Pulmonary arterial hypertension treatment with carvedilol for heart failure: a randomized controlled trial.

BACKGROUND: Right-sided heart failure is the leading cause of death in pulmonary arterial hypertension (PAH). Similar to left heart failure, sympathetic overactivation and ß-adrenoreceptor (ßAR) abnormalities are found in PAH. Based on successful therapy of left heart failure with ß-blockade, the safety and benefits of the nonselective ß-blocker/vasodilator carvedilol were evaluated in PAH. METHODS: PAH Treatment with Carvedilol for Heart Failure (PAHTCH) is a single-center, double-blind, randomized, controlled trial. Following 1-week run-in, 30 participants were randomized to 1 of 3 arms for 24 weeks: placebo, low-fixed-dose, or dose-escalating carvedilol. Outcomes included clinical measures and mechanistic biomarkers. RESULTS: Decreases in heart rate and blood pressure with carvedilol were well tolerated; heart rate correlated with carvedilol dose. Carvedilol-treated groups had no decrease in exercise capacity measured by 6-minute walk, but had lower heart rates at peak and after exercise, and faster heart rate recovery. Dose-escalating carvedilol was associated with reduction in right ventricular (RV) glycolytic rate and increase in ßAR levels. There was no evidence of RV functional deterioration; rather, cardiac output was maintained. CONCLUSIONS: Carvedilol is likely safe in PAH over 6 months of therapy and has clinical and mechanistic benefits associated with improved outcomes. The data provide support for longer and larger studies to establish guidelines for use of ß-blockers in PAH. TRIAL REGISTRATION: ClinicalTrials.gov NCT01586156FUNDING. This project was supported by NIH R01HL115008 and R01HL60917 and in part by the National Center for Advancing Translational Sciences, UL1TR000439.

Prognostic role of inflammatory biomarkers in metastatic breast cancer.

PURPOSE: The effects of inflammation on the prognosis, life expectancy and several parameters such as response to treatment of breast cancer have been previously studied. The purpose of this study was to investigate the effect of inflammatory markers on prognosis in patients with metastatic breast cancer. METHODS: This study was conducted on 81 patients with metastatic breast cancer who have been followed up at the Department of Medical Oncology, Hacettepe University Institute of Oncology, between December, 2009 and March, 2014. For all studied parameters Kaplan-Meier survival estimates and p values computed by log-rank test were calculated. A p value < 0.05 was considered statistically significant. RESULTS: Median follow-up time was 26 months. There were 38 deaths due to disease progression during the follow up. The levels of serum albumin, and erythrocyte sedimentation rate (ESR) were not associated with a significant effect on overall survival (OS). Among patients with a higher serum C-reactive protein (CRP), the estimated mean survival was 84±36 months, compared to 278±113 months among patients with a normal serum CRP (p=0.032). When patients with higher and normal lactate dehydrogenase (LDH) levels were compared, their 2-year OS survival rates were 68.2 and 87.7%, respectively (p=0.034). Among patients with higher serum ferritin levels, the estimated mean survival was 29±10 months, compared to 212±113 months for normal serum ferritin (p=0.01). Among patients with higher serum beta-2 microglobulin (ß2-M), the estimated mean OS survival was 28±8 months, compared to 84±57 months for those with normal levels (p<0.01). CONCLUSION: Serum CRP, ferritin and ß2-M can be useful prognostic factors for OS in patients with metastatic breast cancer.

Endoluminal Bariatric Interventions: Where do we stand? Where are we going?

