Prognostic impact of radiological tumor burden in patients with metastatic urothelial carcinoma treated with pembrolizumab.

PURPOSE: Radiological tumor burden has been reported to be prognostic in many malignancies in the immunotherapy era, yet whether it is prognostic in patients with metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains uninvestigated. We sought to assess the predictive and prognostic value of radiological tumor burden in patients with mUC. METHODS: We performed a retrospective analysis of 308 patients with mUC treated with pembrolizumab. Radiological tumor burden was represented by baseline tumor size (BTS) and baseline tumor number (BTN). Optimal cut-off value of BTS was determined as 50 mm using the Youden index (small BTS: n = 194, large BTS: n = 114). Overall (OS), cancer-specific (CSS), progression-free survival (PFS), and objective response rate (ORR) were compared. Non-linear associations between BTS and OS and CSS were evaluated using restricted cubic splines. RESULTS: Patients with large BTS were less likely to have undergone the surgical resection of the primary tumor (P = 0.01), and more likely to have liver metastasis (P < 0.001) and more metastatic lesions (P < 0.001). On multivariable analyses controlling for the effects of confounders (resection of primary tumor, metastatic site, number of metastases and lactate dehydrogenase level), large BTS and high BTN were independently associated with worse OS (HR 1.52; P = 0.015, and HR 1.69; P = 0.018, respectively) and CSS (HR 1.59; P = 0.01, and HR 1.66; P = 0.031, respectively), but not PFS. Restricted cubic splines revealed BTS was correlated with OS and CSS in linear relationships. Additionally, large BTS was significantly predictive of lower ORR and complete response rate on univariable analyses (P = 0.041 and P = 0.032, respectively), but its association disappeared on multivariable analyses. CONCLUSION: Radiological tumor burden has independent prognostic value with a linear relationship in pembrolizumab-treated patients with mUC and might help drive the earlier introduction of second-line pembrolizumab and/or switching to subsequent therapies.

Relationship between device-detected subclinical atrial fibrillation and heart failure in patients with cardiac resynchronization therapy defibrillator.

BACKGROUND: Atrial fibrillation (AF) is a leading preventable cause of heart failure (HF) for which early detection and treatment is critical. Subclinical-AF is likely to go untreated in the routine care of patients with cardiac resynchronization therapy defibrillator (CRT-D). HYPOTHESIS: The hypothesis of our study is that subclinical-AF is associated with HF hospitalization and increasing an inappropriate therapy. METHODS: We investigated 153 patients with an ejection fraction less than 35%. We divided into three groups, subclinical-AF (n = 30), clinical-AF (n = 45) and no-AF (n = 78). We compared the baseline characteristics, HF hospitalization, and device therapy among three groups. The follow-up period was 50 months after classification of the groups. RESULTS: The average age was 66 ± 15 years and the average ejection fraction was 26 ± 8%. Inappropriate therapy and biventricular pacing were significantly different between subclinical-AF and other groups (inappropriate therapy: subclinical-AF 13% vs clinical-AF 8.9% vs no-AF 7.7%: P = .04, biventricular pacing: subclinical-AF 81% vs clinical-AF 85% vs no-AF 94%, P = .001). Using Kaplan-Meier method, subclinical-AF group had a significantly higher HF hospitalization rate as compared with other groups. (subclinical-AF 70% vs clinical-AF 49% vs no-AF 38%, log-rank: P = .03). In multivariable analysis, subclinical-AF was a predictor of HF hospitalization. CONCLUSIONS: Subclinical-AF after CRT-D implantation was associated with a significantly increased risk of HF hospitalization. The loss of the biventricular pacing and increasing an inappropriate therapy might affect the risk of HF hospitalization.

Idiopathic basal crux ventricular arrhythmias with left bundle branch block and superior axis: A comparison with inferior-septal valvular arrhythmias.

