Review of Immune-Related Adverse Events (irAEs) in Non-Small-Cell Lung Cancer (NSCLC)-Their Incidence, Management, Multiorgan irAEs, and Rechallenge.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies, including non-small cell lung cancer (NSCLC). These agents have improved clinical outcomes and have become quite an attractive alternative alone or combined with other treatments. Although ICIs are tolerated better, they also lead to unique toxicities, termed immune-related adverse events (irAEs). A reconstituted immune system may lead to dysregulation in normal immune self-tolerance and cause inflammatory side effects (irAEs). Although any organ system can be affected, immune-related adverse events most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. They can occur anytime during the treatment course and rarely even after completion. Owen and colleagues showed that approximately 30% of patients with NSCLC treated with ICIs develop irAEs. Kichenadasse et al. conducted a thorough evaluation of multiorgan irAEs, which is of particular interest because information regarding these types of irAEs is currently sparse. It is important to delineate between infectious etiologies and symptom progression during the management of irAEs. Close consultation with disease-specific subspecialties is encouraged. Corticosteroids are the mainstay of treatment of most irAEs. Early intervention with corticosteroids is crucial in the general management of immune-mediated toxicity. Grade 1-2 irAEs can be closely monitored; hypothyroidism and other endocrine irAEs may be treated with hormone supplementation without the need for corticosteroid therapy. Moderate- to high-dose steroids and other additional immunosuppressants such as tocilizumab and cyclophosphamide might be required in severe, grade 3-4 cases. Recently, increasing research on irAEs after immunotherapy rechallenge has garnered much attention. Dolladille and colleagues assessed the safety in patients with cancer who resumed therapy with the same ICIs and found that rechallenge was associated with about 25-30% of the same irAEs experienced previously (4). However, such data should be carefully considered. Further pooled analyses may be required before we conclude about ICIs' safety in rechallenge.

Risk factors and outcomes associated with Left Ventricular Thrombus in patients with Peripartum Cardiomyopathy: An insight from National Inpatient Sample Database.

BACKGROUND: : We sought to assess the prevalence and impact of left ventricular thrombus (LVT) in patients with peripartum cardiomyopathy (PPCM). METHODS: : We performed a retrospective cohort study of all admissions with PPCM as the primary diagnosis from the Nationwide Inpatient Sample database over a 11-year period. Univariate analysis of all risk factors and outcomes and multivariable logistic regression analysis of certain variables were performed and represented as odds ratio (OR) with 95% confidence interval (CI). A p value of < 0.05 was considered statistically significant. Statistical analysis was performed using epiDisplay in 'R' studio. RESULTS: : In the time frame spanning 2005 -2014, 43,986 admissions with PPCM were found which included 43,534 without LVT and 452 patients with LVT. Black race was associated with a higher incidence of LV thrombus, (p value <0.001). Comorbidities more prevalent in the LVT group were smoking, drug abuse, pregnancy induced hypertension, diabetes with complications, valvular heart disease, connective tissue disorders, coagulopathy, anemia and depression. Adverse outcomes such as congestive heart failure, arrhythmias and stroke were higher in LVT group. Conversely, Caucasian race, obesity, preeclampsia (p <0.005) were higher in those without LVT. Mean length of stay (9 vs 5 days, p <0.001), in hospital mortality (3.32% vs 1.41%, p = 0.001) and mean hospitalization charges ($85,390 vs $48,033) were higher in those with LVT. However, on multivariate logistic regression, although stroke was higher in the LVT group (adjusted OR 5.51, 95% CI, 2.2, 13.81, 5.05, p 0.002), in-hospital mortality was not significantly different between the two groups (adjusted OR 1.17, 95% CI,0.32, 4.23, p = 0.817). CONCLUSION: : Our study showed that PPCM patients with LV thrombus had worse outcomes with respect to stroke, length of stay and in hospital mortality. Higher prevalence in patients with black race, complicated diabetes, peripheral vascular disease, valvular disease, coagulopathy, smoking, drug abuse, depression and psychoses calls for special attention to such high-risk groups for aggressive risk factor modification.

Real-Time Closed-Loop Suppression of Repolarization Alternans Reduces Arrhythmia Susceptibility In Vivo.

BACKGROUND: Repolarization alternans (RA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death. METHODS: We have developed a real-time, closed-loop system to record and analyze RA from multiple intracardiac leads, and deliver dynamically R-wave triggered pacing stimuli during the absolute refractory period. We have evaluated the ability of this system to control RA and reduce arrhythmia susceptibility, in vivo. RESULTS: R-wave triggered pacing can induce RA, the magnitude of which can be modulated by varying the amplitude, pulse width, and size of the pacing vector. Using a swine model (n=9), we demonstrate that to induce a 1 µV change in the alternans voltage on the body surface, coronary sinus and left ventricle leads, requires a delivered charge of 0.04±0.02, 0.05±0.025, and 0.06±0.033 µC, respectively, while to induce a one unit change of the Kscore, requires a delivered charge of 0.93±0.73, 0.32±0.29, and 0.33±0.37 µC, respectively. For all body surface and intracardiac leads, both Δ(alternans voltage) and ΔKscore between baseline and R-wave triggered paced beats increases consistently with an increase in the pacing pulse amplitude, pulse width, and vector spacing. Additionally, we show that the proposed method can be used to suppress spontaneously occurring alternans (n=7), in the presence of myocardial ischemia. Suppression of RA by pacing during the absolute refractory period results in a significant reduction in arrhythmia susceptibility, evidenced by a lower Srank score during programmed ventricular stimulation compared with baseline before ischemia. CONCLUSIONS: We have developed and evaluated a novel closed-loop method to dynamically modulate RA in a swine model. Our data suggest that suppression of RA directly reduces arrhythmia susceptibility and reinforces the concept that RA plays a critical role in the pathophysiology of arrhythmogenesis.

