tbuckley/cabot-search huggingface dataset:
Ovarian Cancer Screening Tests Don’t Pass Muster
Authors: Rebecca Voelker
Journal: JAMA (2016)

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The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia
Authors: Thomas Vercruysse, Jolien De Bie, Jasper E. Neggers, Maarten Jacquemyn, Els Vanstreels, Jonathan L. Schmid-Burgk, Veit Hornung, Erkan Baloglu, Yosef Landesman, William Senapedis, Sharon Shacham, Antonis Dagklis, Jan Cools, Dirk Daelemans
Journal: Clinical Cancer Research (2016)

Purpose: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibiting XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in phase-II/IIb clinical trials when dosed 1 to 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily. Here, we investigate and validate the drug-target interaction of KPT-8602 and explore its activity against acute lymphoblastic leukemia (ALL).Experimental Design: We examined the effect of KPT-8602 on XPO1 function and XPO1-cargo as well as on a panel of leukemia cell lines. Mutant XPO1 leukemia cells were designed to validate KPT-8602's drug-target interaction. In vivo, anti-ALL activity was measured in a mouse ALL model and patient-derived ALL xenograft models.Results: KPT-8602 induced caspase-dependent apoptosis in a panel of leukemic cell lines in vitro Using CRISPR/Cas9 genome editing, we demonstrated the specificity of KPT-8602 for cysteine 528 in the cargo-binding groove of XPO1 and validated the drug target interaction. In vivo, KPT-8602 showed potent anti-leukemia activity in a mouse ALL model as well as in patient-derived T- and B-ALL xenograft models without affecting normal hematopoiesis.Conclusions: KPT-8602 is highly specific for XPO1 inhibition and demonstrates potent anti-leukemic activity supporting clinical application of the second-generation SINE compound for the treatment of ALL. Clin Cancer Res; 23(10); 2528-41. ©2016 AACR.
Relationships Between Aberrant Activity of the NF-κB Subunits and Outcome In Chronic Lymphocytic Leukemia: The Dual Role of DNA Damage Sensor Enzymes
Authors: Evan A Mulligan, Jill E Hunter, Arabella EG Baird, Sarah Elliott, Geoffrey P Summerfield, Karen Hamlen, Chris Lowe, Jonathan Wallis, Stephany Veuger, Barbara W Durkacz, Elaine Willmore
Journal: Blood (2010)
Phase 1b/2 Pharmacokinetic/Pharmacodynamic (PK/PD) Study of Combination Voreloxin and Cytarabine in Relapsed or Refractory Acute Myeloid Leukemia Patients.
Authors: Jeffrey E Lancet, Gail J. Roboz, Larry D. Cripe, Michael Maris, Alan F List, Judith Fox, Glenn C Michelson, Judith Karp
Journal: Blood (2009)
Phase 1 study of twice weekly pulse dose and daily low-dose erlotinib as initial treatment for patients with EGFR-mutant lung cancers
Authors: H.A. Yu, C. Sima, D. Feldman, L.L. Liu, B. Vaitheesvaran, J. Cross, C.M. Rudin, M.G. Kris, W. Pao, F. Michor, G.J. Riely
Journal: Annals of Oncology (2016)
Serous Cystadenoma of the Pancreas Showing Uptake on 68Ga PSMA PET/CT
Authors: Mico Chan, Geoffrey Paul Schembri, Edward Hsiao
Journal: Clinical Nuclear Medicine (2016)