BACKGROUND: Obesity is an epidemic leading to high morbidity, mortality, and therefore health-related costs. Thus, there is a huge need for development of safe and effective treatments. Even though success rates of conservative methods are highly limited, the surgical approaches lead to major complications in as many as 25% of the patients. In this study, we aimed to review the currently available, less-invasive, endoscopic bariatric techniques which provides an option to reduce the risks of the patients and the medical costs. METHODS: A systematic literature review through Pubmed and Medline was performed to find the studies on this topic, and all controlled clinical trials, case reports, and case series were reviewed. RESULTS: Endoluminal bariatric interventions include restrictive, malabsorptive approaches, and other techniques including transpyloric shuttle, botulinum toxin, gastric pacing and vagal nerve stimulation. Restrictive procedures act by limiting the gastric volume and leading to early satiety, while malabsorptive procedures create a malabsorption state. Transpyloric shuttle is a device decreasing the rate of gastric emptying. Botox injection causes a delay in gastric emptying, and vagal nerve stimulation modulates eating behavior. CONCLUSION: Endoluminal bariatric techniques can become the primary choice of therapy in the near future for bariatric care.

Impaired right ventricular-pulmonary vascular function in myeloproliferative neoplasms.

BACKGROUND: Increased bone marrow hemangioblast numbers, alterations in erythroid/myeloid lineages, increased reticulin, and greater circulating bone marrow progenitor cells are present in patients with pulmonary arterial hypertension (PAH). The data suggest that myeloid progenitors contribute to the pathogenesis of PAH, but there are little data on the prevalence of pulmonary vascular disease among the different forms of myeloid diseases. We hypothesized that there would be a higher prevalence of pulmonary vascular disease in myeloproliferative neoplasms that have high circulating progenitor cells, such as myelofibrosis and chronic myelogenous leukemia (CML), compared with those with low circulating progenitors, such as in aplastic anemia. METHODS: Patients with myelofibrosis, CML, and aplastic anemia who underwent echocardiographic evaluation of cardiac function in preparation for bone marrow transplantation at the Cleveland Clinic between 1997 and 2012 were identified and their electronic medical records were queried for demographic data, blood cell counts, and pulmonary function tests. All echocardiograms were uniformly analyzed in a blinded fashion by an advanced sonographer and cardiologist for measures of right and left ventricular function and estimation of pulmonary vascular disease. RESULTS: Gender and race distribution among disease groups was similar. Patients with myelofibrosis (n = 19) and aplastic anemia (n = 30) had increased right ventricle (RV) wall thickness compared with CML (n = 82) patients (aplastic anemia, 0.7 ± 0.1; CML, 0.5 ± 0.1; and myelofibrosis, 0.7 ± 0.1; p = 0.02). Patients with myelofibrosis had higher levels of estimated RV systolic pressure compared with the other groups (aplastic anemia, 29.9 ± 1.5; CML, 26.2 ± 1.1; and myelofibrosis, 36.7 ± 3.7 mm Hg; p < 0.01). CONCLUSIONS: The findings suggest an important role for myeloid progenitors in the maintenance of pulmonary-vascular health, in which abnormal myeloproliferative progenitors are associated with RV pathology.

Impact of inflammatory markers on the prognosis of patients with operable breast cancer.

PURPOSE: To investigate the effect of inflammatory markers on the prognosis of patients with operable breast cancer. METHODS: This study was conducted on breast cancer patients followed up between December 2009 and December 2012 at the Division of Medical Oncology, Department of Internal Medicine, Hacettepe University Medical School. A total of 704 patients with stages I to III disease whose inflammatory markers were assessed at the time of diagnosis were included the study. Serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, ferritin, ß2 microglobulin (ß2-M), and lactate dehydrogenase (LDH) levels were evaluated as inflammatory markers. RESULTS: The median age at diagnosis was 50 years (range 25-92). Of the patients 42.8% were premenopausal and 48.2 % postmenopausal. Invasive ductal carcinoma was the most common histology (76.5 %). Serum ferritin, LDH, ß2-M, ESR, and CRP were higher than the normal values in 1.0, 4.3, 9.5, 32.4 and 36.4 % of the patients, respectively. Serum albumin levels were lower than the normal values in 1.7 % of the patients. The median patient follow-up period was 22 months (range 3-227). During follow-up, metastatic disease developed in 31 patients (4.4%) and 11 patients (1.56%) died due to disease progression. Two-year overall survival (OS) and disease free survival (DFS) rates were not statistically different among patients with normal and abnormal values with respect to albumin, ferritin, LDH, ß2-M, CRP, and ESR. CONCLUSION: Our study is the first study to investigate the effect of inflammatory markers on the prognosis of operable breast cancer patients. We showed that inflammatory markers such as ESR, CRP, ferritin, ß2-M, albumin and LDH have no effect on prognosis.

