Background Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs.Methods We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2-T4 pN0-N3 M0 or pTany N1-3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m²) or carboplatin (area under the curve [AUC]4•5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m²) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants.
The concentration of police resources in stable crime hotspots has proven effective in reducing crime, but the extent to which police can disrupt dynamically changing crime hotspots is unknown. Police must be able to anticipate the future location of dynamic hotspots to disrupt them. Here we report results of two randomized controlled trials of near real-time Epidemic Type Aftershock Sequence (ETAS) crime forecasting, one trial within three divisions of the Los Angeles Police Department and the other trial within two divisions of the Kent Police Department (UK). We investigate the extent to which i) ETAS models of short term crime risk outperform existing best practice of hotspot maps produced by dedicated crime analysts, ii) police officers in the field can dynamically patrol predicted hotspots given limited resources, and iii) crime can be reduced by predictive policing algorithms under realistic law enforcement resource constraints. While previous hotspot policing experiments fix treatment and control hotspots throughout the experimental period, we use a novel experimental design to * Department of Mathematics and Computer Science, Santa Clara University † School of Mathematics, Georgia Institute of Technology ‡ Los Angeles Police Department § Kent Police Service ¶ Department of Criminology, University of California, Irvine Department of Mathematics, University of California, Los Angeles * * Department of Anthropology, University of California, Los Angeles 1 allow treatment and control hotspots to change dynamically over the course of the experiment. Our results show that ETAS models predict 1.4-2.2 times as much crime compared to a dedicated crime analyst using existing criminal intelligence and hotspot mapping practice. Police patrols using ETAS forecasts led to a average 7.4% reduction in crime volume as a function of patrol time, whereas patrols based upon analyst predictions showed no significant effect. Dynamic police patrol in response to ETAS crime forecasts can disrupt opportunities for crime and lead to real crime reductions.
Bladder cancer is the second commonest urinary tract malignancy with 70–80 % being non-muscle invasive (NMIBC) at diagnosis. Patients with high-risk NMIBC (T1/Tis, with high grade/G3, or CIS) represent a challenging group as they are at greater risk of recurrence and progression. Intravesical Bacilli Calmette-Guerin (BCG) is commonly used as first line therapy in this patient group but there is a current worldwide shortage. BCG has been shown to reduce recurrence in high-risk NMIBC and is more effective that other intravesical agents including mitomycin C, epirubicin, interferon-alpha and gemcitabine. Primary cystectomy offers a high change of cure in this cohort (80–90 %) and is a more radical treatment option which patients need to be counselled carefully about. Bladder thermotherapy and electromotive drug administration with mitomycin C are alternative therapies with promising short-term results although long-term follow-up data are lacking.
Summary Prostatic adenocarcinoma commonly metastasizes to bone. Unlike most other bony secondaries, the majority of skeletal prostatic metastases are osteoblastic rather than osteolytic i nature. Several growth factors which are known to stimulate bone formation are expressed in benign and malignant prostate cells. bi none has been specifically linked to osteoscierotic metastases. Bone morphogenetic proteins (BMPs) induce ectopic bone formation in vivo. We have reported previously that BMP-6 mRNA and protein are expressed in the majority of primary prostatic carcinomas with established skeletal metastases but rarely in clinically organ-confined tumours. This study examines the expression of BMP-6 mRNA in matched prostatic primary and secondary bony lesions and in isolated skeletal metastases from prostatic adenocarcinomas, as well as other common human malignancies, by in situ hybridization. BMP-6 mRNA was detected in 11 out of 13 bone metastases from prostate carcinoma and in three paired samples of primary prostate carcinoma and matching skeletal metastasis. Weak signals for BMP-6 were also present in 5 out of 17 skeletal deposits from non-prostatic malignancies. BMP-6 mRNA appears to be strongly expressed in prostatic adenocarcinomas, both in the primary tumour and in bone metastases. It is also expressed, though less frequentty, in skeletal metastases from other human carcinomas. Our findings suggest that BMP-6 may hold potential as an attractive marker and possible mediator of skeletal metastases, particularly in prostate carcinoma.Keywords: bone morphogenetic protein-6; prostate carcinoma; skeletal metastasis; in situ hybridization: growth factors Metastases are the most common neoplastic lesions in bone. and more than 80%-7 of the tumours are accounted for by a limited number of primary malignancies (Orr et al. 1995). These include carcinomas of the breast, prostate. thyroid. kidney and lungy. Normal bone is being remodelled continuously with new bone formation by osteoblasts and bone degradation by osteoclasts. In the presence of skeletal metastases. there is a disturbance of the fine balance between the two processes. When bone destruction dominates there is net loss of bone mass and the lesion is described as osteolytic. W'hen excessise amounts of new bone formation takes place with less bone destruction. the lesion is described as osteoblastic or osteosclerotic. This type of increased ossification only occurs in relatively acellular skeletal metastases associated with the deselopment of a fibrous stroma. and is particularly common in metastases from prostatic carcinoma (Galasko. 1982). Human prostatic adenocarcinoma is one of the rare cancers that consistently produces osteoblastic metastases to bone. in approximately 90% of cases. Several growth factors which are known to stimulate osteoblast growth and bone matrix formation are also expressed in benign and malignant prostate cells. These include members of the fibroblast growth factor. insulin-lke growth factor. platelet-denried growth factor and tr...
