New Insights into the Beneficial Electrophysiologic Profile of Ranolazine in Heart Failure: Prevention of Ventricular Fibrillation With Increased Postrepolarization Refractoriness and Without Drug-Induced Proarrhythmia

BackgroundRanolazine inhibits late Na⁺ and K⁺ currents. Earlier studies have reported an antiarrhythmic effect. The aim of the present study was to understand whether ranolazine could still preserve its antiarrhythmic properties in the settings of chronic heart failure (CHF).Methods and ResultsIn 12 female rabbits, CHF was induced by 4 weeks of rapid ventricular pacing leading to a decrease in ejection fraction. Twelve rabbits underwent sham operation. Isolated hearts were Langendorff perfused and demonstrated a significant QT prolongation after induction of heart failure. Ranolazine caused a concentration-dependent (10 and 30 μmol/L) increase of action potential duration (APD₉₀) in sham-operated and failing hearts. Eight endo- and epicardial monophasic action potentials revealed a nonsignificant increase in spatial and temporal dispersion of repolarization. The increase in APD₉₀ was accompanied by a greater increase in refractory period, resulting in a significant increase in postrepolarization refractoriness in sham-operated (+29 ms and +55 ms; P < .01) and failing (+22 ms and +30 ms; P < .05) hearts. In control conditions, programmed ventricular stimulation and a burst pacing protocol led to ventricular fibrillation (VF) in 5 of the 12 sham-operated (6 episodes) and in 7 of the 12 failing (18 episodes) hearts. In the presence of ranolazine, VF was inducible in only 2 of 12 failing hearts (5 episodes). In the presence of low [K⁺], only 1 ranolazine-treated sham-operated heart developed early afterdepolarizations and ventricular tachyarrhythmias despite significant QT prolongation.ConclusionsRanolazine decreases inducibility of VF in the presence of a significant increase in postrepolarization refractoriness. This antiarrhythmic effect in the intact heart is preserved in CHF and is not associated with drug-induced proarrhythmia.     

Gender differences in clinicopathological features and survival in surgically treated patients with renal cell carcinoma: an analysis of the multicenter CORONA database

Purpose

To investigate gender differences in clinicopathological features and to analyze the prognostic impact of gender in renal cell carcinoma (RCC) patients undergoing surgery.

Methods

A total of 6,234 patients (eleven centers; Europe and USA) treated by radical or partial nephrectomy were included in this retrospective study (median follow-up 59 months; IQR 30–106). Gender differences in clinicopathological parameters were assessed. Multivariable Cox regression models were applied to determine the influence of parameters on disease-specific survival (DSS) and overall survival (OS).

Results

A total of 3,751 patients of the study group were male patients (60.2 %), who were significantly younger at diagnosis and received more frequently NSS than women. Significantly, more often high-grade tumors and simultaneous metastasis were present in men. Whereas tumor size and pTN stages did not differ between genders, clear-cell and chromophobe RCC was diagnosed less frequently, but papillary RCC more often in men. Gender also independently influenced DSS (HR 0.75, p < 0.001) and OS (HR 0.80, p < 0.001) with a benefit for women. However, inclusion of gender in multivariable models did not significantly gain predictive accuracies (PA) for DSS (0.868–0.870, p = 0.628) and OS (0.775–0.777, p = 0.522). Furthermore, no significantly different DSS and OS rates were found in patients undergoing NSS.

Conclusions

This study demonstrates important gender differences in clinicopathological features and outcome of RCC patients with improved DSS and OS for women compared to men, even if solely patients with clear-cell RCC or M0-stage are taken into evaluation. However, inclusion of gender in multivariable models does not significantly gain PA of multivariable models.     

Prospective Study Examining Clinical Outcomes Associated with a Negative Pressure Wound Therapy System and Barker’s Vacuum Packing Technique

Background

The open abdomen has become a common procedure in the management of complex abdominal problems and has improved patient survival. The method of temporary abdominal closure (TAC) may play a role in patient outcome.

Methods

A prospective, observational, open-label study was performed to evaluate two TAC techniques in surgical and trauma patients requiring open abdomen management: Barker’s vacuum-packing technique (BVPT) and the ABThera^TM open abdomen negative pressure therapy system (NPWT). Study endpoints were days to and rate of 30-day primary fascial closure (PFC) and 30-day all-cause mortality.