The relationship between fibrosis level and blood neutrophil to lymphocyte ratio in inactive hepatitis B carriers.

AIM: Neutrophil-lymphocyte ratio (NLR) has been used as a simple, affordable, and easily accessible marker to predict prognosis in a variety of inflammatory and neoplastic diseases. However, there are few studies investigating their role in patients with hepatitis B. The aim of this study was to investigate the relationship between NLR and liver fibrosis in patients who were being followed as inactive hepatitis B carriers. MATERIALS AND METHODS: The study included 78 patients who were followed for 1 year as inactive hepatitis B carriers. Liver biopsy was performed and the fibrosis scores of the histological activity index were assessed according to the Metavir scoring system. The patients were divided into two groups on the basis of the fibrosis scores: those with a score below 2 and those with a score above 2. In both groups, demographic data such as sex, age, and BMI were similar. The NLR of patients was calculated from blood samples taken at the same time as the biopsy. RESULTS: Histopathologic analysis of 78 patients showed that 41 (53%) had fibrosis grade 0-1 and 37 (47%) patients had fibrosis grade greater than 2. According to the biopsy results, there were no cirrhotic patients. NLR was found to be statistically significantly lower in the group with fibrosis grade of at least 2 (1.51±0.61 vs. 1.79±0.64, P=0.043). Other biochemical and hematological data were found to be similar in both groups. No correlation was found between laboratory values and NLR. In addition, there was no correlation between NLR with histologic activity. Spearman correlation analysis showed a negative correlation between the fibrosis score and NLR (r=-0.279, P=0.013). CONCLUSION: In inactive hepatitis B carriers, the histological activity index and NLR were found to be correlated negatively. NLR can be used as a predictor of fibrosis in combination with other noninvasive markers.

Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer.

BACKGROUND: Trastuzumab emtansine (T-DM1), a novel drug developed for the treatment of HER2-positive breast cancer, is a human epidermal growth factor receptor (HER2) targeted antibody drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine). It has been shown that, in preclinical studies, it has anti-tumor activity in trastuzumab refractory cancer cells. In this review, we aim to show the clinical data about trastuzumab-DM1 (T-DM1) therapy and to discuss the therapy advantages for the management of patients with HER2-positive breast cancer. SCOPE: T-DM1 showed positive results in clinical studies of HER2-positive metastatic breast cancer. PubMed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched up to September 2012 by using the terms 'trastuzumab emtansine (T-DM1) and anti-HER2 treatment'; papers which were considered relevant for the aim of this review were selected by the authors. FINDINGS: The phase III randomized trial EMILIA has shown that T-DM1 provided objective tumor responses and significantly improved progression free survival and overall survival compared to lapatinib and capacitabine combination in HER2-positive metastatic breast cancer patients treated with a prior taxane and trastuzumab regimen. It is believed that T-DM1 will play a role in the management of patients with advanced and early stage HER2-positive breast cancer, but this awaits further study. In particular, the ongoing phase III trials MARIANNE and TH3RESA will further give information about the place of T-DM1 in the treatment algorithms for HER2-positive disease. CONCLUSION: The trials of T-DM1 as a single agent and in combination with other chemotherapies have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. There are ongoing studies of T-DM1 showing an increasing tendency towards moving the study of these agents to earlier stages of HER2-positive breast cancer.

Impact of sex hormone metabolism on the vascular effects of menopausal hormone therapy in cardiovascular disease.

Epidemiological studies have shown that cardiovascular disease (CVD) is less common in pre-menopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to agerelated changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete responses. The complex interactions between these factors highlight the importance of careful design of MHT RCTs, and the need of a more customized approach for each individual patient in order to enhance the vascular benefits of MHT in postmenopausal CVD.