Ga prostate-specific membrane antigen (PSMA) PET/CT is increasingly used to evaluate extent of disease in prostate carcinoma. Several other benign and malignant pathologies have also been reported to demonstrate PSMA avidity. We present a case of serous cystadenoma of the pancreas showing focal uptake on PSMA PET/CT.
Safety of a Weekly Administration of 10 mg/kg of Liposomal Amphotericin B for Antifungal Prophylaxis in Allogeneic Stem-Cell Transplant and Acute Leukemia Patients.
Authors: Catherine Cordonnier, Mohamad Mohty, Catherine Faucher, Norbert Vey, Cécile Pautas, Marie Robin, Lamine Mahi, Patricia Ribaud
Journal: Blood (2005)
Clinical Significance of Circulating CD33+CD11b+HLA-DR− Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab
Authors: Moshe Sade-Feldman, Julia Kanterman, Yair Klieger, Eliran Ish-Shalom, Mizrahi Olga, Amijai Saragovi, Hani Shtainberg, Michal Lotem, Michal Baniyash
Journal: Clinical Cancer Research (2016)

High levels of circulating myeloid-derived suppressor cells (MDSCs) in various cancer types, including melanoma, were shown to correlate with poor survival. We investigated whether frequencies of circulating CD33+CD11b+HLA-DR- MDSCs could be used as immune system monitoring biomarkers to predict response and survival of patients with stage IV melanoma treated with anti-CTLA4 (ipilimumab) therapy.Peripheral blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for CD33+CD11b+HLA-DR- MDSC percentage, NO-, and hROS levels by flow cytometry. We determined whether MDSC levels and suppressive features detected before anti-CTLA4 therapy correlate with the patients' response and overall survival (OS).Patients with melanoma had significantly higher levels of circulating CD33+CD11b+HLA-DR- MDSCs with suppressive phenotype when compared with HDs. Low levels of MDSCs before CTLA-4 therapy correlated with an objective clinical response, long-term survival, increased CD247 expression in T cells, and an improved clinical status. No predictive impact was observed for lactate dehydrogenase (LDH). Kaplan-Meier and log-rank tests performed on the 56 patients showed that the presence of more than 55.5% of circulating CD33+CD11b+ out of the HLA-DR- cells, were associated with significant short OS (P < 0.003), a median of 6.5 months, in comparison with the group showing lower MDSC frequencies, with a median survival of 15.6 months.Our study suggests the use of CD33+CD11b+HLA-DR- cells as a predictive and prognostic biomarker in patients with stage IV melanoma treated with anti-CTLA4 therapy. This monitoring system may aid in the development of combinatorial modalities, targeting the suppressive environment in conjunction with iplimumab, toward facilitating better disease outcomes. Clin Cancer Res; 22(23); 5661-72. ©2016 AACR.
A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy
Authors: Rashid K. Sayyid, Andrew Evans, Karen Hersey, Ranjena Maloni, Antonio Hurtado-Coll, Girish Kulkarni, Antonio Finelli, Alexandre R. Zlotta, Robert Hamilton, Martin Gleave, Neil E. Fleshner
Journal: Clinical Cancer Research (2016)

Purpose: Degarelix, a new gonadotropin-releasing hormone (GnRH) receptor antagonist with demonstrated efficacy as first-line treatment in the management of high-risk prostate cancer, possesses some theoretical advantages over luteinizing hormone-releasing hormone (LHRH) analogues in terms of avoiding "testosterone flare" and lower follicle-stimulating hormone (FSH) levels. We set out to determine whether preoperative degarelix influenced surrogates of disease control in a randomized phase II study.Experimental Design: Thirty-nine patients were randomly assigned to one of three different neoadjuvant arms: degarelix only, degarelix/bicalutamide, or LHRH agonist/bicalutamide. Treatments were given for 3 months before prostatectomy. Patients had localized prostate cancer and had chosen radical prostatectomy as primary treatment. The primary end point was treatment effect on intratumoral dihydrotestosterone levels.Results: Intratumoral DHT levels were higher in the degarelix arm than both the degarelix/bicalutamide and LHRH agonist/bicalutamide arms (0.87 ng/g vs. 0.26 ng/g and 0.23 ng/g, P < 0.01). No significant differences existed for other intratumoral androgens, such as testosterone and dehydroepiandrosterone. Patients in the degarelix-only arm had higher AMACR levels on immunohistochemical analysis (P = 0.01). Serum FSH levels were lower after 12 weeks of therapy in both degarelix arms than the LHRH agonist/bicalutamide arm (0.55 and 0.65 vs. 3.65, P < 0.01), and inhibin B levels were lower in the degarelix/bicalutamide arm than the LHRH agonist/bicalutamide arm (82.14 vs. 126.67, P = 0.02).Conclusions: Neoadjuvant degarelix alone, compared with use of LHRH agonist and bicalutamide, is associated with higher levels of intratumoral dihydrotestosterone, despite similar testosterone levels. Further studies that evaluate the mechanisms behind these results are needed. Clin Cancer Res; 23(8); 1974-80. ©2016 AACR.
Measures of oxaliplatin-induced neutrotoxicity in 187 patients with FOLFOX4
Authors: S. Matsusaka, N. Mizunuma, M. Matsuda, M. Suenaga, M. Ogura, T. Ichimura, D. Shoji, M. Oya, T. Muto, K. Hatake
Journal: Journal of Clinical Oncology (2007)

