The long-term outcome of treated high-risk nonmuscle-invasive bladder cancer

This article is available open access through the publisher’s website from the link below. Copyright © 2012 American Cancer Society.BACKGROUND: The treatment of high-risk nonmuscle-invasive bladder cancer (NMIBC) is difficult given its unpredictable natural history and patient comorbidities. Because current case series are mostly limited in size, the authors report the outcomes from a large, single-center series. METHODS: The authors reviewed all patients with primary, high-risk NMIBC at their institution from 1994 to 2010. Outcomes were matched with clinicopathologic data. Patients who had muscle invasion within 6 months or had insufficient follow-up (<6 months) were excluded. Correlations were analyzed using multivariable Cox regression and log-rank analysis (2-sided; P < .05). RESULTS: In total, 712 patients (median age, 73.7 years) were included. Progression to muscle invasion occurred in 110 patients (15.8%; 95% confidence interval [CI], 13%-18.3%) at a median of 17.2 months (interquartile range, 8.9-35.8 months), including 26.5% (95% CI, 22.2%-31.3%) of the 366 patients who had >5 years follow-up. Progression was associated with age (hazard ratio [HR], 1.04; P = .007), dysplastic urothelium (HR, 1.6; P = .003), urothelial cell carcinoma variants (HR, 3.2; P = .001), and recurrence (HR, 18.3; P .6). CONCLUSIONS: Within a program of conservative treatment, progression of high-risk NMIBC was associated with a poor prognosis. Surveillance and bacillus Calmette-Guerin were ineffective in altering the natural history of this disease. The authors concluded that the time has come to rethink the paradigm of management of this disease.GlaxoSmithKline, Yorkshire Cancer Research, Sheffield Hospitals Charitable Trust, Astellas Educational Foundation, and the European Union

Immunity toward H1N1 influenza hemagglutinin of historical and contemporary strains suggests protection and vaccine failure

Evolution of H1N1 influenza A outbreaks of the past 100 years is interesting and significantly complex and details of H1N1 genetic drift remains unknown. Here we investigated the clinical characteristics and immune cross-reactivity of significant historical H1N1 strains. We infected ferrets with H1N1 strains from 1943, 1947, 1977, 1986, 1999, and 2009 and showed each produced a unique clinical signature. We found significant cross-reactivity between viruses with similar HA sequences. Interestingly, A/FortMonmouth/1/1947 antisera cross-reacted with A/USSR/90/1977 virus, thought to be a 1947 resurfaced virus. Importantly, our immunological data that didn't show cross-reactivity can be extrapolated to failure of past H1N1 influenza vaccines, ie. 1947, 1986 and 2009. Together, our results help to elucidate H1N1 immuno-genetic alterations that occurred in the past 100 years and immune responses caused by H1N1 evolution. This work will facilitate development of future influenza therapeutics and prophylactics such as influenza vaccines.published_or_final_versio

Perinatal Bisphenol A Exposure Increases Estrogen Sensitivity of the Mammary Gland in Diverse Mouse Strains

BACKGROUND: Studies of low-dose effects of xenoestrogens have yielded conflicting results that may be attributed to differences in estrogen sensitivity between the rodent strains examined. Perinatal exposure of CD-1 mice to low doses of the xenoestrogen bisphenol A (BPA) alters peripubertal mammary gland development. Future studies to assess the role of estrogen receptors as mediators of BPA action require estrogen receptor knock-out mice that were generated on a C57Bl6 background. The sensitivity of the C57Bl6 strain to estradiol and BPA is unknown. OBJECTIVES: In the present study we examined whether the mammary glands of CD-1 and C57Bl6 mice exhibited similar responses to 17β-estradiol (E(2)) and whether perinatal exposure to BPA equally enhanced sensitivity of the mammary glands to E(2) at puberty. METHODS: Immature mice were ovariectomized and treated for 10 days with one of eight doses of E(2). Morphological mammary gland parameters were examined to identify doses producing half-maximal effects. Mice were exposed perinatally to 0 or 250 ng BPA/kg body weight (bw)/day from gestational day 8 until postnatal day (PND) 2. On PND25, female offspring were ovariectomized and given an estrogen challenge of 0, 0.5, or 1 μg E(2)/kg bw/day for 10 days. Morphometric parameters of the mammary gland were compared between strains. RESULTS: Both strains exhibited similar responses to E(2). Perinatal BPA exposure altered responses to E(2) at puberty for several parameters in both strains, although the effect in CD-1 was slightly more pronounced. CONCLUSION: Both mouse strains provide adequate models for the study of perinatal exposure to xenoestrogens

