Abiraterone acetate and enzalutamide both improve outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC). Optimal sequencing for these agents and whether cross-resistance ...occurs is unknown.
Multicentre review of patients with mCRPC treated with abiraterone acetate and prednisone after progressing on enzalutamide. Primary objective was to determine abiraterone acetate response.
Thirty patients identified from four North American centres. At abiraterone initiation, median age was 70 years (56–84 years); 70% had ECOG performance status of 0–1; all had prior docetaxel. Median prior enzalutamide treatment duration was 41 weeks (6–95 weeks), with 70% (21 of 30) having a ≥30% prostate-specific antigen (PSA) decline. Median abiraterone acetate treatment duration was 13 weeks (1–52). No objective radiographic responses were observed. Median abiraterone time to progression (PSA, objective or symptomatic) was 15.4 weeks 95% confidence interval (CI) 10.7–20.2. Median overall survival was 50.1 weeks (95% CI 28.3–72.0). Three patients had a ≥30% PSA decline with abiraterone. Two of these patients had PSA progression as best response with prior enzalutamide.
In this study of patients progressing after enzalutamide, treatment with abiraterone was associated with a modest response rate and brief duration of effect. Primary progression on enzalutamide may not preclude a response to abiraterone.
Highly oriented 111 Cu grains with densely packed nanotwins have been fabricated by direct-current electroplating with a high stirring rate. The 111-oriented and nanotwinned Cu (nt-Cu) allow for the ...unidirectional growth of Cu(6)Sn(5) intermetallics in the microbumps of three-dimensional integrated-circuit packaging; a uniform microstructure in a large number of microbumps of controlled orientation can be obtained. The high-density twin boundaries in the nt-Cu serve as vacancy sinks during the solid-state reaction between Pb-free solder and Cu and greatly reduce the formation of Kirkendall (or Frenkel) voids.
The randomized, double-blind phase III AFFIRM trial demonstrated that enzalutamide, an oral androgen receptor inhibitor, significantly prolonged overall survival (OS) median 18.4 versus 13.6 months ...(hazard ratio, HR) 0.63 (95% confidence interval, CI, 0.53–0.75); P < 0.001 compared with placebo in patients with metastatic castration-resistant prostate cancer who received prior docetaxel chemotherapy.
A post hoc analysis was carried out to assess the efficacy and safety of enzalutamide on outcomes in younger (<75 years) and elderly (≥75 years) patients in the AFFIRM population. Statistics are presented by age group (<75 years, ≥75 years) for efficacy outcomes of OS, radiographic progression-free survival (rPFS), time to prostate-specific antigen (PSA) progression, PSA response, and safety.
OS was significantly improved with enzalutamide over placebo in patients <75 years median not yet reached versus 13.6 months; HR 0.63 (95% CI 0.52–0.78), P < 0.001 and in patients ≥75 years median 18.2 versus 13.3 months; HR 0.61 (95% CI 0.43–0.86), P = 0.004, respectively. rPFS was similarly improved in both the younger HR 0.45 (95% CI 0.38–0.53), P < 0.001 and elderly patient cohorts HR 0.27 (95% CI 0.20–0.37), P < 0.001 relative to placebo, as were time to PSA progression and PSA response. Adverse events (AEs) were similar between the two enzalutamide age groups, with the exception of an increase in patients ≥75 years in the rates of all grade peripheral edema (22.1% versus 12.5%), fatigue (39.7% versus 31.6%), and diarrhea (26.6% versus 19.6%). The overall grade ≥3 AE rates were low with no major difference in frequency or severity between age groups or treatment arms. Five patients were reported with seizure events; three patients <75 years and two patients ≥75 years.
Enzalutamide significantly improves outcomes in both younger (<75 years) and elderly patients (≥75 years), with comparable safety and tolerability.
Few prognostic models for overall survival (OS) are available for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with recently approved agents. We developed a ...prognostic index model using readily available clinical and laboratory factors from a phase III trial of abiraterone acetate (hereafter abiraterone) in combination with prednisone in post-docetaxel mCRPC.
Baseline data were available from 762 patients treated with abiraterone–prednisone. Factors were assessed for association with OS through a univariate Cox model and used in a multivariate Cox model with a stepwise procedure to identify those of significance. Data were validated using an independent, external, population-based cohort.
Six risk factors individually associated with poor prognosis were included in the final model: lactate dehydrogenase > upper limit of normal (ULN) hazard ratio (HR) = 2.31, Eastern Cooperative Oncology Group performance status of 2 (HR = 2.19), presence of liver metastases (HR = 2.00), albumin ≤4 g/dl (HR = 1.54), alkaline phosphatase > ULN (HR = 1.38) and time from start of initial androgen-deprivation therapy to start of treatment ≤36 months (HR = 1.30). Patients were categorized into good (n = 369, 46%), intermediate (n = 321, 40%) and poor (n = 107, 13%) prognosis groups based on the number of risk factors and relative HRs. The C-index was 0.70 ± 0.014. The model was validated by the external dataset (n = 286).
This analysis identified six factors used to model survival in mCRPC and categorized patients into three distinct risk groups. Prognostic stratification with this model could assist clinical practice decisions for follow-up and monitoring, and may aid in clinical trial design.
NCT00638690.
Background
Laparoscopic colorectal resection has become popular. The recently developed da Vinci Surgical System promises to facilitate endoscopic surgery and overcome its disadvantages. This study ...therefore aimed to compare the short-term results between robotic tumor-specific mesorectal excision (R-TSME) using the da Vinci Surgical System and conventional laparoscopic tumor-specific mesorectal excision (L-TSME) in rectal cancer patients.
