tbuckley/cabot-search huggingface dataset:
Pharmacokinetics (PK) of pertuzumab (rhuMAb 2C4) in phase II studies of ovarian, breast, prostate, and lung cancers
Authors: D. E. Allison, C. Ng, M. K. Derynck, S. G. Lutzker, V. Jimenez, S. M. Kelsey
Journal: Journal of Clinical Oncology (2005)

2532 Background: Pertuzumab, a humanized HER2-targeted antibody, represents the first in a new class of targeted therapeutic agents known as HER2 dimerization inhibitors (HDIs). Pertuzumab blocks ligand-associated HER2 dimerization with HER kinase family members (EGFR, HER3, HER4), thereby inhibiting intracellular signaling through MAP and PI3 kinases. Pertuzumab is currently being evaluated in phase II studies as a single-agent in ovarian, breast, prostate, and lung cancers. Interim pertuzumab PK data from the phase II studies is presented. Methods: Pertuzumab was administered once every 3 weeks (q3 week) as an IV infusion at a fixed dose of either 420 mg following an initial 840 mg loading dose (LD), or 1050 mg with no LD. PK data from four phase II studies were pooled for analysis by both descriptive and population PK (PopPK) modeling Methods: Results: PopPK modeling of the data from ovarian and breast cancer studies showed that a linear 2-compartment model best described the concentration-time profiles. For a ‘typical’ patient, pertuzumab clearance (CL), volume of distribution (Vc), and terminal half-life was 0.214 L/day, 2.74 L, and 17.2 days, respectively. Body weight (BW), serum albumin, and alkaline phosphatase were significant covariates affecting CL, with BW explaining only 8.3% of inter-patient variability for CL. Body surface area was the significant covariate affecting Vc. The q3 week 420 mg (840 mg LD) regimen attained mean serum trough concentrations of ≈50 μg/mL and steady-state concentrations were achieved by the 2nd treatment cycle in all studies. Conclusions: Pertuzumab PK supports a q3 week dosing regimen. At a fixed-dose of 420 mg (840 mg LD) steady-state was rapidly attained, and putative target trough concentrations of ≥20 μg/mL, based on in vivo xenograft tumor model data, were achieved in most patients. The PK of pertuzumab was similar to trastuzumab and bevacizumab. PopPK analysis supports the continued use of a fixed dose in women with ovarian and breast cancers. PopPK analysis for the patients in the prostate and lung cancer studies is ongoing and will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Ltd., Genentech Genentech
AtrioVentricular Node vagal Stimulation (AVNS) reduces ventricular rate during atrial fibrillation. Acute results of AVNS software download study
Authors: P. Rossi, S. Bianchi, P. Schauerte, A. Elvan, Carina Blomström Lundqvist, L. Kornet, P. Gal, Elena Sciaraffia, G. Wouters, C. Gemein
Journal: European Journal of Heart Failure (2014)
Correcting overall survival (OS) effect for the impact of cross-over via rank preserving structural failure time (RPSFT) model: Case of mRCC RECORD-1 trial of everolimus (EVE).
Authors: E. Zuber, P. Korhonen, M. Branson, N. Hollaender, T. Katiskalahti, D. E. Lebwohl, T. Haas
Journal: Journal of Clinical Oncology (2010)

4690 Background: The pivotal RECORD-1 trial examined the impact of EVE on PFS (Progression Free Survival) and OS in mRCC patients after failure on a VEGFr-TKI therapy. The study design allowed for crossover to open label EVE following progression on placebo. The ITT analysis of OS indicated a positive effect of EVE (HR=0.87, 95%CI: 0.65- 1.15, p=0.162). The conventional ITT approach is likely to underestimate the true treatment effect due to the crossover. Methods: The RPSFT model is based on a structural accelerated failure time model: each day spent on EVE (whether in the EVE randomization group or after cross-over from placebo) is assumed to prolong survival time compared to a day spent on placebo (Treatment Free Survival Time, TFST), by a multiplicative factor. The method reconstructs each patient's underlying TFST for a range of values of the multiplicative factor until the TFST curves between EVE and placebo cannot be distinguished on the basis of a linear rank test statistic (LRST). This estimation method provides a randomization based estimate of treatment effect corrected for the bias due to crossover. The robustness of the treatment effect estimate was assessed using a family of LRTS for the distance between TSFT curves (Harrington-Fleming family). Results: Using the traditional log-rank test statistic, the RPSFT estimated survival time was 1.9-fold longer (95% CI: 0.5–8.5) with EVE versus placebo. The treatment effect estimate was fairly robust against the distance measure used in the estimation. Conclusions: The treatment effect estimate was fairly robust to the choice of the test and the OS benefit for VEGFr-TKI refractory mRCC patients treated with everolimus was confirmed. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis, sanofi-aventis
Final results of a phase II study of weekly trabectedin in second/third line ovarian carcinoma
Authors: D. S. McMeekin, C. Krasner, S. Chan, P. Braly, S. Kaye, D. Provencher, O. C. Trifan, B. Michiels, M. Gore
Journal: Journal of Clinical Oncology (2005)

