tbuckley/cabot-search huggingface dataset:
Brain nuclear receptors and body weight regulation
Authors: Yong Xu, Bert W. O’Malley, Joel K. Elmquist
Journal: Journal of Clinical Investigation (2017)

Neural pathways, especially those in the hypothalamus, integrate multiple nutritional, hormonal, and neural signals, resulting in the coordinated control of body weight balance and glucose homeostasis. Nuclear receptors (NRs) sense changing levels of nutrients and hormones, and therefore play essential roles in the regulation of energy homeostasis. Understanding the role and the underlying mechanisms of NRs in the context of energy balance control may facilitate the identification of novel targets to treat obesity. Notably, NRs are abundantly expressed in the brain, and emerging evidence indicates that a number of these brain NRs regulate multiple aspects of energy balance, including feeding, energy expenditure and physical activity. In this Review we summarize some of the recent literature regarding effects of brain NRs on body weight regulation and discuss mechanisms underlying these effects.
A novel LSD1 inhibitor NCD38 ameliorates MDS-related leukemia with complex karyotype by attenuating leukemia programs via activating super-enhancers
Authors: N Sugino, M Kawahara, G Tatsumi, A Kanai, H Matsui, R Yamamoto, Y Nagai, S Fujii, Y Shimazu, M Hishizawa, T Inaba, A Andoh, T Suzuki, A Takaori-Kondo
Journal: Leukemia (2017)
Respiratory Syncytial Virus Infections (RVS) after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in the Palivizumab (P) Era.
Authors: Flore Sicre de Fontbrune, Marie Robin, Catherine Scieux, Régis Peffault de Latour, Christèle Ferry, Vanderson Rocha, Karim Boudjedir, Agnès Devergie, Eliane Gluckman, Gérard Socié, Patricia Ribaud
Journal: Blood (2006)
P08.25 de novo transcriptome assembly finds novel glioblastoma subtype-specific transcripts
Authors: M. N. C. Fletcher, A. Bertoni, Y. Wu, Z. Gu, Q. Wang, M. Tönjes, M. Zapatka, C. Herrmann, B. Radlwimmer, P. Lichter, D. Jones
Journal: Neuro-Oncology (2016)
Long-Term Significance of Achieving a Major Cytogenetic Response (MCyR) without a Complete Hematologic Response (CHR) among Patients (pts) with Chronic Myeloid Leukemia (CML) in Advanced Phase Treated with Second Generation Tyrosine Kinase Inhibitors (TKI).
Authors: Carmen Fava, Hagop M. Kantarjian, Elias Jabbour, Mary Beth Rios, Guillermo Garcia-Manero, Susan O’Brien, Jorge Cortes
Journal: Blood (2007)
Dasatinib Is An Effective Inhibitor of Proliferation and Inducer of Apoptosis in the KASUMI Cell Line Bearing the T(8;21)(q22;q22) and the N822K KIT Mutation
Authors: Vassiliki Pappa, F. Kontsioti, E. Liakata, S Papageorgiou, A. Spathis, P Tsirigotis, ED Ioannidou, C Economopoulou, S Chondropoulos, K Girkas, E Papageorgiou, P. Karakitsos, J Dervenoulas, T Economopoulos
Journal: Blood (2008)
Hemoglobin S Oxidation Promotes Plasma-Derived Microparticle Membrane Alterations and Toxicity
Authors: Sirsendu Jana, Michael B Strader, Tigist Kassa, Fantao Meng, Wayne Hicks, Ivan Tarandovskiy, Silvia De Paoli, Jan Simak, Jeffery L Miller, Laurel Mendelsohn, Jim Nichols, Swee Lay Thein, John D. Belcher, Gregory M Vercellotti, Abdu Alayash
Journal: Blood (2016)
Omission of lung radiation in patients with stage IV favorable histology Wilms Tumor (FHWT) showing complete lung nodule response after chemotherapy: A report from Children’s Oncology Group study AREN0533.
