Correlates of Arrhythmia Recurrence After Hybrid Epi- and Endocardial Radiofrequency Ablation for Persistent Atrial Fibrillation.

BACKGROUND: Long-term efficacy of catheter-based treatment of persistent atrial fibrillation is unsatisfactory. Minimally invasive surgical ablation techniques have been developed recently, but their efficacy has never been systematically tested. METHODS AND RESULTS: Seventy patients (median age, 63.5 years) with persistent atrial fibrillation underwent epicardial thoracoscopic radiofrequency pulmonary vein isolation, linear ablation, Marshal ligament disruption, and exclusion of the left atrial appendage. The procedure was followed by electroanatomic mapping and ablation (EAM) 2 to 3 months later. Only 76% of patients were in normal sinus rhythm at the beginning of EAM. All 4 pulmonary veins and the left atrium posterior wall were found isolated in 69% and 23% of patients, respectively. Arrhythmia-free survival off antiarrhythmic drugs 12 months after EAM was 77%. Using previously ineffective antiarrhythmic drugs and reablation procedures, arrhythmia free-survival increased to 97% during follow-up (mean, 936±432 days; range, 346-1509 days). The majority of arrhythmia recurrences occurred during the first 12 months after EAM. In a multivariable-adjusted estimates, left atrium volume >165 mL, absent normal sinus rhythm at admission for EAM, and inducibility of any sustained tachyarrhythmia at the end of EAM procedure were identified as independent correlates of atrial fibrillation recurrence. CONCLUSIONS: Our report demonstrated that the majority of patients after epicardial ablation, using bipolar radiofrequency instruments, required endocardial catheter ablation to complete the linear ablation lesions and a significant proportion of patients required spot-ablations to complete electric pulmonary vein isolation. Noninducibility of any arrhythmia after a staged hybrid procedure seemed to be the strongest correlate of long-term arrhythmia-free survival. CLINICAL TRIAL REGISTRATION: URL: www.ablace.cz. Unique identifier: cz-060520121617.

Outcomes of Patients With Long-Term Treatment Response to Vascular Endothelial Growth Factor-Targeted Therapy for Metastatic Renal Cell Cancer.

BACKGROUND: Although targeted therapies with inhibitors of the vascular endothelial growth factor (VEGF) are the mainstay of treatment for metastatic renal cell carcinoma, there are limited data on the outcome of patients with long-term response to this treatment. PATIENTS AND METHODS: In a retrospective, registry-based study, patients continuously treated with first-line anti-VEGF agents for at least 24 months were included. In total, 219 patients had evaluable data and were included in the outcome analysis. RESULTS: Median progression-free survival (PFS) after initiation of first-line targeted therapy was 39.7 months (95% confidence interval [CI], 35.9-43.5 months), with 5-year PFS of 34.2% (95% CI, 27.2%-41.2%). Median overall survival (OS) reached 79.1 months (95% CI, 65.2-93.0 months) with the 5-year OS of 62.1% (95% CI, 54.5%-69.7%). In this cohort, 28, 103, and 88 patients achieved complete response (CR), partial response (PR), or stable disease (SD) as the best response, respectively. Median PFS and OS were comparable in patients with PR and SD, but significantly longer in patients with CR (log rank test P value for PFS difference < .001 and .009 for OS difference). CONCLUSION: There are marked differences in PFS and OS between patients who receive long-term anti-VEGF treatment, achieving CR and non-CR as the best clinical response. Patients with non-CR experienced a relatively high progression rate shortly after the landmark time point of 2 years.

Outcomes for Patients with Metastatic Renal Cell Carcinoma Achieving a Complete Response on Targeted Therapy: A Registry-based Analysis.

