tbuckley/cabot-search huggingface dataset:
A phase I study of AVE1642, a humanized monoclonal antibody IGF-1R (insulin like growth factor1 receptor) antagonist, in patients(pts) with advanced solid tumor(ST)
Authors: A. W. Tolcher, A. Patnaik, E. Till, C. H. Takimoto, K. P. Papadopoulos, C. Massard, D. Mery-Mignard, A. Deslandes, M. Ozoux, J. Soria
Journal: Journal of Clinical Oncology (2008)

3582 Background: AVE1642, a humanized mAb, binds the human IGF1R specifically and with high affinity (Kd<1nM). It delays growth of cancer cells in vitro and of human tumors xenografted to nude mice. Materiel and Methods: this study aims to select the dose of AVE1642 to be combined with docetaxel 75 mg/m2 (D). AVE1642 was administered as single agent at cycle(cy)1 and then in combination with D from cy2, q3w. Sequential tumor biopsies were performed in a subset of pts. Main eligibility criteria: ≥ 18y.o; measurable or evaluable advanced ST; PS ≤2; HbA1c≤7.5% or FPG≤160mg/dL. PK/PD: blood was collected at d1, d2, d8, d15 and d22 cy1 and cy2 and at d22 of each subsequent cy. Selection of the dose is based on safety (<33% pts with DLT) and on PK, PD parameters. Results: as of 20-Dec-07, 14 pts (4 at 3mg/kg; 4 at 6mg/kg; 4 at 12mg/kg; 2 at 18mg/kg) received 49cy, including 35cy with T. Safety: No DLT/related SAE were reported so far. Gr1/2 related AEs: hyperglycemia(1), hypersensitivity reactions (2), asthenia(2), anemia(1), nail disorder(1), paresthesia(1), pruritus(1). No anti-drug antibodies detected. Activity: 1 pt with breast cancer has had reduction in skin nodules and is on study cy6. In addition, 4 SD confirmed at cy4 are reported (small cell oesophagus, colon, melanoma, epithelioid sarcoma). Preliminary PK/PD data (mean, [CV%], (n)). AVE1642 concentrations increased dose-proportionally. Elimination t½ was ≈ 9 days. No PK interaction was observed. At all dose levels, mean IGF1 levels increased up to 6-fold from baseline, plateauing from 14–21d. Conclusion: AVE1642 is well tolerated as single agent and in combination with D. PK/PD data suggest a substantial and maintained biological effect from dose level 3mg/kg. Dose (mg/kg) AVE1642 IGF1 Cmax (μg/mL) t½(day) CL (L/day) maxEffect (ng/mL) tmax (day) 3 76.4 [12.7] (5) 9.31[17.9] (5) 0.471 [67.9] (5) 558 (3) 63 (3) 6 158 [22.1] (8) 8.60[14] (8) 0.265 [48.4] (8) 589 (3) 63 (3) 12 249 [25.1] (3) 9.01[12.7] (3) 0.281 [23.1] (3) 633 (2) 14 (2) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis
Severe asthma exists despite suppressed tissue inflammation: findings of the U-BIOPRED study
Authors: Susan J. Wilson, Jonathan A. Ward, Ana R. Sousa, Julie Corfield, Aruna T. Bansal, Bertrand De Meulder, Diane Lefaudeux, Charles Auffray, Matthew J. Loza, Frederic Baribaud, Neil Fitch, Peter J. Sterk, Kian Fan Chung, David Gibeon, Kai Sun, Yi-ke Guo, Ian Adcock, Ratko Djukanovic, Barbro Dahlen, Pascal Chanez, Dominick Shaw, Norbert Krug, Jens Hohlfeld, Thomas Sandström, Peter H. Howarth
Journal: European Respiratory Journal (2016)