Authors: David B. Dix, Eric J. Gratias, Nita Seibel, James Robert Anderson, Elizabeth Anne Mullen, James I. Geller, Geetika Khanna, John A. Kalapurakal, Elizabeth Jones Perlman, Peter F. Ehrlich, Marcio H. Malogolowkin, Paul Edward Grundy, Jeffrey S. Dome
Journal: Journal of Clinical Oncology (2015)

10011 Background: In National Wilms Tumor Study-5, patients with stage IV FHWT with metastases limited to the lung had 5-year EFS of 74% in the setting of incomplete lung nodule response by Day 70 versus 85% with complete lung nodule response (CR). All patients were treated with Regimen DD4A (vincristine/dactinomycin/doxorubicin) and whole lung irradiation (RT). To decrease the risk of long-term toxicities associated with RT, the AREN0533 study sought to determine whether patients with lung nodule CR after 6 weeks of chemotherapy would maintain excellent EFS without the use of lung RT. Methods: Patients were enrolled between February 2007 and February 2013 after undergoing central review of surgical reports, pathology slides and chest CT scans on the AREN03B2 Biology and Classification Study. Lung nodule response after 6 weeks of chemotherapy was determined by central radiology review. The null hypothesis was that 4-year EFS for CR when treated with DD4A therapy and pulmonary RT is 85%. The study was designed to have 90% power (testing at 10% 1-sided) to detect an increase in the risk of failure corresponding to 4-year EFS of 75%. Results: Among 391 patients enrolled, 296 had lung-only metastases, of which 105 (39%) had CR. At interim analysis in June 2014, 20 events were observed, compared to 14.5 expected under the null hypothesis (p = 0.15). 19 of the 20 events were recurrences and 1 was a second malignancy. Among the 19 recurrences, there were 2 deaths with a median follow-up of 2.3 years from recurrence. Recurrences were in the lung only (17), lung and liver (1) and abdomen (1). The 4-year EFS and OS estimates for the CR patients were 78% (95% CI: 68%, 86%) and 95% (95% CI: 83%, 98%). Conclusions: Patients with FHWT with week 6 lung nodule CR treated without lung RT had EFS somewhat less than the historical standard treated with lung RT, though this difference was not statistically significant. The excellent OS suggests that omission of lung RT may provide an acceptable treatment approach for this patient subgroup. Clinicians should balance the benefit of avoidance of lung RT against the possibility of a modest increase in relapse risk. Clinical trial information: NCT00379340.
GRAY-B: An open label multicenter phase-2 GEM study on ipilimumab and radiation in patients with melanoma and brain metastases
Authors: J.A. Lopez Martin, Ldela Cruz Merino, A.M. Arance Fernandez, A. Illescas, I. Valduviecu Ruiz, A. Berrocal, J. Lopez-Torrecilla, I. Marquez Rodas, M.V. Soriano Teruel, A. Alvarez Gonzalez, M.L. Chust Vicente, D. Rodriguez Abreu, R. Cabrera, M.C. Penas Sanchez, T. Curiel, E. Munoz Couselo, J.J. Aristu, A. Gomez-Caamano, J. Medina Martinez, S. Martin-Algarra
Journal: Annals of Oncology (2016)
APO010 sensitivity in relapsed multiple myeloma patients
Authors: A.J. Vangsted, P.B. Jensen, M.W. Madsen, P. Gimsing, T. Jensen, A. Hansen, A. Rasmussen, A. Nielsen, U. Buhl, H. Jandu, N. Brunner, B. Pratt, U.C. Frølund, C. Helleberg, N. Abildgaard, S. Knudsen
Journal: Annals of Oncology (2016)