Antibiotic control of antibiotic resistance in hospitals: a simulation study

<p>Abstract</p> <p>Background</p> <p>Using mathematical deterministic models of the epidemiology of hospital-acquired infections and antibiotic resistance, it has been shown that the rates of hospital-acquired bacterial infection and frequency of antibiotic infections can be reduced by (i) restricting the admission of patients colonized with resistant bacteria, (ii) increasing the rate of turnover of patients, (iii) reducing transmission by infection control measures, and (iv) the use of second-line drugs for which there is no resistance. In an effort to explore the generality and robustness of the predictions of these deterministic models to the real world of hospitals, where there is variation in all of the factors contributing to the incidence of infection, we developed and used a stochastic model of the epidemiology of hospital-acquired infections and resistance. In our analysis of the properties of this model we give particular consideration different regimes of using second-line drugs in this process.</p> <p>Methods</p> <p>We developed a simple model that describes the transmission of drug-sensitive and drug-resistant bacteria in a small hospital. Colonized patients may be treated with a standard drug, for which there is some resistance, and with a second-line drug, for which there is no resistance. We then ran deterministic and stochastic simulation programs, based on this model, to predict the effectiveness of various treatment strategies.</p> <p>Results</p> <p>The results of the analysis using our stochastic model support the predictions of the deterministic models; not only will the implementation of any of the above listed measures substantially reduce the incidences of hospital-acquired infections and the frequency of resistance, the effects of their implementation should be seen in months rather than the years or decades anticipated to control resistance in open communities. How effectively and how rapidly the application of second-line drugs will contribute to the decline in the frequency of resistance to the first-line drugs depends on how these drugs are administered. The earlier the switch to second-line drugs, the more effective this protocol will be. Switching to second-line drugs at random is more effective than switching after a defined period or only after there is direct evidence that the patient is colonized with bacteria resistant to the first antibiotic.</p> <p>Conclusions</p> <p>The incidence of hospital-acquired bacterial infections and frequencies of antibiotic resistant bacteria can be markedly and rapidly reduced by different readily implemented procedures. The efficacy using second line drugs to achieve these ends depends on the protocol used for their administration.</p

The Hubble Space Telescope Cluster Supernova Survey: II. The Type Ia Supernova Rate in High-Redshift Galaxy Clusters

We report a measurement of the Type Ia supernova (SN Ia) rate in galaxy clusters at 0.9 < z < 1.45 from the Hubble Space Telescope (HST) Cluster Supernova Survey. This is the first cluster SN Ia rate measurement with detected z > 0.9 SNe. Finding 8 +/- 1 cluster SNe Ia, we determine a SN Ia rate of 0.50 +0.23-0.19 (stat) +0.10-0.09 (sys) SNuB (SNuB = 10^-12 SNe L_{sun,B}^-1 yr^-1). In units of stellar mass, this translates to 0.36 +0.16-0.13 (stat) +0.07-0.06 (sys) SNuM (SNuM = 10^-12 SNe M_sun^-1 yr^-1). This represents a factor of approximately 5 +/- 2 increase over measurements of the cluster rate at z < 0.2. We parameterize the late-time SN Ia delay time distribution with a power law (proportional to t^s). Under the assumption of a cluster formation redshift of z_f = 3, our rate measurement in combination with lower-redshift cluster SN Ia rates constrains s = -1.41 +0.47/-0.40, consistent with measurements of the delay time distribution in the field. This measurement is generally consistent with expectations for the "double degenerate" scenario and inconsistent with some models for the "single degenerate" scenario predicting a steeper delay time distribution at large delay times. We check for environmental dependence and the influence of younger stellar populations by calculating the rate specifically in cluster red-sequence galaxies and in morphologically early-type galaxies, finding results similar to the full cluster rate. Finally, the upper limit of one host-less cluster SN Ia detected in the survey implies that the fraction of stars in the intra-cluster medium is less than 0.47 (95% confidence), consistent with measurements at lower redshifts.Comment: 29 pages, 14 figures. Accepted for publication in ApJ on 16 February 2011. See the HST Cluster Supernova Survey website at http://supernova.lbl.gov/2009ClusterSurvey for a version with full-resolution images and a complete listing of transient candidates from the survey. This version fixes a typo in the metadata; the paper is unchanged from v

Why is there no queer international theory?

