tbuckley/cabot-search huggingface dataset:
Characterization of isolated, uncomplicated neutropenia–related to the CDK4/6 inhibitor palbociclib.
Authors: Angela DeMichele, Mark Andrew Dickson, Amy Sanders Clark, Christopher Colameco, Maryann Gallagher, Kristi Gramlich, Kelly Zafman, David Lewis, Melissa Langer, David J. Vaughn, Gary K. Schwartz, Peter J. O'Dwyer
Journal: Journal of Clinical Oncology (2014)

2547 Background: Palbociclib (P), an oral, selective, reversible CDK4/6 inhibitor induces transient G1 arrest in hematopoietic stem/progenitor cells (HSPC), without DNA damage or apoptosis in preclinical studies. In patients (pts) with advanced malignancy, P had activity in several tumor types, but neutropenia was dose-limiting. We sought to characterize the incidence and patterns of myelosuppression to determine if the mechanisms observed preclinically were reflected in the clinical experience. Methods: Data from 2 phase 2 studies of single agent P in pts with advanced RB+ tumors (UPenn, NCT01037790) and liposarcoma (MSKCC, NCT01209598) were analyzed. Dose (125 mg P), schedule (3 wks on/1 wk off) and safety assessments (baseline, weekly cycle 1 and d 1 of subsequent cycle) were identical. Both trials required P be held for > grade (Gr) 3 myelosuppression until resolved to < Gr 2. Results: 140 patients with breast (36%), sarcoma (21%), germ cell (21%), colon (13%), gastric (7%) tumors were enrolled. Neutropenia, anemia and thrombocytopenia rates in cycle 1 by Gr are shown. Mean absolute neutrophil count was 4.98, 4.24, 2.15, 1.62 and 1.86 at weeks 1, 2, 3, 4 and 5, respectively, reflecting time to nadir. Time to Gr3 neutropenia was 3 wks in 11%, 4 wks in 30%, 5 wks in 14%. Recovery occurred after brief dose delay. Neutropenia led to dose interruption in 19% of pts in cycle 1 and 8% had Gr3 neutropenia on day 1/cycle 2. Despite the high rate of Gr 3/4 neutropenia (39%), only 1 episode of neutropenic fever occurred (in setting of disease progression), with no infections or use of G-CSF. Mucositis was rare and <Gr2. Concurrent Gr3 anemia or thrombocytopenia were rare (6% and 15% respectively). Conclusions: Frequent, isolated and uncomplicated neutropenia in patients receiving P is consistent with preclinically observed quiescence but not death of HSPC and little effect on differentiated myeloid cells. The lack of clinical morbidity or pancytopenia suggests that P-induced neutropenia is short lasting, reversible and may be managed conservatively. PK data will be reported to confirm the relationship between ANC and drug exposure. Clinical trial information: NCT01037790, NCT01209589. Grade Neutropenia Anemia Thrombocytopenia 2 31% 28% 14% 3 36% 4% 9% 4 3% 0 <1%
Final Results of NRG Oncology RTOG 0246: An Organ-Preserving Selective Resection Strategy in Esophageal Cancer Patients Treated with Definitive Chemoradiation
Authors: Stephen G. Swisher, Jennifer Moughan, Ritsuko U. Komaki, Jaffer A. Ajani, Tsung T. Wu, Wayne L. Hofstetter, Andre A. Konski, Christopher G. Willett
Journal: Journal of Thoracic Oncology (2016)
Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results
Authors: Thomas J. Hwang, Daniel Carpenter, Julie C. Lauffenburger, Bo Wang, Jessica M. Franklin, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2016)

Many investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research.To assess factors associated with regulatory approval or reasons for failure of investigational therapeutics in phase 3 or pivotal trials and rates of publication of trial results.Using public sources and commercial databases, we identified investigational therapeutics that entered pivotal trials between 1998 and 2008, with follow-up through 2015. Agents were classified by therapeutic area, orphan designation status, fast track designation, novelty of biological pathway, company size, and as a pharmacologic or biologic product.For each product, we identified reasons for failure (efficacy, safety, commercial) and assessed the rates of publication of trial results. We used multivariable logistic