Docetaxel chemotherapy in metastatic castration-resistant prostate cancer: cost of care in Medicare and commercial populations.

OBJECTIVE: To estimate the healthcare costs and characteristics of docetaxel chemotherapy episodes of care for men with metastatic castration-resistant prostate cancer (mCRPC). METHODS: This study used the Medicare 5% sample and MarketScan Commercial (2010-2013) claims data sets to identify men with mCRPC and initial episodes of docetaxel treatment. Docetaxel episodes included docetaxel claim costs from the first claim until 30 days after the last claim, with earlier termination for death, insurance disenrollment, or the end of a 24-month look-forward period from initial docetaxel index date. Docetaxel drug claim costs were adjusted for 2011 generic docetaxel introduction, while other costs were adjusted to 2015 values using the national average annual unit cost increase. RESULTS: This study identified 281 Medicare-insured and 155 commercially insured men, with 325 and 172 docetaxel episodes, respectively. The average number of cycles (unique docetaxel infusion days) per episode was 6.9 for Medicare and 6.3 for commercial cohorts. The average cost per episode was $28,792 for Medicare and $67,958 for commercial cohorts, with docetaxel drug costs contributing $2,588 and $13,169 per episode, respectively. The average cost per episode on docetaxel infusion days was $8,577 (30%) for Medicare and $28,412 (42%) for commercial. Non-docetaxel infusion day costs included $7,074 (25%) for infused or injected drugs for Medicare, $10,838 (16%) for commercial cohorts, and $6,875 (24%) and $9,324 (14%) for inpatient admissions, respectively. LIMITATIONS: The applicability is only to the metastatic castration-resistance clinical setting, rather than the metastatic hormone-sensitive setting, and the lack of data on the cost effectiveness of different sequencing strategies of a range of systemic therapies including enzalutamide, abiraterone, radium-223, and taxane chemotherapy. CONCLUSION: The majority of docetaxel episode costs in Medicare and commercial mCRPC populations were non-docetaxel drug costs. Future research should evaluate the total cost of care in mCPRC.

Design and manufacture of a novel system to simulate the biomechanics of basic and pitching shoulder motion.

OBJECTIVES: Cadaveric models of the shoulder evaluate discrete motion segments using the glenohumeral joint in isolation over a defined trajectory. The aim of this study was to design, manufacture and validate a robotic system to accurately create three-dimensional movement of the upper body and capture it using high-speed motion cameras. METHODS: In particular, we intended to use the robotic system to simulate the normal throwing motion in an intact cadaver. The robotic system consists of a lower frame (to move the torso) and an upper frame (to move an arm) using seven actuators. The actuators accurately reproduced planned trajectories. The marker setup used for motion capture was able to determine the six degrees of freedom of all involved joints during the planned motion of the end effector. RESULTS: The testing system demonstrated high precision and accuracy based on the expected versus observed displacements of individual axes. The maximum coefficient of variation for displacement of unloaded axes was less than 0.5% for all axes. The expected and observed actual displacements had a high level of correlation with coefficients of determination of 1.0 for all axes. CONCLUSIONS: Given that this system can accurately simulate and track simple and complex motion, there is a new opportunity to study kinematics of the shoulder under normal and pathological conditions in a cadaveric shoulder model.

Methylated-CpG Island Recovery Assay.

Alterations in DNA methylation patterns are implicated in playing a major role in the development of cancer, thus highlighting the need to continually develop new technologies to analyze epigenetic marks. Methylated-CpG Island Recovery Assay (MIRA), based on the high affinity of the MBD2b/MDB3L1 complex for double-stranded methylated DNA, allows for the recovery of methylated DNA without the use of bisulfite conversion or antibody recognition. MIRA is capable of detecting low-density methylation of a single methylated CpG nucleotide. This technique can be used in conjunction with microarrays or next-generation sequencing to analyze recovered methylated DNA on a genome-wide scale.

2D difference gel electrophoresis analysis of different time points during the course of neoplastic transformation of human mammary epithelial cells.

Cell culture models of oncogenesis that use cellular reprogramming to generate a neoplastic cell from a normal cell provide one of the few opportunities to study the early stages of breast cancer development. Human mammary epithelial cells (HMECs) were induced to undergo a neoplastic transformation using defined genetic elements to generate transformed HMECs (THMECs). To identify proteins that displayed significantly different levels of abundance at three consecutive time points in oncogenesis over an 80 day period, protein extracts were analyzed by two-dimensional difference gel electrophoresis (2D-DIGE). Nine proteins were found to be significantly different in abundance: keratin 1, keratin 7, heat shock protein 4A-like, t-complex protein 1, stathmin, gelsolin, FK506 binding protein 5, ribosomal protein P0, and maspin. Keratin 7 and maspin displayed a linear down-regulation over 80 days. All of these proteins have been shown to be involved in the maintenance of a metastatic state including cytoskeletal modifications and motility. We conclude that, following neoplastic induction, THMECs display an early and progressive increase in metastatic potential. Further investigations into the function and regulatory mechanisms of these proteins will provide an unparalleled understanding of the initial states through which a breast cancer cell transitions following acquisition of the genetic abnormalities required for oncogenesis.

