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Robbie G.J.,Clinical Pharmacology and DMPK | Criste R.,Clinical Pharmacology and DMPK | Dall'Acqua W.F.,Protein Discovery | Jensen K.,Biostatistics | And 3 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2013

The study objective was to evaluate the pharmacokinetics (PK), antidrug antibody (ADA), and safety of motavizumab-YTE (motavizumab with amino acid substitutions M252Y/S254T/T256E [YTE]), an Fc-modified anti-respiratory syncytial virus (RSV) monoclonal antibody. Healthy adults (n=31) were randomized to receive a single intravenous (i.v.) dose of motavizumab- YTE or motavizumab (0.3, 3, 15, or 30 mg/kg) and followed for 240 days. Clearance of motavizumab-YTE was significantly lower (71% to 86%) and the half-life (t1/2) was 2- to 4-fold longer than with motavizumab. However, similar peak concentrations and volume-of-distribution values, indicative of similar distribution properties, were seen at all dose levels. The sustained serum concentrations of motavizumab-YTE were fully functional, as shown by RSV neutralizing activity that persisted for 240 days with motavizumab-YTE versus 90 days postdose for motavizumab. Safety and incidence of ADA were comparable between groups. In this first study of an Fc-modified monoclonal antibody in humans, motavizumab-YTE was well tolerated and exhibited an extended half-life of up to 100 days. Copyright © 2013, American Society for Microbiology. All Rights Reserved. Source

De Boer M.,Maastricht University | De Boer M.,Comprehensive Cancer Center East | Van Dijck J.A.A.M.,Comprehensive Cancer Center East | Bult P.,Radboud University Nijmegen | And 2 more authors.
Journal of the National Cancer Institute | Year: 2010

Background The prognostic relevance of isolated tumor cells and micrometastases in lymph nodes from patients with breast cancer has become a major issue since the introduction of the sentinel lymph node procedure. We conducted a systematic review of this issue.Methods Studies published from January 1, 1977, until August 11, 2008, were identified by use of MEDLINE, EMBASE, and the Cochrane Library. A total of 58 studies (total number of patients = 297533) were included and divided into three categories according to the method for pathological assessment of the lymph nodes: cohort studies with single-section pathological examination of axillary lymph nodes (n = 285638 patients), occult metastases studies with retrospective examination of negative lymph nodes by step sectioning and/or immunohistochemistry (n = 7740 patients), and sentinel lymph node biopsy studies with intensified work-up of the sentinel but not of the nonsentinel lymph nodes (n = 4155 patients). We used random-effects meta-analyses to calculate pooled estimates of the relative risks (RRs) of 5-and 10-year disease recurrence and death and the multivariably corrected pooled hazard ratio (HR) of overall survival of the cohort studies.Results In the cohort studies, the presence (vs the absence) of metastases of 2 mm or less in diameter in axillary lymph nodes was associated with poorer overall survival (pooled HR of death = 1.44, 95% confidence interval [CI] = 1.29 to 1.62). In the occult metastases studies, the presence (vs the absence) of occult metastases was associated with poorer 5-year disease-free survival (pooled RR = 1.55, 95% CI = 1.32 to 1.82) and overall survival (pooled RR = 1.45, 95% CI = 1.11 to 1.88), although these endpoints were not consistently assessed in multivariable analyses. Sentinel lymph node biopsy studies were limited by small patient groups and short follow-up.ConclusionThe presence (vs the absence) of metastases of 2 mm or less in diameter in axillary lymph nodes detected on single-section examination was associated with poorer disease-free and overall survival. Source

Shahir A.K.,Nepean Hospital New South Wales | Briggs N.,Biostatistics | Katsoulis J.,Western Hospital | Levidiotis V.,Western Hospital | Levidiotis V.,University of Melbourne
Nephrology | Year: 2013

