tbuckley/cabot-search huggingface dataset:
Pharmacokinetics of an oral VEGF receptor tyrosine kinase inhibitor (PTK787/ZK222584) in patients with myelodysplastic syndrome (MDS): Cancer and Leukemia Group B Study 10105
Authors: P. Gupta, A. A. Miller, K. Owzar, D. J. Murry, B. L. Sanford, R. Vij, D. Yu, R. P. Hasserjian, R. A. Larson, M. J. Ratain
Journal: Journal of Clinical Oncology (2006)

6573 Background: Angiogenesis may contribute to the pathophysiology of myelodysplastic syndromes (MDS). PTK787/ZK222584 (PTK/ZK; Novartis and Schering AG) inhibits vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and c-kit receptor tyrosine kinases. Methods: We evaluated early toxicity and pharmacokinetics in a Phase II trial of PTK/ZK in patients with MDS. Patients received PTK/ZK 1,250 mg orally once daily on 28-day courses until disease progression or unacceptable toxicity. A two compartment model with first order absorption and an inducible clearance was fit to serial concentration time data using a MAP Bayesian algorithm as implemented in ADAPT II software. Results: We report preliminary toxicity and pharmacokinetics on 56 of 80 pts enrolled between March 2004 and January 2005. The most common CTC grade ≥2 non-hematological toxicities observed were fatigue, nausea, vomiting, dizziness and ataxia. The initial area under the concentration-time curve (AUCinit) ranged from 25.5–423.1 mg*h/L (mean, 105 mg*h/L). The induced AUC (AUCind) ranged from 8.2–265.3 mg*h/L (mean, 56.2 mg*h/L). There was a significant decrease in drug exposure (Hodges-Lehmann Estimate 45.2 mg*h/L [95% CI=30.5,60.0]; Wilcoxon signed rank test p &lt;0.0001), likely due to CYP3A4 auto-induction. However, there was no statistical correlation between AUCinit and AUCind for individual patients. Because of marked inter-individual heterogeneity observed in AUCinit and AUCind, we examined if drug exposure correlated with toxicity during the first 2 courses. On exploratory analyses, there was no relationship between pharmacokinetic parameters (AUCinit, AUCind or a function of both AUCs) and the occurrence or grade of non-hematological toxicities. Conclusions: Drug exposure declined significantly within 7–14 days after starting treatment with PTK/ZK. In this sample, there was no statistical evidence suggesting that variability in drug exposure was associated with non-hematological toxicities of PTK/ZK in patients with MDS. No significant financial relationships to disclose.
C-Film as a contraceptive. (Letter to the editor)
Authors: Smith M, Vessey Mp, Bounds W, Warren J
Journal: BMJ (1974)

The Family Planning Association in London conducted a clinical trial in order to assess the efficacy and acceptability of C-Film used as a sole method of contraception.  Of the 45 subjects included in the analysis all had regular menstrual cycles 23 were nulliparous and 1 was lactating at the time of enrollment.  9 of the women experienced an involuntary pregnancy during a total of 175 person-months of exposure to risk representing a use-effectiveness pregnancy rate of 62 per 100 woman-years.  2 pregnancies occurred during the first month of use 1 during the second 2 during the fourth and the remainder during the fifth or later months.  In only 1 case did the woman admit to having had unprotected intercourse.  In addition to the 9 women who became pregnant a further 25 withdrew from the trial: 4 because of side effects 2 because of difficulties with the method and 19 for reasons not connected with the method.  The Family Planning Association terminated the study and does not recommend the use of C-FILM as a sole method of contraception to women attending its clinics.
Effect of acute exacerbations on circulating thrombotic and fibrinolytic markers in COPD patients
Authors: Riccardo Polosa, Mario Malerba, Alessandro Radaeli, Jaymin Morjaria, Raimondo Gullo, Giuseppe Di Maria
Journal: European Respiratory Journal (2011)

