will be randomized to ET or CT. The study will have 85% power to detect an absolute 20% difference in the DCR between arms after 3 months of therapy, assuming a 5% two-sided alpha level and a 10% drop-out rate. Current status: The ET-FES study was approved for funding by the ist Join TRANSCAN European call. 18F-FES production is currently on final development (GMP), and the clinical protocol is being finalized for EC approval in the different EU countries. Clinical trial information: 2013-000287-29.
Effect of a combination of epigenetic agents on the malignant phenotype in models of T-cell lymphoma.
Authors: Enrica Marchi, Matko Kalac, Danielle Bongero, Christine McIntosh, Laura K Fogli, Luigi Scotto, Maura Rossi, Pier Luigi Zinzani, Stefano A Pileri, Pier Paolo Piccaluga, Owen O'Connor
Journal: Journal of Clinical Oncology (2012)

e13569 Background: CHOP and CHOP-like chemotherapy are the most used regimens for the treatment of peripheral T-cell lymphomas (PTCLs) despite sub-optimal results. Histone deacetylase inhibitors (HDACIs) have shown class activity in PTCLs. The interaction between the HDACIs (depsipeptide (R), belinostat (B), vorinostat (V) and panobinostat (P)) and a DNMT inhibitor (decitabine (D) was investigated in vitro, in vivo and at the molecular level in T-cell lymphoma and leukemia cell lines (H9, HH, P12, PF-382). Methods: For cytotoxicity assays, luminescence cell viability assay was used (CellTiter-Glo). Drug:drug interactions were analyzed with relative risk ratios (RRR) based on the GraphPad software (RRR&lt;1 defining synergism). Apoptosis was assessed by Yo-Pro-1 and propidium iodine followed by FACSCalibur acquisition. Gene expression profiling was analyzed using Illumina Human HT-12 v4 Expression BeadChip microarrays and Gene Spring Software for the analysis. Results: The IC 50 s for B, R, V, P, D and 5-Azacytidine alone were assessed at 24, 48 and 72 hours. In cytotoxicity assays the combination of D plus B, R, V or P at 72 hours showed synergism in all the cell lines (RRRs 0.0007-0.9). All the cell lines were treated with D, B or R for 72 hours and all the combinations showed significantly more apoptosis than the single drug exposures and controls (RRR &lt; 1). In vivo, HH SCID beige mice were treated i.p. for 3 cycles with the vehicle solution, D or B or their combination at increasing dose. The combination cohort showed statistically significant tumor growth inhibition compared to all the other cohorts. Gene expression analysis revealed differentially expressed genes and modulated pathways for each of the single agent treatment and the combination. The effects of the two drugs were largely different (only 39 genes modified in common). Most of the effects induced by the single agent were maintained in the combination group. Interestingly, 944 genes were modulated uniquely by the combination treatment. Conclusions: The combination of a DNMTI and HDACIs is strongly synergistic in vitro, in vivo and at the molecular level in model of T-cell lymphoma and these data will constitute the basis for a phase I-II clinical trials.
<sup>18</sup>F-fluorothymidine (FLT) PET-CT for early response assessment in advanced pancreatic cancer.
Authors: Amarnath Challapalli, Harpreet S Wasan, Adil Al-Nahhas, Eric Aboagye, Charles Coombes, Rohini Sharma
Journal: Journal of Clinical Oncology (2012)

e21093 Background: Advanced pancreatic cancer has a poor prognosis with a median survival of 6-10 months. There is a need for early non-invasive assessment of treatment response. We evaluated FLT PET-CT combined with a kinetic spatial filtering method (FLT-PET KSF ) for detecting response to gemcitabine-based chemotherapy in advanced pancreatic cancer. Methods: Dynamic FLT PET-CT data were collected from patients with confirmed locally advanced or metastatic pancreatic cancer before and 2 weeks after the first cycle of chemotherapy. Changes in tumor FLT-PET variables with treatment were determined. Standardized uptake value (SUV) reduction of 18% was taken as cut-off for response. Voxel quantification of each tumor volume was performed on the filtered data. Each voxel-intensity was normalised by injected dose, body weight and decay corrected to obtain the SUV for the voxel. Changes in high intensity voxels (HiVox: SUV ≥ 2) - were computed. Results: Results of the first 5 patients are discussed. There were 4 primary and 9 metastatic tumors. FLT-PET KSF improved tumor-to-background ratio and enabled visualisation of all the primary and metastatic tumors. The mean (± SD) average and maximum SUV at 60 min (SUV 60, av &amp; SUV 60, max ) of the primary lesions was 2.10 (±0.38) &amp; 4.85 (±1.55) and that of the metastatic lesions was 3.74 (±1.49) &amp; 6.90 (±2.05) respectively. The mean (± SD) percentage reduction in the SUV 60, av &amp; SUV 60, max , HIVox was 26 (±44), 18 (±38) and 23 (±50) respectively. The changes in the voxel occurrences correlated strongly with the changes in both SUV 60, av &amp; SUV 60, max (Pearson r-0.9, p=0.001) .Overall, there were 2 partial responders and 3 with stable disease. These responses concurred with response evaluation on mid-treatment CT scan. Conclusions: FLT-PET and FLT-PET KSF enables visualisation of the pancreatic tumors and the liver metastases, and could be used to monitor response to therapy.
Lymphatic System Influence On Acute Lung Injury After Intestinal Ischemia/reperfusion In Female Rats
Authors: W. Tavares-De-Lima, M. B. Amorim, E. T. Fantozzi, F. Y. Ricardo Da Silva, R. M. Oliveira-Filho, B. Boris Vargaftig, A. C. Breithaupt-Faloppa
Journal: American Journal of Respiratory and Critical Care Medicine (2014)
GENE-13. YEAR ONE IN THE MOLECULAR ERA OF PEDIATRIC BRAIN TUMOR DIAGNOSIS: APPLICATION OF UNIVERSAL CLINICAL TARGETED SEQUENCING IN AN UNSELECTED COHORT OF CHILDREN
Authors: Sarah Leary, Bonnie Cole, Christina Lockwood, Shannon Stasi, Jeff Stevens, Amy Lee, Jeffrey Ojemann, Michael Astion
Journal: Neuro-Oncology (2017)

