To report the primary endpoint of biochemical progression-free survival (b-PFS) and secondary survival endpoints from ASCENDE-RT, a randomized trial comparing 2 methods of dose escalation for ...intermediate- and high-risk prostate cancer.
ASCENDE-RT enrolled 398 men, with a median age of 68 years; 69% (n=276) had high-risk disease. After stratification by risk group, the subjects were randomized to a standard arm with 12 months of androgen deprivation therapy, pelvic irradiation to 46 Gy, followed by a dose-escalated external beam radiation therapy (DE-EBRT) boost to 78 Gy, or an experimental arm that substituted a low-dose-rate prostate brachytherapy (LDR-PB) boost. Of the 398 trial subjects, 200 were assigned to DE-EBRT boost and 198 to LDR-PB boost. The median follow-up was 6.5 years.
In an intent-to-treat analysis, men randomized to DE-EBRT were twice as likely to experience biochemical failure (multivariable analysis MVA hazard ratio HR 2.04; P=.004). The 5-, 7-, and 9-year Kaplan-Meier b-PFS estimates were 89%, 86%, and 83% for the LDR-PB boost versus 84%, 75%, and 62% for the DE-EBRT boost (log-rank P<.001). The LDR-PB boost benefited both intermediate- and high-risk patients. Because the b-PFS curves for the treatment arms diverge sharply after 4 years, the relative advantage of the LDR-PB should increase with longer follow-up. On MVA, the only variables correlated with reduced overall survival were age (MVA HR 1.06/y; P=.004) and biochemical failure (MVA HR 6.30; P<.001). Although biochemical failure was associated with increased mortality and randomization to DE-EBRT doubled the rate of biochemical failure, no significant overall survival difference was observed between the treatment arms (MVA HR 1.13; P=.62).
Compared with 78 Gy EBRT, men randomized to the LDR-PB boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years.
Summary Background Heart failure with preserved ejection fraction (HFPEF) is a common, globally recognised, form of heart failure for which no treatment has yet been shown to improve symptoms or ...prognosis. The pathophysiology of HFPEF is complex but characterised by increased left atrial pressure, especially during exertion, which might be a key therapeutic target. The rationale for the present study was that a mechanical approach to reducing left atrial pressure might be effective in HFPEF. Methods The REDUCe Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF) study was an open-label, single-arm, phase 1 study designed to assess the performance and safety of a transcatheter interatrial shunt device (IASD, Corvia Medical, Tewkesbury, MA, USA) in patients older than 40 years of age with symptoms of HFPEF despite pharmacological therapy, left ventricular ejection fraction higher than 40%, and a raised pulmonary capillary wedge pressure at rest (>15 mm Hg) or during exercise (>25 mm Hg). The study was done at 21 centres (all departments of cardiology in the UK, Netherlands, Belgium, France, Germany, Austria, Denmark, Australia, and New Zealand). The co-primary endpoints were the safety and performance of the IASD at 6 months, together with measures of clinical efficacy, including functional capacity and clinical status, analysed per protocol. This study is registered with ClinicalTrials.gov , number NCT01913613. Findings Between Feb 8, 2014, and June 10, 2015, 68 eligible patients were entered into the study. IASD placement was successful in 64 patients and seemed to be safe and well tolerated; no patient had a peri-procedural or major adverse cardiac or cerebrovascular event or need for cardiac surgical intervention for device-related complications during 6 months of follow-up. At 6 months, 31 (52%) of 60 patients had a reduction in pulmonary capillary wedge pressure at rest, 34 (58%) of 59 had a lower pulmonary capillary wedge pressure during exertion, and 23 (39%) of 59 fulfilled both these criteria. Mean exercise pulmonary capillary wedge pressure was lower at 6 months than at baseline, both at 20 watts workload (mean 32 mm Hg SD 8 at baseline vs 29 mm Hg 9 at 6 months, p=0·0124) and at peak exercise (34 mm Hg 8 vs 32 8, p=0·0255), despite increased mean exercise duration (baseline vs 6 months: 7·3 min SD 3·1 vs 8·2 min 3·4, p=0·03). Sustained device patency at 6 months was confirmed by left-to-right shunting (pulmonary/systemic flow ratio: 1·06 SD 0·32 at baseline vs 1·27 0·20 at 6 months, p=0·0004). Interpretation Implantation of an interatrial shunt device is feasible, seems to be safe, reduces left atrial pressure during exercise, and could be a new strategy for the management of HFPEF. The effectiveness of IASD compared with existing treatment for patients with HFPEF requires validation in a randomised controlled trial. Funding Corvia Medical Inc.
