tbuckley/cabot-search huggingface dataset:
Retrospective analysis of effects of dose modification and myelosuppression on response to decitabine and overall survival in patients with myelodysplastic syndromes.
Authors: M. Cornelison, G. Garcia-Manero, J. E. Cortes, F. Ravandi, H. Kantarjian, K. Stein, A. Teng, E. Jabbour
Journal: Journal of Clinical Oncology (2011)

6600 Background: Decitabine is a therapy for myelodysplastic syndromes (MDS). Myelosuppression is typical of MDS and a common toxicity of decitabine, and may result in dose modification (reduction and/or delay) but may not indicate progression of MDS. Methods: We conducted a retrospective analysis of a pooled subset of patients (pts) with MDS from 2 decitabine dosing trials: 5-day (Phase II) and 3-day (Phase III). Pts with ³1 dose of decitabine were included. Cox regression analyses were conducted of on-study red blood cell (RBC) or platelet (PLT) dependence, occurrence of myelosuppression, dose modification (reduction or delay), and survival on baseline variables and some time-dependent covariates. Results: 182 pts were included. RBC or PLT dependence at baseline was a predictor for dose modification on study (RBC: P=.008, hazard ratio [HR]=2.11; PLT: P=.011, HR=1.98) as was myelosuppression on study (P<.0001, HR=8.08). Pts who had dose modification had a better response (P=.0001, HR=2.27) regardless of RBC baseline dependence status, and pts with dose modifications had better overall survival vs those without dose modifications (median [95% CI] 19.2 [15.2, 21.3] vs 10.3 [7.6, 15.7] mo; P=.0039). Time to dose modification also correlated with response; pts with a shorter time to dose modification had a quicker response (P=.0001, HR=2.27). Cycle number may have affected results; pts with dose reduction/delay or modification received a median of 6 cycles vs 2 for other pts. Conclusions: Pts who develop myelosuppression on treatment will likely require dose modification. However, these pts appear to have a significant clinical response. One hypothesis is that decitabine may remove both abnormal and normal rapidly dividing marrow cells during a susceptible phase of the cell cycle, so myelosuppression may indicate decitabine activity. That pts with a shorter time to dose reduction or delay had a better response supports this hypothesis. Based on this retrospective analysis, myelosuppression and dose reductions or delays on treatment may not necessarily indicate lack of efficacy; conversely, they may indicate a response to treatment.
Validation and use of a biomarker for clinical development of the MEK1/2 inhibitor ARRY-142886 (AZD6244)
Authors: M. P. Doyle, T. C. Yeh, B. Suzy, M. Morrow, P. A. Lee, A. M. Hughes, S. Cartlidge, E. Wallace, J. Lyssikatos, S. G. Eckhardt, J. D. Winkler
Journal: Journal of Clinical Oncology (2005)

3075 Background: Optimal transition of a signal transduction inhibitor from discovery into clinical development requires a robust biomarker. We have previously shown that ARRY-142886 (AZD6244), a potent, selective MEK1/2 inhibitor currently in Phase I trials, has demonstrated sustained inhibition of ERK1/2 phosphorylation in tumor models. Here we report on the validation of phosphorylated ERK (pERK) in ex vivo blood as a marker for activity in both preclinical and clinical settings. Methods: Whole blood samples were obtained, stimulated with TPA (12-O-tetradecanoylphorbol-13-acetate) and fixed with formaldehyde. Peripheral blood mononuclear cells (PBMCs) were isolated using sucrose polymer density gradients. Cells were labeled for pERK and analyzed by flow cytometry. ARRY-142886 plasma concentrations were determined by validated LC-MS/MS Methods: Results: During the pre-clinical toxicity studies, blood was taken from study animals to demonstrate the bioactive effects of the drug. Whole blood samples from cynomolgus monkeys at pre-dose and 1h, 2h, 4h, 8h, 12h post-dose were analyzed. Plasma concentrations of ARRY-142886 correlated with inhibition of TPA-induced ERK phosphorylation. Similarly, the