regression models to evaluate factors associated with regulatory approval.Among 640 novel therapeutics, 344 (54%) failed in clinical development, 230 (36%) were approved by the US Food and Drug Administration (FDA), and 66 (10%) were approved in other countries but not by the FDA. Most products failed due to inadequate efficacy (n = 195; 57%), while 59 (17%) failed because of safety concerns and 74 (22%) failed due to commercial reasons. The pivotal trial results were published in peer-reviewed journals for 138 of the 344 (40%) failed agents. Of 74 trials for agents that failed for commercial reasons, only 6 (8.1%) were published. In analyses adjusted for therapeutic area, agent type, firm size, orphan designation, fast-track status, trial year, and novelty of biological pathway, orphan-designated drugs were significantly more likely than nonorphan drugs to be approved (46% vs 34%; adjusted odds ratio [aOR], 2.3; 95% CI, 1.4-3.7). Cancer drugs (27% vs 39%; aOR, 0.5; 95% CI, 0.3-0.9) and agents sponsored by small and medium-size companies (28% vs 42%; aOR, 0.4; 95% CI, 0.3-0.7) were significantly less likely to be approved.Roughly half of investigational drugs entering late-stage clinical development fail during or after pivotal clinical trials, primarily because of concerns about safety, efficacy, or both. Results for the majority of studies of investigational drugs that fail are not published in peer-reviewed journals.
GW27-e0856 Activation of peripheral blood leukocytes in patients with atrial fibrillation following ACE inhibitors or ARBs therapy: differences in CD 11b expression
Authors: Boshui Huang, Meidan Nong, Yin Chen, Fasheng Liang, Huayuan Zeng, Shuxian Zhou
Journal: Journal of the American College of Cardiology (2016)
A switch in regulatory T cells through farm exposure during immune maturation in childhood
Authors: P. C. Schröder, S. Illi, V. I. Casaca, A. Lluis, A. Böck, C. Roduit, M. Depner, R. Frei, J. Genuneit, P. I. Pfefferle, M. Roponen, J. Weber, C. Braun-Fahrländer, J. Riedler, J.C. Dalphin, J. Pekkanen, R. Lauener, E. von Mutius, B. Schaub
Journal: Allergy (2016)

Background Farm exposure protects against development of allergies early in life. At 4.5 years, protection against asthma by farm-milk exposure was partially mediated by regulatory T cells (Tregs). The aim of this study was to investigate the critical time window of the ‘asthma-protective’ farm effect via Tregs during childhood immune maturation. Methods Tregs were assessed longitudinally at 4.5 and 6 years in 111 children (56 farm and 55 reference children) from the PASTURE/EFRAIM birth cohort (flow cytometry). Peripheral blood mononuclear cells were cultured unstimulated (U), with phorbol 12-myristate 13-acetate/ionomycin (PI) or lipopolysaccharide (LPS), and stained for Tregs (CD4+CD25highFOXP3upper20%). mRNA expression of Treg/Th1/Th2/Th17-associated cell markers was measured ex vivo. Suppressive capacity of Tregs on effector cells and cytokines was assessed. Detailed questionnaires assessing farm exposures and clinical phenotypes from birth until age 6 years were answered by the parents. Results Treg percentage before and after stimulation and FOXP3mRNA expression ex vivo decreased from age 4.5 to 6 years (P(U,LPS) < 0.001; P(PI) = 0.051; P(FOXP3) < 0.001). High vs low farm-milk and animal-stable exposure was associated with decreased LPS-stimulated Treg percentage at age 6 years (P(LPS) = 0.045). Elevated LPS-stimulated-Treg percentage at age 6 was associated with increased risk of asthma (aOR = 11.29, CI: 0.96–132.28, P = 0.053). Tregs from asthmatics vs nonasthmatics suppressed IFN-γ (P = 0.015) and IL-9 (P = 0.023) less efficiently. mRNA expression of Th1/Th2/Th17-associated cell markers decreased between 4.5 and 6 years (P < 0.001). Conclusions Tregs at the age of 6 years were decreased with farm exposure and increased within asthmatics, opposite to age 4.5 years. This immunological switch defines a critical ‘time window’ for Treg-mediated asthma protection via environmental exposure before age 6 years.