Cardiovascular optimization using esophageal Doppler significantly improved postoperative markers of gastrointestinal function.
OBJECTIVE To report a large prospective, pragmatic, double‐blind randomized controlled trial to determine whether oral prophylactic antibiotics reduce the risk of bacteriuria after flexible cystoscopy (FC), as up to 10% of patients develop urinary infection afterwards, with significant morbidity and costs for health services. PATIENTS AND METHODS In all, 2481 patients were recruited into a three‐arm placebo controlled trial and 2083 completed it. Patients were randomly assigned to one of three treatments; (i) placebo; (ii) one oral dose of trimethoprim (200 mg); or (iii) one oral dose of ciprofloxacin (500 mg), each administered 1 h before a FC under local anaesthetic. A mid‐stream urine specimen was taken before and 5 days after FC; significant bacteriuria was defined as a pure growth of >105 colony‐forming units/mL. RESULTS The rate of bacteriuria after FC was reduced from 9% in the placebo group to 5% and 3% in patients receiving trimethoprim and ciprofloxacin prophylaxis, respectively. When rates of bacteriuria before FC were considered the odds of developing bacteriuria after FC relative to baseline were 5, 2 and 0.5 for placebo, trimethoprim and ciprofloxacin, respectively. CONCLUSION This large trial shows clearly that one dose of oral ciprofloxacin significantly reduces bacteriuria after FC.
Background and Purpose Inflammatory biomarkers predict incident and recurrent cardiac events, but their relationship to stroke prognosis is uncertain. We hypothesized that high-sensitivity C-reactive protein (hsCRP) predicts recurrent ischemic stroke after recent lacunar stroke. Methods Levels of Inflammatory Markers in the Treatment of Stroke (LIMITS) was an international, multicenter, prospective ancillary biomarker study nested within Secondary Prevention of Small Subcortical Strokes (SPS3), a Phase III trial in patients with recent lacunar stroke. Patients were assigned in factorial design to aspirin versus aspirin plus clopidogrel, and higher versus lower blood pressure targets. Patients had blood samples collected at enrollment, and hsCRP measured using nephelometry at a central laboratory. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (HR, 95%CI) for recurrence risks before and after adjusting for demographics, comorbidities, and statin use. Results Among 1244 lacunar stroke patients (mean 63.3 ± 10.8 years), median hsCRP was 2.16 mg/L. There were 83 recurrent ischemic strokes (including 45 lacunes), and 115 major vascular events (stroke, myocardial infarction, vascular death). Compared with the bottom quartile, those in the top quartile (hsCRP >4.86 mg/L) were at increased risk of recurrent ischemic stroke (unadjusted HR 2.54, 95%CI 1.30–4.96), even after adjusting for demographics and risk factors (adjusted HR 2.32, 95%CI 1.15–4.68). HsCRP predicted increased risk of major vascular events (top quartile adjusted HR 2.04, 95%CI 1.14–3.67). There was no interaction with randomized antiplatelet treatment. Conclusions Among recent lacunar stroke patients, hsCRP levels predict risk of recurrent strokes and other vascular events. HsCRP did not predict response to dual antiplatelets.
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