BMET-13. WHOLE BODY AND INTRACRANIAL EFFICACY OF CERITINIB IN ALK-INHIBITOR (ALKi)-NAIVE PATIENTS WITH ALK-REARRANGED (ALK+) NSCLC AND BASELINE BRAIN METASTASES (BM): RESULTS FROM ASCEND-1 AND -3
Authors: Ranee Mehra, Enriqueta Felip, Daniel Shao-Weng Tan, Dong-Wan Kim, Sergey Orlov, Keunchil Park, Chong-Jen Yu, Tony Mok, Makoto Nishio, Giorgio V. Scagliotti, David R. Spigel, Santosh Sutradhar, Dajana Cesic, Alice Tsang Shaw
Journal: Neuro-Oncology (2016)

Efficacy outcomes are presented in ALK+ NSCLC patients with baseline BM and without prior ALKi treatment, who were treated with the selective oral ALKi, ceritinib, in the ASCEND-1 (ph1/NCT01283516) and ASCEND-3 (ph2/NCT01685138) trials. ALKi-naive patients with ALK+ NSCLC and stable baseline BM received ceritinib, 750 mg/day. Efficacy analyses (blinded independent review committee [BIRC]) assessed whole body responses for ASCEND-1 and -3 by RECIST v1.0/v1.1, respectively. Pooled intracranial responses were evaluated by BIRC (ASCEND-1, retrospectively; ASCEND-3, prospectively) in patients with measureable baseline BM (RECIST v1.1). For ASCEND-1 and ASCEND-3, respectively: 26 and 50 ALKi-naive patients with baseline BM were enrolled (of which 8 and 17 had measureable BM); 88.5% and 100% had prior chemotherapy; 57.7% and 54.0% had prior brain radiotherapy (RT); median follow-up 12.3 (0.6–22.1) and 7.5 (0.6–13.8) months; median times from prior RT to first ceritinib dose 4.6 and 2.7 months. While on ceritinib treatment, 2 (7.7%) and 5 (10.0%) patients received RT to the brain; median times from first ceritinib dose to first RT treatment were 5.2 and 5.5 months. The whole body overall response rates (ORR) were 65.4% and 60.0%; intracranial ORRs in patients with measurable baseline BM were 62.5% and 58.8% (pooled ORR, 60.0%). Whole body disease control rates (DCR) were 76.9% and 78.0%; intracranial DCRs in patients with measurable baseline BM were 62.5% and 82.4% (pooled DCR, 76.0%). Most common adverse events (AEs) (ASCEND-1; ASCEND-3) were nausea (84.6%; 78.0%), diarrhea (92.3%; 76.0%) and vomiting (76.9%; 72.0%); 46 patients (ASCEND-1: 19; ASCEND-3: 27) had dose reductions; 4 patients (ASCEND-1: 3; ASCEND-3: 1) discontinued due to AEs. Clinically meaningful whole body and intracranial activity with an acceptable tolerability profile was observed in ALKi-naive patients with ALK+ NSCLC and baseline BM treated with ceritinib; few patients required brain RT while on ceritinib.
Gemcitabine as single agent second line treatment in patients with advanced wild-type EGFR, negative ALK non-small cell lung cancer: a retrospective study
Authors: S. Rinaldi, F. Morgese, M. Torniai, A. Savini, F. Barbotti, F. Pirani, G. Leoni, C. Grohè, T. Newsom-Davis, V. Paolucci, M. Bower, I. Fiordoliva, R. Berardi
Journal: Annals of Oncology (2016)
Characterization of the Two Populations of NK-Like CD56+ T Cells and KIR+ T Cells in Human
Authors: Wing Keung Chan, Piya Rujkijyanont, Geoffrey A. Neale, Jie Yang, Rafijul Bari, Neha Das Gupta, Martha Holladay, Barbara Rooney, Susanne Wendt, Wing Leung
Journal: Blood (2012)
MNGO-10. PD-1/PD-L1 AND GENOMIC EXPRESSION PROFILING OF MENINGIOMAS
Authors: Shaan Raza, Nader Sanai, Joanne Xiu, Lyndon Kim, Santosh Kesari, Shouhao Zhou, Amy Heimberger
Journal: Neuro-Oncology (2016)