INTRODUCTION: Left bundle branch block (LBBB) with superior axis is common in patients with idiopathic-ventricular arrhythmia (VA) originating from the tricuspid annulus (TA) and rarely from the cardiac basal crux and mitral annulus (MA). We described the electrocardiography and electrophysiological findings of idiopathic-VA presenting with LBBB and superior axis. METHODS AND RESULTS: We described 42 idiopathic-VA patients who had an LBBB and superior axis; 15 basal crux-VA, 17 TA-VA, and 10 MA-VA. No patient had a structural heart disease. Among patients with idiopathic-VA referred for ablation, we investigated the electrocardiogram and clinical characteristics of basal crux-VA as compared with other LBBB and superior axis-VA. The left ventricular ejection fraction with MA-VA was significantly lower in comparison with basal crux-VA (P = .01). All patients had a positive R wave in lead I and aVL. The maximum deflection index with basal crux-VA was significantly higher in comparison with TA-VA or MA-VA (P = .01). Patients with basal crux-VA presented with QS wave in lead II more frequently as compared with TA-VA or MA-VA (P = .001). All MA-VA patients had Rs wave in V6, and basal crux-VA, and TA-VA patients had a monophasic R wave or Rs wave in V6. Basal crux-VA patients underwent ablation in the middle cardiac vein (MCV) or coronary sinus (success rate: 94%, recurrence rate: 6%). CONCLUSIONS: We could distinguish basal crux-VA, TA-VA, and MA-VA, using a combination of clinical and electrocardiographic findings. These findings might be useful for counseling patients about an ablation strategy. Ablation via the MCV is effective for eliminating basal crux-VA.

J-Wave Elevation in the Inferior Leads Predicts Lethal Ventricular Arrhythmia Initiated by Premature Ventricular Contractions With Right Bundle Branch Block and Superior Axis.

BACKGROUND: Lethal ventricular arrhythmia (VA) can be initiated by idiopathic premature ventricular contractions (PVCs) originating from the left ventricular (LV) inferior wall. Furthermore, J-wave elevation in the inferior leads on ECG is sometimes associated with lethal VA. However, the relationship between these PVCs and J-wave elevation in patients with lethal VA is unclear, so we investigated it in the present study.Methods and Results:We studied 32 consecutive patients who underwent radiofrequency (RF) ablation of idiopathic PVCs with right bundle branch block (RBBB) and superior axis. Thee PVCs were originating from the inferior wall of the LV. Lethal VA was defined as ventricular fibrillation (VF) or ventricular tachycardia (VT) with loss of consciousness (LOC). Among 32 patients, 3 had VF and 2 had VT with LOC. Other 27 had non-lethal VA. Baseline clinical characteristics were not significantly difference between lethal and non-lethal VA. The ratio of J-wave elevation in lethal VA was significantly higher as compared with non-lethal VA (100% vs. 11.1%, P<0.0001). Furthermore, no patients with J-wave elevation in the inferior leads had recurrence of lethal VA after RF ablation of the PVCs. CONCLUSIONS: We speculate that J-wave elevation in the inferior leads might be a predictor of lethal VA initiated by PVCs with RBBB and superior axis. RF ablation of these PVCs was a useful method of treating lethal VA.

Association left ventricular lead and ventricular arrhythmias after upgrade to cardiac resynchronization therapy in patients with implantable cardioverter defibrillators.

BACKGROUND: There are some controversial reports related to the pro-arrhythmic or anti-arrhythmic potential of cardiac resynchronization therapy (CRT) and little is known about the relationship between ventricular arrhythmia (VA) and left ventricular (LV)-lead threshold. HYPOTHESIS: Upgrade CRT is anti-arrhythmic effect of VA with implantable cardioverter-defibrillator (ICD) patients and has a relationship with the incident of VA and LV-lead threshold. METHODS: Among 384 patients with the implantation of CRT-defibrillator (CRT-D), 102 patients underwent an upgrade from ICD to CRT-D. We divided patients into three groups; anti-arrhythmic effect after upgrade (n = 22), pro-arrhythmic effect (n = 14), and unchanging-VA events (n = 66). The VA event was determined by device reports. We described the electrocardiography parameters, LV-lead characteristics, and clinical outcomes. RESULTS: Before upgrade, the numbers of VA were 305 episodes and the numbers of ICD therapy were 157 episodes. While after upgrade, the numbers of VA were 193 episodes and the number of ICD therapy were 74 episodes. Ventricular tachycardia cycle length (VT-CL) after upgrade was significantly slower as compared to those with before upgrade. Pro-arrhythmic group was significantly higher with delta LV-lead threshold (after 1 month-baseline) as compared to those with anti-arrhythmic group (0.74 vs -0.21 V). Furthermore, pro-arrhythmic group was significantly bigger with delta VT-CL (after 3 months-before 3 months) as compared to those with anti-arrhythmic group (P = .03). CONCLUSIONS: We described upgrade-CRT was associated with reduction of VA, ICD therapies and VT-CL. While 14 patients had a pro-arrhythmic effect and LV lead threshold might be associated with VA-incidents.