Over the last decade, Queer Studies have become Global Queer Studies, generating significant insights into key international political processes. Yet, the transformation from Queer to Global Queer has left the discipline of International Relations largely unaffected, which begs the question: if Queer Studies has gone global, why has the discipline of International Relations not gone somewhat queer? Or, to put it in Martin Wight’s provocative terms, why is there no Queer International Theory? This article claims that the presumed non-existence of Queer International Theory is an effect of how the discipline of International Relations combines homologization, figuration, and gentrification to code various types of theory as failures in order to manage the conduct of international theorizing in all its forms. This means there are generalizable lessons to be drawn from how the discipline categorizes Queer International Theory out of existence to bring a specific understanding of International Relations into existence

Who should be prioritized for renal transplantation?: Analysis of key stakeholder preferences using discrete choice experiments

Background Policies for allocating deceased donor kidneys have recently shifted from allocation based on Human Leucocyte Antigen (HLA) tissue matching in the UK and USA. Newer allocation algorithms incorporate waiting time as a primary factor, and in the UK, young adults are also favoured. However, there is little contemporary UK research on the views of stakeholders in the transplant process to inform future allocation policy. This research project aimed to address this issue. Methods Discrete Choice Experiment (DCE) questionnaires were used to establish priorities for kidney transplantation among different stakeholder groups in the UK. Questionnaires were targeted at patients, carers, donors / relatives of deceased donors, and healthcare professionals. Attributes considered included: waiting time; donor-recipient HLA match; whether a recipient had dependents; diseases affecting life expectancy; and diseases affecting quality of life. Results Responses were obtained from 908 patients (including 98 ethnic minorities); 41 carers; 48 donors / relatives of deceased donors; and 113 healthcare professionals. The patient group demonstrated statistically different preferences for every attribute (i.e. significantly different from zero) so implying that changes in given attributes affected preferences, except when prioritizing those with no rather than moderate diseases affecting quality of life. The attributes valued highly related to waiting time, tissue match, prioritizing those with dependents, and prioritizing those with moderate rather than severe diseases affecting life expectancy. Some preferences differed between healthcare professionals and patients, and ethnic minority and non-ethnic minority patients. Only non-ethnic minority patients and healthcare professionals clearly prioritized those with better tissue matches. Conclusions Our econometric results are broadly supportive of the 2006 shift in UK transplant policy which emphasized prioritizing the young and long waiters. However, our findings suggest the need for a further review in the light of observed differences in preferences amongst ethnic minorities, and also because those with dependents may be a further priority.</p

A non-randomised, single-centre comparison of induction chemotherapy followed by radiochemotherapy versus concomitant chemotherapy with hyperfractionated radiotherapy in inoperable head and neck carcinomas

BACKGROUND: The application of induction chemotherapy failed to provide a consistent benefit for local control in primary treatment of advanced head and neck (H&N) cancers. The aim of this study was to compare the results of concomitant application of radiochemotherapy for treating locally advanced head-and-neck carcinoma in comparison with the former standard of sequential radiochemotherapy. METHODS: Between 1987 and 1995 we treated 122 patients with unresectable (stage IV head and neck) cancer by two different protocols. The sequential protocol (SEQ; 1987–1992) started with two courses of neoadjuvant chemotherapy (cisplatin [CDDP] + 120-h continuous infusions (c.i.) of folinic acid [FA] and 5-fluorouracil [5-FU]), followed by a course of radiochemotherapy using conventional fractionation up to 70 Gy. The concomitant protocol (CON; since 1993) combined two courses of FA/5-FU c.i. plus mitomycin (MMC) concomitantly with a course of radiotherapy up to 30 Gy in conventional fractionation, followed by a hyperfractionated course up to 72 Gy. Results from the two groups were compared. RESULTS: Patient and tumor characteristics were balanced (SEQ = 70, CON = 52 pts.). Mean radiation dose achieved (65.3 Gy vs. 71.6 Gy, p = 0.00), response rates (67 vs. 90 % for primary, p = 0.02), and local control (LC; 17.6% vs. 41%, p = 0.03), were significantly lower in the SEQ group, revealing a trend towards lower disease-specific (DSS; 19.8% vs. 31.4%, p = 0.08) and overall (14.7% vs. 23.7%, p = 0.11) survival rates after 5 years. Mucositis grades III and IV prevailed in the CON group (54% versus 44%). Late toxicity was similar in both groups. CONCLUSION: Concurrent chemotherapy seemed more effective in treating head and neck tumors than induction chemotherapy followed by chemoradiation, resulting in better local control and a trend towards improved survival

