A Retrospective Cohort Study of Multiple Immune-Related Adverse Events and Clinical Outcomes Among Patients With Cancer Receiving Immune Checkpoint Inhibitors.

BACKGROUND AND OBJECTIVES: Immune checkpoint inhibitors (ICIs) are effective in various types of cancer and cause immune-related adverse events (irAEs). The occurrence of irAEs is associated with improved survival outcome. We investigated the association between the occurrence of irAEs and overall survival (OS) and progression free survival (PFS), and the risk factors for the development of irAEs, in patients with non-small-cell lung cancer (NSCLC), gastric cancer (GC) and melanoma (MM) treated with ICIs. METHODS: This was a retrospective observational cohort study, and the data were taken from inpatients in a hospital. OS and PFS were compared among patients with different numbers of irAEs. Log-rank test and Cox regression and logistic regression analysis were applied, and details of irAEs characteristics were summarized. RESULTS: We obtained data from 200 patients. The major tumor types were NSCLC, GC, and MM. Median OS and PFS in all patients were 9.3 and 3.5 months, respectively. Patients without irAEs tended to have shorter OS or PFS compared with those with a single irAE or multi-system irAEs. Covariate analysis suggested that age (≥75 years), albumin (≥3.5 g/dL) and smoking history were significant for increased occurrence of irAEs. Pneumonitis and thyroiditis tended to occur frequently in patients with NSCLC and MM. The irAE grade was ≤2 in 67.3% of all irAEs, and days of irAEs onset varied. CONCLUSION: We observed patients with irAEs tended to have better OS or PFS in patients with various types of cancers treated with ICIs. We suggest that ICIs should be used appropriately by continuously monitoring the irAEs.

Long-term outcomes of autologous skeletal myoblast cell-sheet transplantation for end-stage ischemic cardiomyopathy.

We evaluated the cardiac function recovery following skeletal myoblast cell-sheet transplantation and the long-term outcomes after applying this treatment in 23 patients with ischemic cardiomyopathy. We defined patients as "responders" when their left ventricular ejection fraction remained unchanged or improved at 6 months after treatment. At 6 months, 16 (69.6%) patients were defined as responders, and the average increase in left ventricular ejection fraction was 4.9%. The responders achieved greater improvement degrees in left ventricular and hemodynamic function parameters, and they presented improved exercise capacity. During the follow-up period (56 ± 28 months), there were four deaths and the overall 5-year survival rate was 95%. Although the responders showed higher freedom from mortality and/or heart failure admission (5-year, 81% versus 0%; p = 0.0002), both groups presented an excellent 5-year survival rate (5-year, 93% versus 100%; p = 0.297) that was higher than that predicted using the Seattle Heart Failure Model. The stepwise logistic regression analysis showed that the preoperative estimated glomerular filtration rate and the left ventricular end-systolic volume index were independently associated with the recovery progress. Approximately 70% of patients with "no-option" ischemic cardiomyopathy responded well to the cell-sheet transplantation. Preoperative renal and left ventricular function might predict the patients' response to this treatment.

Four-quadrant visualization of systemic circulatory equilibrium: right ventricular failure after left ventricular assist device implantation.

