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Previous studies have reported on prognostic factors for castration-resistant prostate cancer (CRPC); however, most of these studies were conducted before docetaxel chemotherapy was approved for CRPC.To evaluate the prognostic value of multiple parameters in men with bone metastases due to CRPC using a contemporary dataset.The analysis included 1901 patients with metastatic CRPC enrolled in an international, multicenter, randomized, double-blind phase 3 trial conducted between May 2006 and October 2009.We developed multivariate validated Cox proportional hazards models and nomograms to estimate 12-mo and 24-mo survival probabilities and median survival time.The median (95% confidence interval) overall survival was 20 (18, 21) mo. The final model included 12 of the 15 potential prognostic variables evaluated (concordance index 0.72). Seven bone-related variables were associated with longer survival in the final model: alkaline phosphatase ≤143 U/l (p0.0001); bone-specific alkaline phosphatase (BSAP)146 U/l (p0.0001); corrected urinary N-telopeptide (uNTx) ≤50 nmol/mmol (p=0.0008); mild or no pain (Brief Pain Inventory-Short Form [BPI-SF] score ≤4) (p0.0001); no previous skeletal-related event (SRE; p=0.0002); longer time from initial diagnosis to first bone metastasis (p0.0001); and longer time from first bone metastasis to randomization (p0.0001). Other significant predictors of improved survival included prostate-specific antigen (PSA) level10 ng/ml (p0.0001), hemoglobin128g/l (p0.0001), absence of visceral metastases (p0.0001), Eastern Co-operative Oncology Group (ECOG) score ≤1 (p=0.017), and younger age (p=0.008). Nomograms were generated based on the parameters included in the final validated models (with/without uNTx and BSAP). One limitation was that lactate dehydrogenase (LDH) levels, a known prognostic factor, were not available in this study.Bone-related parameters are strong prognostic variables for overall survival in patients with bone metastases from CRPC.Survival time is variable in patients with bone metastases from prostate cancer. We found that factors related to bone help to predict how long a patient will live.

We present a method for calculating the dynamics of a bosonic mixture, the multi-component correlated basis function (CBF) method. For single components, CBF results for the excitation energies agree quite well with experimental results, even for highly correlated systems like $^4$He, and recent systematic improvements of CBF achieve perfect agreement. We give a full derivation of multi-component CBF, and apply the method to a dipolar Bose gas cut into two-dimensional layers by a deep optical lattice, with coupling between layers due to the long-ranged dipole-dipole interaction. We consider the case of strong coupling, leading to large positive interlayer correlations. We calculate the spectrum for a system of 8 layers and show that the strong coupling can lead to a simpler spectrum than in the uncoupled case, with a single peak carrying most of the spectral weight., 14 pages, 8 figures

This analysis examined the effects of darbepoetin alfa on hemoglobin and fatigue outcomes in patients with cancer using latent growth curve modeling (LGM). Data from 4 clinical trials of darbepoetin alfa in lung cancer (2 studies; n = 547; n = 288), lymphoproliferative malignancies (n = 339), and non-myeloid malignancies (n = 320) were analyzed separately. Fatigue was assessed using the FACT-Fatigue (FACT-F) scale. Effects of darbepoetin alfa on changes in hemoglobin and FACT-F scores were evaluated using LGM, controlling for age, gender, Eastern Cooperative Oncology Group performance status, health status, and total transfusions. Patients receiving darbepoetin alfa had higher rates of change in hemoglobin (standardized regression coefficient [ $$ \hat{\beta } $$ ] = 0.30 to 0.53, all P

Summary Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00321620, and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1 months (15·0–19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71–0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the zoledronic acid group (55 [6%]; p vs 12 [1%]; p=0·09). Interpretation Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Funding Amgen.

