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Men with high serum prostate specific antigen usually undergo transrectal ultrasound-guided prostate biopsy (TRUS-biopsy). TRUS-biopsy can cause side-effects including bleeding, pain, and infection. Multi-parametric magnetic resonance imaging (MP-MRI) used as a triage test might allow men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. We did this multicentre, paired-cohort, confirmatory study to test diagnostic accuracy of MP-MRI and TRUS-biopsy against a reference test (template prostate mapping biopsy [TPM-biopsy]). Men with prostate-specific antigen concentrations up to 15 ng/mL, with no previous biopsy, underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was done blind to other test results. Clinically significant cancer was defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer. This study is registered on ClinicalTrials.gov, NCT01292291. Between May 17, 2012, and November 9, 2015, we enrolled 740 men, 576 of whom underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. On TPM-biopsy, 408 (71%) of 576 men had cancer with 230 (40%) of 576 patients clinically significant. For clinically significant cancer, MP-MRI was more sensitive (93%, 95% CI 88–96%) than TRUS-biopsy (48%, 42–55%; p<0·0001) and less specific (41%, 36–46% for MP-MRI vs 96%, 94–98% for TRUS-biopsy; p<0·0001). 44 (5·9%) of 740 patients reported serious adverse events, including 8 cases of sepsis. Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer. PROMIS is funded by the UK Government Department of Health, National Institute of Health Research–Health Technology Assessment Programme, (Project number 09/22/67). This project is also supported and partly funded by UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre and is coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. It is sponsored by University College London (UCL).

Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1–3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer. In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov, number NCT00532194; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003. We randomly assigned 486 women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14–26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4–11·7) in arm C and 8·7 months (7·7–9·4) in arm A (hazard ratio 0·56, 0·44–0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4–10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation. Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up. Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca.

We previously published the performance evaluation of an automated electroencephalography (EEG)-based single-channel sleep-wake detection algorithm called Z-ALG used by the Zmachine(®) sleep monitoring system. The objective of this paper is to evaluate the performance of a new algorithm called Z-PLUS, which further differentiates sleep as detected by Z-ALG into Light Sleep, Deep Sleep, and Rapid Eye Movement (REM) Sleep, against laboratory polysomnography (PSG) using a consensus of expert visual scorers. Single night, in-lab PSG recordings from 99 subjects (52F/47M, 18-60 years, median age 32.7 years), including both normal sleepers and those reporting a variety of sleep complaints consistent with chronic insomnia, sleep apnea, and restless leg syndrome, as well as those taking selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor antidepressant medications, previously evaluated using Z-ALG were re-examined using Z-PLUS. EEG data collected from electrodes placed at the differential-mastoids (A1-A2) were processed by Z-ALG to determine wake and sleep, then those epochs detected as sleep were further processed by Z-PLUS to differentiate into Light Sleep, Deep Sleep, and REM. EEG data were visually scored by multiple certified polysomnographic technologists according to the Rechtschaffen and Kales criterion, and then combined using a majority-voting rule to create a PSG Consensus score file for each of the 99 subjects. Z-PLUS output was compared to the PSG Consensus score files for both epoch-by-epoch (eg, sensitivity, specificity, and kappa) and sleep stage-related statistics (eg, Latency to Deep Sleep, Latency to REM, Total Deep Sleep, and Total REM). Sensitivities of Z-PLUS compared to the PSG Consensus were 0.84 for Light Sleep, 0.74 for Deep Sleep, and 0.72 for REM. Similarly, positive predictive values were 0.85 for Light Sleep, 0.78 for Deep Sleep, and 0.73 for REM. Overall, kappa agreement of 0.72 is indicative of substantial agreement. This study demonstrates that Z-PLUS can automatically assess sleep stage using a single A1-A2 EEG channel when compared to the sleep stage scoring by a consensus of polysomnographic technologists. Our findings suggest that Z-PLUS may be used in conjunction with Z-ALG for single-channel EEG-based sleep staging.

The United States relies on uncompensated family caregivers to provide most of the long-term care required by older adults as they age. But such care comes at a significant financial cost to these caregivers in the form of lower lifetime earnings and diminished (or even no) Social Security retirement benefits, ineligibility for Medicare coverage of their healthcare costs, and minimal retirement savings. To reduce the impact of uncompensated caregiving on the intergenerational transmission of poverty, this paper discusses three possible mechanisms of compensating family caregivers: public payments, deemed wage credits under Social Security, and income tax incentives.