BACKGROUND: It is currently not known whether treatment with anti-vascular endothelial growth factor agents for metastatic renal cell carcinoma (mRCC) can be safely discontinued in patients achieving a complete response (CR). OBJECTIVE: To assess outcomes for patients with mRCC achieving CR on targeted therapy (TT) and the survival of patients discontinuing TT after CR. DESIGN, SETTING, AND PARTICIPANTS: A national registry was used to identify patients achieving CR during first-line TT using bevacizumab, sunitinib, sorafenib, or pazopanib. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcomes were analysed using a log-rank test. RESULTS AND LIMITATIONS: A total of 100 patients achieving CR were identified out of 2803 patients. The median time to CR was 10.1 mo. Median progression-free survival (PFS) from TT initiation was 3.8 yr (95% confidence interval [CI] 2.9-4.6 yr) and the 5-yr overall survival (OS) was 80% (95% CI 70-91%). Patients discontinuing TT within 1 mo after achieving CR and those continuing TT beyond CR had similar OS (CI for difference in 2-yr post-CR OS -13% to 19%; p=0.3) and PFS (CI for difference in 2-yr post-CR PFS -29% to 17%; p=0.7). The limitations include the retrospective, registry-based data analysis. CONCLUSIONS: Achievement of CR on TT for mRCC was associated with excellent long-term prognosis. No significant differences in post-CR survival were observed between patients discontinuing TT after the date of CR and those who continued on TT, although the wide CIs cannot exclude important differences between the groups. PATIENT SUMMARY: According to this registry-based analysis, patients with metastatic renal cancer with no signs of disease (complete response) after treatment with targeted agents experience excellent long-term survival even if the treatment does not continue beyond the date of complete response.

Exercise training combined with electromyostimulation in the rehabilitation of patients with chronic heart failure: A randomized trial.

AIM: Both aerobic training (AT) and electromyostimulation (EMS) of leg muscles improve exercise tolerance in patients suffering from chronic heart failure (CHF). It was speculated that combination of both methods might have an additive effect. This study was performed to evaluate the effects of a combination of AT and EMS in rehabilitation (RHB) of CHF patients. PATIENTS AND METHODS: Patients (n=71; age 59 ± 10.2 yrs, NYHA II/III, EF 32 ± 7.1%) were randomized into 3 groups: a) group AT, b) group EMS, and c) group AT+EMS. AT protocol included standard activity on bicycle 3x a week at the level of individual anaerobic threshold. EMS (10 Hz, mode 20s "on"/20s "off") was applied to leg extensors for 2 h/day. Total time of given type of RHB was 12 weeks. RESULTS: Data analysis revealed statistically significant improvements of patients in all experimental groups (averaged difference after 12 weeks of exercise as related to initial value: ∆VO2peak: +12.9%, ∆VO2AT: +9.3%, ∆Wpeak: +22.7%). No statistically significant difference among experimental groups was found. Quality of life (Minnesota Living with Heart Failure - MLHF) global score was significantly improved in all 3 groups: AT (∆MLHF: -27.9%; P=0.001), AT+EMS (∆MLHF: -29.1%; P=0.002), and EMS (∆MLHF: -16.6%; P=0.008). MLHF score in EMS group showed the smallest time-related improvement compared to AT and AT+EMS groups, and this difference in improvement between the groups was statistically significant (P=0.021). CONCLUSION: No significant difference was found between the two types of exercise training.and nor did, their combination have any significant additional improvement.

Clinical and laboratory prognostic factors in patients with metastatic renal cell carcinoma treated with sunitinib and sorafenib after progression on cytokines.