Background: The proteasome inhibitor bortezomib undergoes oxidative biotransformation via multiple cytochrome P450 (CYP) enzymes, with CYP3A4 identified as a partial, yet potentially important, contributor based on in vitro drug metabolism studies. Objective: The aim of this study was to assess the effect of concomitant administration of ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib. Methods: This was a prospective, multicenter, openlabel, randomized, multiple-dose, 2-way crossover study in patients with advanced solid tumors. All patients received bortezomib 1.0 mg/m2 IV (on days 1, 4, 8, and 11 of two 21-day cycles) and were randomized to receive concomitant ketoconazole 400 mg on days 6, 7, 8, and 9 of cycle 1 or 2. Serial blood samples were collected over the day-8 dosing interval (immediately prior to bortezomib administration, and from 5 minutes to 72 hours after administration) in cycles 1 and 2 for measurement of plasma bortezomib concentrations for noncompartmental PK analysis and blood 20S proteasome inhibition for PD analysis. All adverse events (AEs) were recorded during each cycle including serious AEs and all neurotoxicity events for up to 30 days after the last dose of bortezomib. Results: Twenty-one patients (median age, 57 years; sex, 67% male; race, 86% white; median body surface area, 2.01 m2) were randomized to treatment. Twelve pa- tients completed the protocol-specified dosing and PK sampling in both cycles 1 and 2. Assessment of the effect of ketoconazole on bortezomib PK and PD was based on data in these 12 PK-evaluable patients. The ratio of geometric mean bortezomib AUC0-tlast(AUC from time 0 to last quantifiable concentration) for bortezomib plus ketoconazole versus bortezomib alone was 1.352 (90% CI, 1.032–1.772). Consistent with this observed mean increase in bortezomib exposure, concomitant administration of ketoconazole was associated with a corresponding increase (24%–46%) in the blood proteasome inhibitory effect. Conclusion: Concomitant administration of the CYP3A inhibitor ketoconazole with bortezomib resulted in a mean increase of 35% in bortezomib exposure. ClinicalTrials.gov identifier: NCT00129207.

Dipolar bilayers with antiparallel polarization, i.e. opposite polarization in the two layers, exhibit liquid-like rather than gas-like behavior. In particular, even without external pressure a self-bound liquid puddle of constant density will form. We investigate the symmetric case of two identical layers, corresponding to a two-component Bose system with equal partial densities. The zero-temperature equation of state $E(\rho)/N$, where $\rho$ is the total density, has a minimum, with an equilibrium density that decreases with increasing distance between the layers. The attraction necessary for a self-bound liquid comes from the inter-layer dipole-dipole interaction that leads to a mediated intra-layer attraction. We investigate the regime of negative pressure towards the spinodal instability, where the bilayer is unstable against infinitesimal fluctuations of the total density, conformed by calculations of the speed of sound of total density fluctuations., Comment: 16 pages, 6 figures

The impact of first- and subsequent-cycle growth factor use in the community setting has not been studied extensively. We conducted this large, prospective, noncomparative study to assess neutropenia and related complications in patients receiving myelotoxic chemotherapy with pegfilgrastim support in community practices. Patientsor = 18 years old with cancers other than leukemia or myelodysplastic syndrome, including those with major comorbidities, were eligible. Pegfilgrastim (6 mg) was to be administered approximately 24 hours after chemotherapy in all cycles (minimum, four cycles). A total of 2,112 patients was included in the analyses. The most common tumor types were breast cancer (46%), non-Hodgkin's lymphoma (15%), and non-small cell lung cancer (13%). Chemotherapies administered most often were a platinum plus a taxane (18%), and anthracycline plus an alkylating agent (18%), and a taxane plus an anthracycline plus an alkylating agent (16%). The percentage of patients with neutropenia-related hospitalization was 2.9% in cycle 1 and 5.6% across all cycles. Chemotherapy dose reductions and delays were attributed to neutropenia in 1.8% and 0.9% of patients, respectively, in cycle 2 and 2.9% and 2.1% of patients, respectively, across all cycles. Febrile neutropenia (absolute neutrophil count1.0 x 10(9)/l with temperatureor = 38.2 degrees C) occurred in 3.6% of patients in cycle 1 and in 6.3% of patients across all cycles. The most frequently reported serious adverse events were febrile neutropenia (3.4%), neutropenia (2.6%), and dehydration (2.6%). Bone pain (0.1%) was the only related serious adverse event reported in more than one patient. Data from this community-based study suggest that patients undergoing chemotherapy benefit from pegfilgrastim support beginning in the first cycle of chemotherapy.

OBJECTIVE: To describe how primary care physicians document antidepressant prescriptions. DESIGN: Retrospective chart review performed as part of a quality-improvement program. SETTING: A Midwestern health maintenance organization (HMO). PATIENTS: Records of 3,037 patients who were prescribed an antidepressant in primary care during an 18-month interval were randomly requested and reviewed until a sample of 100 was reached. METHODS: Demographic variables, indications for antidepressant treatment, comorbid conditions, use of screening instruments, educational processes, and indicators of outcomes were recorded. RESULTS: Seventy percent of charts documented one or no symptoms of major depression, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), while 90% contained documentation of three or fewer symptoms. Use of screening tools was documented in 4% of charts. Only 57% of the charts indicated a scheduled depression focused follow-up visit, while 5% of charts reflected an educat...