Right ventricular failure (RVF) is a serious adverse event after left ventricular assist device (LVAD) implantation but difficult to be characterized. This study aimed to visualize the dynamic circulatory equilibrium of acute RVF after LVAD implantation using a new four-quadrant diagram constructed by 1) cardiac function with central venous pressure (CVP) and cardiac index (CI) axes, 2) arterial vascular resistance with CI and mean blood pressure (mBP) axes, 3) pressure-diuretic function with mBP and net urinary sodium output (net U-Na) axes, and 4) venous compliance with net U-Na and CVP axes. Twenty LVAD patients were stratified into two groups, group S (≤10 days) and group L (>10 days), according to duration of postoperative inotropic support. The preoperative equilibrium loops were small in both groups. In the early postoperative phase, the loop in group S became dramatically enlarged to the left and upward, indicating increased CVP and CI by LVAD support. In group L, however, augmentation of CI was smaller despite similarly increased CVP, and net U-Na was decreased despite increased mBP. In the late postoperative phase, the equilibrium loop in group L recovered as similar to that seen in group S. Thus, acute RVF, as shown in group L, was characterized by the shape of the loop constructed by marked increased CVP, a relatively small increase in CI, and concomitant impairment of pressure natriuresis. In conclusion, the novel four-quadrant presentation of systemic circulatory equilibrium provides clear visualization of RVF after LVAD implantation, thus serving as a useful guide for prompt and optimal management.NEW & NOTEWORTHY Systemic circulatory dynamics are regulated by various negative feedback systems, including cardiac, arterial, venous, and renal functions, as well as autonomic nervous systems. The present novel four-quadrant presentation of their functions allows clear visualization of dynamic organ-to-organ interactions that can lead to a new circulatory equilibrium after therapeutic intervention. This new system physiological framework can serve as a useful guide for prompt and optimal management of circulatory malfunction.

Bilateral Internal Thoracic Artery Grafting Improves Survival for Severe Left Ventricular Dysfunction and Diabetes.

BACKGROUND: In patients with severe left ventricular (LV) dysfunction requiring coronary artery bypass grafting (CABG), the association between diabetic status and outcomes after surgery, as well as with survival benefit following bilateral internal thoracic artery (ITA) grafting, remain largely unknown.Methods and Results:Patients (n=188; mean [±SD] age 67±9 years) with LV ejection fraction ≤40% who underwent isolated initial CABG were classified into non-diabetic (n=64), non-insulin-dependent diabetic (NIDM; n=74), and insulin-dependent diabetic (IDM; n=50) groups. During follow-up (mean [±SD] 68±47 months), the 5-year survival rate was 84% and 65% among non-diabetic and diabetic patients, respectively (P=0.034). After adjusting for all covariates, both NIDM and IDM were associated with increased mortality, with hazard ratios (HRs) of 1.9 (95% confidence interval [CI] 1.0-3.7; P=0.049) and 2.4 (95% CI 1.2-4.8; P=0.016), respectively. Among non-diabetic patients, there was no difference in the 5-year survival rate between single and bilateral ITA grafting (86% vs. 80%, respectively; P=0.95), whereas bilateral ITA grafting increased survival among diabetic patients (57% vs. 81%; P=0.004). Multivariate analysis revealed that bilateral ITA was significantly associated with a decreased risk of mortality (HR 0.3; 95% CI 0.1-0.8; P=0.024). CONCLUSIONS: NIDM and IDM were significantly associated with worse long-term clinical outcome after CABG for severe LV dysfunction. Bilateral ITA grafting has the potential to improve survival in diabetic patients with severe LV dysfunction.

Complex HeartWare left ventricular assist device infection treated with pump exchange: clinical alert for the driveline location.

Infection is a major complication in patients with a left ventricular assist device (LVAD). Once a driveline exit-site infection (DLI) reaches the LVAD component, LVAD exchange may become necessary for radical treatment, although clinical results are not satisfactory. In this report, we describe two cases of LVAD infection successfully treated with pump exchange. During LVAD support, the DLI extended into the pump pocket and the outflow graft despite aggressive surgical debridement and negative pressure wound therapy. These two patients required LVAD exchange for radical treatment, because the estimated waiting period for heart transplantation was at least more than 1 year. The LVAD exchange was performed through median re-sternotomy, and the infected HeartWare ventricular assist device (HVAD) was completely removed under cardiopulmonary bypass. Then, a new LVAD covered with the omentum flap was implanted. These two patients were successfully bridged to heart transplantation after 10 months and 2 years of support without recurrence of infection. These two cases may suggest that the driveline of the HVAD needs to be kept away from the outflow graft to prevent refractory outflow graft infection.

Factors Associated With Efficacy and Nivolumab-Related Interstitial Pneumonia in Non-Small Cell Lung Cancer: A Retrospective Survey.