OBJECTIVES: The aim of this retrospective study was to analyze prognostic factors in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors (TKIs) sunitinib or sorafenib after progression on cytokine therapy. MATERIALS AND METHODS: A national database of patients treated with targeted agents was used as the data source. A total of 319 patients treated with sunitinib (n = 181) or sorafenib (n = 138) after progression on cytokine therapy were analyzed. RESULTS: Prognostic factors significantly associated with poor overall survival in a multivariable Cox model included the time from diagnosis to the start of treatment with TKIs<1 year, increased neutrophil counts, increased lactate dehydrogenase, and Eastern Oncology Cooperative Group performance status 2 or higher. The parameters showing statistically significant association with progression-free survival included time from diagnosis to the beginning of treatment with TKI<1 year, increased lactate dehydrogenase, and Eastern Oncology Cooperative Group performance status 2 or higher. We have also validated the International Metastatic Renal Cell Carcinoma Database Consortium prognostic model in our cohort of patients. CONCLUSION: We demonstrate that the International Database Consortium prognostic model performs well for European patients treated with TKIs, including sunitinib or sorafenib, after progression on cytokines and suggest that a reduction from original 6 down to 4 parameters is possible.

Effects of neuromuscular electrical stimulation and aerobic exercise training on arterial stiffness and autonomic functions in patients with chronic heart failure.

Neuromuscular electrical stimulation (NMES) of leg muscles has been introduced in clinical practice as a rehabilitation (RHB) method in patients with chronic heart failure (CHF); however, the role of NMES on the reduction of arterial stiffness and autonomic disbalance in these patients has not yet been studied. Sixty-one patients with stable CHF (mean age 58.9 [2.1] years; mean ejection fraction 31 [4.2]%, New York Heart Association II-III) were randomly assigned into two groups. Patients in (i) exercise training group (ET; n = 30) underwent 12 weeks of bicycle ET (3 × 40 min/week); (ii) group NMES (n = 31) performed 12 weeks of NMES of quadriceps and calf muscles (frequency 10 Hz, mode "20 s on-20 s off," intensity 60 mA), 2 × 60 min/day. Noninvasive assessment of arterial stiffness was done using the cardio-ankle vascular index (CAVI). CAVI and heart rate variability (HRV) and ·VO(2peak) were evaluated before and after RHB program. Both types of RHB reduced significantly CAVI (ET from 9.6 [0.2] to 8.9 [0.2], P < 0.012; NMES from 9.3 [0.2] to 8.7 [0.2], P < 0.013), increased high frequency (HF) component of HRV (+65.6%; P = 0.001) and decreased ratio of low frequency (LF) component with HF component (LF/HF ratio) in group ET (-39.8%; P < 0.001). Changes of HRV parameters in group NMES were not significant; however, a marked tendency to autonomic stabilization was present. Both types of RHB led also to significant increase of ·VO(2peak) (ET from 18.7 [0.7] to 20.8 [0.7] mL/kg/min, P < 0.004; NMES from 17.3 [0.7] to 19.0 [0.7] mL/kg/min, P < 0.001). ET or NMES has been shown to improve significantly arterial stiffness and to stabilize autonomic balance.

Lipid alterations in human colon epithelial cells induced to differentiation and/or apoptosis by butyrate and polyunsaturated fatty acids.

The present study highlights the important association between lipid alterations and differentiation/apoptotic responses in human colon differentiating (FHC) and nondifferentiating (HCT-116) cell lines after their treatment with short-chain fatty acid sodium butyrate (NaBt), polyunsaturated fatty acids (PUFAs), and/or their combination. Our data from GC/MS and LC/MS/MS showed an effective incorporation and metabolization of the supplemented arachidonic acid (AA) or docosahexaenoic acid (DHA), resulting in an enhanced content of the respective PUFA in individual phospholipid (PL) classes and an altered composition of the whole cellular fatty acid spectrum in both FHC and HCT-116 cells. We provide novel evidence that NaBt combined with PUFAs additionally modulated AA and DHA cellular levels and caused their shift from triacylglycerol to PL fractions. NaBt increased, while AA, DHA and their combination with NaBt decreased endogenous fatty acid synthesis in FHC but not in HCT-116 cells. Fatty acid treatment also altered membrane lipid structure, augmented cytoplasmic lipid droplet accumulation, reactive oxygen species (ROS) production and dissipation of the mitochondrial membrane potential. All these parameters were significantly enhanced by combined NaBt/PUFA treatment, but only in FHC cells was this accompanied by highly increased apoptosis and suppressed differentiation. Moreover, the most significant changes of ROS production, differentiation and apoptosis among the parameters studied, the highest effects of combined NaBt/PUFA treatment and a lower sensitivity of HCT-116 cells were confirmed using two-way ANOVA. Our results demonstrate an important role of fatty acid-induced lipid alterations in the different apoptotic/differentiation response of colon cells with various carcinogenic potential.

