The impact of prolonged lower limb ischemia on amputation, mortality, and functional status: the FRIENDS registry.

BACKGROUND Peripheral artery disease (PAD) is a major cause of cardiovascular ischemic events and amputation. Knowledge gaps exist in defining and measuring key factors that predict these events. The objective of this study was to assess whether duration of limb ischemia would serve as a major predictor of limb and patient survival. METHODS The FReedom from Ischemic Events: New Dimensions for Survival (FRIENDS) registry enrolled consecutive patients with limb-threatening peripheral artery disease at a single tertiary care hospital. Demographic information, key clinical care time segments, functional status and use of revascularization, and pharmacotherapy data were collected at baseline, and vascular ischemic events, cardiovascular mortality, and all-cause mortality were recorded at 30 days and 1 year. RESULTS A total of 200 patients with median (interquartile range) age of 76 years (65-84 years) were enrolled in the registry. Median duration of limb ischemia was 0.75 days for acute limb ischemia (ALI) and 61 days for chronic critical limb ischemia (CLI). Duration of limb ischemia of <12, 12 to 24, and >24 hours in patients with ALI was associated with much higher rates of first amputation (P = .0002) and worse amputation-free survival (P = .037). No such associations were observed in patients with CLI. CONCLUSIONS For individuals with ischemic symptoms <14 days, prolonged limb ischemia is associated with higher 30-day and 1-year amputation, systemic ischemic event rates, and worse amputation-free survival. No such associations are evident for individuals with chronic CLI. These data imply that prompt diagnosis and revascularization might improve outcomes for patients with ALI.

Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019)

BACKGROUND Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa-the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)-includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.

Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study.

BACKGROUND Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING European Commission and the Wellcome Trust.

Depositional modes and lake-level variability at Lake Towuti, Indonesia, during the past ~29 kyr BP

Lake Towuti (2.5°S, 121.5°E) is a long-lived, tectonic lake located on the Island of Sulawesi, Indonesia, and in the center of the Indo-Pacific warm pool (IPWP). Lake Towuti is connected with upstream lakes Matano and Mahalona through the Mahalona River, which constitutes the largest inlet to the lake. The Mahalona River Delta is prograding into Lake Towuti’s deep northern basin thus exerting significant control on depositional processes in the basin. We combine high-resolution seismic reflection and sedimentological datasets from a 19.8-m-long sediment piston core from the distal edge of this delta to characterize fluctuations in deltaic sedimentation during the past ~29 kyr BP and their relation to climatic change. Our datasets reveal that, in the present, sedimentation is strongly influenced by deposition of laterally transported sediments sourced from the Mahalona River Delta. Variations in the amount of laterally transported sediments, as expressed by coarse fraction amounts in pelagic muds and turbidite recurrence rates and cumulative thicknesses, are primarily a function of lake-level induced delta slope instability and delta progradation into the basin. We infer lowest lake-levels between ~29 and 16, a gradual lake level rise between ~16 and 11, and high lake-levels between ~11 and 0 kyr BP. Periods of highest turbidite deposition, ~26 to 24 and ~18 to 16 kyr BP coincide with Heinrich events 2 and 1, respectively. Our lake-level reconstruction therefore supports previous observations based on geochemical hydroclimate proxies of a very dry last glacial and a wet Holocene in the region, and provides new evidence of millennial-scale variations in moisture balance in the IPWP.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

BACKGROUND Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.