Results

Altogether, 280 patients were enrolled from 20 study sites. Among them, 168 patients underwent at least 48 hours of consistent TAC therapy (111 NPWT, 57 BVPT). The two study groups were well matched demographically. Median days to PFC were 9 days for NPWT versus 12 days for BVPT (p = 0.12). The 30-day PFC rate was 69 % for NPWT and 51 % for BVPT (p = 0.03). The 30-day all-cause mortality was 14 % for NPWT and 30 % for BVPT (p = 0.01). Multivariate logistic regression analysis identified that patients treated with NPWT were significantly more likely to survive than the BVPT patients [odds ratio 3.17 (95 % confidence interval 1.22–8.26); p = 0.02] after controlling for age, severity of illness, and cumulative fluid administration.

Conclusions

Active NPWT is associated with significantly higher 30-day PFC rates and lower 30-day all-cause mortality among patients who require an open abdomen for at least 48 h during treatment for critical illness.     

Rectal Cancer and Teaching Hospitals: Hospital Teaching Status Affects Use of Neoadjuvant Radiation and Survival for Rectal Cancer Patients

Background

For rectal cancer, it is unknown how use of radiation, treatment cost, and survival differ based on hospital teaching designation.

Methods

Private insurance claims data linked with the Pennsylvania Cancer Registry were used to identify rectal cancer patients undergoing surgery from 2004 to 2006. Patients with missing data of interest were excluded. Hospitals were characterized as follows: large (≥200 beds) versus small size (<200 beds), teaching versus nonteaching, and urban versus rural. Logistic regression was used to model the use of neoadjuvant radiotherapy, and Cox proportional hazards models were used to compare cancer-specific survival between hospital types.

Results

A total of 432 patients were analyzed. There was no difference in the distribution of cancer stages among the various hospital types (all p > 0.20). Teaching hospitals were associated with significantly higher utilization of neoadjuvant radiotherapy for stage II and III cancers compared with nonteaching facilities (57 vs. 28 %; p < 0.0001). On multivariate analysis, teaching status was the only hospital designation associated with use of neoadjuvant radiation (p < 0.001); hospital size and rural/urban designation were not significant. Nonteaching hospitals were more likely to use adjuvant radiotherapy for stage II and III disease (13 vs. 30 %; p < 0.01). Teaching hospitals had lower odds of death from rectal cancer when evaluating all stages [hazard ratio (HR) = 0.35; p < 0.0001] with similar costs of inpatient treatment (teaching: US $30,769 versus nonteaching: US $26,892; p = 0.22).

Conclusions

Teaching designation was associated with higher incidence of neoadjuvant radiotherapy for stage II and III disease, with improved cancer-specific survival compared with nonteaching hospitals, and with similar treatment costs.     

Results of phase II levetiracetam trial following acute head injury in children at risk for posttraumatic epilepsy

Posttraumatic seizures develop in up to 20% of children following severe traumatic brain injury (TBI). Children ages 6–17 years with one or more risk factors for the development of posttraumatic epilepsy, including presence of intracranial hemorrhage, depressed skull fracture, penetrating injury, or occurrence of posttraumatic seizure were recruited into this phase II study. Treatment subjects received levetiracetam 55 mg/kg/day, b.i.d., for 30 days, starting within 8 h postinjury. The recruitment goal was 20 treated patients. Twenty patients who presented within 8–24 h post‐TBI and otherwise met eligibility criteria were recruited for observation. Follow‐up was for 2 years. Forty‐five patients screened within 8 h of head injury met eligibility criteria and 20 were recruited into the treatment arm. The most common risk factor present for pediatric inclusion following TBI was an immediate seizure. Medication compliance was 95%. No patients died; 19 of 20 treatment patients were retained and one observation patient was lost to follow‐up. The most common severe adverse events in treatment subjects were headache, fatigue, drowsiness, and irritability. There was no higher incidence of infection, mood changes, or behavior problems among treatment subjects compared to observation subjects. Only 1 (2.5%) of 40 subjects developed posttraumatic epilepsy (defined as seizures >7 days after trauma). This study demonstrates the feasibility of a pediatric posttraumatic epilepsy prevention study in an at‐risk traumatic brain injury population. Levetiracetam was safe and well tolerated in this population. This study sets the stage for implementation of a prospective study to prevent posttraumatic epilepsy in an at‐risk population.