Introduction:  Patients with COPD are prone to clinical exacerbations which are associated with increased airway inflammation, a potent pro-thrombotic stimulus.   Aim:  To investigate whether activation of the endothelial-coagulative system occurs in association with COPD exacerbation.   Methods:  Surrogate markers of inflammation were collected: interleukin-6 (IL-6); endothelium damage: von Willebrand9s factor (vWF); clotting activation: D-dimer (D-D), and prothrombin fragment 1+2 (F1+2); fibrinolytic response: plasminogen activator inhibitor 1 (PAI-1), in COPD subjects during exacerbation.   Results:  In 30 COPD subjects, IL-6, vWF, D-D and F1+2 levels were elevated during exacerbation and decreased significantly at clinical stability (IL-6, p=0.005; vWF, p   Conclusions:  COPD exacerbations are associated with endothelial activation and clotting initiation. This was not associated with a change in PAI-1, implying a defect in the fibrinolytic response to inflammation. The pro-thrombotic nature of COPD exacerbations appears to be mitigated by excessive fibrinolysis
Initial results of ongoing phase I/II studies of weekly doxorubicin (Doxo)/docetaxel (Doce) in men with hormone refractory (HRPC) and hormone sensitive prostate cancer (HSPC)
Authors: H. D. Mannuel, N. Dawson, I. Khan, M. Feldman, L. Boyle, M. Besche, J. Smoot, C. Engstrom, M. Monroe, A. Hussain
Journal: Journal of Clinical Oncology (2005)

4665
Interleukin‐9 Overexpression and Th9 Polarization Characterize the Inflamed Gut, the Synovial Tissue, and the Peripheral Blood of Patients With Psoriatic Arthritis
Authors: Francesco Ciccia, Giuliana Guggino, Angelo Ferrante, Stefania Raimondo, Rodolfo Bignone, Vito Rodolico, Sergio Peralta, Melissa Van Tok, Alessandra Cannizzaro, Claudia Schinocca, Piero Ruscitti, Paola Cipriani, Roberto Giacomelli, Riccardo Alessandro, Francesco Dieli, Aroldo Rizzo, Dominique Baeten, Giovanni Triolo
Journal: Arthritis & Rheumatology (2016)

Objective To investigate the expression and tissue distribution of Th9‐related cytokines in patients with psoriatic arthritis (PsA). Methods Quantitative gene expression analysis of Th1, Th17, and Th9 cytokines was performed in intestinal biopsy samples obtained from patients with PsA, HLA−B27−positive patients with ankylosing spondylitis (AS), patients with Crohn's disease (CD), and healthy controls. Expression and tissue distribution of interleukin‐23 (IL‐23), IL‐17, IL‐22, IL‐9, and IL‐9 receptor (IL‐9R) were evaluated by immunohistochemistry and confocal microscopy. Flow cytometry was used to study the frequency of Th9 cells among peripheral blood, lamina propria, and synovial fluid mononuclear cells. The functional relevance of IL‐9R expression on epithelial cells was assessed in functional in vitro studies. Th9 cells in synovial tissue from patients with PsA were also studied. Results Subclinical gut inflammation in PsA patients was characterized by a clear Th17 and Th22, but not Th1, polarized immune response. Unlike AS and CD, a strong and significant up‐regulation of IL‐9 was observed in PsA gut, especially among infiltrating mononuclear cells, high endothelial venules, and Paneth cells. IL‐9−positive mononuclear cells were demonstrated to be in large part Th9 cells. IL‐9 overexpression was accompanied by significant Paneth cell hyperplasia. Paneth cells strongly overexpressed IL‐9R, and stimulation of epithelial cells, isolated from PsA patients, with IL‐9 resulted in overexpression of α‐defensin 5 and IL‐23p19. Peripheral and synovial expansion of α4β7+ Th9 cells was also observed in patients with PsA. Increased expression of IL‐9 and IL‐9R was also found in synovial tissue. Conclusion Strong IL‐9/Th9 polarization seems to be the predominant immunologic signature in patients in PsA.
Impact of Rantes and MCP-1 Chemokines on In Vivo Basophilic Cell Recruitment in Rat Skin Injection Model and Their Role in Modifying the Protein and mRNA Levels for Histidine Decarboxylase
Authors: Pio Conti, Xinzhu Pang, William Boucher, Richard Letourneau, Marcella Reale, Renato C. Barbacane, Jean Thibault, Theoharis C. Theoharides
Journal: Blood (1997)
Syphilis and Social Upheaval in China
Authors: Therese Hesketh, Wei Xing Zhu, Xu Dong Zhou
Journal: New England Journal of Medicine (2010)