INTRODUCTION: The 2016 revision of the WHO classification of CNS tumors defines molecular subtypes and diagnosis in addition to histopathology. However, there is not an established standard diagnostic test or panel. We evaluated the universal application of a next-generation sequencing(NGS) panel in an unselected single-institution cohort of pediatric brain tumor patients. METHODS: We prospectively sequenced 262 cancer-related genes using a clinical laboratory-developed NGS platform (UW-Oncoplex) in all pediatric brain tumors diagnosed at Seattle Children's Hospital from 11/2015 to 11/2016. Results were reviewed at a molecular tumor board and returned to patients and families with the assistance of a genetic counselor. RESULTS: Ninety patients were included in this study; 64 at diagnosis and 26 at recurrence. Histology included low-grade glioma(38), medulloblastoma(20), high-grade glioma(11), ependymoma(7) and other rare tumors(14). Results were returned for 87/90(97%) at a median of 35 days (range 9–78). Molecular alterations were identified in 69 patients(78%), which were disease defining or modifying in 58(64%). All medulloblastoma were characterized as SHH-activated(7), WNT-activated(1) or non-WNT, non-SHH(12). Only 2 of 8 H3KF3A K28M occured in classic DIPG. Potentially targetable changes were found in 40 patients(46%), most commonly KIAA1549-BRAF translocation(10), BRAFV600E(9), FGFR(9) followed by multiple rare targets each found in <5% of patients(12). To date, six patients have been prescribed targeted therapy based on this testing, two on clinical trial. Potential germline mutations were identified in 33(37%) patients. Of patients tested 5/7 were confirmed to have germline mutations. CONCLUSION: Targeted NGS may be used in clinical practice to diagnose and subclassify pediatric brain tumors, and identify targets for therapy. Efforts to decrease turnaround time and expand panels to include rare variants in pediatric tumors may increase clinical utility.
Association and Causation in Brain Imaging in the Case of OCD: Response to McKay et al.
Authors: Premika S.W. Boedhoe, Lianne Schmaal, David Mataix-Cols, Neda Jahanshad, Paul M. Thompson, Dan Stein, Odile A. van den Heuvel, Yoshinari Abe, Pino Alonso, Stephanie H. Ameis, Paul D. Arnold, Nuria Bargalló, Marcelo C. Batistuzzo, Francesco Benedetti, Jan C. Beucke, Premika S.W. Boedhoe, Irene Bollettini, Anushree Bose, Silvia Brem, Geraldo F. Busatto, Anna Calvo, Rosa Calvo, Danielle C. Cath, Yuqi Cheng, Kang Ik K. Cho, Sara Dallaspezia, Froukje E. de Vries, Stella J. de Wit, Damiaan Denys, Yu Fang, Kate D. Fitzgerald, Martine Fontaine, Jean-Paul Fouche, Mònica Giménez, Patricia Gruner, Gregory L. Hanna, Derrek P. Hibar, Marcelo Q. Hoexter, Hao Hu, Chaim Huyser, Keisuke Ikari, Neda Jahanshad, Norbert Kathmann, Christian Kaufmann, Sabin Khadka, Kathrin Koch, Jun Soo Kwon, Luisa Lazaro, Yanni Liu, Christine Lochner, Rachel Marsh, Ignacio Martínez-Zalacaín, David Mataix-Cols, José M. Menchón, Euripedes C. Miguel, Luciano Minuzzii, Astrid Morer, Takashi Nakamae, Tomohiro Nakao, Janardhanan C. Narayanaswamy, Fabrizio Piras, Federica Piras, Christopher Pittenger, Y.C. Janardhan Reddy, Joao R. Sato, H. Blair Simpson, Lianne Schmaal, Noam Soreni, Carles Soriano-Mas, Gianfranco Spalletta, Dan J. Stein, Michael C. Stevens, Philip R. Szeszko, Paul M. Thompson, David F. Tolin, Dick J. Veltman, Ganesan Venkatasubramanian, Odile A. van den Heuvel, Ysbrand D. van der Werf, Guido A. van Wingen, Susanne Walitza, Zhen Wang, Jian Xu, Xiufeng Xu, Je-Yeon Yun, Qing Zhao
Journal: American Journal of Psychiatry (2017)
Treatment with Hypomethylating Agent 5-Azacytidine Induces Sustained Response in Angioimmunoblastic T Cell Lymphomas
Authors: Richard Delarue, Jehan Dupuis, Pierre Sujobert, Sarah Barbieux, Ambroise Marçais, Olivier Tournilhac, Florence Lachenal, Morgane Cheminant, Clementine Sarkozy, Virginie Fataccioli, Franck Morschhauser, Olivier Hermine, Corinne Haioun, Philippe Gaulard, Francois Lemonnier
Journal: Blood (2016)
White flat lesions in the gastric corpus may be intestinal metaplasia
Authors: Pedro Pimentel-Nunes, Daniela Dobru, Diogo Libânio, Mário Dinis-Ribeiro
Journal: Endoscopy (2017)