Abstract This article, from the “To The Point” series prepared by the Association of Professors of Gynecology and Obstetrics Undergraduate Medical Education Committee, provides an overview of the ...characteristics of Millennials, and describes how medical educators can customize and reframe their curricula and teaching methods to maximize Millennial learning. A literature search was performed to identify articles on generational learning. We summarize the importance of understanding the attitudes, ideas, and priorities of Millennials in order to tailor educational methods to stimulate and enhance learning. Where relevant, a special focus on the Obstetrics and Gynecology curriculum is highlighted.
To compare the second malignancy incidence in prostate cancer patients treated with brachytherapy (BT) relative to radical prostatectomy (RP) and to compare both groups with the cancer incidence in ...the general population.
From 1998 to 2010, 2418 patients were treated with Iodine 125 prostate BT monotherapy at the British Columbia Cancer Agency, and 4015 referred patients were treated with RP. Cancer incidence was compared with the age-matched general population using standardized incidence ratios (SIRs). Pelvic malignancies included invasive and noninvasive bladder cancer and rectal cancer. Cox multivariable analysis was performed with adjustment for covariates to determine whether treatment (RP vs BT) was associated with second malignancy risk.
The median age at BT was 66 years and at RP 62 years. The SIR comparing BT patients with the general population was 1.06 (95% confidence interval CI 0.91-1.22) for second malignancy and was 1.53 (95% CI 1.12-2.04) for pelvic malignancy. The SIR comparing RP patients with the general population was 1.11 (95% CI 0.98-1.25) for second malignancy and was 1.11 (95% CI 0.82-1.48) for pelvic malignancy. On multivariable analysis, older age (hazard ratio HR 1.05) and smoking (HR 1.65) were associated with increased second malignancy risk (P<.0001). Radical prostatectomy was not associated with a decreased second malignancy risk relative to BT (HR 0.90, P=.43), even when excluding patients who received postprostatectomy external beam radiation therapy (HR 1.13, P=.25). Older age (HR 1.09, P<.0001) and smoking (HR 2.17, P=.0009) were associated with increased pelvic malignancy risk. Radical prostatectomy was not associated with a decreased pelvic malignancy risk compared with BT (HR 0.57, P=.082), even when excluding postprostatectomy external beam radiation therapy patients (HR 0.87, P=.56).
After adjustment for covariates, BT patients did not have an increased second malignancy risk compared with RP patients. Further follow-up of this cohort is needed given the potential latency of radiation-induced malignancies.
Although often short-lived and self-limiting, postoperative atrial fibrillation (POAF) is a well-recognized postoperative complication of cardiac surgery and is associated with a 2-fold increase in ...cardiovascular mortality and morbidity.
Our aim was to determine whether intraoperative bilateral pulmonary vein radiofrequency ablation decreases the incidence of POAF in patients undergoing coronary artery bypass grafting (CABG).
A total of 175 patients undergoing CABG was prospectively randomized to undergo adjuvant bilateral radiofrequency pulmonary vein ablation in addition to CABG (group A; n = 89) or CABG alone (group B; n = 86). Intraoperative pulmonary vein isolation was confirmed by the inability to pace the heart via the pulmonary veins after ablation. All patients received postoperative β-blocker.