In their Perspective article Tucker et al. (May 6 issue)1 report that rapid increases in cases of congenital syphilis in China have generated great concern. Although sexually transmitted diseases (STDs) have become major notifiable diseases in China2 a review by an expert panel concluded in February 2008 that the rapid increase in reported cases of syphilis was primarily caused by systematic changes in diagnosis and reporting because a nationwide Web-based real-time reporting system was introduced in 2004.3 National surveillance of pregnant women with syphilis in China suggested that there was no significant change in the incidence between 2005 and 2009. In 2008 the Shanghai Center for Quality Control of STD Treatment conducted a specific investigation of the increase in reports of congenital syphilis; it revealed that most reported cases were misdiagnosed. For example among 42 infants with congenital syphilis who were followed for 12 months all the rapid plasma reagin tests and Treponema pallidum particle agglutination assays became negative between 3 and 10 months after birth. Such misdiagnosis and overreporting of congenital syphilis have also occurred in Detroit.4 These findings remind us that we must understand how data are being collected and reported so that we can interpret them appropriately.  (full-text)
Aromatase Inhibitors in Postmenopausal Breast Cancer Patients
Authors: Alyssa G. Rieber, Richard L. Theriault
Journal: Journal of the National Comprehensive Cancer Network (2005)

Aromatase inhibitors (AIs) have greatly enriched the treatment of hormone receptor-positive breast cancer in postmenopausal patients. Before the introduction of the well-tolerated third-generation AIs, tamoxifen was the mainstay of endocrine therapy for hormone receptor-positive breast cancer. Many clinical trials have shown the superiority of AIs compared with tamoxifen in adjuvant breast cancer treatment, as well as their benefit in metastatic breast cancer. NCCN guidelines recommendations for their use are based on the evidence provided by these clinical trials. This discussion reviews the evidence supporting the current guidelines for use of AI therapy in the treatment of hormone receptor-positive postmenopausal breast cancer patients.
Final results of a meta-analysis testing HER2 and topoisomerase IIα genes as predictors of incremental benefit from anthracyclines in breast cancer.
Authors: A. Di Leo, C. Desmedt, J. M. Bartlett, B. Ejlertsen, K. I. Pritchard, C. J. Poole, D. Larsimont, M. Tanner, F. Piette, M. E. Buyse
Journal: Journal of Clinical Oncology (2010)

519 Background: Five trials comparing anthracyclines (A) with CMF in the early setting tested HER2 and topoisomerase IIα (TOP2A) genes as predictors of benefit from A. An interim report of this meta-analysis suggested that both genes are clinically modest predictors (SABCS 2008 abs 705). Methods: HER2 and TOP2A were tested in four national laboratories by FISH (amplification: ratio ≥2; TOP2A deletion: ratio ≤ 0.8). National lab (NL) scores were validated by submitting randomly selected cases to a central lab (CL) for FISH (Abbott labs, USA). Individual patient data were centralized. Onsite visits were performed. Results: Final results are based on 3,452 and 3,102 pts for HER2 and TOP2A, respectively. HER2 NL scores were validated in 137 cases (discordance 8/137, 5.8%), TOP2A NL scores in 123 cases (discordance 38/123, 30.9%). Conclusions: HER2 and TOP2A genes have clinically modest and statistically borderline predictive value. Some HER2-negative pts derive benefit from A. Disease-free survival (DFS) hazard ratio A versus CMF (95% CI) HER2 TOP2A Study No. pts Amp (No. 843) NA (No. 2,609) No. pts Amp (No. 275) N (No. 2,511) D (No. 316) Belgium 353 0.72 (0.37, 1.39) 1.31 (0.90, 1.91) 89 0.37 (0.12, 1.17) 0.89 (0.42, 1.87) * Canada 626 0.60 (0.39, 0.92) 0.95 (0.73, 1.22) 437 0.71 (0.34, 1.50) 1.01 (0.76, 1.36) 0.26 (0.09, 0.76) Denmark 670 0.73 (0.52, 1.03) 0.83 (0.62, 1.10) 773 0.54 (0.30, 0.97) 0.92 (0.72, 1.17) 0.62 (0.36, 1.06) UK-NEAT 1,508 0.73 (0.51, 1.04) 0.88 (0.71, 1.08) 1,508 0.69 (0.31, 1.54) 0.87 (0.71, 1.06) 0.78 (0.47, 1.28) UK- BR9601 295 0.81 (0.42, 1.60) 0.54 (0.34, 0.85) 295 2.35 (0.39, 14.07) 0.60 (0.39, 0.92) 0.47 (0.19, 1.16) Meta-analysis [p value heterogeneity test] 3,452** 0.71 (0.58, 0.86) p.0004 [p.94] 0.89 (0.79, 1.01) p.07 [p.06] 3,102*** 0.62 (0.43, 0.90) p.01 [p.51] 0.88 (0.78, 1.00) p.052 [p.38] 0.63 (0.46, 0.87) p.004 [p.45] Abbreviations: Amp, amplified; NA, nonamplified; N, normal; D, deleted; No., number. * Only 8 cases; ** interaction test = p.048; *** interaction test = p.051. Overall survival and DFS results are similar. A planned analysis tested both genes in distinct groups: highly or moderately hormone sensitive (MHS), HER2+, triple negative (TN). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline, Pfizer, Roche, sanofi-aventis GlaxoSmithKline, Pfizer, Roche, sanofi-aventis Pfizer, sanofi-aventis
Abstract 18245: Results of the Chronic Heart Failure Intervention to Improve Medication Adherence (CHIME) Study: A Randomized Self-Management Intervention in High Risk Non-Adherent Patients
Authors: Bradi B Granger, Hayden Bosworth, Adrian Hernandez, Shelby Reed, Inger Ekman
Journal: Circulation (2013)