With increasing healthcare resource constraints, it has become important to understand the incremental cost-effectiveness of new medicines. Subcutaneous denosumab is superior to intravenous zoledronic acid (ZA) for the prevention of skeletal-related events (SREs) in patients with advanced solid tumors and bone metastases. This study sought to determine the lifetime cost-effectiveness of denosumab vs ZA in this setting, from a US managed-care perspective.A lifetime Markov model was developed, with relative rate reductions in SREs for denosumab vs ZA derived from three pivotal Phase 3 trials involving patients with castration-resistant prostate cancer (CRPC), breast cancer, and non-small-cell lung cancer (NSCLC), and bone metastases. The real-world SRE rates in ZA-treated patients were derived from a large commercial database. SRE and treatment administration quality-adjusted life year (QALY) decrements were estimated with time-trade-off studies. SRE costs were estimated from a nationally representative commercial claims database. Drug, drug administration, and renal monitoring costs were included. Costs and QALYs were discounted at 3% annually. One-way and probabilistic sensitivity analyses were conducted.Across tumor types, denosumab was associated with a reduced number of SREs, increased QALYs, and increased lifetime total costs vs ZA. The costs per QALY gained for denosumab vs ZA in CRPC, breast cancer, and NSCLC were $49,405, $78,915, and $67,931, respectively, commonly considered good value in the US. Costs per SRE avoided were $8567, $13,557, and $10,513, respectively. Results were sensitive to drug costs and SRE rates.Differences in pain severity and analgesic use favoring denosumab over ZA were not captured. Mortality was extrapolated from fitted generalized gamma function beyond the trial duration.Denosumab is a cost-effective treatment option for the prevention of SREs in patients with advanced solid tumors and bone metastases compared to ZA. The overall value of denosumab is based on superior efficacy, favorable safety, and more efficient administration.

Ethical issues of information and communication technologies (ICTs) are important because they can have significant effects on human liberty, happiness, and people’s ability to lead a good life. They are also of functional interest because they can determine whether technologies are used and whether their positive potential can unfold. For these reasons, policy makers are interested in finding out what these issues are and how they can be addressed. The best way of creating ICT policy that is sensitive to ethical issues pertain to being proactive in addressing such issues at an early stage of the technology life cycle. The present paper uses this position as a starting point and discusses how knowledge of ethical aspects of emerging ICTs can be gained. It develops a methodology that goes beyond established futures methodologies to cater for the difficult nature of ethical issues. The authors outline how the description of emerging ICTs can be used for an ethical analysis.

Background: Patients with bone metastases from advanced cancer often experience skeletal-related events (SRE), which cause substantial pain and morbidity. Denosumab, a fully human monoclonal antibody that inhibits RANK Ligand (RANKL), is a novel bone-targeted agent with a distinct mechanism of action relative to the bisphosphonate zoledronic acid, for prevention of SRE. This pre-planned analysis evaluates the efficacy and safety of denosumab versus zoledronic acid across three pivotal studies. Methods: Patient-level data from three identically designed, randomised, double-blind, active-controlled, phase 3 trials of patients with breast cancer, prostate cancer, other solid tumours or multiple myeloma were combined. End-points included time to first SRE, time to first and subsequent (multiple) SRE, adverse events, time to disease progression and overall survival. Findings: Denosumab was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21 months, reducing the risk of a first SRE by 17% (hazard ratio, 0.83 [95% confidence interval (CI): 0.76-0.90]; P < 0.001). Efficacy was demonstrated for first and multiple events and across patient subgroups (prior SRE status; age). Disease progression and overall survival were similar between the treatments. In contrast to zoledronic acid, denosumab did not require monitoring or dose modification/withholding based on renal status, and was not associated with acute-phase reactions. Hypocalcaemia was more common for denosumab. Osteonecrosis of the jaw occurred at a similar rate (P = 0.13). Conclusion: Denosumab was superior to zoledronic acid in preventing SRE with favourable safety and convenience in patients with bone metastases from advanced cancer. (C) 2012 Elsevier Ltd. All rights reserved.

Aktuelle Diskussionen in Wissenschaft und Technik kreisen immer wieder um die so genannten konvergierenden Technologien. Aufgrund der vielfältigen thematischen Bereiche und den Bezügen zu Wissenschaft wie auch Technik ist eine Definition schwierig. Wie kann dieser Begriff gefasst werden?