There was no difference in the incidence of POAF in the treatment group who underwent adjuvant pulmonary vein ablation (group A; 37.1%) compared with the control group who did not (group B; 36.1%) (P = .887). There were no differences in postoperative inotropic support, antiarrhythmic drug use, need for oral anticoagulation, and complication rates. The mean length of postoperative hospital stay was 8.2 ± 6.5 days in the ablation group and 6.7 ± 4.6 days in the control group (P < .001).
Adjuvant pulmonary vein isolation does not decrease the incidence of POAF or its clinical impact but increases the mean length of stay in the hospital. The mechanism of POAF does not appear to depend on the pulmonary veins.
This study examined patterns of recurrence after low-dose-rate prostate brachytherapy (LDR-PB), estimated local recurrence rate and compared that rate to the estimated local recurrence rate after ...radical prostatectomy (RP).
A prospective database was maintained with clinical, dosimetric, and outcome data for all LDR-PB implantation procedures performed at our institution. From 1998 to 2008, 2223 patients with prostate cancer received LDR-PB without supplemental external beam radiation therapy. Patients who developed Phoenix-defined biochemical failure were reviewed for sites of relapse and investigations completed.
At a median follow-up of 5 years, 108 of 2223 patients (4.8%) developed biochemical relapse. In 1 additional patient, local relapse was found on transurethral prostate resection, but his prostate-specific antigen concentration was well short of triggering Phoenix-defined failure. Of the 109 patients with disease relapse, 18 of 2223 (0.8%) had a proven local recurrence, and 30 of 2223 (1.3%) had a proven distant recurrence. The remaining 61 of 2223 patients (2.7%) had unidentified sites of recurrence; of these, 57 patients (93%) had digital rectal examinations (DREs), 18 (30%) had post-treatment biopsies, 45 (74%) had bone scans, and 34 (56%) had computed tomography imaging of the abdomen and pelvis. If every biochemical failure were local, the local recurrence rate would be as high as 4.9%; however, by excluding those with proven distant failure and those with both a negative DRE and biopsy, we estimate that the local recurrence rate is 2.7% or less.
In the context of limitations of the study design, our population-based analysis indicates that the local recurrence rate after LDR-PB is as low or lower than that after RP in our jurisdiction.
Abstract Background Significant morbidity associated with acute liver failure (ALF) is from the systemic inflammatory response syndrome (SIRS). Toll-like receptor 4 (TLR4) has been shown to play an ...integral role in the modulation of SIRS. However, little is known about the mechanistic role of TLR4 in ALF. Also, no cell type has been identified as the key mediator of the TLR4 pathway in ALF. This study examines the role of TLR4 and Kupffer cells (KCs) in the development of the SIRS following acetaminophen (APAP)-induced ALF. Materials and methods Five groups of mice were established: untreated wild-type, E5564-treated (a TLR4 antagonist), gadolinium chloride -treated (KC-depleted), clodronate-treated (KC-depleted), and TLR4-mutant. Following APAP administration, 72-h survival, biochemical and histologic liver injury, extent of lung injury and edema, and proinflammatory gene expression were studied. Additionally, TLR4 expression was determined in livers of wild-type and KC-depleted mice. Results Following APAP administration, wild-type, TLR4-mutant, E5564-treated, and KC-depleted mice had significant liver injury. However, wild-type mice had markedly worse survival compared with the other four treatment groups. TLR4-mutant, E5564-treated, and KC-depleted mice had less lung inflammation and edema than wild-type mice. Selected proinflammatory gene expression (interleukin 1β, interleukin 6, tumor necrosis factor) in TLR4-mutant, E5564-treated, and KC-depleted mice was significantly lower compared with wild-type mice after acute liver injury. Conclusion This study demonstrates that survival in APAP-induced ALF potentially correlates with the level of proinflammatory gene expression. This study points to a link between TLR4 and KCs in the APAP model of ALF and, more importantly, demonstrates benefits of TLR4 antagonism in ALF.