Surgery and radiation are the standard treatment options for meningiomas; however, this is not always feasible. Alternative targeted- or immune-therapeutic- approaches could be considered and prioritized based on tumor expression profiling. Meningioma patients were profiled by Caris Life Sciences using immunohistochemistry (IHC) to detect PD-1 on tumor-infiltrating lymphocytes and PD-L1 on tumor cells with the SP142 antibody. Next-generation sequencing, pyrosequencing, IHC, fragment analysis, and fluorescence in situ hybridization were used to determine mutational and expression status. A total of 115 meningioma tumors were analyzed across grades (I: n=22; II: n=36; III: n=30, indeterminate: n=27). The median age of the cohort was 60, with a range spanning 6-90 years; 52% were female. The most frequent mutation (frameshift or truncating) across all grades occurred in the NF2 gene, at 63% (7/11). Occasionally (1-14%), other mutations were identified in the APC (L1129S), AKT1 (E13K), PIK3CA (H1047R, N345K), FBXW7 (L583X), TP53 (V197E, G112fs), PTCH1 (F88FS), and FOXO3 (L382fs) genes. The most frequently overexpressed genes, regardless of grade, were EGFR (93%; n=44), followed by PTEN (77%; n=110), MRP1 (65%, n=23), PGP (62%; n=84), and then MGMT (55%; n=97). PD-L1 was expressed in 25% of grade III cases (2/8) but not in grade I or II tumors. PD-1+ T cells were present in 46% (24/52) of meningiomas, with enrichment in grade II. TOP2A and thymidylate synthase expression increased with grade (I=5%, II=22%, III=68% and I=5%, II=27%, III=46%, respectively), whereas progesterone receptor expression and the TP53 mutation frequency decreased with grade (I=78%, II=39%, III=30% and I=7%, II=4% and III=0, respectively). IDH1/2 mutations were not present. If predicated on tumor expression, our data suggest that therapeutics directed toward NF2, EGFR, PTEN, MRP1, PGP, TS and PD-1 could be considered for most meningioma patients.
RARE-03. EPENDYMOMAS ARISING OUTSIDE OF THE CENTRAL NERVOUS SYSTEM: A CASE SERIES
Authors: Shlomit Yust-Katz, David Cachia, Carlos Kamiya-Matsuoka, Brett J Theeler, Adriana Olar, Marta Penas Prado, Terri Armstrong, Mark Gilbert
Journal: Neuro-Oncology (2016)

Extracranial and extraspinal ependymomas are extremely rare tumors mostly published in the literature as case reports. Our institutional database was screened for patients with extra CNS ependymomas over a 25 year period. Eight patients with extra CNS ependymoma were identified. Five cases originated in the sacrum or subcutaneous sacral area, and the other 3 cases originating in the breast, lung and adnexa of the uterus. By histology, most cases were myxopapilary ependymomas (5 cases), 2 cases were grade 2 ependymoma and 1 case was an anaplastic ependymoma. Metastases occurred in 6 cases and 3 patients died due to progressive disease. Most cases required surgery, radiation and chemotherapy. Extra CNS ependymomas are very rare tumors that tend to metastasize, even though most cases are histologically classified as low grade ependymomas, suggesting that the tumor biology does not correlate with conventional histologic findings. Future plans include molecular phenotyping to determine if these rare cancers are molecular similar to the recent findings from infratentorial, supratentorial ependymomas or the metabolic profile of classic spinal myxopapillary ependymoma.
Romedepsin (RM), a HDACi, Significantly Increases the Expression of NKG2D Ligands, MIC A/B, in Leukemia/Lymphoma Cells (LL), in Part through the Glycogen Synthase Kinase-3 (GSK-3) Pathway, Resulting in Enhanced NK Cytotoxicity.