Adjuvant (A) and neoadjuvant (NeoA) chemotherapy (C) in resected synovial sarcoma (SS): A study of the French Sarcoma Group (GSF-GETO)
Authors: A. Italiano, A. Dufresne, B. N. Bui, A. LeCesne, J. Y. Blay, Y. ROBIN, J. Coindre, S. Piperno-Neumann, M. Tubiana-Hulin, N. Penel
Journal: Journal of Clinical Oncology (2008)

10527 Background: The impact of AC for soft-tissue sarcoma is debated, notably because previous randomized trials included a variety of histologic subtypes. We report here a database study assessing the role of AC and NeoAC in patients with SS. Methods: 212 patients (pts) with primary SS were included prospectively in the GSF GETO database from September 1988 to October 2006. Survival was estimated with Kaplan-Meier method from the date of histological diagnosis. Prognostic factors (PF) were identified by log-rank test followed by Cox model. Impact of AC and NeoAC were adjusted to PF using a Cox model. Results: Surgery with a curative intent was performed in all the cases but one (96 males, 115 females) and followed by radiotherapy in 79% of cases. Median age was 35 (range 15–76). Median tumor size was 7 cm (range 1–35). 52% of tumors were grade 3. AC and Neo-AC were performed in 47%, and 14% of pts (both in 4%). 27.5% of pts received an ifosfamide-based regimen. Median follow-up for survivors was 48 months. Median overall survival (OS) was 130 months (range 1- 251). Local and metastatic failures occurred in 22% and 30% of cases respectively. Univariate analysis identified the following PF for OS: male gender (p=0.041), age>35 (0.038), size>8 cm (0.008), Grade 3 (0.0001) and surgery as first treatment (0.002). Cox model identified 2 independent PF: age>35 (Hazard Ratio HR 1.7 [1.1–2.8]) and Grade 3 (HR=4.0 [2.2–7.2]). After adjustment to these 2 PF, AC and neo-AC had no significant impact on OS (HR=0.9 [0.5–1.5]) and 0.8 [0.5–1.4]). Nevertheless, dose-intensity of ifosfamide (DII) significantly influenced OS with a relation dose-effect both in A and Neo-A settings. Adjusted HR were respectively 0.7 [0.6–1.1], 0.6 [0.3–1.1], 0.5 [0.3–1], 0.2 [0.0–0.7] and 0.1 [0–0.3] for the following DII: =0 g/m2/week, >0.5 g/m2/week, >1g/m2/week, >1.5g/m2/week and >2 g/m2/week, and 0.3 [0.1–0.7] for a total dose > 30 g. Dose-intensity of doxorubicine did not influence OS. Conclusions: These findings indicate that ifosfamide-based regimens may be associated with improved outcome in patients with resected primary SS and justify further investigations in this setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline, Novartis, Pfizer, PharmaMar GlaxoSmithKline, Novartis, Pfizer, PharmaMar Novartis
A phase Ib study of AZD1775 and olaparib combination in patients with refractory solid tumors.