ex vivo addition of ARRY-142886 to human whole blood from volunteers resulted in the inhibition of ERK phosphorylation in isolated PBMCs. Blood samples were also obtained from cancer patients enrolled in an ongoing Phase I study. There is a strong correlation between plasma drug concentration and inhibition of ERK phosphorylation in blood from these patients, demonstrating the effectiveness of pERK as a mechanistic biomarker for MEK inhibition in the clinical setting. Conclusions: A strong correlation between ARRY-142886 plasma concentrations and inhibition of ERK phosphorylation was seen in whole blood samples from monkeys dosed orally with ARRY-142886 and ex vivo treated human blood. This methodology was applied to whole blood samples obtained from patients in a Phase I trial, where it was shown that ERK phosphorylation was inhibited in response to administration of ARRY-142886. Therefore, PBMC pERK appears to be a robust and reproducible mechanistic biomarker of MEK 1/2 inhibition. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Array BioPharma, AstraZeneca Array BioPharma Array BioPharma, AstraZeneca
THU0104 Physical Function in Relation to Gender in Patients with Rheumatoid Arthritis – A 15 Year Follow up Study from the Barfot Cohort
Authors: K. Eberhardt, K. Forslind, A. Bremander, B. Svensson, M. Andersson
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Objectives</h3> The aim was to study physical function in individuals with rheumatoid arthritis (RA) as measured by SOFI (observed physical function) and HAQ (self-rated physical function) over 15 years and describe associated variables, with focus on gender differences. <h3>Methods</h3> In all 2558 patients (847 men and 1711 women) age (SD) 58 (16) were recruited from the BARFOT inception cohort of patients with early RA. They had at inclusion a disease duration of one year or less and fulfilled the ACR 1987 criteria. At 15 years follow-up 663 out of 690 patients participated. Physical function was assessed by the SOFI (Signals of functional impairment) test, (scores 0-44, best to worst) which includes 12 performance tests measuring objective physical function, and the HAQ (Health Assessment Questionnaire) (scores 0-3, best to worst) measuring self-reported activity. A logistic regression model was performed to assess if being in the highest quartile of SOFI and HAQ, respectively, at the15 year follow up visit was associated to gender. Age, disease duration at inclusion, disease activity, smoking habits, RF positivity and pain were included in the model. <h3>Results</h3> Women had lower mean SOFI than men at inclusion and during the first study year, p&lt;0.001. HAQ showed a conversed pattern, where women reported worse physical function than men on all occasions, p&lt;0.001. During the first year SOFI and HAQ decreased in both genders, p&lt;0.001. Thereafter throughout the study period mean SOFI and HAQ increased in men and women, p&lt;0.001, figure 1A and B. At the 15 year follow up visit being in the highest quartile of SOFI (score ≥10) was not associated with gender while women had a higher risk to be in the highest quartile of HAQ (score ≥1.13) OR (95% CI) 2.86 (1.73-4.74), p&lt;0.001. DAS 28 at inclusion showed a weak association with SOFI, OR (95% CI) 1.36 (1.11-1.68), p=0.003 while pain at inclusion was somewhat closer associated with HAQ, 1.02 (1.01-1.03), p&lt;0.001. The correlation between the two functional test was r=0.54. <h3>Conclusions</h3> Women had an almost three times higher risk of worse outcome of HAQ after 15 years while the outcome of SOFI was not associated with gender. These two measures provide information of different aspects of physical function and should be used concomitantly. <h3>Disclosure of Interest</h3> None declared
Changing the treatment paradigm for patients with MDS: How the development of therapeutics influences population-based care in community oncology, the Georgia Cancer Specialists Outcomes Database experience
Authors: B. A. Feinberg, J. Gilmore, W. Hawke, T. Gondesen