Objective The purpose of this study was to estimate the odds of morbidity and death that are associated with cesarean delivery, compared with vaginal delivery, for breech fetuses who are delivered ...from 23-24 6/7 weeks’ gestational age. Study Design We conducted a retrospective cohort study of state-level maternal and infant hospital discharge data that were linked to vital statistics for breech deliveries that occurred from 23-24 6/7 weeks’ gestation in California, Missouri, and Pennsylvania from 2000-2009 (N = 1854). Analyses were stratified by gestational age (23-23 6/7 vs 24-24 6/7 weeks' gestation). Results Cesarean delivery was performed for 46% (335 fetuses) and 77% (856 fetuses) of 23- and 24-week breech fetuses. In multivariable analyses, overall survival was greater for cesarean-born neonates (adjusted odds ratio AOR, 3.98; 95% confidence interval CI, 2.24–7.06; AOR, 2.91; 95% CI, 1.76–4.81, respectively). When delivered for nonemergent indications, cesarean-born survivors were more than twice as likely to experience major morbidity (intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, asphyxia composite; AOR, 2.83; 95% CI, 1.37–5.84; AOR, 2.07; 95% CI, 1.11–3.86 at 23 and 24 weeks’ gestation, respectively). Among intubated neonates, despite a short-term survival advantage, there was no difference in survival to >6-month corrected age (AOR, 1.77; 95% CI, 0.83–3.74; AOR, 1.50; 95% CI, 0.81–2.76, respectively). There was no difference in survival for intubated 23-week neonates who were delivered by cesarean for nonemergent indications or cesarean-born neonates who weighed <500 g. Conclusion Cesarean delivery increased overall survival and major morbidity for breech periviable neonates. However, among intubated neonates, despite a short-term survival advantage, there was no difference in 6-month survival. Also, cesarean delivery did not increase survival for neonates who weighed <500 g. Patients and providers should discuss explicitly the trade-offs related to neonatal death and morbidity, maternal morbidity, and implications for future pregnancies.
Abstract Purpose The purpose of this study was to examine, using a US electronic medical records (EMR) database, the clinical characteristics and real-world treatment sequences in men with advanced ...prostate cancer who initiated treatment with abiraterone acetate or enzalutamide. Methods This retrospective, observational study evaluated adult male patients with a diagnosis of prostate cancer ( International Classification of Diseases, Ninth Revision, Clinical Modification code 185) in the EMR database between July 1, 2011, and March 31, 2014, who had initiated first-line treatment with abiraterone acetate or enzalutamide between September 1, 2012, and March 31, 2014. The first record for a patient initiating abiraterone acetate or enzalutamide was the index date. Patients had 6 months of pre-index medical record history and a variable length follow-up period, extending from the index date to the end of medical record data availability or date of the end of the study (March 31, 2014). The sequence of first- and second-line therapies for advanced prostate cancer therapy was reported. Findings A total of 809 patients met study inclusion and exclusion criteria. This study found that the majority of patients who initiated treatment with either abiraterone acetate or enzalutamide between September 1, 2012, and March 31, 2014, received a single line of therapy (72%); abiraterone acetate was the most common first-line treatment (74% of first-line patients). A subset of patients treated first-line with either abiraterone acetate or enzalutamide were transitioned to an oral second-line agent (17% of first-line abiraterone acetate–treated patients transitioned to second-line enzalutamide, and 16% of first-line enzalutamide-treated patients transitioned to second-line abiraterone acetate). Chemotherapy with docetaxel was also a commonly observed second-line treatment selection, occurring in 8% of first-line abiraterone acetate–treated patients and in 7% of first-line enzalutamide-treated patients. Implications This EMR study is among the first to present evidence of US physician practice prescribing patterns regarding initiation of oral antineoplastic agents and use of subsequent therapies in patients with advanced prostate cancer.
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