BACKGROUND AND OBJECTIVES: Immune-checitors have been established as a novel standard treatment for non-small cell lung cancer (NSCLC). The aim of this study was to identify factors associated with efficacy and nivolumab-related interstitial pneumonia in NSCLC by evaluating clinical data at the initiation of and during treatment. METHODS: We retrospectively reviewed the medical records of patients who underwent treatment with nivolumab between October 2015 and December 2017. Using pretreatment patient data, we investigated factors associated with overall survival (OS) and the onset of nivolumab-related pneumonitis. We investigated serum biochemistry during treatment to identify the determinants associated with progressive disease (PD) and the onset of nivolumab-related pneumonitis. RESULTS: A total of 94 patients were included. Eleven patients continued treatment, and 54 patients were diagnosed with progressive disease. Nivolumab-related pneumonitis occurred in 15 patients. A pretreatment Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0 was linked to significantly longer OS than ECOG PS = 1 (median: 20.1 vs. 6.5 months, respectively; p < 0.001). There was a higher incidence of nivolumab-related pneumonitis in patients with a history of interstitial pneumonia than in those without it (p = 0.008). During treatment, the level of albumin gradually decreased prior to PD and onset of nivolumab-related pneumonitis. CONCLUSION: These results suggest that the pretreatment ECOG PS is the determining factor that is associated with OS, whereas history of interstitial pneumonia is the factor associated with nivolumab-related pneumonitis. A decrease in albumin during treatment may be associated with both PD and nivolumab-related pneumonitis.

Recovery From Exhaustion of the Frank-Starling Mechanism by Mechanical Unloading With a Continuous-Flow Ventricular Assist Device.

BACKGROUND: We describe our original left ventricular assist device (LVAD) speed ramp and volume loading test designed to evaluate native heart function under continuous-flow LVAD support.Methods and Results:LVAD speed was decreased in 4 stages from the patient's optimal speed to the minimum setting for each device. Under minimal LVAD support, patients were subjected to saline loading (body weight [kg]×10 mL in 15 min). Echocardiographic and hemodynamic data were obtained at each stage of the LVAD speed ramp and every 3 min during saline loading. Patients were divided into Recovery (with successful LVAD removal; n=8) and Non-recovery (others; n=31) groups. During testing, increased pulmonary capillary wedge pressure caused by volume loading was milder in the Recovery than Non-recovery group (repeated measures analysis of variance; group effect, P=0.0069; time effect, P<0.0001; interaction effect, P=0.0173). Increased cardiac output from volume loading was significantly higher in the Recovery than Non-recovery group (group effect, P=0.0124; time effect, P<0.0001; interaction effect, P=0.0091). Therefore, the Frank-Starling curve of the Recovery group was located upward and to the left of that of the Non-recovery group. CONCLUSIONS: The LVAD speed ramp and volume loading test facilitates the precise evaluation of native heart function during continuous-flow LVAD support.

Impact of turbulent blood flow in the aortic root on de novo aortic insufficiency during continuous-flow left ventricular-assist device support.

Severe aortic insufficiency (AI) after implantation of continuous-flow left ventricular-assist device (LVAD) affects device performance and outcomes. However, the mechanism for the occurrence and progression of AI has not been elucidated. We investigated the impact of nonphysiological retrograde blood flow in the aortic root on AI after LVAD implantation. Blood flow pattern was analyzed in patients with and without AI (n = 3 each) who underwent LVAD implantation, by computational fluid dynamics with patient-specific geometries, which were reproduced using electrocardiogram-gated 320-slice computed tomographic images. The total volume of retrograde blood flow during one cardiac cycle (716 ± 88 mL) was higher and the volume of slow blood flow (<0.1 cm/s) (0.16 ± 0.04 cm3 ) was lower in patients with AI than in those without AI (360 ± 111 mL, P = .0495, and 0.49 ± 0.08 cm3 , P = .0495, respectively). No significant difference in wall shear stress on the aortic valve was observed between the groups. Patients with AI had a perpendicular anastomosis at the distal ascending aorta and the simulation in the modified anastomosis model of patients with AI showed that the retrograde blood flow pattern depended on the angle and position of anastomosis. Computational fluid dynamics revealed strong retrograde blood flow in the ascending aorta and aortic root in patients with AI after LVAD implantation. The angle and position of LVAD outflow anastomosis might impact retrograde blood flow and de novo AI after LVAD implantation.