Authors: Erika Paige Hamilton, Judy Sing-Zan Wang, Gerald Falchook, Suzanne Fields Jones, Carl Cook, Ganesh Mugundu, Philip John Jewsbury, Mark J. O'Connor, Andrew J Pierce, Bob T. Li, Amit M. Oza, Jeffrey R. Infante, Howard A. Burris, David R. Spigel
Journal: Journal of Clinical Oncology (2016)

5562 Background: Tumors with G1/S checkpoint deficiencies rely on Wee1 kinase to arrest cell cycle progression at G2/M to repair damaged DNA. AZD1775 is a potent inhibitor of Wee1. Olaparib (Lynparza) is a PARP inhibitor approved in the EU and US for the treatment of patients (pts) with ovarian cancer with BRCA1/2 mutations (US: monotherapy, gBRCAm, 3L+; EU: maintenance, BRCAm platinum sensitive-relapsed serous ovarian cancer [PSR SOC]). Given that PARP inhibition by olaparib results in DNA double-strand breaks in S phase, it is hypothesized that combined Wee1 kinase and PARP inhibition could induce tumor cell death. Remarkable synergy was observed using an AZD1775/olaparib combination in small-cell lung cancer (SCLC) xenograft models (O’Connor, EORTC 2015). The primary objective of this dose-escalation study is to determine the maximum tolerated dose (MTD) of AZD1775 plus olaparib in patients with refractory solid tumors. Methods: Adult pts with refractory solid tumors were given AZD1775 PO BID on Days 1-3 and 8-10 of a 21-day cycle. Olaparib was dosed PO BID on Days 1-14 every 21 days. Olaparib dosing began in Cycle 1 with a Day-3 lead-in period to assist with assessment of a potential drug-drug interaction. Results: A total of 6 pts (1 male; 5 female; median age 59) have been enrolled in 2 cohorts: AZD1775 125 mg (3 pts), AZD1775 150 mg (3 pts); all pts received 100 mg olaparib. Pts have received a median of 3 cycles of treatment (range, 2-6). No dose-limiting toxicities have been observed. Adverse events (any grade) include: nausea, diarrhea (4 pts each), cough, fatigue, constipation, muscle spasms, hot flash, thrombocytopenia (2 pts each), anemia, headache, pain in extremity, and back pain (1 pt each). The evaluable responses were PR (1 pt; anal cancer), SD (4 pts), and PD (1 pt). Enrollment to cohort 3 is ongoing in two arms. Arm 1: AZD1775 175 mg BID, Days 1-3 and 8-10 with olaparib 100 mg BID on Days 1-14. Arm 2: AZD1775 150 mg BID, Days 1-3 and 8-10 with olaparib 200 mg BID on Days 1-14. Conclusions: AZD1775 and olaparib are being studied in this ongoing Phase I trial. Early safety and efficacy have been observed. Expansion is planned in multiple tumor settings once the optimal dosing and schedule have been established with this novel combination. Clinical trial information: NCT02511795.
Cytotoxic T Lymphocyte Responses to PR1 Peptide in Chronic Myeloid Leukemia Patients Inversely Correlate with Proteinase 3 and Elastase Expression but Donor PR1 Responses Determine Survival after Stem Cell Transplantation.
Authors: Agnes S.M. Yong, Katayoun Rezvani, Bipin N. Savani, Rhoda Eniafe, Stephan Mielke, John M. Goldman, A. John Barrett
Journal: Blood (2006)
High expression of the chemokine receptor CXCR4 is associated with estrogen receptor-negative breast cancer
Authors: J. J. Wheler, A. S. Doane, I. Linkov, C. A. Hudis, W. Gerald
Journal: Journal of Clinical Oncology (2006)

642 Background: Chemokine receptor CXCR4 and its ligand CXCL12 (SDF-1alpha) are important in the metastatic spread of breast cancer. Previous studies have shown that CXCR4 is overexpressed in breast cancers as compared to normal breast tissue and that estradiol increases levels of CXCL12. The association between CXCR4 and estrogen receptor (ER) status is unclear. Methods: We performed genome-wide molecular analysis of 61 primary breast cancer tissue samples. Total RNA was extracted and hybridized to Affymetrix HG-U133 oligonucleotide microarrays, and differentially expressed genes between groups were identified using a Welch t-test. CXCR4 protein expression was evaluated by immunohistochemistry (IHC) using a monoclonal antibody (R&amp;D Systems, Minneapolis, MN). We characterized CXCR4 nuclear staining as high vs low-medium. Several clinico-pathologic variables were correlated with CXCR4 expression. Results: A predominantly nuclear staining pattern was noted for CXCR4. Of 61 primary tumors, 15 had high nuclear expression and 46 had low-medium expression. High levels of nuclear CXCR4 expression were significantly correlated with ER-negativity (p =0.0005). CXCR4 protein expression had no association with Her-2 status (gene copy number or IHC 3+), tumor size, or lymph node status. Using p&lt;0.001, protein expression of CXCR4 was associated with 105 significantly differentially expressed genes including relative under expression of ER and ER-related genes and over expression of VEGF. Conclusion: High nuclear protein expression levels of CXCR4 in primary breast cancers are significantly associated with ER-negativity and with low differential expression of ER and ER-related genes. Since estrogen may play a role in CXCR4 activation, further investigation of the association of high CXCR4 expression and ER-negativity is planned. No significant financial relationships to disclose.