Intra-dialytic electrostimulation of leg extensors may improve exercise tolerance and quality of life in hemodialyzed patients.

Hemodialyzed (HD) patients with end-stage renal disease (ESRD) exhibit lower fitness as a consequence of chronic uremic changes that trigger various structural, metabolic, and functional abnormalities in skeletal muscles. The aim of this randomized study was to compare the effect of rehabilitation (RHB) training on a bicycle ergometer and electromyostimulation (EMS) of leg extensors in HD patients with ESRD. Thirty-two HD patients (18 men/14 women; mean age 61.1 ± 8.8 years) were randomized into three groups: (i) exercise training (ET; n = 11) on bicycle ergometer 2 × 20 min; (ii) EMS (n = 11) where stimulation (10 Hz) of leg extensors was applied for 60 min; and (iii) controls (CON; n = 10) without exercise. Exercising was performed between the 2nd and the 3rd hour of HD, three times a week, 20 weeks in total. Ergometric test was performed in order to evaluate peak workload (W(peak)), 6-min corridor walking test (CWT) to evaluate the distance walked, and dynamometry of leg extensors to assess muscle power (F(max)). Urea clearance was monitored and expressed as standard parameters: spKt/V, spKt/V equilibrated (spKt/V-e), and the urea removal ratio (URR). Quality of life (QoL) was assessed by the questionnaire SF-36. A significant increase of F(max) (P = 0.040 in group ET; P = 0.032 in group EMS), of 6-min CWT (P < 0.001 in ET group; P = 0.042 in EMS group), and of W(peak) (P = 0.041 in ET group) was observed. In both exercising groups, significant increase of spKt/V, spKt/V-e, and URR was found as compared with initial values (P < 0.05). In both exercising groups, highly significant changes in summarized mental functions were found (P = 0.001); in summarized physical components, significant improvement was observed in the ET group (P = 0.006). Intradialytic RHB showed comparable positive effects on functional parameters, urea clearance, and QoL. Intradialytic EMS might represent wide therapeutic possibility in the near future.

Pretreatment plasma folate modulates the pharmacodynamic effect of high-dose methotrexate in children with acute lymphoblastic leukemia and non-Hodgkin lymphoma: "folate overrescue" concept revisited.

BACKGROUND: To evaluate the influence of pretreatment plasma folate concentrations on methotrexate exposure in children with acute lymphoblastic leukemia/non-Hodgkin lymphoma treated with high-dose methotrexate, we assessed time profiles of plasma homocysteine, folate, and vitamin B(12) concentrations in children treated with high-dose methotrexate with leucovorin rescue. METHODS: We analyzed 98 treatment courses. The study endpoints were to determine how methotrexate exposure is related to homocysteine accumulation and whether it is influenced by pretreatment plasma folate. RESULTS: Peak concentrations of homocysteine increased from the start of the intravenous infusion through cessation of methotrexate therapy up to time point t(42), when this trend was reversed by administration of folinic acid. The area under the curve (AUC) for plasma homocysteine showed decreasing course-to-course tendencies with a statistically significant decrease only between courses 1 and 2 (P 10 nmol/L. Correspondingly, in the courses with low initial folate, peak plasma concentrations of methotrexate were significantly higher than in courses with high precourse concentrations of plasma folate. CONCLUSION: Endogenous pretreatment plasma folate modulates the magnitude of the methotrexate effect, providing support for a "folate overrescue" concept.