Jarvik 2000 with postauricular cable as destination therapy: first clinical case in Japan.

Currently in Japan, a left ventricular assist device powered by an abdominal driveline is the only type of left ventricular assist device available. The driveline is vulnerable to infection secondary to inappropriate fixation and the traditional Japanese custom of bathing is prohibited in patients with an abdominal driveline. The Jarvik 2000 with postauricular cable is a left ventricular assist device in which the driveline exits the body behind the ear (postauricular) instead of exiting through an abdominal site. This case report is the first to describe the implantation of Jarvik 2000 with postauricular cable as destination therapy in a Japanese patient. This device enables patients to take a bath and may reduce the incidence of driveline infection.

Safety profile and immunological response of dual sublingual immunotherapy with house dust mite tablet and Japanese cedar pollen tablet.

BACKGROUND: There have been no studies of dual administration of sublingual immunotherapy (SLIT) tablets for perennial and seasonal allergic rhinitis. This trial (JapicCTI-184014) was conducted to investigate the safety profile and immunological response during dual therapy with SQ house dust mite (HDM) and Japanese cedar pollen (JCP) SLIT tablets. METHODS: This was a multicenter, open-label, randomized trial of 109 Japanese patients with coexisting HDM and JCP allergic rhinitis who had positive tests for HDM- and JCP specific IgE (≥0.7 kU/L). Patients were allocated to receive HDM (N = 54) or JCP (N = 55) SLIT tablets alone for 4 weeks followed by 8 weeks of dual therapy with both SLIT tablets administered within 5 min of each other. Adverse events (AEs), adverse drug reactions (ADRs), and serum IgE and IgG4 specific for HDM (Dermatophagoides farinae, Dermatophagoides pteronyssinus) and JCP were recorded. RESULTS: The percentage of subjects with AEs and ADRs was similar between the two groups and between the two periods of monotherapy and dual therapy. Most AEs and ADRs were mild in severity, and no serious events were observed. The most common ADRs were local events in the oral cavity. Levels of IgE and IgG4 specific for HDM (D. farinae, D. pteronyssinus) and JCP were increased after treatment with HDM and JCP SLIT tablets, respectively. CONCLUSIONS: Dual therapy with both SLIT tablets administered within 5 min after 4 weeks of monotherapy with HDM or JCP tablet was well tolerated and induced the expected immunological responses.

[EFFICACY, SAFETY AND IMMUNOLOGICAL RESPONSE WITH SQ HOUSE DUST MITE SUBLINGUAL IMMUNOTHERAPY-TABLET BY BODY WEIGHT IN CHILDREN].

BACKGROUND: Sublingual immunotherapy-tablet (SLIT-tablet) treatment includes the same dose regardless of the patients' age or body weight. We investigated the efficacy, safety and immunological response of SQ house dust mite (HDM) SLIT-tablet treatment in relation to body weight in children. METHODS: Total combined rhinitis score (TCRS), adverse events (AEs), adverse drug reactions (ADRs) and immunological response (IgE, IgG4) were evaluated post hoc in three subgroups (body weight < 30kg, 30-44kg, ≥ 45kg) of patients from a clinical trial for Japanese children with HDM allergic rhinitis (JapicCTI-152953). RESULTS: No apparent differences in TCRS were observed between the three subgroups. No differences in the frequency or nature of AEs were detected between the subgroups but the incidence of ADRs was decreased in the lower body weight subgroup. The most common ADRs occurred locally in the oral cavity and were categorized as mild. The levels of HDM specific IgE and IgG4 were increased compared to baseline in all subgroups. CONCLUSION: There were no influences of body weight for efficacy, safety, and immunological response in treatment with SQ HDM SLIT-tablet. These results indicated that SLIT dosage in children is same as adults without any concern in safety.

Specialized movement and laterality of fin-biting behaviour in Genyochoromis mento in Lake Malawi.

