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The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m2 every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5–9·9) in the atrasentan group and 9·1 months (8·4–10·2) in the placebo group (hazard ratio 1·02, 0·89–1·16; p=0·81). Median overall survival was 17·8 months (16·4–19·8) in the atrasentan group versus 17·6 months (16·4–20·1) in the placebo group (1·04, 0·90–1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.

BackgroundThe fibroblast growth factor receptor (FGFR) signaling pathway is activated in multiple tumor types through gene amplifications, single base substitutions, or gene fusions. Multiple small molecule kinase inhibitors targeting FGFR are currently being evaluated in clinical trials for patients with FGFR chromosomal translocations. Patients with novel gene fusions involving FGFR may represent candidates for kinase inhibitors.MethodsA targeted RNA-sequencing assay identified a KLK2-FGFR2 fusion gene in two patients with metastatic prostate cancer. NIH3T3 cells were transduced to express the KLK2-FGFR2 fusion. Migration assays, Western blots, and drug sensitivity assays were performed to functionally characterize the fusion.ResultsExpression of the KLK2-FGFR2 fusion protein in NIH3T3 cells induced a profound morphological change promoting enhanced migration and activation of downstream proteins in FGFR signaling pathways. The KLK2-FGFR2 fusion protein was determined to be highly sensitive to the selective FGFR inhibitors AZD-4547, BGJ398, JNJ-42756943, the irreversible inhibitor TAS-120, and the non-selective inhibitor Ponatinib. The KLK2-FGFR2 fusion did not exhibit sensitivity to the non-selective inhibitor Dovitinib.ConclusionsImportantly, the KLK2-FGFR2 fusion represents a novel target for precision therapies and should be screened for in men with prostate cancer.

Radium-223 (223Ra) dichloride is an approved intravenous radiotherapy for patients with osseous metastases from castration-resistant prostate cancer (CRPC). In addition to the therapeutic alpha radiation, there is additional 223Ra radiation generated which produces photons that can be imaged with conventional gamma cameras. No studies have evaluated real-time and quality imaging during intravenous 223Ra administration to verify systemic circulation and exclude 223Ra extravasation at the injection site. A retrospective review was performed for fifteen 223Ra administrations for CRPC patients which were imaged using a large field of view portable gamma camera (LFOVPGC) for the purposes of quality control and patient safety. Dynamic imaging of the chest was performed before, during, and after the 223Ra administration to verify systemic circulation, per institutional clinical protocol. Before and after 223Ra administration, a static image was obtained of the intravenous access site. Dynamic imaging of the chest confirmed systemic administration early during the 1-minute injection period for all patients. There were no cases of focal 223Ra extravasation at the site of intravenous access. These results verify that systemic 223Ra administrations can be quantified with real-time imaging using an LFOVPGC. This simple approach can confirm and quantify systemic circulation of 223Ra early during injection and exclude focal extravasation for the purposes of quality control.

Background A 59-year-old man who had undergone a left nephrectomy for renal cell carcinoma was found to have metastatic disease during a restaging examination. The patient was started on treatment with interferon α2b plus bevacizumab, a humanized monoclonal anti-vascular endothelial growth factor antibody. After 9 months of this therapy, the patient developed proteinuria, which gradually increased to over 6 g/day. Investigations Physical examination, urine and blood analysis, biopsy of the right kidney, and histologic evaluation of the non-neoplastic portion of the left nephrectomy specimen. Diagnosis Thrombotic microangiopathy and IgA immune-complex deposition in the glomerular capillary walls and mesangium. Management Discontinuation of interferon α2b and bevacizumab, control of blood pressure with an angiotensin-converting-enzyme inhibitor and an angiotensin-receptor blocker.

Summary Purpose Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G. Experimental Design Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m 2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured. Results Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m 2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome. Conclusions This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.

Background Exercise and dietary (EX+D) interventions could represent an optimal treatment for attenuating or reversing adverse effects of androgen deprivation therapy (ADT) in prostate cancer (PCa) patients. The Individualized Diet and Exercise Adherence‐Pilot (IDEA‐P) trial compared the effects of an EX+D intervention relative to standard‐of‐care (SC) treatment among PCa patients undergoing ADT. The present study evaluated the effects of the EX+D intervention on body composition (BC) obtained via dual‐energy X‐ray absorptiometry (DXA) in a subsample of IDEA‐P patients. A secondary objective was to explore the association of adiposity and lean mass with mobility performance and strength. Methods Complete DXA data were acquired from a subsample of 22 PCa patients (EX+D: n = 13; SC: n = 9) at baseline and 3 month follow‐up. Intention‐to‐treat analysis included data from 30 participants (M age = 66.28; SD = 7.79) with baseline DXA assessments. Results Intention‐to‐treat analysis revealed EX+D resulted in significant improvements in fat mass (P = 0.022), per cent fat mass (P = 0.028), trunk fat mass (P = 0.017), fat mass/lean mass (P = 0.040), and per cent lean mass (P = 0.026) vs. SC. EX+D also resulted in more favourable changes in appendicular lean mass/body mass (d = 0.59). Select BC outcomes were also significantly correlated with mobility performance and strength (P < 0.05) at 3 month follow‐up. Conclusions Findings suggest the EX+D intervention resulted in superior preservation of lean tissue and improvement in adiposity relative to SC treatment. Results underscore the utility of implementing EX+D interventions for preserving muscle mass and reducing adiposity in PCa patients undergoing ADT.