Methods
Between April 2006 and February 2007, 36 patients were randomly assigned to receive R-TSME or L-TSME. During the study, 18 patients underwent robotic low anterior resection using the da Vinci Surgical System, and 18 patients had conventional laparoscopic low anterior resection. Patient characteristics, perioperative clinical results, complications, and pathologic details were compared between the two groups.
Results
The patient characteristics were not significantly different between the two groups. The mean operating time, hemoglobin change, and conversion rate were not significantly different between the groups. Complications were treated conservatively and did not require surgical intervention in the R-TSME group. The average length of stay was 6.9 ± 1.3 days in the R-TSME group and 8.7 ± 1.3 days in the L-TSME group (
p
< 0.001). The specimen quality of the R-TSME group was acceptable.
Conclusion
Tumor-specific mesorectal excision was performed safely and effectively using the da Vinci Surgical System and the perioperative outcomes were acceptable.
In this analysis of a phase III trial in patients with castration-resistant prostate cancer and bone metastases, treatment with denosumab reduced the risk of skeletal complications vs zoledronic acid ...regardless of whether the end point was defined as SSE or SRE. Both SSEs and SREs were associated with development of moderate/severe pain among patients with no/mild pain at baseline.
In a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point.
Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form.
Treatment with denosumab significantly reduced the risk of developing first SSE HR, 0.78; 95% confidence interval (CI) 0.66–0.93; P = 0.005 and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65–0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE.
In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE.
We present sensitive 850 m imaging of the Cosmological Evolution Survey (COSMOS) field using 640 hr of new and archival observations taken with SCUBA-2 at the East Asian Observatory's James Clerk ...Maxwell Telescope. The SCUBA-2 COSMOS survey (S2COSMOS) achieves a median noise level of 850 m = 1.2 mJy beam−1 over an area of 1.6 sq. degree (main; Hubble Space Telescope/Advanced Camera for Surveys footprint), and 850 m = 1.7 mJy beam−1 over an additional 1 sq. degree of supplementary (supp) coverage. We present a catalog of 1020 and 127 sources detected at a significance level of >4 and >4.3 in the main and supp regions, respectively, corresponding to a uniform 2% false-detection rate. We construct the single-dish 850 m number counts at S850 > 2 mJy and show that these S2COSMOS counts are in agreement with previous single-dish surveys, demonstrating that degree-scale fields are sufficient to overcome the effects of cosmic variance in the S850 = 2-10 mJy population. To investigate the properties of the galaxies identified by S2COSMOS sources we measure the surface density of near-infrared-selected galaxies around their positions and identify an average excess of 2.0 0.2 galaxies within a 13″ radius (∼100 kpc at z ∼ 2). The bulk of these galaxies represent near-infrared-selected submillimeter galaxies and/or spatially correlated sources and lie at a median photometric redshift of z = 2.0 0.1. Finally, we perform a stacking analysis at submillimeter and far-infrared wavelengths of stellar-mass-selected galaxies (M = 1010-1012 M ) from z = 0-4, obtaining high-significance detections at 850 m in all subsets (signal-to-noise ratio, S/N = 4-30), and investigate the relation between far-infrared luminosity, stellar mass, and the peak wavelength of the dust spectral energy distribution. The publication of this survey adds a new deep, uniform submillimeter layer to the wavelength coverage of this well-studied COSMOS field.
Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), ...particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2).
Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS) were assessed.
Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 95% confidence interval (CI) 0.39-0.78; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed.
MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.
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•Niraparib + AAP reduced risk of radiographic progression/death by 45% in BRCA1/2-altered mCRPC (median follow-up 24.8 mo).•Niraparib + AAP improved secondary endpoints and patient-reported outcomes in the BRCA1/2 subgroup.•Adverse events of niraparib + AAP were tolerable, manageable, and consistent with previous reports; no new safety signals.•MAGNITUDE second interim analysis continues to support niraparib + AAP for mCRPC and HRR alterations, especially BRCA1/2.•MAGNITUDE supports genomic testing for BRCA1/2 alterations in mCRPC due to poor outcomes and emerging treatment options.
Children with developmental coordination disorder show difficulties in making rapid online corrections, and this has been demonstrated in experiments where reaching/pointing movements were employed. ...However, typical hand movements in real-life contexts involve subsequent movements, such as grasping and manipulating objects after reaching. This study aimed to reinvestigate online correction of reaching movements that were connected with grasping and object manipulation and to explore its impact on the coordination of subsequent hand movements in children with developmental coordination disorder.
Five children with developmental coordination disorder and five children with typical development were recruited. Their reach-to-manipulate movements in a double-step task were recorded using motion analysis. The manipulative movements included simple and complex forms of pencil rotation. Movement time, movement velocity, and correlation coefficients between finger joints were derived to quantify their motor performances.
Children with developmental coordination disorder showed longer movement time and deceleration phases during online correction of reaching movement than children without developmental coordination disorder. In subsequent grasping and manipulation movements after online correction, they also exhibited lower correlation coefficients in four to five finger joint couplings that are essential for movement completion, compared to children without developmental coordination disorder.
Our findings from the current pilot study suggest that children with developmental coordination disorder have impairments in online correction when reaching for objects and may also have reduced coordination of some finger movements that are important for subsequent grasping and object manipulation. Future studies with larger sample sizes are warranted to confirm these findings.
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