Journal: Journal of Clinical Oncology (2007)

7080 Background: Clinical trials that lead to approval of new cancer therapeutics are based upon rigorous studies of safety &amp; efficacy in a highly-restricted pt population. Community oncology practices are evolving to contribute to our understanding of the population- based effectiveness of these therapeutics by capturing and analyzing outcomes data. Georgia Cancer Specialists, a group practice of 41 hematologists/oncologists has been routinely tracking outcomes data since 1999. We now report outcomes for pts with MDS from our database. MDS was selected since this is a Medicare population, has typically been treated with supportive care only, and 3 new agents, 5-azacytadine (VID), lenalidomide (REV) and decitabine (DAC) have recently been approved allowing assessment of their impact on this cancer population. Methods: The Georgia Cancer Specialists Outcomes Database is an integrated electronic medical records and billing database that captures over 45 parameters on every pt visit at 31 sites. This study is a retrospective, observational study using de-identified pt-level information. Results: We followed 824 MDS pts from Jan-Oct, 2006, with 63% women; mean age 71 yrs; 61% Medicare/Medicaid. Only 7% of pts received at least one MDS-indicated chemotherapeutic. Of these, 44% received VID; 36% REV, and 43% DAC and 18% received at least two. At initial therapy, more REV pts (73%) were transfusion-dependent than VID (20%) and DAC (55%) (p=0.034). Average duration of observed therapy ranged from 2.3–3.25 cycles. A greater proportion of DAC pts (93%) had an improvement in RBC count within the first 4 cycles when compared to VID (44%) and REV (62.5%) (p&lt;0.01). The treatment response profile for platelets was similar for VID and DAC. Conclusions: Practice patterns of elderly pts with MDS are changing as new therapies are adopted in community oncology practice. DAC appears to be very active, with the shortest time to initial response. Rigorous population based outcomes analyses at the practice level is an important component of quality cancer care and must supplement information generated by randomized clinical trials. No significant financial relationships to disclose.
The predictive role of CA 19–9 kinetics for time-to-progression (TTP) and overall survival (OS) in patients receiving palliative first-line chemotherapy for advanced pancreatic cancer
Authors: M. Haas, S. Boeck, P. Stieber, R. P. Laubender, H. Buchner, C. Klose, F. Kullmann, C. J. Bruns, U. Mansmann, V. Heinemann
Journal: Journal of Clinical Oncology (2009)

e15637 Background: Previous studies showed contradictory results for a predictive role of CA 19–9 kinetics during chemotherapy in patients (pts) with pancreatic cancer (PC). Methods: We performed a retrospective, multicenter study in order to evaluate the role of CA 19–9 as a biomarker for TTP and OS in PC. Main inclusion criteria: histological confirmed diagnosis of PC, treatment with first-line chemotherapy for advanced disease, pre-treatment CA 19–9 level of &gt; 5.2 U/ml. As CA 19–9 measurements were conducted in different laboratories using different commercial assays, we defined a subgroup of pts where CA 19–9 was assessed exclusively by the Elecsys assay (Roche Diagnostics). For the analysis of CA 19–9 kinetics, at least one follow-up measurement between day 20 and 64 during first-line chemotherapy had to be available. Pts were divided into two subgroups of CA 19–9 responders and non-responders by cut-offs of a 25% and 50% decline, respectively. OS and TTP were estimated with the Kaplan-Meier-Method, differences between the subgroups were analyzed by using the log-rank test. Results: One hundred and eighty-six pts were included, 83 of them were tested with the Elecsys method. Median age was 63 years, 90 % of the pts were treated within prospective clinical trials. Median pre-treatment CA 19–9 was 1076 U/ml (range 5.7–100,000 U/ml), the median bilirubin was 0.6 mg/dl. Median OS and TTP were 9.8 months (mo) and 5.4 mo, respectively. In univariate analysis, pts with a CA 19–9 decline of at least 25% during chemotherapy lived significantly longer (11.9 mo vs. 8.2 mo, p=0.003) and had a significantly prolonged TTP (5.8 mo vs. 4.4 mo, p=0.018) than those with a lower decline or even CA 19–9 increase. Data for the Elecsys-measurements were comparable (OS: 13.4 mo vs. 8.6 mo, p=0.004; TTP: 7.0 mo vs. 2.6 mo, p=0.003). None of the analyses demanding a CA 19–9 drop of at least 50% reached the level of statistical significance. Conclusion: An early CA 19–9 decline of 25% during first-line chemotherapy may predict OS and TTP in pts with advanced PC. Innovative statistical methods are required to improve our understanding of the utility of CA 19–9 as a predictive biomarker in PC. [Table: see text]
Gemcitabine (G) plus capecitabine (C) versus G alone in locally advanced or metastatic pancreatic cancer. A randomized phase III study of the Swiss Group for Clinical Cancer Research (SAKK) and the Central European Cooperative Oncology Group (CECOG)
Authors: R. Herrmann, G. Bodoky, T. Ruhstaller, B. Glimelius, P. Saletti, E. Bajetta, J. Schueller, J. Bernhard, D. Dietrich, W. Scheithauer
Journal: Journal of Clinical Oncology (2005)

LBA4010 Background: While G is a widely accepted treatment for pts with advanced pancreatic cancer, C has shown single agent activity and promising efficacy in combination with G in phase II studies. Therefore, we compared the combination of G + C with G alone in a randomized phase III study. Methods: Major eligibility criteria: KPS ≥ 60, WBC ≥ 3.5 x 109/l, platelets ≥ 100 x 109/l, hemoglobin ≥ 10.0 g/dl, sufficient liver function (bilirubin/ASAT/ALAT/ alkaline phosphatase < 5 x upper normal limit), creatinine clearance ≥ 30 ml/min and no previous chemotherapy for metastatic disease. Stratification factors: locally advanced/metastatic disease, absence/presence of pain, institution, KPS 60–80/90–100. The primary endpoint is overall survival. Secondary endpoints are quality of life, clinical benefit response, objective tumor response, duration of response, time to progression and safety. Pts were randomized to receive G 1000 mg/m2 i.v. over 30’ d 1+8 and C 650 mg/m2 orally q12hrs d 1–14, q3w, or G 1000 mg/m2 weekly x7, 1w rest and then weekly x3, q4w. Treatment continued until progression or for 6 months and could be resumed upon progression. The study was designed to detect an increase of median survival from 5 to 7 months. The survival analysis will be conducted after more than 80% of patients have died. An independent safety monitoring board is monitoring the trial data. Results: From June 2001 to June 2004, 319 pts with advanced disease from 30 institutions in 8 countries were randomized. 80% of all pts had metastatic disease, 67% had pain requiring pain medication and 84% had a KPS of 90 or 100 with a well-balanced distribution. Results on the primary and the secondary endpoints will be presented for both treatment groups during the meeting. Conclusions: To be reached after data becomes available. Supported in part by Hoffmann-La Roche and Eli Lilly Switzerland Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Roche Lilly
Abstract 18804: Relationship of Left Ventricular Circumferential Strain with Preload and Afterload Using Feature-Tracking MRI
Authors: Dvorah G Holtzman, Jeannette McLaughlin, Peter Rhee, Madhavi Kadiyala, Jie J Cao
Journal: Circulation (2012)

Background: Myocardial Strain is a sensitive measure of left ventricular (LV) global and regional myocardial deformation. Its association with preload and afterload is yet to be elucidated. We assessed circumferential strain using Feature-tracking (FT) MRI and investigated the relationship of strain with preload and afterload using hemodynamics assessed during left heart catheterization. Methods: Forty nine patients undergoing clinical cardiac catheterization were prospectively recruited for same day research cardiac MRI. Circumferential strain was assessed by analyzing endocardial deformation of the cine