Concomitant use of oral anticoagulants in patients with advanced prostate cancer receiving apalutamide: A post-hoc analysis of TITAN and SPARTAN studies

Apalutamide, an androgen receptor signaling inhibitor, in combination with androgen-deprivation therapy (ADT), is approved for treatment of patients with nonmetastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer, based on the data from the phase 3 SPARTAN and TITAN studies respectively. Apalutamide is an inducer of cytochrome P450 enzymes and P-glycoprotein, which are involved in the metabolism of oral anticoagulants (OACs) and may thus have potential drug-drug interactions when co-administered with OACs. Concomitant use of certain OACs such as apixaban, rivaroxaban, edoxaban, dabigatran, and warfarin was allowed in the SPARTAN and TITAN studies. A post-hoc analysis was conducted to evaluate the incidence of treatment-emergent thrombotic and embolic adverse events (AEs) in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT in both the studies. Anticoagulants were identified by WHO Drug Anatomical Therapeutic Chemical level 4 classifications. Thrombotic and embolic AEs were coded using the Medical Dictionary for Regulatory Activities Version 22.1. Data were analyzed from patients receiving concurrent OACs among all treated patients in SPARTAN (apalutamide + ADT: 95/803 [11.8%]; placebo + ADT: 48/398 [12.1%]) and TITAN (apalutamide + ADT: 31/524 [5.9%]; placebo + ADT: 28/527 [5.3%]). No consequential differences were observed in the occurrence of thrombotic and embolic events between apalutamide + ADT and placebo + ADT groups receiving concomitant OACs in SPARTAN (11.6% vs 12.5%) or TITAN (19.4% vs 21.4%). Grade 3/4 thrombotic and embolic AEs observed in patients receiving concomitant OACs with apalutamide + ADT or placebo + ADT were 6 (6.3%) vs 5 (10.4%) in SPARTAN and 3 (9.7%) vs 1 (3.6%) in TITAN. This analysis suggests that when necessary, concomitant OACs can be used with apalutamide with appropriate monitoring.     

The effect of transurethral resection on prognosis in carcinoma of the prostate: real or imaginary?

From January 1970 to June 1983, a total of 702 patients received radical external beam radiation therapy for carcinoma of the prostate. The estimated 5- to 10-year disease-free survival are 67% and 52%. A comparison was made between those patients whose diagnosis was established by needle biopsy as compared with those who had a positive transurethral resection of the prostate (TURP). Within Stages B & C combined, the 5-year disease-free survival was 65% for needle biopsy as compared with 59% for TURP. The corresponding figures at 10 years are 50% and 43%. This difference is significant with a p-value of less than 0.01. In addition to histological grade, identifiable prognostic factors in the literature are clinical stage, serum acid phosphatase, and extent of radiation (local only or prophylactic pelvic nodal radiation). Assessment of histological grade using the Gleason method has been carried out in all except 7 cases. The amount of tissue from a needle biopsy constitutes less than 3% of the material obtained from a TURP. As a result, there is a potential sampling error. The Gleason grading can be used in at least three ways: (a) the conventional Gleason score, (b) the most malignant grade identified, or, (c) the primary (most frequent) grade identified. Analyzing use of these three methods of histological stratification yields conflicting results. The difference between the needle and TURP groups is present in late stage disease when the primary grade is used for stratification but absent when the worst grade is used. The significance of these results remains more or less constant irrespective of end point (uncorrected, disease specific or disease-free survival). However, when stratified by Gleason score, it is significant for disease specific survival, approaches significance for uncorrected survival but not for disease free survival. Since the significance can be altered by changing one stratification factor, there must be some doubt about the validity of other studies which either confirm or refute the hypothesis that TURP has an adverse influence on the disease process.     

A 10-year (2000-2010) systematic review of interventions to improve quality of care in hospitals

ABSTRACT: BACKGROUND: Against a backdrop of rising healthcare costs, variability in care provision and an increased emphasis on patient satisfaction, the need for effective interventions to improve quality of care has come to the fore. This is the first ten year (2000--2010) systematic review of interventions which sought to improve quality of care in a hospital setting. This review moves beyond a broad assessment of outcome significance levels and makes recommendations for future effective and accessible interventions. METHODS: Two researchers independently screened a total of 13,195 English language articles from the databases PsychInfo, Medline, PubMed, EmBase and CinNahl. There were 120 potentially relevant full text articles examined and 20 of those articles met the inclusion criteria. RESULTS: Included studies were heterogeneous in terms of approach and scientific rigour and varied in scope from small scale improvements for specific patient groups to large scale quality improvement programmes across multiple settings. Interventions were broadly categorised as either technical (n = 11) or interpersonal (n = 9). Technical interventions were in the main implemented by physicians and concentrated on improving care for patients with heart disease or pneumonia. Interpersonal interventions focused on patient satisfaction and tended to be implemented by nursing staff. Technical interventions had a tendency to achieve more substantial improvements in quality of care. CONCLUSIONS: The rigorous application of inclusion criteria to studies established that despite the very large volume of literature on quality of care improvements, there is a paucity of hospital interventions with a theoretically based design or implementation. The screening process established that intervention studies to date have largely failed to identify their position along the quality of care spectrum. It is suggested that this lack of theoretical grounding may partly explain the minimal transfer of health research to date into policy. It is recommended that future interventions are established within a theoretical framework and that selected quality of care outcomes are assessed using this framework. Future interventions to improve quality of care will be most effective when they use a collaborative approach, involve multidisciplinary teams, utilise available resources, involve physicians and recognise the unique requirements of each patient group.     