Several vertebrates, including fish, exhibit behavioural laterality and associated morphological asymmetry. Laterality may increase individual fitness as well as foraging strength, accuracy and speed. However, little is known about which behaviours are affected by laterality or what fish species exhibit obvious laterality. Previous research on the predatory behaviour of the scale-eating Lake Tanganyika cichlid Perissodus microlepis indicates behavioural laterality that reflects asymmetric jaw morphology. The Lake Malawi cichlid Genyochromis mento feeds on the fins of other fish, a behaviour that G. mento developed independently from the Tanganyikan Perissodini scale eaters. We investigated stomach contents and behavioural laterality of predation in aquarium to clarify the functional roles and evolution of laterality in cichlids. We also compared the behavioural laterality and mouth asymmetry of G. mento and P. microlepis The diet of G. mento mostly includes fin fragments, but also scales of several fish species. Most individual G. mento specimens showed significant attack bias favouring the skew mouth direction. However, there was no difference in success rate between attacks from the preferred side and those from the non-preferred side, and no lateralized kinetic elements in predation behaviour. Genyochromismento showed weaker laterality than P. microlepis, partly because of their different feeding habits, the phylogenetic constraints from their shorter evolutionary history and their origin from ancestor Haplochromini omnivorous/herbivorous species. Taken together, this study provides new insights into the functional roles of behavioural laterality: predatory fish aiming for prey that show escape behaviours frequently exhibit lateralized behaviour in predation.

Rescuing Patients With Severe Biventricular Failure in the Era of Continuous-Flow Left Ventricular Assist Device.

BACKGROUND: We evaluated clinical outcomes of left ventricular assist device (LVAD) support in patients with or without severe right heart failure, in order to determine what kind of organ allocation system could help severe biventricular failure patients to be safely bridged to heart transplantation (HTx), even in Japan where the waiting time for HTx is extremely long. Methods and Results: One hundred and seventy consecutive patients who were implanted with continuous-flow LVAD at the present institution were included in this study. The patients were divided into 2 groups: 158 patients with isolated LVAD (group-LVF) and 12 patients who required long-term mechanical or inotropic right heart support (group-BVF). Post-LVAD survival in group-BVF was significantly worse than in group-LVF (P<0.0001). Given that many patients in group-BVF died between 1 and 2 years after LVAD implantation, Kaplan-Meier survival curve simulation was carried out under the condition that all the patients in group-BVF who died on LVAD support >1 year after LVAD implantation had received HTx at 365 days after LVAD implantation and survived thereafter. In this simulation, no significant difference in survival was seen between the groups (P=0.2424). CONCLUSIONS: A new allocation system that allows severe right heart failure patients to receive HTx at around 1 year would enable rescue of the patients with severe right heart failure.

Rapid Deployment Aortic Valve Replacement via Right Lateral Mini-Thoracotomy　- First Clinical Experience in Japan.

BACKGROUND: Rapid deployment aortic valve replacement has been developed to shorten procedural times and to facilitate minimally invasive cardiovascular surgery. Methods and Results: As a representative rapid-deployment valve, the balloon-expanding INTUITY Elite (the 2nd-generation Edwards INTUITY Valve System) was uneventfully implanted via a right lateral mini-thoracotomy in 2 patients with severe aortic valve stenosis. Both of them recovered quickly and were discharged from hospital without significant adverse events. CONCLUSIONS: Implantation of the INTUITY Elite valve via right mini-thoracotomy is feasible and safe.

Infective endocarditis of bovine pericardial patch in the aortic position in a patient with left ventricular assist device.

A 53-year old woman, who had a history of left ventricular assist device implantation for acromegalic cardiomyopathy and aortic valve closure with bovine pericardial patch, was diagnosed with active endocarditis of aortic valve closure patch. The investigation revealed that infection was limited to the aortic valve closure patch; thus, redo aortic valve closure with a new bovine pericardial patch was performed. The postoperative course was uneventful and the infection was sufficiently controlled. Early surgical intervention is mandatory for a good result without spread of infection to the left ventricular assist device pump and formation of embolism.