Predictors of Mortality, Rehospitalization for Syncope and Cardiovascular Events in Patients With Cardiovascular Syncope.

BACKGROUND: Predictors of poor outcomes remain unknown for cardiovascular syncope patients after discharge.Methods and Results:We reviewed the medical records of consecutive patients admitted to hospital with cardiovascular syncope. We then performed Cox stepwise logistic regression analysis to identify significant independent factors for death, rehospitalization for syncope, and cardiovascular events. The study group was 206 patients with cardiovascular syncope. Of them, bradycardia was diagnosed in 50%, tachycardia in 27%, and structural disease in 23%. During a 1-year follow-up period, 18 (8%) and 45 (23%) patients, respectively, were rehospitalized for syncope or a cardiovascular event, and 10 (4%) died. Independent predictors of cardiovascular events were systolic blood pressure <100 mmHg (odds ratio [OR] 3.25; 95%confidence interval [CI] 1.41-7.51, P=0.006) and implantation of a pacemaker (OR 0.19; 95% CI 0.05-0.51, P=0.0005) (inverse association). Drug-induced syncope (OR 4.57; 95% CI 1.54-12.8, P=0.007) was an independent risk factor for rehospitalization. Finally, a history of congestive heart failure (OR 11.0; 95% CI 2.78-54.7, P=0.0006) and systolic blood pressure <100 mmHg (OR 5.40; 95% CI 1.30-22.7, P=0.02) were identified as significant independent prognostic factors for death. CONCLUSIONS: Drug-induced syncope, hypotension, no indication for a pacemaker, and a history of congestive heart failure are risk factors post-discharge for patients with cardiovascular syncope and careful follow-up of these patients for at least 1 year is recommended.

Effects of Aging on the Coagulation Fibrinolytic System in Outpatients of the Cardiovascular Department.

BACKGROUND: Although clinical trials demonstrate that the elderly with atrial fibrillation have risks of thrombosis and bleeding, the relationship between aging and coagulation fibrinolytic system in "real-world" cardiology outpatients is uncertain. METHODS AND RESULTS: We retrospectively evaluated 773 patients (mean age: 58 years; 52% men; Asian ethnicity). To thoroughly investigate markers of coagulation and fibrinolysis, we simultaneously measured levels of D-dimer, prothrombin-fragment1+2 (F1+2), plasmin-α2 plasmin inhibitor complex (PIC), and thrombomodulin (TM). There were correlations between aging and levels of F1+2, D-dimer, PIC, and TM (R=0.61, 0.57, 0.49, and 0.30, respectively). We compared 3 age groups, which were defined as the Y group (<64 years), M group (65-74 years), and the O group (>75 years). Levels of markers were higher in older individuals (D-dimer: 1.0±0.8 vs. 0.8±0.8 vs. 0.6±0.4 µg/ml, F1+2: 281.8±151.3 vs. 224.6±107.1 vs. 155.5±90.0 pmol/L, PIC: 0.9±0.3 vs. 0.8±0.3 vs. 0.6±0.5 µg/ml, and TM: 2.9±0.8 vs. 2.7±0.7 vs. 2.5±0.7FU/ml). We performed logistic regression analysis to determine F1+2 and PIC levels. Multivariate analysis revealed that aging was the most important determinant of high F1+2 and PIC levels. CONCLUSIONS: Hypercoagulable states develop with advancing age in "real-world" cardiology outpatients. (Circ J 2016; 80: 2133-2140).

Recurrence of atrial fibrillation within three months after pulmonary vein isolation for patients with paroxysmal atrial fibrillation: Analysis using external loop recorder with auto-trigger function.

BACKGROUND: Pulmonary vein isolation (PVI) via catheter ablation has been shown to be a highly effective treatment option for patients with symptomatic paroxysmal atrial fibrillation (AF). The recurrence of AF within 3 months after PVI is not considered to be the result of ablation procedure failure, because early recurrence of AF is not always associated with late recurrence. We examined the usefulness of an external loop recorder with an auto-trigger function (ELR-AUTO) for the detection of atrial fibrillation following PVI to characterize early recurrence and to determine the implications of AF occurrence within 3 months after PVI. METHODS: Fifty-three consecutive symptomatic patients with paroxysmal AF (age 61.6±12.6 years, 77% male) who underwent PVI and were fitted with ELR-AUTO for 7±2.0 days within 3 months after PVI were enrolled in this study. RESULTS: Of the 33 (62.2%) patients who did not have AF recurrence within 3 months after PVI, only 1 patient experienced AF recurrence at 12 months. Seven (35%) of the 20 patients who experienced AF within 3 months of PVI experienced symptomatic AF recurrence at 12 months. The sensitivity, specificity, positive predictive value, and negative predictive value of early AF recurrence for late recurrence were 87.5%, 71.1%, 35.0%, and 96.9%, respectively. CONCLUSIONS: AF recurrence measured by ELR-AUTO within 3 months after PVI can predict the late recurrence of AF. Freedom from AF in the first 3 months following ablation significantly predicts long-term AF freedom. ELR-AUTO is useful for the detection of symptomatic and asymptomatic AF.