The U-BIOPRED study is a multicentre European study aimed at a better understanding of severe asthma. It included three steroid-treated adult asthma groups (severe nonsmokers (SAn group), severe current/ex-smokers (SAs/ex group) and those with mild–moderate disease (MMA group)) and healthy controls (HC group). The aim of this cross-sectional, bronchoscopy substudy was to compare bronchial immunopathology between these groups. In 158 participants, bronchial biopsies and bronchial epithelial brushings were collected for immunopathologic and transcriptomic analysis. Immunohistochemical analysis of glycol methacrylate resin-embedded biopsies showed there were more mast cells in submucosa of the HC group (33.6 mm −2 ) compared with both severe asthma groups (SAn: 17.4 mm −2 , p&lt;0.001; SAs/ex: 22.2 mm −2 , p=0.01) and with the MMA group (21.2 mm −2 , p=0.01). The number of CD4 + lymphocytes was decreased in the SAs/ex group (4.7 mm −2 ) compared with the SAn (11.6 mm −2 , p=0.002), MMA (10.1 mm −2 , p=0.008) and HC (10.6 mm −2 , p&lt;0.001) groups. No other differences were observed. Affymetrix microarray analysis identified seven probe sets in the bronchial brushing samples that had a positive relationship with submucosal eosinophils. These mapped to COX-2 (cyclo-oxygenase-2), ADAM-7 (disintegrin and metalloproteinase domain-containing protein 7), SLCO1A2 (solute carrier organic anion transporter family member 1A2), TMEFF2 (transmembrane protein with epidermal growth factor like and two follistatin like domains 2) and TRPM-1 (transient receptor potential cation channel subfamily M member 1); the remaining two are unnamed. We conclude that in nonsmoking and smoking patients on currently recommended therapy, severe asthma exists despite suppressed tissue inflammation within the proximal airway wall.
European symposium on the awareness of allergy: report of the promotional campaign in the European Parliament (26-28 April 2016)
Authors: A. Muraro, B. Steelant, S. Pietikainen, D. Borrelli, N. Childers, I. Callebaut, I. Kortekaas Krohn, K. Martens, B. Pugin, F.-D. Popescu, M. Vieru, M. Jutel, I. Agache, P. W. Hellings
Journal: Allergy (2016)

From 26 to 28 of April 2016, an allergy awareness campaign was organized by the European Academy of Allergy and Clinical Immunology and the European Federation of Allergy and Airway Diseases Patients Associations in the European Parliament in Brussels, with support of the European Parliament's Interest group on Allergy and Asthma and was co-hosted by the Members of the European Parliament David Borrelli, Sirpa Pietikainen and Nessa Childers. Skin prick tests (SPTs) were performed to gain attention for the increasing prevalence of allergic airway diseases in Europe. Since more than 30% of the total European population suffers from airway allergies and asthma, reaching a higher level of awareness and elaboration of an active prevention plan is mandatory. Of the 406 individuals undergoing SPT in the European Parliament, 211 participants (52%) reported to have suffered from an allergy in the past, with allergic symptoms being present in the nose and eyes (40% and 36%, respectively), the skin (27%), lower airways (14%) and the gut (8%). Of the 381 SPT with reliable results, cutaneous hypersensitivity was found in 201 (53%) participants. Of those with positive SPT (n = 201), 70 participants (35%) were monosensitized while 131 participants (65%) were polysensitized. The positive skin reactions were found mostly for grass pollen (n = 108), followed by Dermatophagoides pteronyssinus (n = 105), Dermatophagoides farina (n = 96) and birch pollen (n = 85). Of note, 54 individuals (14% of the total tested population) without reported allergy or allergic symptoms showed a positive SPT without clinical relevance. This report summarizes the main idea and goals of the symposium: chronic airway diseases are a major and growing health problem in Europe. Therefore, a joint preventive action plan needs to be developed for a better health status of European citizens.
Survival trends among patients with advanced renal cell carcinoma (RCC) in the United States.
Authors: Binay Kumar Shah, Krishna Bilas Ghimire
Journal: Journal of Clinical Oncology (2013)

