Abstract Purpose This multi-disciplinary, evidence-based guideline for clinically non-metastatic muscle-invasive bladder cancer focuses on the evaluation, treatment, and surveillance of ...muscle-invasive bladder cancer guided toward curative intent. Materials and Methods A systematic review utilizing research from the Agency for Healthcare Research and Quality (AHRQ) as well as additional supplementation by the authors and consultant methodologists was used to develop the guideline. Evidence-based statements were based on body of evidence strengths Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions. (Table 1) Results For the first time, for any type of malignancy, the American Urological Association (AUA), the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO) have formulated an evidence-based guideline based on a risk-stratified clinical framework for the management of muscle-invasive urothelial bladder cancer. This document is designed to be used in conjunction with the associated treatment algorithm. Conclusions The intensity and scope of care for muscle-invasive bladder cancer should focus on the patient, disease, and treatment response characteristics. This guideline attempts to improve a clinician’s ability to evaluate and treat each patient, but higher quality evidence in future trials will be essential to improve level of care for these patients.
Summary Background Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect ...of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. Methods Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , number NCT02295033. Findings Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17·2 years (IQR 13·0–19·0). 20-year overall survival was 59·7% (99% CI 56·3–63·0) in the boost group versus 61·1% (57·6–64·3) in the no boost group, hazard ratio (HR) 1·05 (99% CI 0·92–1·19, p=0·323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0·65 (99% CI 0·52–0·81, p<0·0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16·4% (99% CI 14·1–18·8) in the no boost group versus 12·0% (9·8–14·4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1·8% (99% CI 1·1–2·5) in the no boost group versus 5·2% (99% CI 3·9–6·4) in the boost group (p<0·0001). Interpretation A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. Funding Fonds Cancer, Belgium.
Objective The purpose of this study was to compare intraamniotic inflammation vs microbial invasion of the amniotic cavity (MIAC) as predictors of adverse outcome in preterm labor with intact ...membranes. Study Design Interleukin-6 (IL-6) was measured in prospectively collected amniotic fluid from 305 women with preterm labor. MIAC was defined by amniotic fluid culture and/or detection of microbial 16S ribosomal DNA. Cases were categorized into 5 groups: infection (MIAC; IL-6, ≥11.3 ng/mL); severe inflammation (no MIAC; IL-6, ≥11.3 ng/mL); mild inflammation (no MIAC; IL-6, 2.6-11.2 ng/mL); colonization (MIAC; IL-6, <2.6 ng/mL); negative (no MIAC; IL-6, <2.6 ng/mL). Results The infection (n = 27) and severe inflammation (n = 36) groups had similar latency (median, <1 day and 2 days, respectively) and similar rates of composite perinatal morbidity and mortality (81% and 72%, respectively). The colonization (n = 4) and negative (n = 195) groups had similar outcomes (median latency, 23.5 and 25 days; composite morbidity and mortality rates, 21% and 25%, respectively). The mild inflammation (n = 47) groups had outcomes that were intermediate to the severe inflammation and negative groups (median latency, 7 days; composite morbidity and mortality rates, 53%). In logistic regression adjusting for gestational age at enrollment, IL-6 ≥11.3 and 2.6-11.2 ng/mL, but not MIAC, were associated significantly with composite morbidity and mortality rates (odds ratio OR, 4.9; 95% confidence interval CI, 2.2–11.2, OR, 3.1; 95% CI, 1.5–6.4, and OR, 1.8; 95% CI, 0.6–5.5, respectively). Conclusion We confirmed previous reports that intraamniotic inflammation is associated with adverse perinatal outcomes whether or not intraamniotic microbes are detected. Colonization without inflammation appears relatively benign. Intraamniotic inflammation is not simply present or absent but also has degrees of severity that correlate with adverse outcomes. We propose the designation amniotic inflammatory response syndrome to denote the adverse outcomes that are associated with intraamniotic inflammation.