5011 Background: Trabectedin (Yondelis, ET-743) is a marine-derived compound, which binds to the minor groove of DNA and is active at nM concentrations. Trabectedin is thought to act through transcription-coupled nucleotide excision repair system. Methods: In October '02, a multicenter phase II study in patients with advanced ovarian cancer was initiated, using a weekly schedule of trabectedin (0.58 mg/m2 IV) for three weeks followed by a week of rest. All treated patients were premedicated with dexamethasone. Major eligibility criteria included measurable disease and no more than 2 platinum (Pt) containing regimens. Treatment free interval (± 6 months) defined the Pt sensitive (≥ 6 months) and Pt resistant (<6months) groups. Results: In the Pt sensitive group 55 patients were treated; the median RDI for the first 6 cycles was 80.5%. Out of 52 evaluable patients the response rate was 28.8% (95% CI:17.1, 43.1%) (4 CR). The median PFS was 5.1 months (95% CI:3.1, 6.5). In the Pt resistant group 64 patients were treated; the median RDI for the first 6 cycles was 86.4%. Out of 62 evaluable patients the response rate was 4.8% (95% CI:1.0, 13.5%). The median PFS was 2.0 months (95% CI:1.7, 3.5). A total of 448 cycles were administered and 74 cycles were delayed (43 related to adverse events). The grade 3–4 toxicities in pooled cycles were reversible liver ALT elevation (12%), neutropenia (8%), fatigue (5%), and nausea/vomiting (4%). Conclusions: This study confirms the activity of trabectedin in ovarian cancer. The good safety profile of this weekly regimen is in part due to a lower than planned dose intensity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Johnson & Johnson Johnson & Johnson Johnson & Johnson Johnson & Johnson
Epidemiology of dysphoria and depression in an elderly population
Authors: D Blazer, C D Williams
Journal: American Journal of Psychiatry (1980)

The authors surveyed 997 elderly people living in the community and found that the rate of significant dysphoric symptomatology was 14.7%. Forty-five (4.5%) of these individuals suffered from dysphoric symptoms only, and 37 (3.7%) had symptoms of a major depressive disorder. Eighteen (1.8%) suffered from symptoms of primary depressive disorder and 19 (1.9%) from symptoms of secondary depressive disorder. Sixty-five (6.5%) had depressive symptoms associated with impaired physical health. The frequency of widowhood, impairment in social resources, and impairment in economic resources was greater for individuals with symptoms of a major depressive disorder. The entire sample used psychiatric services at a very low rate.
Model development of human sarcomas for identification and validation of new targets
Authors: R. G. Bagley, C. Rouleau, W. Weber, X. Cao, B. A. Teicher
Journal: Journal of Clinical Oncology (2006)

13080 Background: Soft tissue sarcomas are malignant tumors that can develop from a variety of tissues. There is a lack of targeted therapies directed specifically against sarcomas with surgery, radiation, and chemotherapy being the standard of care. By employing multiple strategies, new targets that may advance sarcoma therapy can be identified. Methods: Profiling of secreted cytokines that may drive tumor growth was performed on cell lines representing osteosarcomas, liposarcomas, fibrosarcomas, and rhabdomysarcomas. Of 27 cytokines analyzed from cultured media, the following were most highly expressed: IL-6, IL-8, IL-12p40, SDF-1, and MCP-1. Results: Results were compared against gene expression data from publicly available oligonucleotide microarrays derived from human tumors. Ewing’s sarcoma and rhabdomysarcoma samples confirmed higher expression levels of VEGF. Further analysis of array data from 16 classes of sarcomas and 181 tumors indicated that IL-7 was more predominantly expressed than IL-6 and IL-8. To evaluate efficacy of novel agents, xenograft models were established using human cell lines A673 rhabdomyosarcoma and SW872 liposarcoma. Tumor growth and response to therapy was characterized. Paclitaxel (75 mg/kg, days 7, 9, 11) delayed tumor growth for about one week following treatment in both models, however only SW872 liposarcoma tumors responded after dosing with anti-angiogenic agent, Avastin (5 mg/kg, days 4, 7, 11, 14, 17, and 21). Conclusions: In addition to killing cancer cells, destabilization of the vasculature/stroma may be beneficial. Immunohistochemical (IHC) analysis was performed on sarcoma tumors from the clinic. CD31 and SMA staining identified vasculature and stromal regions. Subsequent to identification of novel targets specific to sarcomas, IHC methods can further define localization of antigens between various tumor components. A variety of techniques are being utilized in order to recognize new targets in sarcomas. Cell-based assays and preclinical models are incorporated into the drug development pathway to evaluate novel drugs. Analysis of differential gene expression between tumor types and amongst sarcoma subtypes will be essential in identifying which patient population will gain the greatest benefits from targeted therapies. [Table: see text]
Development of a functional assessment of side-effects to therapy (FAST) questionnaire to assess dermatology-related quality of life in patients treated with EGFR inhibitors (EGFRI): The FAST-EGFRI
Authors: L. Wagner, S. E. Lai, M. Aneja, P. Lorusso, R. Perez-Soler, B. O’Brien, J. Patel, M. E. Lacouture
Journal: Journal of Clinical Oncology (2007)