422 Background: Since approval of sorafenib in December 2005, several targeted therapeutic agents have been approved by the FDA for the treatment of advanced renal cell carcinoma. This study was conducted to find out whether the improvements in survival of advanced RCC patients with targeted agents have translated into survival benefit in population-based cohort. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER) 18 registry database to compare 1- and 3-year relative survival rates among advanced RCC patients during 2001-2009, 2001-2004, and 2006-2009. We also evaluated the survival rates by age (&lt;65 and ≥65 years) and sex. We used SEER*Stat software to analyze the data. Results: The total number of advanced RCC patients during 2001-2009, 2001-2004, and 2006-2009 were 7,055, 3,355 and 2,985 respectively. During 2001-2009, the 1- and 3-year relative survival rates were 26.7± 0.6% and 10.0±0.4% respectively. The 1-year relative survival rates during 2001-2004 and 2006-2009 were 27.0±0.8% and 27.1±0.9%, (p value=1.3) respectively. Similarly, the 3-year survival rates during 2001-2004 and 2006-2009 were 10.1±0.6% and 9.6±0.8%, (p value=1.42), respectively. There was no significant difference in survival rates during 2001-2004 and 2006-2009 periods by age and sex. Conclusions: This population based study showed that there was no significant improvement in relative survival rates among advanced RCC patients in the era of targeted agents. As with other database analyses, limitations of this large study may be incomplete reporting practices and lack of data on treatment.
Phase IB dose escalation study of bortezomib and sunitinib in patients with refractory solid tumors.
Authors: J. S. Kauh, R. D. Harvey, D. H. Lawson, T. K. Owonikoko, M. Tighiouart, S. S. Ramalingam, D. M. Shin, C. M. Lewis, B. F. El-Rayes, F. R. Khuri
Journal: Journal of Clinical Oncology (2010)

2538 Background: Sunitinib (S) inhibits several receptor tyrosine kinases (RTKs) involved in tumor proliferation and angiogenesis, specifically PDGFR, VEGFR, KIT, FLT-3, and RET. Bortezomib (B), a proteasome inhibitor, interrupts multiple signaling pathways, including NF- κB, which is involved in proliferative and pro-angiogenic signaling. Based on favorable preclinical interaction between the two compounds, we conducted a phase IB study with the combination. Methods: The primary objectives were: (1) Determine the maximum tolerated doses (MTD) of B IV weekly for 4 weeks in combination with S for 4 weeks, followed by a 14 day rest period. (2) Define the dose-limiting toxicity (DLT) of the combination. A secondary objective was to obtain preliminary information on the anticancer activity of the regimen. Starting doses were S 25 mg daily and B 1 mg/m2 weekly. Escalation of study agents was performed utilizing escalation with overdose control (EWOC) method. Results: Twenty-five patients have been enrolled of which 24 are evaluable; median age 64.5 years, 18 male 8 female. The study was conducted in two phases. In the first phase the dose of S was increased while the dose of B was fixed. Once the MTD was determined for the first phase (which was S 37.5 mg and B 1 mg/m2), the dose of B was increased while the dose of S was fixed. The DLTs were grade 4 thrombocytopenia (16%) and neutropenia (4%) at doses of S 50 mg and B 1 mg/m2. The most common grade 3/4 toxicities observed include: diarrhea (4%), fatigue (4%), nausea (4%), and nephrotic syndrome (4%). Three partial responses by RECIST were noted (1 Hurthle cell carcinoma [CA], 1 squamous cell CA of the nasopharynx, 1 papillary thryoid CA). Stable disease lasting > 6 months was noted in 5 patients (1 papillary thyroid CA, 1 neuroendocrine CA of the pancreas, 1 Hurthle cell CA, 1 medullary thyroid CA, 1 pleomorphic sarcoma). Conclusions: The combination of B and S is well tolerated and has demonstrated anticancer activity in various solid tumors. A phase II study with the combination in thyroid neoplasms is under development. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer
Mast cells are associated with exacerbations and eosinophilia in children with severe asthma
Authors: Guillaume Lezmi, Louise Galmiche-Rolland, Sabine Rioux, Francis Jaubert, Isabelle Tillie-Leblond, Pierre Scheinmann, Philippe Gosset, Jacques de Blic
Journal: European Respiratory Journal (2016)