Background Data on overtube-assisted enteroscopy to facilitate ERCP in patients with surgically altered pancreaticobiliary anatomy, or long-limb surgical bypass, is limited. Objective To evaluate and ...compare ERCP success by using single-balloon (SBE), double-balloon (DBE), or rotational overtube enteroscopy. Design Consecutive patients identified retrospectively. Setting Eight U.S. referral centers. Patients Long-limb surgical bypass patients with suspected pancreaticobiliary diseases. Intervention Overtube-assisted enteroscopy ERCP. Main Outcome Measurements Enteroscopy success: visualizing the pancreaticobiliary-enteric anastomosis or papilla. ERCP success: completing the intended pancreaticobiliary intervention. Clinical success: greater than 50% reduction in abdominal pain or level of hepatic enzyme elevations or resolution of jaundice. Results From January 2008 through October 2009, 129 patients had 180 enteroscopy-ERCPs. Anatomy was Roux-en-Y: gastric bypass (n = 63), hepaticojejunostomy (n = 45), postgastrectomy (n = 6), Whipple procedure (n = 10), and other (n = 5). ERCP success was 81 of 129 (63%). Enteroscopy success: 92 of 129 (71%), of whom 81 of 92 (88%) achieved ERCP success. Reasons for ERCP failure (n = 48): afferent limb entered but pancreaticobiliary anastomosis and/or papilla not reached (n = 23), cannulation failure (n = 11), afferent limb angulation (n = 8), and jejunojejunostomy not identified (n = 6). Select interventions: anastomotic stricturoplasty (cautery ± dilation, n = 16), stone removal (n = 21), stent (n = 25), and direct cholangioscopy (n = 11). ERCP success rates were similar between Roux-en-Y gastric bypass and other long-limb surgical bypass and among SBE, DBE, and rotational overtube enteroscopy. Complications were 16 of 129, 12.4%. Limitations Retrospective study. Conclusion (1) ERCP is successful in nearly two-thirds of long-limb surgical bypass patients and in 88% when the papilla or pancreaticobiliary-enteric anastomosis is reached. (2) Enteroscopy success in long-limb surgical bypass is similar among SBE, DBE, and rotational overtube enteroscopy methods. (3) Referral of long-limb surgical bypass patients who require ERCP to high-volume institutions may be considered before more invasive percutaneous or surgical alternatives.
Background Asthma exacerbations remain common, even in children and adolescents, despite optimal medical management. Identification of host risk factors for exacerbations is incomplete, particularly ...for seasonal episodes. Objective We sought to define host risk factors for asthma exacerbations unique to their season of occurrence. Methods This is a retrospective analysis of patients aged 6 to 20 years who comprised the control groups of the Asthma Control Evaluation study and the Inner City Anti-IgE Therapy for Asthma study. Univariate and multivariate models were constructed to determine whether patients' demographic and historical factors, allergic sensitization, fraction of exhaled nitric oxide values, spirometric measurements, asthma control, and treatment requirements were associated with seasonal exacerbations. Results The analysis included 400 patients (54.5% male; 59.0% African American; median age, 13 years). Exacerbations occurred in 37.5% of participants over the periods of observation and were most common in the fall (28.8% of participants). In univariate analysis impaired pulmonary function was significantly associated with greater odds of exacerbations for all seasons, as was an exacerbation in the previous season for all seasons except spring. In multivariate analysis exacerbation in the previous season was the strongest predictor in fall and winter, whereas a higher requirement for inhaled corticosteroids was the strongest predictor in spring and summer. The multivariate models had the best predictive power for fall exacerbations (30.5% variance attributed). Conclusions Among a large cohort of inner-city children with asthma, patients' risk factors for exacerbation vary by season. Thus information on individual patients might be beneficial in strategies to prevent these seasonal events.
Summary Background Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with ...metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours. Methods We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice. Findings Eight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes. Interpretation Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.
Background Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity. Objectives We sought to examine the effectiveness of episodic use of an inhaled ...corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing. Methods In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome. Results The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy ( P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% P = .003 and 37% P = .003, respectively) and interference with activity scores (32% P = .01 and 40% P = .001, respectively) that were most evident in those with positive asthma predictive indices. Conclusions In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.