J-Wave in Patients With Syncope.

BACKGROUND: Syncope is a common occurrence. The presence of J-wave, also known as early repolarization, on electrocardiogram is often seen in the general population, but the relationship between syncope and J-wave is unclear. METHODS AND RESULTS: After excluding 67 patients with structural heart disease from 326 with syncope, we classified 259 patients according to the presence or absence of J-wave (≥1 mm) in at least 2 inferior or lateral leads. Head-up tilt test (HUT) was performed for 30 min. If no syncope or presyncope occurred, HUT was repeated after drug loading. Before tilt, 97/259 (37%) had J-wave (57 male, 47.6±22.5 years) and 162 patients had no remarkable change (89 male, 51.1±21.2 years). HUT-positive rate was higher in patients with J-wave, compared with patients without (P<0.0001). The combination of J-wave and descending/horizontal ST segment in the inferior leads was more strongly associated with positive HUT than J-wave with ascending ST segment (odds ratio, 3.23). CONCLUSIONS: Prevalence of J-wave in the inferior or lateral leads was high in patients with syncope and was associated with HUT-induced neurally mediated reflex syncope (NMRS). Furthermore, the combination of J-wave and descending/horizontal ST segment in the inferior leads could be associated with a much higher risk of NMRS.

Single center experience in Japanese patients with syncope.

BACKGROUND AND PURPOSE: The present diagnostic method and features of syncope in Japan are unclear. Implantable loop recorder (ILR) and head-up tilt tests have recently become available for diagnosing syncope. The examination method and rates of diagnosing syncope may vary. This study aimed to clarify the present diagnostic method and features of syncope in a single Japanese medical center. METHODS AND RESULTS: We retrospectively reviewed the medical records of consecutive patients who were seen at our hospital from January 1, 2009, to December 31, 2012. A total of 547 patients (328 men, 60.4±21.5 years) with syncope were seen at our hospital. Reflex syncope was diagnosed in 29.1% of the cases, orthostatic hypotension in 11.7%, cardiac syncope in 34.0%, and unexplained syncope in 23.9% by initial and early evaluations. The number of patients with situational syncope and orthostatic hypotension that could be diagnosed in the initial evaluation of the first examination was significantly greater than that in subsequent evaluations. Forty-three percent of the unexplained syncope patients received an ILR. The consent rate for ILR implantations in the unexplained syncope patients with a suspected arrhythmia nature was 53.1%. The cumulative ILR diagnostic rates were 47% and 65% at 1 and 2 years after the ILR implantation, respectively. The estimated ILR diagnostic rates were significantly greater than that for conventional test without using an ILR. When patients with unexplained syncope could be diagnosed, the recurrent symptoms were greatly reduced. CONCLUSIONS: Syncope is induced by various causes in Japan. It is important that we understand the characteristics of each syncope cause. The consent rate for implanting an ILR in appropriate unexplained syncope patients is low. We need to educate these patients about the importance of making a diagnosis of syncope.

Non-enzymatic in vitro production of circular hammerhead ribozyme targeting the template region of human telomerase RNA.

Circular RNA is more stable than linear RNA both in vitro and in vivo because of its inaccessibility to exoribonucleases. Therefore, circularization of functional RNAs is a potentially useful methodology for designing therapeutic RNA reagents. We designed a circular hammerhead ribozyme that can cleave the template region of human telomerase RNA. This circular hammerhead ribozyme was generated by in vitro transcription followed by spontaneous self-circularization activity using the permuted intron-exon (PIE) method. Two-dimensional gel electrophoresis and alkaline digestion of the in vitro transcription products revealed that the circular hammerhead ribozyme could be produced by the PIE method. The purified circular hammerhead ribozyme cleaved the template region of human telomerase RNA in a magnesium-dependent manner. These results indicated that the circular hammerhead ribozyme generated by the PIE method maintained the specific feature of canonical hammerhead catalytic activity.