Background: Heart failure (HF) remains a primary cause of avoidable hospitalizations, disability and death. Taking evidenced-based medications is one component of guideline-based self-management, and is associated with improved clinical outcomes. Despite benefits, patients struggle with medication adherence in daily life and adherence remains less than 50%. Interventions to improve medication adherence have been limited in their ability to show an effect over time. Purpose: To evaluate the efficacy of a self-management intervention designed to develop person-centered symptom identification and to improve symptom response and medication adherence in high-risk persons with HF. Methods: Patients with HF and at high risk for non-adherence (n=84) were randomized to an attention control or the intervention. A prospective, randomized controlled design was used to pilot test the efficacy of an intervention to promote adherence to the medication regimen in high risk patients with chronic heart failure. The intervention was administered at 3 month intervals by a nurse over the phone with a focus on skill-based teaching for symptom recognition and rapid response, medication adherence strategies, and self-management activities. Longitudinal analysis was performed to evaluate the magnitude of change in adherence and symptom-related events at 3, 6 and 12-month clinic visits. Efficacy was measured as improved adherence using the Morisky adherence scale and pill count. Results: Patients in the intervention arm were almost four times as likely to be adherent to medications at 12 months as compared to attention control (OR 3.92; 95% C.I. 1.83, 8.40; p= .0006). Symptom recognition; accuracy and timeliness of medication reconciliation; appointment keeping; and caregiver engagement scores were improved in the intervention group. Readmissions and emergency department use were not statistically different. Conclusions: A nurse administered self-management intervention that includes a symptom recognition and response plan component improves medication adherence and shows a trend in decreased hospitalizations.
High throughput transcriptome sequencing of pediatric relapsed acute lymphoblastic leukemia (ALL).
Authors: L. E. Hogan, C. Mason, J. Meyer, J. Wang, Z. Tang, S. Brown, D. J. Morrison, S. Hunger, E. A. Raetz, W. L. Carroll
Journal: Journal of Clinical Oncology (2010)

9521 Background: Relapsed ALL carries a very poor prognosis despite intensive therapy, indicating the need for new insights into disease mechanisms. We have previously used global gene expression profiling and copy number analysis in diagnosis/relapse pairs to better understand the biologic mechanisms leading to relapse. To create an integrated genomic profile we have now focused on high throughput RNA sequencing to detect mutations, insertions, deletions and fusion transcripts. Methods: To date we have sequenced 4 pediatric matched diagnosis/relapse pairs (i.e. 8 marrow samples) from B-precursor ALL patients. RNA sequencing was performed using the Illumina GAIIx Analyzer. Each sample was sequenced in 7 lanes using single-read 54 base pair sequencing to cover 52% of genes at 5X and 34% of genes at 20X. BWA (v0.5.5) and Samtools (v1.7) were used to align the reads to the human genome and predict single nucleotide variants (SNVs) and insertion/deletions (indels) across the genome. Known single nucleotide polymorphisms (SNPs) were filtered out by comparison to diagnostic samples and through use of dbSNP (r130) and 1,000 Genomes Project databases. We have focused our initial analysis on relapse specific lesions shared by samples presumably indicating selection for common chemoresistance pathways. Results: We found 232 variants that were relapse specific and shared among all 4 patients. Sixty-seven of the variants were within exons: 14 deletions, 6 indels, 34 insertions and 13 SNVs. There were 2,454 variants that were relapse specific and shared among 3 of 4 patients. Of these, 766 variants were within exons: 144 deletions, 69 indels, 344 insertions and 209 SNVs. There were 16,100 relapse specific variants found in 2 of 4 patients. Of these, 5,184 were within exons: 1,058 deletions, 300 indels, 2,146 insertions and 1,680 SNVs. Validation of a subset of these variants in a larger cohort of patients using Taqman assays and Sanger sequencing is underway. Conclusions: RNA sequencing in relapsed pediatric ALL reveals many novel relapse specific variants that are shared among patients. Furthur analysis of these variants will be necessary to determine their functional significance and potential therapeutic relevance. No significant financial relationships to disclose.
Adjuvant hormonal therapy (AHT) in women with early stage breast cancer (BC).
Authors: X. Song, G. Nicholas, S. Dent, S. Verma
Journal: Journal of Clinical Oncology (2007)