Abstract Background Beta-blockers improve outcomes in patients with systolic heart failure. However, it is unknown whether their initial negative inotropic effect may increase 30-day all-cause ...readmission, a target outcome for Medicare cost reduction and financial penalty for hospitals under the Affordable Care Act. Methods Of the 3067 Medicare beneficiaries discharged alive from 106 Alabama hospitals (1998-2001) with a primary discharge diagnosis of heart failure and ejection fraction <45%, 2202 were not previously on beta-blocker therapy, of which 383 received new discharge prescriptions for beta-blockers. Propensity scores for beta-blocker use, estimated for each of the 2202 patients, were used to assemble a matched cohort of 380 pairs of patients receiving and not receiving beta-blockers who were balanced on 36 baseline characteristics (mean age 73 years, mean ejection fraction 27%, 45% women, 33% African American). Results Beta-blocker use was not associated with 30-day all-cause readmission (hazard ratio HR 0.87; 95% confidence interval CI, 0.64-1.18) or heart failure readmission (HR 0.95; 95% CI, 0.57-1.58), but was significantly associated with lower 30-day all-cause mortality (HR 0.29; 95% CI, 0.12-0.73). During 4-year postdischarge, those in the beta-blocker group had lower mortality (HR 0.81; 95% CI, 0.67-0.98) and combined outcome of all-cause mortality or all-cause readmission (HR 0.87; 95% CI, 0.74-0.97), but not with all-cause readmission (HR 0.89; 95% CI, 0.76-1.04). Conclusions Among hospitalized older patients with systolic heart failure, discharge prescription of beta-blockers was associated with lower 30-day all-cause mortality and 4-year combined death or readmission outcomes without higher 30-day readmission.
Background Heart failure is the leading cause for 30-day all-cause readmission, the reduction of which is a goal of the Affordable Care Act. There is a growing interest in understanding the impact of ...evidence-based heart failure therapy on 30-day all-cause readmission. In the current study, we examined the impact of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI-ARBs) on 30-day all-cause readmission in heart failure. Methods Of the 1384 hospitalized Medicare beneficiaries with heart failure and left ventricular ejection fraction <45% discharged alive from 106 Alabama hospitals (1998–2001) without prior ACEI-ARB use and without known contraindications to ACEI-ARB use, 734 received new pre-discharge prescriptions for these drugs. Using propensity scores for ACEI-ARB initiation, we assembled a matched cohort of 477 pairs of patients balanced on 32 baseline characteristics (mean age 75 years, 46% women, 26% African American). Results 30-day all-cause readmissions occurred in 18% and 24% of matched patients receiving and not receiving ACEI-ARBs, respectively (hazard ratio {HR}, 0.74; 95% confidence interval {CI}, 0.56–0.97; p=0.030). ACEI-ARB use was also associated with lower risk of 30-day all-cause mortality (HR, 0.56; 95% CI, 0.33–0.98; p=0.041) and of the combined endpoint of 30-day all-cause readmission or 30-day all-cause mortality (HR, 0.73; 95% CI, 0.56–0.94; p=0.017). All associations remained significant at 1-year post-discharge. Conclusions –Among hospitalized patients with heart failure and reduced ejection fraction, the use of ACEI-ARBs was associated with a significantly lower risk of 30-day all-cause readmission and 30-day all-cause mortality; both beneficial associations persisted during long-term follow-up.
Summary Background Preliminary evidence is equivocal about the role of exhaled nitric oxide (NO) in clinical asthma management. We aimed to assess whether measurement of exhaled NO, as a biomarker of ...airway inflammation, could increase the effectiveness of asthma treatment, when used as an adjunct to clinical care based on asthma guidelines for inner-city adolescents and young adults. Methods We did a randomised, double-blind, parallel-group trial at ten centres in the USA. We screened 780 inner-city patients, aged 12–20 years, who had persistent asthma. All patients completed a run-in period of 3 weeks on a regimen based on standard treatment. 546 eligible participants who adhered to treatment during this run-in period were then randomly assigned to 46 weeks of either standard treatment, based on the guidelines of the National Asthma Education and Prevention Program (NAEPP), or standard treatment modified on the basis of measurements of fraction of exhaled NO. The primary outcome was the number of days with asthma symptoms. We analysed patients on an intention-to-treat basis. This trial is registered with clinicaltrials.gov , number NCT00114413. Findings During the 46-week treatment period, the mean number of days with asthma symptoms did not differ between the treatment groups (1·93 95% CI 1·74 to 2·11 in the NO monitoring group vs 1·89 1·71 to 2·07 in the control group; difference 0·04 −0·22 to 0·29, p=0·780). Other symptoms, pulmonary function, and asthma exacerbations did not differ between groups. Patients in the NO monitoring group received higher doses of inhaled corticosteroids (difference 119 μg per day, 95% CI 49 to 189, p=0·001) than controls. Adverse events did not differ between treatment groups (p>0·1 for all adverse events). Interpretation Conventional asthma management resulted in good control of symptoms in most participants. The addition of fraction of exhaled NO as an indicator of control of asthma resulted in higher doses of inhaled corticosteroids, without clinically important improvements in symptomatic asthma control. Funding US National Institute of Allergy and Infectious Diseases, US National Institutes of Health.
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