The Novel Retinoid, 9cUAB30, Inhibits Telomerase and Induces Apoptosis in HL60 Cells.

Telomerase, a ribonucleoprotein important to neoplastic immortality, is up-regulated in approximately 85% of cancers, including leukemias. In this study, 9cUAB30, a novel retinoic acid, resulted in differentiation of HL60 leukemia cells as indicated by morphologic changes characteristic of granulocytes. It also caused a down-regulation of hTERT gene expression and a decrease in telomerase activity. Telomerase inhibition was followed by loss of proliferative capacity, induction of apoptosis, and partial differentiation. These findings demonstrate the effectiveness of 9cUAB30 at inhibiting telomerase activity by down-regulating hTERT gene expression in human leukemic cells.

An overview of epigenetic assays.

A significant portion of ongoing epigenetic research involves the investigation of DNA methylation and chromatin modification patterns seen throughout many biological processes. Over the last few years, epigenetic research has undergone a gradual shift and recent studies have been directed toward a genome-wide assessment. DNA methylation and chromatin modifications are essential components of the regulation of gene activity. DNA methylation effectively down-regulates gene activity by addition of a methyl group to the five-carbon of a cytosine base. Less specifically, modification of the chromatin structure can be carried out by multiple mechanisms leading to either the upregulation or down-regulation of the associated gene. Of the many assays used to assess the effects of epigenetic modifications, chromatin immunoprecipitation (ChIP), which serves to monitor changes in chromatin structure, and bisulfite modification, which tracks changes in DNA methylation, are the two most commonly used techniques.

Geminofloxacin for the management of community-acquired respiratory tract infections.

Community-acquired lower respiratory tract infections (LRTIs) exert a growing clinical and financial burden on healthcare systems and employers. In addition, antimicrobial resistance among pathogens, such as Streptococcus pneumoniae, has compromised the use of commonly prescribed antimicrobial compounds. Newer fluoroquinolones have been developed to meet these emerging demands. Gemifloxacin is a potent, dual-acting fluoroquinolone with excellent activity against S. pneumoniae (MIC(90)0.03-0.06 microg/ml) including those strains demonstrating resistance to other classes of antibiotics. Gemifloxacin demonstrated excellent clinical success in community-acquired lower respiratory infections, has an acceptable safety profile, and is a cost-effective alternative in the management of LRTIs including those caused by resistant pathogens.

Differential patterns of cocaine-induced organ toxicity in murine heart versus liver.

To determine cocaine's toxicity in different organs, BALB/c mice were intraperitoneally injected daily for 15 days with either saline or cocaine: 10 mg/kg, 30 mg/kg, or 60 mg/kg. Cardiac function, hepatic pathophysiology, heart and liver apoptosis, and tumor necrosis factor (TNF-alpha) levels were analyzed. After administration of cocaine, cardiac function decreased. Inflammatory cell infiltration and eosinophilic contraction bands were visible in the hearts of mice treated with 60mg/kg cocaine. Moreover, histopathology demonstrated that cocaine caused hepatic necrosis. TdT-mediated dUTP nick end-labeling (TUNEL) staining and DNA ladder analysis indicated that cocaine caused apoptosis in both the heart and liver. Moreover, immunoassay showed that TNF-alpha levels significantly increased in the heart and liver with cocaine administration. However, our RT-PCR study showed that there was no significant difference in either the heart or liver in the levels of mRNA for TNF-alpha between cocaine-treated and saline control mice. The present study demonstrated that cocaine is toxic to multiple organs, and at low dose can induce hepatic damage without gross pathological injury to the heart. The results suggest that the liver is more sensitive than the heart to cocaine toxicity, and induction of apoptosis or TNF-alpha elevation may be a common mechanism responsible for cocaines toxicity.

Enhanced gene expression of Na(+)/Ca(2+) exchanger attenuates ischemic and hypoxic contractile dysfunction.

Enhanced gene expression of the Na(+)/Ca(2+) exchanger in failing hearts may be a compensatory mechanism to promote influx and efflux of Ca(2+), despite impairment of the sarcoplasmic reticulum (SR). To explore this, we monitored intracellular calcium (Ca(i)(2+)) and cardiac function in mouse hearts engineered to overexpress the Na(+)/Ca(2+) exchanger and subjected to ischemia and hypoxia, conditions known to impair SR Ca(i)(2+) transport and contractility. Although baseline Ca(i)(2+) and function were similar between transgenic and wild-type hearts, significant differences were observed during ischemia and hypoxia. During early ischemia, Ca(i)(2+) was preserved in transgenic hearts but significantly altered in wild-type hearts. Transgenic hearts maintained 40% of pressure-generating capacity during early ischemia, whereas wild-type hearts maintained only 25% (P < 0.01). During hypoxia, neither peak nor diastolic Ca(i)(2+) decreased in transgenic hearts. In contrast, both peak and diastolic Ca(i)(2+) decreased significantly in wild-type hearts. The decline of Ca(i)(2+) was abbreviated in hypoxic transgenic hearts but prolonged in wild-type hearts. Peak systolic pressure decreased by nearly 10% in hypoxic transgenic hearts and >25% in wild-type hearts (P < 0.001). These data demonstrate that enhanced gene expression of the Na(+)/Ca(2+) exchanger preserves Ca(i)(2+) homeostasis during ischemia and hypoxia, thereby preserving cardiac function in the acutely failing heart.