images in mid LV short axis planes using FT-MRI (Diogenes TomTec Imaging Systems). LV end diastolic pressure (LVEDP) and LV end systolic pressure (LVESP) were assessed during cardiac catheterization. Meridional wall stress was calculated using the formula: σ m =PR/2h (l+h/2R) where p was the pressure, R the radius and h the average myocardial wall thickness. LV preload and afterload were defined as the meridional wall stress at end diastole and systole. Results: The cohort mean age was 60 ± 13 years, 32 (65%) male. The average circumferential strain was -22.5±7.9%, LV ejection fraction (LVEF) 50 ± 14%, LVEDP 16±7 mmHg and LVESP 135±28 mmHg. In a univariate analysis, circumferential strain was most strongly associated with LVEF (r=-0.91, p &lt; 0.001) followed by LV end systolic volume (r= 0.864, p&lt; 0.001), LV end diastolic volume (r= 0.790, p &lt; 0.001) and LV mass (r=0.572, p&lt;0.001). Of LV hemodynamic properties, strain was associated with LVEDP (r=0.517, p&lt; 0.001) but not with LVESP (r=-0.110, p = 0.450). However, the association became much stronger when hemodynamics were expressed as preload (r=0.681, p&lt;0.001) and afterload (r= 0.820, p&lt; 0.001). In a multivariate linear regression model adjusting for LVEF, LV mass, LVESP, LVEDP, preload and afterload , circumferential strain was only associated with LVEF (p &lt;0.001) and afterload (p=0.009). Conclusion: Circumferential strain assessed by FT- MRI is a sensitive measure of left ventricular systolic function. Preload and afterload are more important than intraventricular pressure alone in the relationship of strain to hemodynamics. However, afterload is likely the most important hemodynanic variable.
Phase I study of docetaxel, oxaliplatin, and capecitabine as first-line therapy to patients with advanced gastroesophageal cancer
Authors: K. R. Schønnemann, M. Andersen, M. Yilmaz, H. A. Jensen, L. W. Vestermark, P. Pfeiffer
Journal: Journal of Clinical Oncology (2009)

e15613 Background: Previously, epirubicin, cisplatin, and 5-FU (ECF) were often recommended as first line therapy to patients (pts) with advanced gastro-esophageal cancer (GE). If cisplatin is substituted by oxaliplatin (E) and 5-FU by capecitabine (X) this regimen can easily be administered with comparable efficacy and lower toxicity. In addition, recent studies have shown that efficacy can be improved by adding docetaxel (T) to CF. We therefore initiated a phase I trial of docetaxel, short-time infusion of oxaliplatin and continuously capecitabine (TEX) as first line therapy to establish the recommended dose for further therapy. Methods: Pts were enrolled in cohorts of 3 at each dose level ( Table ). All pts had non resectable histologically GE adenocarcinoma. No pts had received prior chemotherapy. Therapy was given day 1 with escalating doses of docetaxel (60 mg/m 2 to 75 mg/m 2 , as a 60 minutes infusion), capecitabine (1000 to1250 mg/m 2 /day continuously) and oxaliplatin (85 to 130 mg/m 2 as a 30 minutes infusion). Cycles were repeated every 3 weeks for a maximum of 8 cycles. Toxicity was evaluated according to NCIC-CTC 3.0. DLT was evaluated after the first TEX cycle and defined as non-hematological toxicity grade ≥ 3, neutropenia grade 4 or febrile neutropenia more than 7 days. Results: From June 2007 to July 2008, 16 consecutive pts were treated with escalating doses of TEX. Median age was 59 years (43–74), median performance status was 1 (0–1). At dose level 5, two of 4 pts had DTL (1 pt had grade 3 vomiting and nausea and 1 pt had grade 3 nausea, vomiting and diarrhea). In addition 3 of 4 pts had neutropenia grade 4 without fever at dose level 5. Presently, 12 pts are still alive. Conclusions: First line taxotere, oxaliplatin and capecitabine every 3 weeks is easily administered in an out-patient setting but with substantial GI and haematological toxicity at dose level 5. An additional 6 pts will be included at dose level 4 to confirm tolerability at dose level 4. [Table: see text] No significant financial relationships to disclose.