See also: Multiple white flat lesions in the gastric corpus are not intestinal metaplasiaEndoscopy 2017; 49(06): 615-616DOI: 10.1055/s-0043-106434
Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study
Authors: Kenneth K C Man, Esther W Chan, Patrick Ip, David Coghill, Emily Simonoff, Phyllis K L Chan, Wallis C Y Lau, Martijn J Schuemie, Miriam C J M Sturkenboom, Ian C K Wong
Journal: BMJ (2017)

Objective To assess the potential association between prenatal use of antidepressants and the risk of attention-deficit/hyperactivity disorder (ADHD) in offspring.Design Population based cohort study.Setting Data from the Hong Kong population based electronic medical records on the Clinical Data Analysis and Reporting System.Participants 190 618 children born in Hong Kong public hospitals between January 2001 and December 2009 and followed-up to December 2015.Main outcome measure Hazard ratio of maternal antidepressant use during pregnancy and ADHD in children aged 6 to 14 years, with an average follow-up time of 9.3 years (range 7.4-11.0 years).Results Among 190 618 children, 1252 had a mother who used prenatal antidepressants. 5659 children (3.0%) were given a diagnosis of ADHD or received treatment for ADHD. The crude hazard ratio of maternal antidepressant use during pregnancy was 2.26 (P<0.01) compared with non-use. After adjustment for potential confounding factors, including maternal psychiatric disorders and use of other psychiatric drugs, the adjusted hazard ratio was reduced to 1.39 (95% confidence interval 1.07 to 1.82, P=0.01). Likewise, similar results were observed when comparing children of mothers who had used antidepressants before pregnancy with those who were never users (1.76, 1.36 to 2.30, P<0.01). The risk of ADHD in the children of mothers with psychiatric disorders was higher compared with the children of mothers without psychiatric disorders even if the mothers had never used antidepressants (1.84, 1.54 to 2.18, P<0.01). All sensitivity analyses yielded similar results. Sibling matched analysis identified no significant difference in risk of ADHD in siblings exposed to antidepressants during gestation and those not exposed during gestation (0.54, 0.17 to 1.74, P=0.30).Conclusions The findings suggest that the association between prenatal use of antidepressants and risk of ADHD in offspring can be partially explained by confounding by indication of antidepressants. If there is a causal association, the size of the effect is probably smaller than that reported previously.
Increased Risk of Second Hematological and Non-Hematological Malignancies in CLL Patients Treated with Chemotherapy As Compared to Untreated Patients and Matched Controls - Results from a Danish Population Based Study
Authors: Caspar Da Cunha-Bang, Klaus Rostgaard, Jacob Simonsen, Christian H Geisler, Henrik Hjalgrim, Henrik Frederiksen, Kirsten Grønbæk, Carsten Utoft Niemann
Journal: Blood (2016)
COMPARAISON DES TECHNIQUES D'ASPIRATION et de CAPILLARITE DANS LA PONCTION SOUS ECHOENDOSCOPIE
Authors: J Winkler, M Barraud-Blanc, E Norguet monnereau, L Heyries, R Laugier, P Grandval
Journal: Endoscopy (2016)

L'echoendoscopie est devenu un examen incontournable dans le diagnostic des lésions pancréatiques en particulier pour l'obtention d'une preuve histologique. Actuellement la ponction par aspiration est la technique la plus répandue. La ponction par capillarité ou «Slow pull» a été décrite plus récemment. Les données comparant les performances de ces techniques sont cependant contradictoires.