Reviewer agreement trends from four years of electronic submissions of conference abstract

BACKGROUND: The purpose of this study was to determine the inter-rater agreement between reviewers on the quality of abstract submissions to an annual national scientific meeting (Canadian Association of Emergency Physicians; CAEP) to identify factors associated with low agreement. METHODS: All abstracts were submitted using an on-line system and assessed by three volunteer CAEP reviewers blinded to the abstracts' source. Reviewers used an on-line form specific for each type of study design to score abstracts based on nine criteria, each contributing from two to six points toward the total (maximum 24). The final score was determined to be the mean of the three reviewers' scores using Intraclass Correlation Coefficient (ICC). RESULTS: 495 Abstracts were received electronically during the four-year period, 2001 – 2004, increasing from 94 abstracts in 2001 to 165 in 2004. The mean score for submitted abstracts over the four years was 14.4 (95% CI: 14.1–14.6). While there was no significant difference between mean total scores over the four years (p = 0.23), the ICC increased from fair (0.36; 95% CI: 0.24–0.49) to moderate (0.59; 95% CI: 0.50–0.68). Reviewers agreed less on individual criteria than on the total score in general, and less on subjective than objective criteria. CONCLUSION: The correlation between reviewers' total scores suggests general recognition of "high quality" and "low quality" abstracts. Criteria based on the presence/absence of objective methodological parameters (i.e., blinding in a controlled clinical trial) resulted in higher inter-rater agreement than the more subjective and opinion-based criteria. In future abstract competitions, defining criteria more objectively so that reviewers can base their responses on empirical evidence may lead to increased consistency of scoring and, presumably, increased fairness to submitters

The helicobacter eradication aspirin trial (HEAT): demographic data for randomised (H.pylori positive) patients

Introduction The Helicobacter Eradication Aspirin Trial (HEAT) is a multicentre, double blind, randomised controlled trial investigating whether Helicobacter pylori eradication reduces the incidence of hospitalisation for peptic ulcer bleeding [1]. Participants are subjects aged over 60, taking low dose aspirin for at least four months at the time of recruitment; all participants were recruited from primary care. H. pylori positive participants were randomised to receive one week active trial treatment (lansoprazole 30mg, clarithromycin 500mg and metronidazole 400mg twice daily) or placebo. Recruitment to the trial started in 2012 and completed in 2017; follow-up is endpoint driven and is ongoing. Methods Participants are followed up using a bespoke web-based trial management system that communicates directly with HEAT Toolkit software downloaded at participating GP practices, which issues MIQUEST [2] queries searching follow-up criteria. The primary endpoint of the study is the rate of hospitalisation due to definite or probable peptic ulcer bleeding. The study will end when 87 adjudicated events have occurred. Events are tracked by accumulating information from MIQUEST searches of GP databases via the HEAT toolkit, patient contact, review of national secondary care admission and mortality data. Results HEAT is being conducted in practices across the whole of the UK with 188,428 invitation letters sent from 1,208 GP practices. A total of 37,247 positive responses were received, representing a 20% response rate. Of those, 30,025 patients were consented to the study of whom 5,356 H. pylori positive patients were randomised. The percent of H. pylori positive patients varied from 13% to 39% throughout the country. Multiple deprivation scores applied to the data indicated an increase in response with less deprivation, but a decrease in the number of randomised patients. The mean age at randomisation for all participants was 73.6 ± 7.0 (SD) years, and 73.8% of participants are male. Only 7.2% of participants are smokers although 52.9% are ex-smokers. A total of 15% of the randomised patients have withdrawn from the trial, and 100 patients have died so far. Discussion The trial methodology has shown that recruitment of large numbers of patients from primary care is attainable, with the assistance of the NIHR Clinical Research Network, and could be applied to other outcomes studies at relatively low cost. Last year, there were almost 17,000 hospital admissions for gastric ulcers [3] and more than 1,850 recorded deaths [4] for gastric and duodenal ulcers. If successful, the study will help to reduce NHS costs and improve health outcomes by reducing hospital admissions, increasing patient safety and preventing premature deaths