The role of mast cells in the pathogenesis of childhood asthma is poorly understood. We aimed to estimate the implication of airway mucosal mast cells in severe asthma and their relationship with clinical, functional, inflammatory and remodelling parameters.Bronchial biopsies were performed in 36 children (5-18 years) with severe asthma: 24 had frequent severe exacerbations and/or daily symptoms in the previous year (symptomatic group), and 12 had few symptoms and a persistent obstructive pattern (paucisymptomatic group). Nine children without asthma were included as control subjects. We assessed mast cells in the submucosa and airway smooth muscle using c-kit antibodies and in the entire biopsy area using Giemsa.The number of submucosal mast cells was higher in the symptomatic group than in the paucisymptomatic group (p=0.02). The number of submucosal mast cells correlated with the number of severe exacerbations (p=0.02, r=0.37). There were positive correlations between the number of submucosal mast cells (p<0.01, r=0.44), airway smooth muscle mast cells (p=0.02, r= 0.40), mast cells stained by Giemsa (p<0.01, r=0.44) and submucosal eosinophils.Mast cells are associated with severe exacerbations and submucosal eosinophilic inflammation in children with severe asthma.
Desipramine improves upper airway collapsibility and reduces OSA severity in patients with minimal muscle compensation
Authors: Luigi Taranto-Montemurro, Scott A. Sands, Bradley A. Edwards, Ali Azarbarzin, Melania Marques, Camila de Melo, Danny J. Eckert, David P. White, Andrew Wellman
Journal: European Respiratory Journal (2016)

We recently demonstrated that desipramine reduces the sleep-related loss of upper airway dilator muscle activity and reduces pharyngeal collapsibility in healthy humans without obstructive sleep apnoea (OSA). The aim of the present physiological study was to determine the effects of desipramine on upper airway collapsibility and apnoea–hypopnea index (AHI) in OSA patients. A placebo-controlled, double-blind, randomised crossover trial in 14 OSA patients was performed. Participants received treatment or placebo in randomised order before sleep. Pharyngeal collapsibility (critical collapsing pressure of the upper airway ( P crit )) and ventilation under both passive ( V′ 0,passive ) and active ( V′ 0,active ) upper airway muscle conditions were evaluated with continuous positive airway pressure (CPAP) manipulation. AHI was quantified off CPAP. Desipramine reduced active P crit (median (interquartile range) −5.2 (4.3) cmH 2 O on desipramine versus −1.9 (2.7) cmH 2 O on placebo; p=0.049) but not passive P crit (−2.2 (3.4) versus −0.7 (2.1) cmH 2 O; p=0.135). A greater reduction in AHI occurred in those with minimal muscle compensation (defined as V′ 0,active − V′ 0,passive ) on placebo (r=0.71, p=0.009). The reduction in AHI was driven by the improvement in muscle compensation (r=0.72, p=0.009). In OSA patients, noradrenergic stimulation with desipramine improves pharyngeal collapsibility and may be an effective treatment in patients with minimal upper airway muscle compensation.
Activity trackers, even with cash incentives, do not improve health
Authors: Jacqui Wise
Journal: BMJ (2016)

Activity trackers, either alone or with cash incentives, do not seem to improve health outcomes at 12 months, a randomised trial published in the Lancet Diabetes and Endocrinology has found.

Cash incentives did increase exercise levels at six months, but this was not sustained after incentives were stopped. Researchers also found no evidence that wearing an activity tracker promoted weight loss or improved blood pressure or cardiorespiratory fitness.1

Eric Finkelstein from Duke-NUS Medical School in Singapore, lead author of the study, said, “While there was some progress early on, once the incentives were stopped, volunteers did worse than if the incentives had never been offered, and most stopped wearing the trackers.”