Depressed tolerance to fluorocarbon-simulated ischemia in failing myocardium due to impaired [Ca(2+)](i) modulation.

The aim of this study was to investigate the tolerance of failing myocardium from postinfarction rats to simulated ischemia. Myocardial infarction (MI) was induced by ligation of the left coronary artery in male Wistar rats. Isometric force and free intracellular Ca(2+) concentration ([Ca(2+)](i)) were measured in isolated left ventricular papillary muscles from sham-operated and post-MI animals 6 wk after surgery. Ischemia was simulated by using fluorocarbon immersion with hypoxia. Results showed that mechanical performance was depressed during the period of hypoxia in physiological salt solution (44 +/- 7% of baseline in sham vs. 30 +/- 6% of baseline in MI, P < 0.05) or ischemia (16 +/- 2% of baseline in sham vs. 9 +/- 1% of baseline in MI, P < 0.01) accompanied by no corresponding decrease of peak [Ca(2+)](i) (hypoxia: 51 +/- 8% of baseline in sham vs. 46 +/- 7% of baseline in MI, P = NS; ischemia: 47 +/- 5% of baseline in sham, 39 +/- 7% of baseline in MI, P = NS). After reoxygenation, [Ca(2+)](i) rapidly returned to near preischemic basal levels, whereas developed tension in fluorocarbon remained significantly lower. This dissociation between peak [Ca(2+)](i) and isometric contractility was more pronounced in the failing myocardium from postinfarction rats. In conclusion, more severe impairment of [Ca(2+)](i) homeostasis in the failing myocardium from postinfarction rats increases susceptibility to ischemia-reperfusion injury.

Differential depressant effects of general anesthetics on the cardiovascular response to cocaine in mice.

In recent years, murine models have gained increasing importance for studies of cardiovascular physiology and pharmacology, largely due to the development of transgenic strains with specific alterations in phenotype. Differential effects of general anesthetic agents on the cardiovascular responses to cocaine have been reported in larger mammals; therefore, we studied the effects of commonly used anesthetics on heart function and on blood pressure responses to cocaine in Swiss Webster mice. We positioned a polyethylene catheter (PE-10) in the right carotid artery or left ventricle of mice anesthetized with equivalent anesthetic dose of either ketamine-xylazine (KX, 40 mg/kg + 5 mg/kg), pentobarbital (PEN, 40 mg/kg) or alpha-chloralose-urethane (CU, 80 mg/kg + 100 mg/kg). Cocaine (0.3 mg/kg, 1 mg/kg and 3 mg/kg) was administrated via the left jugular vein by bolus injection. In the KX group, the basal mean arterial pressure (MAP) and systolic left ventricular pressure (LVP) were 110 +/- 12 and 120 +/- 13 mmHg, respectively, close to conscious values. However, PEN and CU significantly decreased the basal parameters (P < 0.01 compared to the KX group). The lowest dose of cocaine (0.3 mg/kg) elicited minimal changes. Significant responses were obtained with a 1-mg/kg dose of cocaine (P < 0.01 compared to baseline). However, at 3 mg/kg, a toxic effect of cocaine appeared in all three anesthetic groups. Compared to published conscious animal data, anesthetic agents attenuated the cardiovascular effects of cocaine. Taken together, our results indicate that minimally effective doses of general anesthetics may significantly alter the basal hemodynamic state and the responses to sympathomimetic agents in the murine model, as has been reported in larger mammalian species. We concluded that anesthesia with ketamine-xylazine provides baseline hemodynamic values close to reported values in conscious animals, but also attenuates the hemodynamic response to cocaine.

[Eosinophilic polypoid cystitis with flat carcinoma in situ of the overlying epithelium]. / Cistitis eosinofílica polipoide con carcinoma in situ plano del epitelio suprayacente.

A case of eosinophilic polypoid cystitis with flat carcinoma in situ of the overlying epithelium is described. This is the first case with such an association encountered in our series comprised of 26 bladder surgical specimens and represents an incidence rate of 0.38%. The clinical case described herein is that of a 62-year-old male patient with a clinical picture of hematuria, frequency and urgency. Patient cystoscopic evaluation revealed a congestive and edematous mucosa at the level of the trigone and sessile polyps. Microscopic examination revealed flat urothelium with anisokaryosis, hyperchromatic nuclei, atypical mitosis, and loss of polarity; chorion with diffuse, dense inflammatory infiltrate comprised of eosinophils accounting for greater than 90% of the cell population, plasma cells, mastocytes, edema and vascular congestion. Epithelial erosion and capillary thrombosis were also observed. We discuss the etiology, clinical features and treatment reported elsewhere.