Authors: Aniket Saha, Sejal Bavishi, Frances Zhao, Janet Ayello, Carmella van de Ven, Prakash Satwani, Mitchell S. Cairo
Journal: Blood (2009)
Prospective study of cetuximab with cisplatin plus docetaxel followed by concurrent radiotherapy plus cetuximab and cisplatin in patients with chemotherapy-naive metastatic nasopharyngeal carcinoma
Authors: T. Lin, M. Zhang, H. Huang, X. Li, Y. Huang, C. Chen, Z. Wang, X. Fang
Journal: Annals of Oncology (2016)
Breast Cancer Version 2.2015
Authors: William J. Gradishar, Benjamin O. Anderson, Ron Balassanian, Sarah L. Blair, Harold J. Burstein, Amy Cyr, Anthony D. Elias, William B. Farrar, Andres Forero, Sharon Hermes Giordano, Matthew Goetz, Lori J. Goldstein, Clifford A. Hudis, Steven J. Isakoff, P. Kelly Marcom, Ingrid A. Mayer, Beryl McCormick, Meena Moran, Sameer A. Patel, Lori J. Pierce, Elizabeth C. Reed, Kilian E. Salerno, Lee S. Schwartzberg, Karen Lisa Smith, Mary Lou Smith, Hatem Soliman, George Somlo, Melinda Telli, John H. Ward, Dorothy A. Shead, Rashmi Kumar
Journal: Journal of the National Comprehensive Cancer Network (2015)

Breast cancer is the most common malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. The overall management of breast cancer includes the treatment of local disease with surgery, radiation therapy, or both, and the treatment of systemic disease with cytotoxic chemotherapy, endocrine therapy, biologic therapy, or combinations of these. This portion of the NCCN Guidelines discusses recommendations specific to the locoregional management of clinical stage I, II, and IIIA (T3N1M0) tumors.
First-line icotinib versus cisplatine/pemetrexed plus pemetrexed maintenance therapy in lung adenocarcinoma patients with EGFR mutation (CONVINCE)
Authors: Y.-K. Shi, L. Wang, B. Han, W. Li, P. Yu, Y. Liu, C. Ding, X. Song, Z. Ma, X. Ren, J. Feng, H. Zhang, G. Chen, N. Wu, X. Han, C. Yao, Y. Song, S. Zhang, L. Ding, F. Tan
Journal: Annals of Oncology (2016)
Novel Human Monoclonal Antibody Against CD47 Induces Cell Death in Lymphoid Malignant Cells In Vitro and In Vivo: Potential Novel Therapeutic Agent for B-CLL.
Authors: Takatsune Shimizu, Yoshitaka Miyakawa, Naoshi Fukushima, Yasufumi Kikuchi, Shigeyuki Iijima, Yasuko Kinoshita, Yumiko Azuma, Iwao Ohizumi, Hisafumi Okabe, Yasuo Ikeda, Masahiro Kizaki
Journal: Blood (2004)
Gemcitabine and nab-paclitaxel combination therapy for the treatment of metastatic pancreatic cancer
Authors: Takashi Sasaki, Ryo Kanata, Kei Saito, Ikuhiro Yamada, Masato Matsuyama, Masato Ozaka, Kouichi Takano, Naoki Sasahira
Journal: Annals of Oncology (2016)
SpyGlass DS-guided conversion of transmural pancreaticogastrostomy drainage to transpapillary drainage by rendezvous via a lumen-apposing metal stent
Authors: Joan Gornals, Claudia Consiglieri, Susana Redondo
Journal: Endoscopy (2017)

Recently, we reported a successful endoscopic ultrasound-guided pancreatic duct (PD) drainage using a lumen-apposing metal stent (LAMS) plus a pigtail stent in a 44-year-old man with chronic pancreatitis and PD stricture [1]. The patient's course was satisfactory and 5 months later conversion of the transmural drainage to transpapillary drainage was planned.