Chemotherapy Plus Hematopoietic Growth Factor for Refractory Paroxysmal Nocturnal Hemoglobinuria: Diminishing PNH Clone and Stimulating Hematopoisis
Authors: Zonghong Shao, Xifeng Dong, Rong Fu, Wen Qu, Yong Liang, Yuhong Wu, Guojin Wang, Hong Liu, Jia Song, Xiaoming Wang, Limin Xing, Erbao Ruan, Jing Guan, Jun Wang, Huaquan Wang
Journal: Blood (2011)
A novel retrieval method using a Cusco speculum for large colorectal resection specimens following endoscopic treatment
Authors: Yosho Fukita, Takefumi Takeda, Michifumi Toyomizu, Seitaro Adachi, Ikuma Yasuda, Tsutoshi Asaki, Hiroyuki Ishibashi
Journal: Endoscopy (2016)

Endoscopic submucosal dissection (ESD) was performed for early rectal cancer in a 70-year-old man ([Fig. 1]). The bulky tumor occupied nearly half of the lumen. As the forcible removal of the resected specimen from the rectum using only the retrieval net (Disposable Loop Retrieval Net; net diameter 40 × 75 mm; Meditalia, Palermo, Italy) could have resulted in its fragmentation, we decided to take a different approach.
TCT-414 A Novel Drug-Coated Scoring Balloon for the Treatment of Coronary In-Stent Restenosis: Two Years Follow-up Results from the PATENT-C First in Human Trial
Authors: Bruno Scheller, Daniel Chamié, Norman Mangner, Stefan Hoffmann, Klaus Bonaventura, Yvonne P. Clever, Tobias Fontaine, Jose D. Costa, Gary Gershony, Bettina Kelsch, Maren Kutschera, Philippe Genereux, Bodo Cremers, Ulrich Speck, Alexandre Abizaid
Journal: Journal of the American College of Cardiology (2015)
Monitoring of Minimal Residual Disease (MRD) of DNMT3A Mutations (DNMT3Amut) in Acute Myeloid Leukemia (AML): A Study of the AML Study Group (AMLSG)
Authors: Verena I. Gaidzik, Daniela Weber, Peter Paschka, Anna Kaumanns, Stefan Krieger, Andrea Corbacioglu, Jan Kroenke, Silke Kapp-Schwoerer, Doris Krämer, Heinz A. Horst, Ingo Schmidt-Wolf, Gerhard Held, Andrea Kuendgen, Mark Ringhoffer, Katharina Goetze, Thomas Kindler, Walter Fiedler, Mohammad Amen Wattad, Lars Bullinger, Brigitte Schlegelberger, Felicitas Thol, Michael Heuser, Arnold Ganser, Richard F. Schlenk, Hartmut Döhner, Konstanze Döhner
Journal: Blood (2015)
12-Lipoxygenase is a potential therapeutic target in non-small cell lung cancer
Authors: G. P. Pidgeon, K. Gately, J. Lysaght, M. C. Cathcart, V. Campbell, E. Kay, K. J. O’Byrne
Journal: Journal of Clinical Oncology (2007)

18129 Background: Platelet-type 12-LOX is an arachidonic acid metabolising enzyme resulting in the formation of 12(S)-HETE, which stimulates tumour cell adhesion, invasion and metastasis. We examined the expression of 12-LOX in NSCLC and its role in cell survival. Methods: A549 (adenocarcinoma), SK-MES1 (squamous cell lung carcinoma), H460 and H647 (large cell lung carcinoma) were grown in serum depleted media (0.5%) and screened for 12-LOX expression by RT-PCR and western blot analysis. Cells were treated with baicalein (10uM), a selective inhibitor