Aims To conduct an observational outcomes study examining pregnancy and neonatal outcomes of dialysed women aged 15-49, from 1966-2008, using data from the ANZDATA Registry. Methods Data from the ANZDATA Registry were captured and analysed from 1966-2008. Specific pregnancy outcomes included: live birth (LB), spontaneous abortion, stillbirth (SB) or termination of pregnancy. Delivery and neonatal outcomes, since 2001, were also analysed. Results There were 23 700 person-years (PY) of observational data during the study period with 49 pregnancies, of which 30 (79%) resulted in a LB, once terminations were excluded. Pregnancy rates: Overall the pregnancy rate was 2.07 per 1000 PY for the study interval. A significant increase in the pregnancy rate was noted for the 1996-2008 time interval (3.3 per 1000 PY, compared with 0.54 and 0.67 in the eras 1976-1985 and 1986-1995, respectively; P = 0.004). Most pregnancies were observed in the 25-29 age group: 20-24, 25-29 and 30-34 (5.31, 5.61 and 3.87 per 1000 PY, respectively). Patients on peritoneal dialysis were less likely to achieve a pregnancy compared with haemodialysis patients (P < 0.02). Live birth rates: The overall LB rate was 1.26 per 1000 PY. The rate for each of the age brackets was as follows: 3.54 for 20-24, 3.61 for 25-29, and 2.39 per 1000 PY for 30-34, compared with 0 in the 15-19 group, and 1.22, 0.2 and 0.16 per 1000 PY among the groups 35-39, 40-44 and 45-49 years, respectively. LB rates were more favourable in the younger age groups. There was no significant era, disease, dialysis modality or race effect on LB rates. Excluding terminations, the LB rate was 79%. Age-effect on pregnancy outcomes: Pregnancy outcome was not affected by age (mean ages shown): spontaneous abortions, 28.7 years (n = 3); LB, 29.3 years (n = 24); SB, 32.4 years (n = 5); terminations 30.6 years (n = 11). Maternal mortality and complications: The preeclampsia rate was 19.4% (6/31). No post-partum maternal deaths were reported. Neonatal outcomes: Since 2001, 21 neonatal outcomes were reported. One baby developed polyhydramnios, one had a congenital malformation and one post-natal death was reported. In total 53.4% were born preterm; 65% had a birthweight <2.5 kg (low birthweight) and 35% <1.5 kg (very low birthweight). Low birthweight correlated with prematurity. Conclusion Seventy-nine per cent of women achieving a pregnancy in our cohort achieved a LB, although 53.4% of babies were born preterm and 65% were of low birthweight (<2.5 kg). Summary at a Glance This is an observational outcomes study examining pregnancy and neonatal outcomes of dialysed women aged 15-49, from 1966-2008, using data from the ANZDATA Registry. Seventy-nine per cent of women achieving a pregnancy resulted in a live birth and 53.4% of babies were born preterm and 65% were of low birthweight. © 2013 The Authors. Nephrology © 2013 Asian Pacific Society of Nephrology. Source

Sherrill B.,RTI Health Solutions | Kaye J.A.,RTI Health Solutions | Cappelleri J.C.,Biostatistics | Chen C.,Global Outcomes Research
OncoTargets and Therapy | Year: 2012

Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta-analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression-related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types. © 2012 Sherrill et al, publisher and licensee Dove Medical Press Ltd. Source

Lichtenstein G.R.,University of Pennsylvania | Feagan B.G.,University of Western Ontario | Cohen R.D.,University of Chicago | Salzberg B.A.,Atlanta Gastroenterology Associates | And 5 more authors.
American Journal of Gastroenterology | Year: 2012

OBJECTIVES:The objective of this study was to contribute long-term safety data for infliximab and other therapies in Crohn's disease (CD).METHODS:We prospectively evaluated CD patients enrolled in the large, observational Crohn's Therapy, Resource, Evaluation, and Assessment Tool registry, established to compare infliximab safety with conventional nonbiological medications in CD.RESULTS:A total of 6,273 patients were enrolled and evaluated on or before 23 February 2010; 3,420 received infliximab (17,712 patient-years; 89.9% received 2 infusions) and 2,853 received other-treatments-only (13,251 patient-years). Mean length of patient follow-up was 5.2 years. More infliximab-than other-treatments-only-treated patients had moderate-to-severe (30.6% vs. 10.7%) or severe-to-fulminant (2.5% vs. 0.6%) disease severity (P0.001). In the year before enrollment, more infliximab-than other-treatments-only-treated patients required surgical intervention (17.4% vs. 13.6%), medical hospitalization (14.2% vs. 8.8%), prednisone (47.8% vs. 31.4%), immunomodulators (52.0% vs. 32.1%), and narcotic analgesics (17.3% vs. 9.1%). Patient mortality was similar for infliximab-and other-treatments-only-treated patients (0.58 vs. 0.59/100 patient-years). In multivariate logistic regression analyses, treatment with prednisone (hazard ratio (HR)2.14, 95% confidence interval (CI)1.55, 2.95; P0.001) or narcotic analgesics (HR1.79, 95% CI1.29, 2.48; P0.001) and age (HR1.08, 95% CI1.07, 1.09; P0.001) were associated with increased mortality risk. Neither infliximab nor immunomodulator treatment was associated with increased mortality risk. Factors independently associated with serious infections included moderate-to-severe disease activity (HR2.24, 95% CI1.57, 3.19; P0.001), narcotic analgesic treatment (HR1.98, 95% CI1.44, 2.73; P0.001), prednisone therapy (HR1.57, 95% CI1.17, 2.10; P0.002), and infliximab treatment (HR1.43, 95% CI1.11, 1.84; P0.006).CONCLUSIONS:Mortality was similar between infliximab-and other-treatments-only-treated CD patients. An increased risk of serious infection with infliximab was observed, although CD severity and use of prednisone or narcotic analgesics carried higher risks. © 2012 by the American College of Gastroenterology. Source

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