14552 Background: Oxaliplatin-based regimen (FOLFOX regimen) for patients with colorectal cancer have improved survival. Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Various strategies and pharmacologic agents are currently under investigation to prevent or treat oxaliplatin-induced neurotoxicity. One of them is Stop-and-Go strategy based on the observation of reversibility of the neurotoxic symptoms after discontinuation of oxaliplatin. Stop-and-Go concept will prolong the time of oxaliplatin-based therapy as long as antitumor efficacy is still maintained. Methods: Patients with a histologically verified advanced colorectal carcinoma were eligible for the study. From April 2005 to March 2006 at Cancer Institute Hospital, 187 patients whom treated with bimonthly oxaliplatin-based regimen (FOLFOX4) were enrolled. An oxaliplatin specific neurotoxicity scale are distinct from the National Cancer Institute common toxicity criteria classification (CTC-AE vol. 3). This study was performed to carefully assess the onset and duration to recovery of oxaliplatin neurotoxicity and resumption rate of FOLFOX4. Results: Neurotoxicity was observed in 72 patients with Grade 1, 56 patients with Grade 2 and 33 patients with Grade 3. Oxaliplatin-induced cumulative neurotoxicity develops progressively. The median cumulative doses of oxaliplatin were 170 mg/m 2 with Gr. 1; 845.8 mg/m 2 with Gr. 2; and 850 mg/m 2 with Gr. 3. The median time to onset were 16 days with Gr. 1; 174 days with Gr. 2; and 177 days with Gr. 3. The median time to recovery after stopping the therapy and the median time to progression during the discontinuation of oxaliplatin were 56 and 59 days, respectively, in patients allocated to Gr. 2 compared with 106 and 73 days, respectively, in patients allocated to Gr. 3. The recovery time during the discontinuation showed a statistically significant reduction of the values in the Gr. 2 but not in Gr. 3 (p = 0.0024). The resumption rates of oxaliplatin were 73.7% with Gr. 2 and 46.4% with Gr. 3. Conclusions: Our results may focus to manage time course of Stop-and-Go strategy in clinical practice. No significant financial relationships to disclose.
Pegylated Recombinant Human Granulocyte Colony Stimulating Factor (pegfilgrastim) Reduces Hematological Toxicity in Dose-Adjusted (DA) R-EPOCH in the treatment of Diffuse Large B Cell Lymphoma.
Authors: Susanna Hong, Nouneh J. Gostanian, Douglas E. Gladstone, Kenneth W. Zamkoff
Journal: Blood (2004)
Multicenter Study with Mbvd Regimen in Elderly or Younger Patients with Cardiac Disorders Affected By Hodgkin’s Lymphoma. a Phase II Study on Behalf of the Fondazione Italiana Linfomi (FIL)
Authors: Flavia Salvi, Michele Spina, Alessandro Pulsoni, Sergio Storti, Alessandra Tucci, Marianna Chiozzotto, Stefania Massidda, Isabel Alvarez, Caterina Stelitano, Anna Marina Liberati, Valentina Lenti, Manuela Ceccarelli, Alessandro Levis
Journal: Blood (2014)
Less is more: low expression of MT1-MMP is optimal to promote migration and tumourigenesis of breast cancer cells
Authors: Mario A. Cepeda, Jacob J. H. Pelling, Caitlin L. Evered, Karla C. Williams, Zoey Freedman, Ioana Stan, Jessica A. Willson, Hon S. Leong, Sashko Damjanovski
Journal: Molecular Cancer (2016)

Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) is a multifunctional protease implicated in metastatic progression ostensibly due to its ability to degrade extracellular matrix (ECM) components and allow migration of cells through the basement membrane. Despite in vitro studies demonstrating this principle, this knowledge has not translated into the use of MMP inhibitors (MMPi) as effective cancer therapeutics, or been corroborated by evidence of in vivo ECM degradation mediated by MT1-MMP, suggesting that our understanding of the role of MT1-MMP in cancer progression is incomplete. MCF-7 and MDA-MB 231 breast cancer cell lines were created that stably overexpress different levels of MT1-MMP. Using 2D culture, we analyzed proMMP-2 activation (gelatin zymography), ECM degradation (fluorescent gelatin), ERK signaling (immunoblot), cell migration (transwell/scratch closure/time-lapse imaging), and viability (colorimetric substrate) to assess how different MT1-MMP levels affect these cellular parameters. We also utilized Matrigel 3D cell culture and avian embryos to examine how different levels of MT1-MMP expression affect morphological changes in 3D culture, and tumourigenecity and extravasation efficiency in vivo. In 2D culture, breast cancer cells expressing high levels of MT1-MMP were capable of widespread ECM degradation and TIMP-2-mediated proMMP-2 activation, but were not the most migratory. Instead, cells expressing low levels of MT1-MMP were the most migratory, and demonstrated increased viability and ERK activation. In 3D culture, MCF-7 breast cancer cells expressing low levels of MT1-MMP demonstrated an invasive protrusive phenotype, whereas cells expressing high levels of MT1-MMP demonstrated loss of colony structure and cell fragment release. Similarly, in vivo analysis demonstrated increased tumourigenecity and metastatic capability for cells expressing low levels of MT1-MMP, whereas cells expressing high levels were devoid of these qualities despite the production of functional MT1-MMP protein. This study demonstrates that excessive ECM degradation mediated by high levels of MT1-MMP is not associated with cell migration and tumourigenesis, while low levels of MT1-MMP promote invasion and vascularization in vivo.
Phase 1/1b Study of the Efficacy and Safety of the Combination of Panobinostat + Carfilzomib in Patients with Relapsed and/or Refractory Multiple Myeloma
Authors: Jatin J. Shah, Sheeba K. Thomas, Donna M. Weber, Michael Wang, Raymond Alexanian, Muzaffar H. Qazilbash, Qaiser Bashir, Simrit Parmar, Nina Shah, Uday R. Popat, Robert Z. Orlowski
Journal: Blood (2012)
Specific airway resistance in preschool children: why not panting after all?
Authors: Iulia Ioan, Silvia Demoulin-Alexikova, Laurianne Coutier, Claude Bonabel, Jane Kirkby, Kim G. Nielsen, Waldemar Tomalak, Bruce Thompson, Cyril Schweitzer, Paul D. Robinson, François Marchal
Journal: European Respiratory Journal (2016)