19532 Background: Despite their beneficial antitumor effects, 75–87% patients who undergo EGFRI therapy develop dermatological toxicities (derm tox), including rash, paronychia, hair alterations, and pruritus. The purpose of this study was to develop a patient (pts) self-report questionnaire based on pts and expert (exp) input and to identify the most significant skin tox health-related quality of life (HRQL) factors. Methods: To generate the questionnaire, 20 pts with derm tox to EGFRIs and 12 expert clinicians (&gt;50 treated pts) were asked interview questions and rated 62 items to assess the most bothersome aspects of derm tox and the impact on pts’ skin-specific HRQL. The questionnaire included items from the Skindex-29, a validated skin disease-specific HRQL questionnaire. Items were rated from 0 (not at all important) to 3 (extremely important) (range = 0–3) based on the items’ significance to patients’ HRQL. Both groups were also asked to circle 20 of the most concerning HRQL factors. Results: Eighteen pts and 11 exp completed the questionnaire. Symptoms reported frequently by both pts and exp that affected patients’ HRQL included painful (mean score 2.29 (pts), 2.70, (exp), burning (2.41 (pts), 2.70 (exp)), itchy (2.00 (pts), 2.20 (exp) skin, pain in fingers/toes (2.00 (pts), 2.40 (exp)) increased facial hair (1.93(pts), 1.70 (exp)). Both pts and exp also frequently reported that the patient’s skin condition makes them feel depressed (1.88 (pts), 2.60 (exp)) and makes work or hobbies difficult (2.00 (pts), 2.20 (exp)). The top three most concerning HRQL factors for pts were skin pain, burning and stinging, and irritation, while exp reported depression, skin pain, and derm tox affecting pts’ social life. Conclusions: These results document the trajectory of symptom burden and derm tox HRQL in EGFRI treated pts. These findings underscore that in addition to the psychosocial discomfort, physical symptoms impact HRQL. Further studies to validate the FAST-EGFRI, so that effects on HRQL of interventions against derm tox and differences between agents can be assessed are underway. No significant financial relationships to disclose.
Correlation of serum interleukin-6 (IL-6) levels and clinical outcome in hormone-independent (HI) prostate cancer (PC) patients (PTS) treated with docetaxel
Authors: L. Visa, E. Pineda, B. Farrus, J. Codony-Servat, X. Filella, S. Albiol, A. Martinez, J. M. Domingo-Domench, P. Gascon, B. Mellado
Journal: Journal of Clinical Oncology (2009)