Although antiretroviral therapy (ART) is known to be associated with time-dependent reductions in tuberculosis (TB) incidence, the long-term impact of ART on incidence remains imprecisely defined due to limited duration of follow-up and incomplete CD4 cell count recovery in existing studies. We determined TB incidence in a South African ART cohort with up to 8 years of follow-up and stratified rates according to CD4 cell count recovery. We compared these rates with those of HIV-uninfected individuals living in the same community. Prospectively collected clinical data on patients receiving ART in a community-based cohort in Cape Town were analysed. 1544 patients with a median follow-up of 5.0 years (IQR 2.4-5.8) were included in the analysis. 484 episodes of incident TB (73.6% culture-confirmed) were diagnosed in 424 patients during 6506 person-years (PYs) of follow-up. The TB incidence rate during the first year of ART was 12.4 (95% CI 10.8-14.4) cases/100PYs and decreased to 4.92 (95% CI 3.64-8.62) cases/100PYs between 5 and 8 years of ART. During person-time accrued within CD4 cell strata 0-100, 101-200, 201-300, 301-400, 401-500, 501-700 and ≥700 cells/µL, TB incidence rates (95% CI) were 25.5 (21.6-30.3), 11.2 (9.4-13.5), 7.9 (6.4-9.7), 5.0 (3.9-6.6), 5.1 (3.8-6.8), 4.1 (3.1-5.4) and 2.7 (1.7-4.5) cases/100PYs, respectively. Overall, 75% (95% CI 70.9-78.8) of TB episodes were recurrent cases. Updated CD4 cell count and viral load measurements were independently associated with long-term TB risk. TB rates during person-time accrued in the highest CD4 cell count stratum (>700 cells/µL) were 4.4-fold higher that the rate in HIV uninfected individuals living in the same community (2.7 versus 0.62 cases/100PYs; 95%CI 0.58-0.65). TB rates during long-term ART remained substantially greater than rates in the local HIV uninfected populations regardless of duration of ART or attainment of CD4 cell counts exceeding 700 cells/µL.

ObjectiveIn 2001, the National Institute for Health Research Cancer Research Network (NCRN) was established, leading to a rapid increase in clinical research activity across the English NHS. Using colorectal cancer (CRC) as an example, we test the hypothesis that high, sustained hospital-level participation in interventional clinical trials improves outcomes for all patients with CRC managed in those research-intensive hospitals.DesignData for patients diagnosed with CRC in England in 2001–2008 (n=209 968) were linked with data on accrual to NCRN CRC studies (n=30 998). Hospital Trusts were categorised by the proportion of patients accrued to interventional studies annually. Multivariable models investigated the relationship between 30-day postoperative mortality and 5-year survival and the level and duration of study participation.ResultsMost of the Trusts achieving high participation were district general hospitals and the effects were not limited to cancer ‘centres of excellence’, although such centres do make substantial contributions. Patients treated in Trusts with high research participation (≥16%) in their year of diagnosis had lower postoperative mortality (p<0.001) and improved survival (p<0.001) after adjustment for casemix and hospital-level variables. The effects increased with sustained research participation, with a reduction in postoperative mortality of 1.5% (6.5%–5%, p<2.2×10−6) and an improvement in survival (p<10−19; 5-year difference: 3.8% (41.0%–44.8%)) comparing high participation for ≥4 years with 0 years.ConclusionsThere is a strong independent association between survival and participation in interventional clinical studies for all patients with CRC treated in the hospital study participants. Improvement precedes and increases with the level and years of sustained participation.

Advanced colorectal cancer is treated with a combination of cytotoxic drugs and targeted treatments. However, how best to minimise the time spent taking cytotoxic drugs and whether molecular selection can refine this further is unknown. The primary aim of this study was to establish how cetuximab might be safely and effectively added to intermittent chemotherapy. COIN-B was an open-label, multicentre, randomised, exploratory phase 2 trial done at 30 hospitals in the UK and one in Cyprus. We enrolled patients with advanced colorectal cancer who had received no previous chemotherapy for metastases. Randomisation was done centrally (by telephone) by the Medical Research Council Clinical Trials Unit using minimisation with a random element. Treatment allocation was not masked. Patients were assigned (1:1) to intermittent chemotherapy plus intermittent cetuximab or to intermittent chemotherapy plus continuous cetuximab. Chemotherapy was FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil). Patients in both groups received FOLFOX and weekly cetuximab for 12 weeks, then either had a planned interruption (those taking intermittent cetuximab) or planned maintenance by continuing on weekly cetuximab (continuous cetuximab). On RECIST progression, FOLFOX plus cetuximab or FOLFOX was recommenced for 12 weeks followed by further interruption or maintenance cetuximab, respectively. The primary outcome was failure-free survival at 10 months. The primary analysis population consisted of patients who completed 12 weeks of treatment without progression, death, or leaving the trial. We tested BRAF and NRAS status retrospectively. The trial was registered, ISRCTN38375681. We registered 401 patients, 226 of whom were enrolled. Results for 169 with KRAS wild-type are reported here, 78 (46%) assigned to intermittent cetuximab and 91 (54%) to continuous cetuximab. 64 patients assigned to intermittent cetuximab and 66 of those assigned to continuous cetuximab were included in the primary analysis. 10-month failure-free survival was 50% (lower bound of 95% CI 39) in the intermittent group versus 52% (lower bound of 95% CI 41) in the continuous group; median failure-free survival was 12·2 months (95% CI 8·8–15·6) and 14·3 months (10·7–20·4), respectively. The most common grade 3–4 adverse events were skin rash (21 [27%] of 77 patients vs 20 [22%] of 92 patients), neutropenia (22 [29%] vs 30 [33%]), diarrhoea (14 [18%] vs 23 [25%]), and lethargy (20 [26%] vs 19 [21%]). Cetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials. UK Medical Research Council, Merck KGaA.