The impact of traveling distance to the hospital in cases of treatment using EGFR tyrosine kinase inhibitors
Authors: Taichi Miyawaki, Shigehiro Yagishita, Mitsuhiro Hujii, Ai Nakamura, Naohisa Matsumoto, Ryo Kou, Munechika Hara, Naoko Iwakami, Toshiji Ishiwata, Shinichirou Iwakami, Kazuhisa Takahashi
Journal: Annals of Oncology (2016)
High-dose methotrexate (HD-MTX) as CNS prophylaxis significantly improves outcome in patients with high-risk diffuse large B-cell lymphoma (DLBCL)
Authors: T. Calimeri, C. Cecchetti, A. Vignati, M. Sassone, M. Foppoli, L. Scarfò, M. Ponzoni, A. Ferreri
Journal: Annals of Oncology (2016)
Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice
Authors: Almut Grenz, Jessica D. Bauerle, Julee H. Dalton, Douglas Ridyard, Alexander Badulak, Eunyoung Tak, Eóin N. McNamee, Eric Clambey, Radu Moldovan, German Reyes, Jost Klawitter, Kelly Ambler, Kristann Magee, Uwe Christians, Kelley S. Brodsky, Katya Ravid, Doo-Sup Choi, Jiaming Wen, Dmitriy Lukashev, Michael R. Blackburn, Hartmut Osswald, Imogen R. Coe, Bernd Nürnberg, Volker H. Haase, Yang Xia, Michail Sitkovsky, Holger K. Eltzschig
Journal: Journal of Clinical Investigation (2014)

It has come to our attention that multiple gel images in Figure 1A were inappropriately duplicated from a previous
Gemtuzumab-Ozogamicin Containing Regimens As Induction Therapy Give the Highest Complete Remission Rate and the Longest Overall Survival Compared with Other Induction Regimens in Patients with Newly Diagnosed Acute Myeloid Leukemia
Authors: Cristina Papayannidis, Anna Candoni, Michele Malagola, Giovanni Marconi, Marco Manfrini, Giorgia Simonetti, Elisa Zuffa, Maria Chiara Abbenante, Sarah Parisi, Stefania Paolini, Chiara Sartor, Eugenia Franchini, Emanuela Ottaviani, Claudia Venturi, Maria Chiara Fontana, Antonella Padella, Viviana Guadagnuolo, Maria Teresa Bochicchio, Anna Ferrari, Simona Soverini, Nicoletta Testoni, Carmen Baldazzi, Renato Fanin, Domenico Russo, Michele Cavo, Giovanni Martinelli
Journal: Blood (2015)
Active Chromatin Structure near MYB Occupancy at the Mir-155 Host Gene Promoter Coincides with Increased Mir-155 and MYB Levels In Chronic Lymphocytic Leukemia
Authors: Tomas Stopka, Karin Vargova, Nikola Curik, Pavel Burda, Petra Basova, Vit Pospisil, Vojtech Kulvait, Filipp Savvulidi, Emanuel Necas, Adela Berkova, Petra Obrtlikova, Josef Karban, Marek Trneny, Jiri Zavadil
Journal: Blood (2010)
Osimertinib in EGFR T790M positive advanced NSCLC (aNSCLC) – real–life data from the French temporary authorization for use (ATU) program
Authors: D. Planchard, M. Pérol, X. Quantin, A. Cortot, J. Cadranel, R. Schott, E. Dansin, G. Fraboulet, D. Moro-Sibilot, J.-C. Soria, J. Mazieres, S.L.e. Moulec, M. Coudurier, E. Pichon, M. Licour, D. Maribas, A. Gourion, N. Radu, N. Varoqueaux, C. Chouaid
Journal: Annals of Oncology (2016)
Phase II open-label single-arm study of pre-operative panitumumab and external pelvic radiotherapy (RTE) in locally advanced rectal cancer (LARC) patients (pts) (RaP/STAR-03 Study)
Authors: C. Pinto, M. Di Bisceglie, F. Di Fabio, A.M. Bochicchio, T. Latiano, S. Cordio, G. Rosati, C. Aschele, A. Marino, F. Bergamo, S. Bustreo, L. Frassineti, F. Ciardiello, S. Giaquinta, D. Baldari, L. Boni
Journal: Annals of Oncology (2016)
P21.03 Efficacy of bevacizumab in a primary diffuse leptomeningeal glioneuronal tumor of the adult
Authors: A. Pellerino, R. Rudà, M. Magistrello, F. Franchino, E. Nicolotto, L. Bertero, F. Giangaspero, R. Soffietti
Journal: Neuro-Oncology (2016)
Statins Increase Antileukemic Potency of Imatinib Through the Inhibition of MDR/ABCB1 and BCRP/ABCG2 Drug Transporters Activity
Authors: Eliza Glodkowska-Mrowka, Piotr Mrowka, Magdalena Winiarska, Grzegorz Basak, Joanna Niesiobedzka-Krezel, Ilona Seferynska, Pawel Krzysztof Wlodarski, Marek Jakobisiak, Tomasz Stoklosa
Journal: Blood (2011)
Flt3-Ligand Plays a Critical Role in Restoring Function of NOD Facilitating Cells.