Summary Purpose To determine the maximally tolerated dose (MTD) and pharmacokinetics of carboplatin plus KOS-862 (Epothilone D) a novel cytotoxic macrolide capable of causing mitotic arrest, in patients with advanced solid malignancies. Experimental Design Patients who have progressed on standard regimens were treated at four different levels of KOS-862(mg/m 2 )/Carboplatin(AUC): 50/5,75/5, 75/6 and 100/6 in a “3 + 3” phase I study study design to determine MTD. Patients received KOS-862 on Days 1 and 8, and carboplatin on day 1, of 3-week cycles. Pharmacokinetics of KOS-862 and Carboplatin were studied. Results Twenty-seven patients enrolled in the study. At the top dose level, 2 out of the 9 patients experienced Dose Limiting Toxicity. (grade 3 peripheral motor neuropathy in both patients) Twenty-seven patients had sufficient plasma data points for pharmacokinetic analysis Both the parent drug, KOS-862, and the major inactive metabolite Seco-D KOS-862 (KOS-1965) were quantified in plasma. Kinetics of KOS-862 were the same as seen in monotherapy studies using the same route and time of administration. Two patients had tumor response after study treatment. Ten of 20 evaluable patients had stable disease after 2 cycles of study treatment. The MTD in the present study was KOS-862 100 mg/m 2 + carboplatin AUC = 6. Conclusions The pharmacokinetics of KOS-862 were similar in this combination study to those seen in previous monotherapy studies using the same route and time of administration. We have described the MTD of this schedule. The neurotoxicity seen with this regimen should be considered prior to its administration in unselected populations.

Interleukin-2 (IL-2) activates extracellular signal-regulated protein kinase (ERK) within immune cells. To examine the profile of phosphorylated ERK (p-ERK) in IL-2 stimulated immune cells of normal donors and patients receiving IL-2 therapy, we developed a dual parameter flow-cytometric assay. An analysis of PBMCs stimulated with IL-2 indicated that IL-2 exposure induced p-ERK in CD56 bright NK cells and CD14 + monocytes, but not in CD3 + T cells or CD21 + B cells. CD3 + T cells that were induced to express functional high-affinity IL-2R did not exhibit enhanced p-ERK following IL-2 treatment. Measurement of p-ERK within PBMCs from cancer patients 1 h following their first dose of IL-2 revealed a complete absence of circulating NK cells, consistent with earlier observations. However, the total number of circulating CD14 + monocytes increased in these samples and 97% of these cells exhibited ERK activation. p-ERK was not observed in T cells post-IL-2 therapy. Analysis of PBMCs obtained 3 weeks post-IL-2 therapy revealed high-p-ERK levels in CD56 bright NK cells in a subset of patients, while levels of p-ERK returned to baseline in monocytes. These studies reveal an effective method to detect ERK activation in immune cells and demonstrate that IL-2 activates ERK in a subset of NK cells and monocytes but not T cells.

Electrochromic materials can change their properties under the influence of an electrical voltage or current. Different classes of materials show this behavior such as transition metal oxides, conjugated polymers, metal-coordinated complexes and organic molecules. As the color change is persistent, the electric field needs only to be applied to initiate the switching, allowing for applications such as low-energy consumption displays, light-adapting mirrors in the automobile industry and smart windows for which the amount of transmitted light and heat can be controlled. The first part of this book describes the different classes and processing techniques of electrochromic materials. The second part highlights nanostructured electrochromic materials and device fabrication, and the third part focuses on the applications such as smart windows, adaptive camouflage, biomimicry, wearable displays and fashion. The last part rounds off the book by device case studies and environmental impact issues.

Total joint replacements for end-stage osteoarthritis of the hip and knee are cost-effective and demonstrate significant clinical improvement. However, robust population based lifetime-risk data for implant revision are not available to aid patient decision making, which is a particular problem in young patient groups deciding on best-timing for surgery. We did implant survival analysis on all patients within the Clinical Practice Research Datalink who had undergone total hip replacement or total knee replacement. These data were adjusted for all-cause mortality with data from the Office for National Statistics and used to generate lifetime risks of revision surgery based on increasing age at the time of primary surgery. We identified 63 158 patients who had undergone total hip replacement and 54 276 who had total knee replacement between Jan 1, 1991, and Aug 10, 2011, and followed up these patients to a maximum of 20 years. For total hip replacement, 10-year implant survival rate was 95·6% (95% CI 95·3–95·9) and 20-year rate was 85·0% (83·2–86·6). For total knee replacement, 10-year implant survival rate was 96·1% (95·8–96·4), and 20-year implant survival rate was 89·7% (87·5–91·5). The lifetime risk of requiring revision surgery in patients who had total hip replacement or total knee replacement over the age of 70 years was about 5% with no difference between sexes. For those who had surgery younger than 70 years, however, the lifetime risk of revision increased for younger patients, up to 35% (95% CI 30·9–39·1) for men in their early 50s, with large differences seen between male and female patients (15% lower for women in same age group). The median time to revision for patients who had surgery younger than age 60 was 4·4 years. Our study used novel methodology to investigate and offer new insight into the importance of young age and risk of revision after total hip or knee replacement. Our evidence challenges the increasing trend for more total hip replacements and total knee replacements to be done in the younger patient group, and these data should be offered to patients as part of the shared decision making process. Oxford Musculoskeletal Biomedical Research Unit, National Institute for Health Research.