Effects of positive and negative pressure ventilation on cerebral blood volume of newborn infants

The effects of intermittent positive airway and continuous negative extrathoracic pressure ventilation on cerebral blood volume in preterm infants were studied using near infrared spectroscopy. In 12 infants continuous negative extrathoracic pressure caused a median decrease in cerebral blood volume of 0.14ml/100ml brain (95% confidence intervals (CI) 0.035–0.280) compared with no respiratory support. Oxygenated and deoxygenated haemoglobin also decreased, implying increased venous drainage as the main effect. In 17 infants intermittent positive pressure ventilation also caused a median reduction in cerebral blood volume of 0.06 ml/100 ml brain (95% CI 0.010–0.115) compared with endotracheal positive airway pressure. Deoxygenated haemoglobin increased by 0.07 ml/100 ml brain (95% CI 0.010–0.100) while oxygenated haemoglobin decreased by O.lOml/lOOml brain (95% CI 0.005–0.175). The increase in deoxygenated haemoglobin implies decreased venous drainage and the decrease in oxygenated haemoglobin implies that other factors may also be significant. Heart rate, blood pressure and oxygen saturation were monitored continuously and remained stable.     

The effects of long- and short-term maternal caffeine ingestion on human fetal breathing and body movements in term gestations

The possible effects of long- and short-term maternal ingestion of caffeine during normal human pregnancy on the breathing and body movements of third-trimester fetuses were studied in 14 patients, selected by a dietary questionnaire, and divided into two equal groups: high consumers (greater than 500 mg/day) (group 1) and low consumers (less than 250 mg/day) (group 2). All mothers followed a standard study protocol and underwent overnight fasting; studies began with a 30-minute control period, followed by oral administration of 200 mg caffeine, and a 180-minute subsequent observation period with continued maternal fasting. Blood samples for glucose and caffeine were obtained every 30 minutes and continuous recording of fetal breathing and body movements were entered on a microcomputer for off-line analysis. The two groups were similar for all obstetric outcome features. Plasma glucose levels were similar and constant in both groups whereas caffeine levels increased significantly at 60 minutes after administration; mean plasma caffeine levels were significantly higher in group 1 than in group 2 at all intervals. Fetal breathing rates and body movement incidences were similar in both groups before and after caffeine administration. Fetal breathing movement incidence decreased significantly in group 2 but was sustained at baseline levels in group 1 throughout the study. High long-term ingestion of caffeine during pregnancy is associated with higher maternal plasma caffeine levels and fetal breathing activity when compared with low caffeine ingestion. Short-term administration of 200 mg caffeine does not appear to have a significant physiologic impact on these activities.     

Particulate air pollution and hospital admissions in Christchurch, New Zealand

AIMS: Winter air pollution in Christchurch is dominated by particulate matter from solid fuel domestic heating. The aim of the study was to explore the relationship between particulate air pollution and admissions to hospital with cardio-respiratory illnesses. METHODS: Particulate air pollution statistics (PM10) were obtained from the Canterbury Regional Council monitoring station in the city. The New Zealand Health Information Service provided data on admissions to the Princess Margaret and Christchurch Hospitals for the period June 1988 through December 1998 for both adults and children with cardiac and respiratory disorders. The relationship between PM10 and admissions was explored using a time series analysis approach controlling for weather variables. Missing values were interpolated from carbon monoxide data for the same time period, as carbon monoxide and PM10 were highly correlated. RESULTS: There was a significant association between PM10 levels and cardio-respiratory admissions. For all age groups combined there was a 3.37% increase in respiratory admissions for each interquartile rise in PM10 (interquartile value 14.8 mcg/m3). There was also a 1.26% rise in cardiac admissions for each interquartile rise in PM10. There was no relationship between PM10 and admissions for appendicitis, the control condition selected. CONCLUSIONS: In keeping with overseas studies, there is evidence in Christchurch of a relationship between ambient particulate levels and admissions with cardiac and respiratory illnesses. The size of the effect is consistent with overseas data, with the greatest impact for respiratory disorders. Implications: These results indicate that measures to control ambient particulate levels have the potential to reduce hospital admissions for cardio-respiratory illnesses.     

Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent,selective, melanocortin subtype-4 receptor agonist

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.