of 12-LOX, or 12(S)-HETE (100ng/ml) and cell survival / proliferation determined by BrdU assay. Apoptosis was determined using the multi-parameter apoptosis kit and In-cell Analyser, and also by FACS. Gene alterations following 12-LOX inhibition in both A549 and SKMES-1 cells were assessed by quantitative PCR arrays and validated by RT-PCR. A panel of retrospective resected lung tumours were stained for 12-LOX expression by immunhistochemistry. Results: All lung cancer cells lines expressed moderate levels of platelet-type 12-LOX, which was reduced following treatment for 24h with the baicalein. Baicalein decreased lung cancer survival in all cell lines, while 12(S)-HETE increased cellular proliferation. Inhibition of 12-LOX induced apoptosis in a dose dependent manner, with decreased f-actin filaments and loss of mitochondrial mass potential. QPCR array data implicated a number of genes regulating these effects which were validated by RT-PCR, many of which control apoptosis and angiogenesis. The subset of genes downregulated included bcl-2, VEGF, integrin a2 and a4. 12-LOX expression was observed in a variety of human lung cancers with different histological subtypes. Conclusions: 12- LOX is a survival factor in NSCLC. 12-LOX inhibitors decreased NSCLC survival, inducing apoptosis through mechanisms including downregulation of the bcl family of proteins, integrin receptor and angiogenic growth factors. Expression of 12-LOX in fresh resected and retrospective tissue suggests that inhibition of this enzyme is a potential therapeutic strategy in the treatment of NSCLC. No significant financial relationships to disclose.
Changes to the Definition of Posttraumatic Stress Disorder in the <i>DSM-5</i>
Authors: Jeffrey Guina
Journal: JAMA Psychiatry (2016)

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Targeted Locus Amplification &amp; Next Generation Sequencing for the Detection of Recurrent and Novel Gene Fusions for Improved Treatment Decisions in Pediatric Acute Lymphoblastic Leukemia
Authors: Roland P. Kuiper, Simon V. van Reijmersdal, Marieke Simonis, Jiangyan Yu, Edwin Sonneveld, Blanca Scheijen, Judith M. Boer, Aurélie Boeree, Petra Klous, Peter M Hoogerbrugge, Mehmet Yilmaz, Frank N. van Leeuwen, Monique L. Den Boer, Erik Splinter
Journal: Blood (2015)
Turnover of Heme-Bound Iron Is Associated with Activation of TLR4 and Chemokine Receptor Pathways in the Peripheral Blood Mononuclear Cell Transcriptome in Sickle Cell Anemia
Authors: Eduard J. van Beers, Yanqin Yang, Susan Yuditskaya, Nalini Raghavachari, Gregory J. Kato
Journal: Blood (2012)
A High-Risk Survival Classifier for Multiple Myeloma
Authors: Rowan Kuiper, Annemiek Broyl, Yvonne de Knegt, Martin H. van Vliet, Erik H. van Beers, Bronno van der Holt, Laila el Jarari, George Mulligan, Gareth Morgan, Walter M Gregory, Hartmut Goldschmidt, Henk M. Lokhorst, Mark van Duin, Pieter Sonneveld
Journal: Blood (2011)