Authors: Yiming Huang, Isabelle J. Fugier-Vivier, Thomas Miller, Mary J. Elliott, Michael K. Tanner, Hong Xu, Safinur Atay, Lala-Rukh Hussain, Larry D. Bozulic, Paula M. Chilton, Suzanne T. Ildstad
Journal: Blood (2007)
Phase I study of receptor tyrosine kinase (RTK) inhibitor, MGCD265, in patients (pts) with advanced solid tumors.
Authors: Christian K. Kollmannsberger, Sunil Sharma, Geoffrey Shapiro, Kim N. Chi, James Christensen, Vanessa Roberts Tassell, Richard C. Chao, Demiana Faltaos, Herbert Hurwitz
Journal: Journal of Clinical Oncology (2015)

2589 Background: MGCD265 is a spectrum-selective and ATP-competitive inhibitor with MET and Axl as clinically relevant RTK targets. In nonclinical studies, MGCD265 demonstrated anti-tumor activity in cancer models exhibiting dysregulation of MET or Axl RTKs. Methods: Phase I objectives were to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of MGCD265. Eligible pts with advanced solid tumors received MGCD265 on Cycle 1 Day 1, then continuous dosing starting on Cycle 1 Day 3 for 21-day cycles. PK/PD were evaluated after single dose and repeated administration. Results: 12 pts (6 males; median age 57 years; range 48-75) with advanced malignancies were treated with 600, 1200 or 1050 mg BID of MGCD265 in non-aqueous suspension capsules. At 1200 mg BID, 2 out of 6 evaluable pts experienced DLT (G3 fatigue; G3 diarrhea). 1050 mg BID was defined as the MTD with no DLTs in 3 pts. Treatment-related AEs ( > 20% all grades) included diarrhea, nausea, vomiting, fatigue, AST increase, ALT increase and lipase increase. Stable disease of at least 6 weeks was observed (n = 2). At MTD, preliminary data show that steady state average and maximum concentrations were 501 and 562 ng/mL, respectively; the area under the concentration-time curve for the dosing interval was 6010 ng•h/mL. Preliminary data show that plasma concentrations exceeded levels projected for near complete inhibition of both MET and Axl for the full dosing interval. Maximal increase of plasma soluble MET ectodomain (sMET) was observed at each dose level including those associated with sustained steady state plasma concentrations (Cmin) as low as 200 ng/mL, suggesting that the MET pathway was inhibited at all 3 dose levels and concentrations achieved in this study. Conclusions: MGCD265 is well tolerated at the MTD of 1050 mg BID. Based on safety, PK data and PD data suggesting robust inhibition of MET and Axl, the expansion phase of the study began recruitment in December 2014. Patients with NSCLC and other solid tumors with specific genetic alterations for MET and AXL will be enrolled. Clinical trial information: NCT00697632.
Empiric or Presumptive Anti-Aspergillus Treatments for Allogeneic Hematopoietic Stem Cell Transplant Recipients with Sustained Febrile Neutropenia.
Authors: Kumi Oshima, Yoshinobu Kanda, Yuki Asano-Mori, Hiroyuki Sato, Takuro Watabane, Noriko Hosoya, Koji Izutsu, Takashi Asai, Akira Hangaishi, Toru Motokura, Shigeru Chiba, Mineo Kurokawa
Journal: Blood (2006)