e16044 Background: IL-6 acts as an autocrine and paracrine growth factor in PC, linked to HI progression. We previously reported preliminary data on the correlation of serum IL-6 and D response in metastatic HI PC pts. We present here a larger group of pts tested to asses the clinical relevance of IL-6 in these pts. Methods: Pts with HIPC treated with D were prospectively tested for IL-6 levels by ELISA before D. Prostate-specific antigen (PSA) response, time to PSA progression, overall survival (OS) and PC specific survival (SpS) were analyzed. Evaluated variables were age, performance status, PSA, Gleason, number (n) of D cycles, time to HI progression, presence of visceral metastasis, n of bone metastasis, hemoglobin, lactate deshydrogenase and alkaline phosphatase. Results: Seventy-two pts were included. At the time of the analysis 5 pts had died from non-PC related causes, two from treatment toxicity and 29 (40%) from PC. Mean of age was 69 ± 7 years. Median baseline IL-6 level was 14 pg/ml (range 0.1–1100). Thirty-five pts (49 %) had IL-6 levels &gt; 14 pg/ml. IL-6 &gt; 14 pg/ml correlated with lower D response (13 % vs 40%, p= 0.039); lower time to PSA progression (4 months vs 6, p=0.023); lower OS (10 months vs 25, p= 0.001) and lower PC SpS (12 months vs 26, p= 0.001), in contrast to pts with IL-6 ≤ 14pg/ml. In the multivariate analysis, serum IL-6 (p=0.002), n of bone metastasis (p=0.008) and n of D cycles (p=0.002), were independent prognostic factor for OS and PC SpS. Conclusions: High serum IL-6 correlates with an adverse clinical outcome of pts with HIPC treated with D. IL-6 determination may be a potential tool to select patients for D-based or targeted therapies. FIS ( PI070388 ) No significant financial relationships to disclose.
Abstract 257: Clinical Decision Tree Model in Patients with Out-of-Hospital Cardiac Arrest for Predicting Neurological Outcome at the Emergency Department
Authors: Yoshikazu Goto, Tetsuo Maeda, Yumiko Goto, Keisuke Ohta
Journal: Circulation (2012)

Introduction: The ideal factors for predicting neurological outcomes in patients with out-of-hospital cardiac arrest (OHCA) remain elusive. Hypothesis: We hypothesized that a novel decision tree model using 4 pre-hospital variables can predict neurological outcome after OHCA at the emergency department. Methods: We analyzed 390226 adults in whom resuscitation was attempted after non-traumatic OHCAs in a prospectively recorded nationwide Utstein-style database in Japan over 5 years (2005-2009). The endpoint was 1-month survival with good neurological outcome (cerebral performance category scale, 1-2). We developed a prediction model using data from 4 years (2005-2008, n = 307896), with validation using external data from 2009 ( n = 82330). Results: Overall 1-month survival and good neurological outcome rates were 4.19% and 1.99%, respectively. Multivariate logistic regression analysis indicated the following pre-hospital factors to be significant: shockable initial rhythm (odds ratio [OR] 5.87; 95% confidence interval [CI] 5.23-6.60), emergency medical service (EMS) personnel witnessed (OR 3.40; 95%CI 3.15-3.69), witnessed arrest (OR 3.05; 95%CI 2.83-3.28), and age (OR 3.24; 95%CI 2.97-3.53). Using recursive partitioning analysis with these 4 predictors, we developed a clinical decision tree model: if a witnessed OHCA patient had shockable initial rhythm, the probability of good outcome was 20.0% (age&lt;71) or 10.3% (age&gt;or=71); if an unwitnessed OHCA patient had shockable initial rhythm, the probability of good outcome was 6.8% (age&lt;81) or 1.8% (age&gt;or=81); if a witnessed OHCA patient had unshockable initial rhythm, the probability of good outcome was 3.8% (EMS personnel witnessed arrest) or 1.1% (EMS personnel unwitnessed arrest); if an unwitnessed OHCA patient had unshockable initial rhythm, the probability of good outcome was 0.5% (age&lt;71) or 0.2% (age&gt;or=71). The c-statistics for this model in the groups for development and validation were 0.867 (95%CI 0.861-0.873) and 0.887 (95%CI 0.877-0.896), respectively. Conclusions: Stratification of patients using a decision tree model accurately provides the severity of OHCA classification rules and can predict good neurological outcomes after OHCA at the emergency department.
Treatment of stage I breast cancer (T1N0M0): A long-term follow-up study
Authors: J. Iturbe, J. P. Leone, A. O. Zwenger, J. A. Lacava, C. T. Vallejo, R. R. Scuteri, P. Cabaleiro, J. Castro, B. A. Leone
Journal: Journal of Clinical Oncology (2008)