The findings come after a similar study published in JAMA found that people who wore a fitness device lost less weight over …
Randomized comparison of VAC versus VAI chemotherapy (CT) as consolidation for standard risk (SR) Ewing sarcoma tumor (ES): Results of the Euro-EWING.99-R1 trial.
Authors: O. Oberlin, M. Le Deley, U. Dirksen, I. J. Lewis, A. Ranft, J. M. Michon, M. Paulussen, J. Whelan, R. L. Ladenstein, B. Brennan, P. Marec Bérard, V. Laurence, H. Van Den Berg, L. Hjorth, C. Douglas, K. Wheatley, M. M. Van Glabbeke, I. R. Judson, A. W. Craft, H. Juergens
Journal: Journal of Clinical Oncology (2011)

9517 Background: Anthracyclines and alkylating agents are the main effective drugs known for ES. Ifosfamide and cyclophosphamide are widely used, have different toxicity profiles and unknown relative efficiency. The Euro-EWING.99-R1 trial compared, in SR localized ES, two consolidation regimens combining either ifosfamide or cyclophosphamide with vincristine and D-actinomycin (VAI vs VAC) given after an intense induction CT containing vincristine, ifosfamide, doxorubicin and etoposide (VIDE) (NCT00020566). Methods: SR tumors were localized ES with either a good histological response to VIDE chemo (<10% cells), or small tumors (< 200 ml) resected at diagnosis or receiving radiotherapy alone as local treatment. Pts entered the trial after 6 VIDE + 1 VAI courses. Allocated treatment was either 7 VAI courses with ifo = 6 g/m²/course or 7 VAC courses with cyclo = 1.5 g/m²/course. Randomization was stratified by gender, age, local treatment and data center. It was a non-inferiority trial comparing VAC to VAI with a limit of non-inferiority set at -8.5% for 3-y event-free survival rate (EFS). Overall, 806 pts were required to achieve 80%-power with 1-sided alpha = 5%. 91.4%-confidence intervals (CI) are given for this final analysis performed after 3 interim analyses. Results: 856 pts were recruited between 02/2000 and 08/2010 in 202 European pediatric and adult oncology centers in 11 countries: 424 VAI and 432 VAC. With a median FU of 4.6 y, the main results were: 3-y EFS = 77.1 and 76.0% respectively, 3-y EFS difference = -1.1% (-6.3; +4.2), hazard ratio (HR) of event = 1.06 (0.83; 1.36), HR of death = 1.05 (0.78; 1.41) (intention to treat). Results were stable on the per protocol population. Major modifications of CT were significantly more frequent in the VAI arm (13%) than in the VAC arm (6%) due to toxicity but also to an inferior compliance. We observed more thrombocytopenia in the VAC arm but more grade 2-4 acute tubular renal toxicity in the VAI arm (31 vs 16%). Conclusions: Cyclophosphamide and ifosfamide have a similar efficacy in consolidation treatment of standard risk Ewing sarcoma. Late effects studies are on-going to compare renal and gonadal toxicity of both arms.
International clinical practice guidelines including guidance for direct oral anticoagulants in the treatment and prophylaxis of venous thromboembolism in patients with cancer
Authors: Dominique Farge, Henri Bounameaux, Benjamin Brenner, Francis Cajfinger, Philippe Debourdeau, Alok A Khorana, Ingrid Pabinger, Susan Solymoss, James Douketis, Ajay Kakkar
Journal: The Lancet Oncology (2016)
Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model
Authors: Cristian A. Lasagna-Reeves, Maria de Haro, Shuang Hao, Jeehye Park, Maxime W.C. Rousseaux, Ismael Al-Ramahi, Paymaan Jafar-Nejad, Luis Vilanova-Velez, Lauren See, Antonia De Maio, Larissa Nitschke, Zhenyu Wu, Juan C. Troncoso, Thomas F. Westbrook, Jianrong Tang, Juan Botas, Huda Y. Zoghbi
Journal: Neuron (2016)
Immune modulatory nanoparticle therapeutics for intracerebral glioma
Authors: Nasser K Yaghi, Jun Wei, Yuuri Hashimoto, Ling-Yuan Kong, Konrad Gabrusiewicz, Edjah K Nduom, Xiaoyang Ling, Neal Huang, Shouhao Zhou, Brittany C Parker Kerrigan, Jonathan M Levine, Virginia R Fajt, Gwendolyn Levine, Brian F Porter, Eric G Marcusson, Kiyoshi Tachikawa, Padmanabh Chivukula, David C Webb, Joseph E Payne, Amy B Heimberger
Journal: Neuro-Oncology (2016)