TB remains a leading cause of mortality and morbidity in sub-Saharan Africa, due to the HIV epidemic. As TB treatment is lengthy, the completion of the full course of treatment may be especially challenging for young people. We therefore aimed to identify the extent of and reasons underlying loss to follow-up from TB treatment among young people in Cape Town. Accordingly, we reviewed the outcomes of young people treated for TB in Cape Town during 2009-2013, across three age groups: younger adolescents (10-14 years); older adolescents; (15-19 years) and young adults (20-24 years). We employed logistic regression analysis to identify risk factors for loss from TB care. 23,737 patients aged 10-24 were treated for drug sensitive TB over the study period. Of these, the HIV co-infection prevalence was 18.5% for younger adolescents, 12.9% for older adolescents and 33.1% for young adults. From age 16, HIV prevalence increased disproportionately among young women: by age 22, over 50% of women were TB/HIV co-infected compared to 14% of men. TB treatment success (cure plus completion) was 84.4%, while 1.7% of patients died, 9.5% were lost-to follow-up and 0.4% failed treatment. Being an older adolescent (aOR 1.75 [95% CI: 1.38-2.21]) or young adult (aOR: 1.96 [95% CI: 1.57-2.45]) increased the risk of loss-to-follow up, relative to being a younger adolescent. Further risk factors for loss from TB care were male gender (aOR: 1.33 [95% CI:1.20-1.46]), being a TB/HIV co-infected young person (aOR 1.74 [95% CI: 1.57-1.93]) and having had prior treatment for TB (aOR 3.17 [95% CI 2.87-3.51]). We identified risk factors for loss to follow-up and highlighted the need to focus on HIV prevention and retention in TB care among young people. TB care tailored to the needs of young people could improve patient retention, similar to improved outcomes reported by youth friendly HIV clinics.

Background: The phase III COntinuous or INtermittent (COIN) trial failed to show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in overall survival (OS). The present analysis evaluated whether the derived neutrophil to lymphocyte ratio (dNLR) could predict the effect of intermittent vs continuous chemotherapy on OS in patients with advanced colorectal cancer. Methods: A post hoc exploratory analysis of COIN arms A and C was performed. Landmark analysis was conducted on all patients with available WBC and neutrophils data. The dNLR was calculated using a formula which has previously demonstrated predictive power in cancer patients: dNLR=ANC/(WBC−ANC). A high dNLR was defined using a cut-off value of ⩾2.22. Derived neutrophil to lymphocyte ratio was then correlated with clinical outcomes. Survival curves were generated based on dNLR using the Kaplan–Meier method. Comparison between groups was performed using Cox regression. Results: A total of 1630 patients were assigned to the continuous ( N =815) or intermittent ( N =815) arms. There was a strong association between dNLR level and OS. The median survival times in the ITT population were 18.6 months and 12.5 months for patients with low and high dNLR, respectively (HR=1.70; 95% CI=1.52–1.90; P <0.001). The estimate of the hazard ratio did not alter substantially (HR=1.54) after adjusting for treatment, tumour status, number of metastatic sites, alkaline phosphate and platelet count. Conclusions: Derived neutrophil to lymphocyte ratio is strongly prognostic for survival in the COIN intermittent vs continuous treatment arms. Derived neutrophil to lymphocyte ratio does not predict for detrimental survival in patients treated with intermittent therapy.

Background/aimsTo evaluate the effect of adjuvant intravitreal triamcinolone acetonide (ITA) for radiation maculopathy (RM) recalcitrant to high-dose bevacizumab in patients with choroidal melanoma after plaque radiotherapy.MethodsEight eyes of eight patients with RM secondary to plaque radiotherapy for choroidal melanoma, recalcitrant to high-dose bevacizumab (3.0 mg) were retrospectively evaluated. Intravitreal injections of ITA (4 mg/0.1 mL) were performed at 4-week to 16-week intervals as an adjunct to continued bevacizumab therapy. Change in central foveal thickness (CFT) as measured by optical coherence tomography and change in visual acuity (VA) were the main outcome measures.ResultsAt the time of diagnosis of choroidal melanoma, VA was 20/20 to 20/50 in 88% (n=7) and 20/60 to 20/200 in 12% (n=1). The mean radiation dose to the fovea was 81 Gy (median 75.2 Gy; range: 22.72–132.8 Gy). The mean onset to RM was 25 months after plaque therapy (median 25 months; range 12–44 months). At the time of initiation of ITA, VA was 20/20 to 20/50 in 38% (3/8), and 20/60 to 20/200 in 62% (5/8). After initiation of ITA, VA was stable or improved in 100% of patients (n=8) at 3 months, 88% at 6 months, 88% at 9 months and 75% at 12 months. Mean CFT was 417 µm at ITA initiation, 339 µm at 1 month, 355 µm at 6 months, 339 µm at 9 months and 359 µm at 1 year.ConclusionIntravitreal triamcinolone can be added to preserve vision and decrease macular oedema in patients with RM recalcitrant to high-dose anti-vascular endothelial growth factor agents.