11053 Background: The ASCO technology assessment on adjuvant use of AI states that optimal AHT for a postmenopausal woman with HR-positive BC should now include an AI. We assessed uptake and patterns of AHT use in early stage HR-positive BC at a regional cancer center. Methods: A retrospective review of patients diagnosed with HR-positive early stage BC from January 2004 to December 2005 treated at our center was performed. Data included patient demographics, dates of diagnosis, treatment, last follow-up, AHT choices considered, patient compliance, and treatment toxicity. Patient risks for disease recurrence and mortality were estimated using adjuvantonline. Factors predicting a preference for AI use were identified using univariable and multivariable analysis. Results: 900 patients were identified for the stated period of time with HR-positive early stage BC. 340 patients have been evaluated. Median age was 59 years. Menopausal status was post-/ pre- in 267/73 patients. Stage was I/IIA/IIB in 202/95/43 patients. 267 patients were lymph node (LN) negative. ER, PR and Her2/neu status were positive/negative/unknown in 332/7/1, 292/46/2 and 11/69/260 patients. Initial AHT choice was tamoxifen/anastrozole/letrozole/exemastane/none in 196/79/9/2/54 patients. Of those started upfront on tamoxifen, plan to switch to an AI was stated in 41%. Statistically significant factors associated with any adjuvant AI use included disease stage, menopausal status as well as individual physician preferences. In further analysis, patients’ compliance and toxicity will be reported. Correlation of recurrence risk, as determined through adjuvantonline, with upfront selection of an AI has also been performed. Conclusion: Guidelines have stated the use of an AI (upfront, sequential or extended) should be considered in HR-positive early stage BC. Results from this study provide further insights on the uptake of such therapy as well as factors (disease related, patient and physician preferences) influencing adjuvant treatment decision-making. A prospective trial assessing treatment decision regarding AHT is also in progress. (This study is sponsored by the Canadian Breast Cancer Foundation) No significant financial relationships to disclose.
Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis
Authors: H Cypers, G Varkas, S Beeckman, K Debusschere, T Vogl, J Roth, M B Drennan, M Lavric, D Foell, C A Cuvelier, M De Vos, J Delanghe, F Van den Bosch, D Elewaut
Journal: Annals of the Rheumatic Diseases (2015)

Microscopic bowel inflammation is present in up to 50% of patients with spondyloarthritis (SpA) and is associated with more severe disease. Currently no reliable biomarkers exist to identify patients at risk. Calprotectin is a sensitive marker of neutrophilic inflammation, measurable in serum and stool.To assess whether serum and faecal calprotectin in addition to C-reactive protein (CRP) can be used to identify patients with SpA at risk of microscopic bowel inflammation.Serum calprotectin and CRP were measured in 125 patients with SpA. In 44 of these patients, faecal samples were available for calprotectin measurement. All 125 patients underwent an ileocolonoscopy to assess the presence of microscopic bowel inflammation.Microscopic bowel inflammation was present in 53 (42.4%) patients with SpA. Elevated serum calprotectin and CRP were independently associated with microscopic bowel inflammation. Faecal calprotectin was also significantly higher in patients with microscopic bowel inflammation. Patients with CRP and serum calprotectin elevated had a frequency of bowel inflammation of 64% vs 25% in patients with low levels of both. When either CRP or serum calprotectin was elevated, the risk was intermediate (40%) and measuring faecal calprotectin provided further differentiation. Hence we suggest a screening approach where initially serum calprotectin and CRP are assessed and, if necessary, faecal calprotectin. The model using this scenario provided an area under the ROC curve of 74.4% for detection of bowel inflammation.Calprotectin measurements in stool and serum, in addition to CRP, may provide a promising strategy to identify patients with SpA at risk of bowel inflammation and could play a role in overall patient stratification.