Previously we showed therapeutic efficacy of unprotected miR-124 in preclinical murine models of glioblastoma, including in heterogeneous genetically engineered murine models by exploiting the immune system and thereby negating the need for direct tumor delivery. Although these data were promising, to implement clinical trials, we required a scalable formulation that afforded protection against circulatory RNases.We devised lipid nanoparticles that encapsulate and protect the miRs from degradation and provide enhanced delivery into the immune cell compartment and tested in vivo antitumor effects.Treatment with nanoparticle-encapsulated miR-124, LUNAR-301, demonstrated a median survival exceeding 70 days, with an associated reversal of tumor-mediated immunosuppression and induction of immune memory. In both canine and murine models, the safety profile of LUNAR-301 was favorable.For the first time, we show that nanoparticles can direct a therapeutic response by targeting intracellular immune pathways. Although shown in the context of gliomas, this therapeutic approach would be applicable to other malignancies.
Bone Marrow Stroma-Mediated Paracrine Inhibition of Ruxolitinib (INCB018424) Induced Apoptosis of JAK2V617F-Mutated Cells
Authors: Taghi Manshouri, Alfonso Quintás-Cardama, Zeev Estrov, Liza Knez, Ying Zhang, Hagop Kantarjian, Srdan Verstovsek
Journal: Blood (2010)
Ruxolitinib As Sparing Agent for Steroid-Dependent Chronic Graft-Versus-Host Disease (cGVHD)
Authors: H. Jean Khoury, Vamsi Kota, Martha Arellano, Stephanie L Bauer, Anand P Jillella, Amelia Langston, Zaid Al-Kadhimi, Zachariah DeFilipp, Audrey S Kim, Elliott F. Winton, John F Dipersio
Journal: Blood (2015)
Involvement of Primary Care Physicians in the Decision Making and Care of Patients With Breast Cancer
Authors: Lauren P. Wallner, Paul Abrahamse, Jaspreet K. Uppal, Christopher R. Friese, Ann S. Hamilton, Kevin C. Ward, Steven J. Katz, Sarah T. Hawley
Journal: Journal of Clinical Oncology (2016)

Purpose Collaborative care between cancer specialists and primary care providers (PCPs) may improve the delivery of high-quality cancer care. Yet, patient perspectives about how involved the PCPs were in their breast cancer care and treatment decisions remain unknown. Patients and Methods A weighted random sample of women newly diagnosed with breast cancer in 2013 to 2014, as reported to the SEER registries in Los Angeles, California, and Georgia, were sent a survey approximately 6 months after diagnosis (N = 2,279, 71% response rate). The distributions of patient-perceived PCP quality (six questions about PCP access and awareness of values) and the following three measures of patient-reported PCP involvement were assessed: how informed the respondent felt her PCP was about her breast cancer (engagement); how often the respondent talked with her PCP (communication); and how often the respondent felt the PCP participated in treatment decisions (participation). Adjusted mean scores of patient-reported satisfaction with and deliberation about the surgical treatment decision were then compared across levels of PCP engagement, communication, and participation using multivariable linear regression. Results The majority of women in this sample perceived high PCP quality (63.6%), high PCP breast cancer engagement (66.2%), and high PCP communication (69.1%). More than a third of women (35.4%) reported that their PCP participated in their treatment decisions. Higher PCP engagement was associated with higher decision satisfaction when compared with low PCP engagement (adjusted P = .003). Conclusion Patient perceptions of PCP quality and PCP involvement in breast cancer care during treatment are high for most women, and PCPs often participate in breast cancer treatment decisions. However, PCP involvement did not lead to meaningful improvements in patients' appraisals of their decision making.