Gemcitabine in metastatic breast cancer
Authors: A. Bensalem, K. Bouzid
Journal: Journal of Clinical Oncology (2006)

10735 Background: Gemcitabine (GEM) has shown efficacy in metastatic breast cancer (MBC). We conducted studies with GEM-based regimens to assess the efficacy and toxicity of GEM combined with other drugs in MBC. GEM was combined with docetaxel (DXL) in pre-treated MBC with an anthracycline-based regimen and GEM was combined with doxorubicin (DXR) in chemonaive patients (pts) with MBC. The studies’ objectives were to show clinically relevant hematologic toxicity and response rates among pts treated with GEM-DXL either in combination in pre-treated pts with anthracycline regimen or GEM-DXR in chemonaive pts with MBC to assess the efficacy of GEM in MBC either in neoadjuvant or first-line treatment. Methods: For GEM-DXL: 42 pts were enrolled; GEM: 1250 mg /m 2 D1 &amp; D8, DXL: 75 mg /m 2 D1, every 21 days with classical premedication for DXL. For GEM-DXR: 51 pts were enrolled; GEM: 1250 mg /m 2 D1 &amp; D 8, DXR: 25 mg/m 2 D1 &amp; D8, every 21 days. Results: See table below. In the GEM-DXR group, surgery was performed in 30 pts, and 13 (43.2%) had histologically complete response. The median TTP in this group was 13.3 months (range, 2–53). Conclusions: GEM in MBC is very efficient and produced an interesting objective response and clinical benefit. This activity is consistent in either chemonaive pts or in pts with relapsing breast cancer. [Table: see text] No significant financial relationships to disclose.
Use of zoledronic acid (ZA) and interleukin-2 (IL-2) to activate and expand Vγ9Vδ2 T cells for therapeutic use in patients with metastatic renal cell carcinoma (mRCC)
Authors: M. Malkovsky, D. G. McNeel, M. Wallace, K. Schell, G. Wilding, J. Eikhoff, M. J. Staab, D. Horvath, J. Straus, G. Liu
Journal: Journal of Clinical Oncology (2006)

14607 Background: Approximately 3–6% of human peripheral blood lymphocytes express the γδ T cell receptor (TCR). The majority of these cells express the Vδ2 TCR variable segment associated with the Vγ9 segment. Vγ9Vδ2 T cells can recognize phosphorylated nonpeptidic microbial metabolites and alkylamines. This recognition of phosphorylated molecules requires neither antigen uptake/processing, nor MHC class I/II expression, allowing for a rapid response to immune challenge. Aminobisphosphonates are a class of agents capable of activating human Vγ9Vδ2 T cells. Here we conduct a study using ZA with low-dose IL-2 in order to augment Vγ9Vδ2 T cells for therapeutic use in mRCC. Methods: Patients with immunotherapy naïve mRCC were treated with ZA (4 mg IV d1) with IL-2 (ranging from 1–7 MU/m 2 SQ days 1–5, repeated weekly × 3, in 4 week cycles). Blood was collected at various timepoints between day 1 and 15 of the first cycle of therapy to assess the relative frequency, proliferative capacity, and cytolytic activity of each subjects’ Vg9Vd2 T cells. Clinical responses were assessed using RECIST criteria. Results: To date, 7 patients have received treatment on protocol. No objective clinical responses were observed by RECIST criteria but prolonged stable disease (with one minor response) was observed in 2 patients (on study for 280 and 224 days respectively) on this trial. A relative increase in Vγ9Vδ2 T cell frequency could be detected by day 8 of therapy including one patient with an increase in Vγ9/Vδ2 positive T cells from 9.6 to 19.4%. Results of the change in Vγ9Vδ2 T cell frequency, proliferative capacity, and cytolytic activity against RCC cell lines will be presented in detail. Conclusions: Modest amplification of Vγ9Vδ2 T cell frequency was seen; however, not to the degree appreciated in preclinical models. At present, we are planning a dose-titration of ZA with fixed dosed IL-2 in order to optimize this therapeutic strategy. The exploitation of Vγ9Vδ2 T cells as a therapy for mRCC is novel, and the current study suggests this approach deserves further evaluation. No significant financial relationships to disclose.