Specific airway resistance (s R aw) is measured with minimal cooperation in the preschool child during tidal breathing [1]. Methodological difficulties have been encountered in modern plethysmographs when the warming and humidification of the inspired gas [2] are replaced by numerical algorithms to eliminate the thermo hygrometric artefact [1, 3, 4]. Measuring s R aw during panting [5] had been dismissed in preschool children based on the assumption that the ventilatory manoeuvre would be difficult to perform and standardise. The feasibility of such an assumption, however, has not been verified. Therefore, the aim of this study was to assess the feasibility of measuring s R aw during panting in preschool children with asthma and compare the outcome with the tidal breathing method. Specific airway resistance may be measured in preschool children during routine lung function <http://ow.ly/pvxr3034Bo8> Waldemar Tomalak passed away while the study was progressing. The members of the working group miss a good friend and an esteemed collaborator. They address their sincere condolences to his family.
GW26-e4746 Quantification of Compacted Myocardial T1 in Isolated Left Ventricular Non-compaction and Its Relation to Disease Severity: A 3.0T MR Imaging Study
Authors: Hongmei Zhou, Xue Lin, Haiyan Ding, Xihai Zhao, Ligang Fang, Quan Fang
Journal: Journal of the American College of Cardiology (2015)
Dose-finding study of fixed dose rate (FDR) infusion of gemcitabine in combination with bevacizumab and escalating doses of irinotecan in patients with advanced gastrointestinal (GI) tumors
Authors: A. Chopitea, J. Rodríguez, A. Viúdez, S. Viteri, J. De La Cámara, C. Reyna, C. Olier, J. M. Aramendía, J. García-Foncillas
Journal: Journal of Clinical Oncology (2006)

13068 Background: Gemcitabine (GMB), Bevacizumab and Irinotecan (CPT-11) are active agents in GI tumors with preclinical evidence of synergism. The purpose of this study was to assess the maximum tolerated dose (MTD) of FDR GMB, Bevacizumab and CPT-11 in patients (pts) with advanced GI malignancies. Preliminary evidence of antitumor activity was also evaluated. Methods: A biweekly schedule of FDR GMB at a dose of 1000 mg/m 2 , Bevacizumab 5 mg/kg and CPT-11 (100–160 mg/m 2 with a 10 mg/m 2 increase in each cohort level) was analysed. The dose of CPT-11 was escalated in cohorts of three pts until the MTD was defined. Results: Thirty eligible pts with GI tumors were included (oesophagus: 2; gastroesophagic junction: 1; gastric: 2; pancreas: 2; colon: 17; rectum: 6) The median age was 60 years. ECOG status was 0–1 in 70% of pts. Male/female ratio was 21/9. Twenty-nine pts had received prior chemotherapy. The median number of cycles administered was six. Two of three pts at a CPT-11 dose of 160mg/m 2 had grade 3 asthenia that required hospitalization. Recommended dose was thus established at CPT-11 dose of 150 mg/m 2 . Nine additional pts were included in this cohort and no further toxicity was observed. Antitumor activity was seen in 13 pts, with 3 complete responses and 10 partial responses. Conclusions: The recommended dose for phase II studies is CPT-11 150 mg/m 2 , GMB 1000 mg/m 2 in FDR infusion and Bevacizumab 5 mg/kg on a biweekly schedule. Overall, this is a feasible regimen with a promising activity. No significant financial relationships to disclose.
GW26-e1481 Sphingosine Kinase-2 Protects Against Myocardial Infarction-induced Heart Failure by Inhibiting Histone Deacetylase Activation
Authors: Fuyang Zhang, Yunlong Xia, Shihao Zhao, Wei Wang, Wenjun Yan, Ling Tao
Journal: Journal of the American College of Cardiology (2015)
Recommendations for the Conduct and Reporting of Modeling and Simulation Studies in Health Technology Assessment
Authors: Issa J. Dahabreh, Thomas A. Trikalinos, Ethan M. Balk, John B. Wong
Journal: Annals of Internal Medicine (2016)