A Novel Point-of-Care Smartphone Based System for Monitoring the Cardiac and Respiratory Systems.

Cardio-respiratory monitoring is one of the most demanding areas in the rapidly growing, mobile-device, based health care delivery. We developed a 12-lead smartphone-based electrocardiogram (ECG) acquisition and monitoring system (called "cvrPhone"), and an application to assess underlying ischemia, and estimate the respiration rate (RR) and tidal volume (TV) from analysis of electrocardiographic (ECG) signals only. During in-vivo swine studies (n = 6), 12-lead ECG signals were recorded at baseline and following coronary artery occlusion. Ischemic indices calculated from each lead showed statistically significant (p < 0.05) increase within 2 min of occlusion compared to baseline. Following myocardial infarction, spontaneous ventricular tachycardia episodes (n = 3) were preceded by significant (p < 0.05) increase of the ischemic index ~1-4 min prior to the onset of the tachy-arrhythmias. In order to assess the respiratory status during apnea, the mechanical ventilator was paused for up to 2 min during normal breathing. We observed that the RR and TV estimation algorithms detected apnea within 7.9 ± 1.1 sec and 5.5 ± 2.2 sec, respectively, while the estimated RR and TV values were 0 breaths/min and less than 100 ml, respectively. In conclusion, the cvrPhone can be used to detect myocardial ischemia and periods of respiratory apnea using a readily available mobile platform.

Percutaneous Mechanical Support in Cardiogenic Shock: A Review.

Cardiogenic shock (CS) is a life-threatening condition associated with significant morbidity and mortality. Pharmacological therapy is often the first line of treatment but mechanical support can provide substantial hemodynamic improvement in refractory CS. Percutaneous mechanical support devices are placed in a minimally invasive manner and provide life-saving assistance to the failing myocardium. We review the percutaneous devices currently available, the evidence behind their use, and the new advances in percutaneous technology being evaluated for the treatment of CS.

A novel method to capture the onset of dynamic electrocardiographic ischemic changes and its implications to arrhythmia susceptibility.

BACKGROUND: This study investigates the hypothesis that morphologic analysis of intracardiac electrograms provides a sensitive approach to detect acute myocardial infarction or myocardial infarction-induced arrhythmia susceptibility. Large proportions of irreversible myocardial injury and fatal ventricular tachyarrhythmias occur in the first hour after coronary occlusion; therefore, early detection of acute myocardial infarction may improve clinical outcomes. METHODS AND RESULTS: We developed a method that uses the wavelet transform to delineate electrocardiographic signals, and we have devised an index to quantify the ischemia-induced changes in these signals. We recorded body-surface and intracardiac electrograms at baseline and following myocardial infarction in 24 swine. Statistically significant ischemia-induced changes after the initiation of occlusion compared with baseline were detectable within 30 seconds in intracardiac left ventricle (P<0.0016) and right ventricle-coronary sinus (P<0.0011) leads, 60 seconds in coronary sinus leads (P<0.0002), 90 seconds in right ventricle leads (P<0.0020), and 360 seconds in body-surface electrocardiographic signals (P<0.0022). Intracardiac leads exhibited a higher probability of detecting ischemia-induced changes than body-surface leads (P<0.0381), and the right ventricle-coronary sinus configuration provided the highest sensitivity (96%). The 24-hour ECG recordings showed that the ischemic index is statistically significantly increased compared with baseline in lead I, aVR, and all precordial leads (P<0.0388). Finally, we showed that the ischemic index in intracardiac electrograms is significantly increased preceding ventricular tachyarrhythmic events (P<0.0360). CONCLUSIONS: We present a novel method that is capable of detecting ischemia-induced changes in intracardiac electrograms as early as 30 seconds following myocardial infarction or as early as 12 minutes preceding tachyarrhythmic events.

Epidemiology of vancomycin-resistant Enterococcus faecalis: a case-case-control study.

Although much is known about vancomycin-resistant (VR) Enterococcus faecium, little is known about the epidemiology of VR Enterococcus faecalis. The predilection of VR E. faecalis to transfer the vancomycin resistance determinant to Staphylococcus aureus is much greater than that of VR E. faecium. The epidemiology of VR E. faecalis has important implications regarding the emergence of vancomycin-resistant S. aureus (VRSA); 8 of 13 reported VRSA cases have been from Michigan. A retrospective case-case-control study was conducted at the Detroit Medical Center, located in southeastern Michigan. Unique patients with VR E. faecalis infection were matched to patients with strains of vancomycin-susceptible (VS) E. faecalis and to uninfected controls at a 1:1:1 ratio. Five hundred thirty-two VR E. faecalis cases were identified and were matched to 532 VS E. faecalis cases and 532 uninfected controls. The overall mean age of the study cohort (n = 1,596) was 63.0 ± 17.4 years, and 747 (46.8%) individuals were male. Independent predictors for the isolation of VR E. faecalis (but not VS E. faecalis) compared to uninfected controls were an age of ≥65 years, nonhome residence, diabetes mellitus, peripheral vascular disease, exposure to cephalosporins and fluoroquinolones in the prior 3 months, and immunosuppressive status. Invasive procedures and/or surgery, chronic skin ulcers, and indwelling devices were risk factors for both VR E. faecalis and VS E. faecalis isolation. Cephalosporin and fluoroquinolone exposures were unique, independent predictors for isolation of VR E. faecalis. A majority of case patients had VR E. faecalis present at the time of admission. Control of VR E. faecalis, and ultimately VRSA, will likely require regional efforts focusing on infection prevention and antimicrobial stewardship.