11509 Background: Most cases of breast cancer are diagnosed at early stage of disease, therefore treatment is oriented to increase the relapse-free survival (RFS) and overall survival (OS). The prognosis, in comparison to other malignancies, has improved in the last decades as a result of mammographic screening. The objective of this study was to evaluate the incidence of local and distant recurrence, RFS and OS in women with early breast cancer within our institution. Methods: Between January 1978 and December 2006, 251 women with T1N0M0 (AJCC) breast cancer were identified. Tumor size was determined from the pathology report. RFS was analyzed from the date of initial diagnosis to the date of local or distant recurrence. OS was estimated from the date of initial diagnosis to the last follow-up or date of death. Multivariate regression analyses were carried out using the proportional hazard model proposed by Cox. RFS and OS were evaluated by the product-limit method of Kaplan and Meier, and differences between curves were assessed by means of the log-rank test. Results: The median age at the time of diagnosis was 52 years (28–84). Conservative surgery was performed in 92% of patients (pts) and 98% underwent nodal dissection. The median number of nodes examined was 18.5. ER was positive in 74% of pts and PR was positive in 66%. Adjuvant radiation therapy was administered to 89% of pts whereas adjuvant chemotherapy and/or hormone therapy were given to 59% and 72%, respectively. The median follow-up was 91 months (7–325). Local recurrence was documented in 8 pts (3.1%). Twenty-two pts developed distant recurrence (8.7%). Bilateral breast cancer was seen in 5 cases (2%). Nine pts (3.5%) developed 2nd malignancies. RFS rate at 10 and 15 years was 84.6% and 72.6%, respectively. OS at 5, 10 and 15 years was 96%, 84% and 74%, respectively. Factors that had an effect in OS demonstrated by the multivariate regression analysis were primary tumor size, age and family history of cancer (p < 0.03). Conclusions: Clinical outcomes of stage I breast cancer in our practice is similar to that reported in international literature. This group of pts continues to have an excellent prognosis as shown by the OS rate at 5, 10 and 15 years, although high percentage of pts continue to have recurrence and die from breast cancer after 5, 10 and 15 years of follow-up. No significant financial relationships to disclose.
Phase Ii Study of Lenvatinib (Len), a Multi-Targeted Tyrosine Kinase Inhibitor, in Patients (Pts) with All Histologic Subtypes of Advanced Thyroid Cancer (Differentiated, Medullary and Anaplastic)
Authors: S. Takahashi, M. Tahara, N. Kiyota, T. Yamazaki, N. Chayahara, K. Nakano, R. Inagaki, K. Toda, T. Enokida, H. Minami, Y. Imamura, T. Sasaki, T. Suzuki, K. Fujino, C. Dutcus
Journal: Annals of Oncology (2014)
Prolaris: A novel genetic test for prostate cancer prognosis.
Authors: Michael K. Brawer, Jack M. Cuzick, Matthew R. Cooperberg, Gregory P. Swanson, Stephen J. Freedland, Julia E. Reid, Gabrielle Fisher, Jerry S. Lanchbury, Alexander Gutin, Steven Stone, Peter Carroll
Journal: Journal of Clinical Oncology (2013)

5005 Background: The natural history of prostate cancer is highly variable and difficult to predict. Improved tools are needed to match treatment more appropriately to a patient’s risk of progression. Therefore, we developed an expression signature composed of genes involved in cell cycle progression (Prolaris) and tested its utility in prostate cancer. Methods: We developed an expression signature composed of 31 cell cycle progression and 15 housekeeper genes. An expression score (Prolaris score) was derived as the mean of all cell cycle progression genes. The signature was tested at disease diagnosis in two conservatively managed cohorts from the UK (N=337 and 349), after radical prostatectomy in two cohorts from the U.S. (N=366 Scott &amp; White Hospital, TX and 413 USCF, CA), and after external beam radiation therapy (N=141) in a cohort from Durham VA Medical Center. All studies were retrospective. Results: The cell cycle progression signature was a highly significant predictor of outcome in all five studies. In conservatively managed patients, the Prolaris score was the dominant variable for predicting death from prostate cancer in univariate analysis (p = 6.1 x 10 -22 after diagnosis by TURP, and p = 8.6 x 10 -10 after diagnosis by needle biopsy). In both studies, the Prolaris score remained highly significant in multivariate analysis making it a stronger predictor of disease-specific mortality than other prognostic variables. After prostatectomy, Prolaris predicted biochemical recurrence (BCR) in univariate analysis (S&amp;W p = 5.6 x 10 -9 ; UCSF p= 2.23 x 10 -6 ) and provided additional prognostic information in multivariate analysis (S&amp;W p = 3.3 x10 -6 ; UCSF 9.5 x10 -5 ). After radiation therapy, Prolaris predicted BCR (Phoenix) in univariate (p=0.0017) and multivariate analysis (p=0.034). In all five studies the HR per unit change in the Prolaris score was remarkably similar, ranging from 1.89 to 2.92, indicating that the effect size for the Prolaris score is robust to clinical setting and patient composition. Conclusions: The Prolaris test predicts prostate cancer outcome in multiple patient cohorts and diverse clinical settings. In all cases, it provides information beyond clinicopathologic variables to help differentiate aggressive from indolent disease.