Models and simulations are valuable tools for addressing the uncertainty, tradeoffs, and heterogeneous preferences that complicate research questions in health technology assessment. This article presents recommendations for the conduct and reporting of modeling and simulation studies based on a systematic review of published recommendation statements, a survey of Web sites of international health technology assessment organizations, and input from experts and other stakeholders. The recommendations apply to mathematical models that represent structural relationships among model components and integrate information from multiple sources; they address model identification, estimation, verification, and validation, as well as the conduct of sensitivity, stability, and uncertainty analyses. They are organized into model conceptualization and structure, data, model assessment and consistency, and interpreting and reporting results. They should contribute to increased use and better conduct and reporting of modeling and simulation studies in health technology assessment.
Priming with Granulocyte Colony-Stimulating Factor (G-CSF) Has No Impact on Treatment Outcome but Impairs Mobilization of Peripheral Blood Stem Cells (PBSC) in Elderly Patients with Acute Myeloid Leukemia: Results of a Randomized Oligocenter Trial.
Authors: Gesine Bug, Steffen Koschmieder, S. Wiebe, Gerd Heil, Carla Delfs, Wolf-Karsten Hofmann, Caroline Zander, Juergen Krauter, Wolfgang Heit, Arnold Ganser, Dieter Hoelzer, Oliver G. Ottmann
Journal: Blood (2004)
Interim Analysis Of Dose-Escalation Stage Of a Phase 1b Study Evaluating Safety and Pharmacology Of GS-9820, a Second-Generation, Selective, PI3Kd-Inhibitor in Recurrent Lymphoid Malignancies
Authors: Arnon P. Kater, Sanne H. Tonino, Marie Jose Kersten, Anton Hagenbeek, Marjolein Spiering, Marinus H van Oers, Yan Xin, Srinivasan Ramanathan, Maria Aiello, Susie Jun
Journal: Blood (2013)
Phase I/I Clinical Trial for the Evaluation of Bortezomib within the Reduced Intensity Conditioning Regimen (RIC) and Post-Allogeneic Transplantation As Gvhd Prophylaxis Among High-Risk Myeloma Patients. EudraCT: 2005–004858-27
Authors: Jose Antonio Perez-Simón, Teresa Caballero-Velazquez, Cristina Encinas, Cristina Castilla-Llorente, Rodrigo Martino, Laura Rosiñol, Antonia Sampol, Dolores Caballero, David Serrano, Inmaculada Heras, Jesus F San Miguel
Journal: Blood (2011)
Impact of ethnicity and insurance on colorectal cancer outcomes.
Authors: K. B. Young, J. D. Acoba
Journal: Journal of Clinical Oncology (2010)

3598 Background: Previous studies have demonstrated ethnic disparities in mortality rates among colorectal cancer patients. The following analysis was performed to quantify disparities in a diverse ethnic population and explore reasons for the demonstrated differences. Methods: Data from 4,232 consecutive colorectal cancer patients were collected from hospital tumor registries between 1990 and 2007. Measures of association (chi-square, Cox regression) were used to analyze differences in colorectal cancer mortality and ethnicity as well as factors hypothesized to contribute to cancer mortality including age at diagnosis, sex, area of residence, place of birth, insurance, site of disease, histologic grade, stage, and initial treatment. Results: Filipino and native Hawaiian patients were significantly younger than white patients at the time of diagnosis (p < 0.0005) and Native Hawaiians were more likely than other groups to be uninsured or covered by Medicaid (p < 0.0005). Although there were no differences in stage at diagnosis among the ethnic groups, Filipinos and Native Hawaiians more often received chemotherapy (p < 0.0005). Multivariate Cox regression revealed that Filipino [HR 1.7 (1.3-2.3, 95% CI), p < 0.0005] and Native Hawaiian [HR 1.6 (1.2-2.0, 95% CI), p = 0.001] ethnicity adversely impacted survival even after adjusting for age, stage, histologic grade, treatment and insurance status. Conclusions: Among colorectal cancer patients, ethnic disparities exist that cannot be solely explained by differences in clinical tumor characteristics, treatment or insurance status. Further study into molecular characteristics of tumors and utilization of healthcare services is warranted. No significant financial relationships to disclose.