Therapeutic hypothermia after global cerebral ischemia due to left ventricular assist device malfunction.

Herein we report the case of a patient who suffered from global cerebral ischemia due to pump stoppage of Jarvik2000 Left ventricular assist device (LVAD) for unknown reason and fatal ventricular arrhythmia at home. Cardiopulmonary resuscitation was started by paramedics 6-7 min after the patient fell down. The patient was transferred to our hospital after the restoration of the LVAD function by exchanging external cables. Mild therapeutic hypothermia was induced and body temperature was kept at 33 °C for 24 h. After rewarming, the patient recovered his consciousness without any neurological deficit.

A case of Mycobacterium chelonae mediastinitis and acute humoral rejection after heart transplantation.

Mediastinitis is one of the life-threating complications that can occur after cardiac surgery. However, to the best of our knowledge, there has been no report of mediastinitis caused by Mycobacterium chelonae, which is one of the rapidly growing nontuberculous mycobacteria species. As far as we know, our case is the first case describing the curative management for mediastinitis caused by M. chelonae after heart transplantation.

Midterm Clinical Outcomes of the St Jude Medical Epic Porcine Bioprosthesis in the Mitral Position.

BACKGROUND: The aim of this single-center study was to report the midterm clinical outcomes and hemodynamic performance of the St Jude Medical Epic porcine bioprosthesis, a tricomposite glutaraldehyde-preserved porcine bioprosthesis, in mitral position. Methods and Results: Between January 2011 and March 2017, 117 patients (62 men, 55 women; mean age, 66.7±12.8 years) who underwent mitral valve replacement (MVR) with the Epic valve were retrospectively analyzed for early and mid-term morbidity and mortality. The mean follow-up period was 2.6±1.7 years. Three operative deaths occurred, and the operative mortality rate was 2.6%. Sixteen patients died during the follow-up period. On Kaplan-Meier analysis, freedom from all-cause death and major adverse cardiovascular and cerebrovascular events at 5-year follow-up were 80.9% and 54.8%, respectively. There were 6 reoperations: 2 for structural valve deterioration (SVD), 2 for prosthetic valve endocarditis, and 2 for thrombosis. Freedom from valve-related reoperation and SVD at 5 years were 89.0% and 93.1%, respectively. On multivariate analysis, age ≥71 years (HR, 6.78; 95% CI: 2.12-25.2, P<0.01), and NYHA functional class ≥III (HR, 3.20; 95% CI: 1.03-10.4, P=0.04) were independent predictors for all-cause death. Mean mitral pressure gradient at 1 year and 2 years were 5.1±1.9 mmHg and 4.5±1.4 mmHg, respectively. CONCLUSIONS: Mid-term clinical results and durability of the Epic valve in the mitral position are satisfactory.

Cardiac Function and Type of Mitral Valve Surgery Affect Postoperative Blood Flow Pattern in the Left Ventricle.

BACKGROUND: To determine the impact of cardiac function and type of mitral valve (MV) surgery on blood flow and energy loss in the left ventricle (LV). Methods and Results: This study enrolled patients with ejection fraction (EF) <35% or >50%; both groups had native (n=27 and n=16), repaired (n=19 and n=33), or prosthetic MVs (n=18 and n=19). They were examined by echocardiography-based vector flow mapping to assess the LV blood flow pattern and energy loss per heartbeat. Among patients with preserved EF, those with native MVs displayed a clockwise vortex and relatively low energy loss. In contrast, MV replacement induced a counterclockwise vortex producing higher energy loss than MV repair, which induced a normal clockwise vortex. This indicated the need for MV repair to minimize LV energy loss after surgery. Among the patients with reduced EF, those with native MVs showed a blood flow pattern similar to those with preserved EF and native MVs; furthermore, those with repaired MVs and half of the patients with prosthetic MVs displayed a clockwise vortex, resulting in no difference in energy loss between the 2 types of MV surgery. CONCLUSIONS: Cardiac function and the type of MV surgery are factors affecting the postoperative LV blood flow pattern. MV replacement resulted in abnormal blood flow with normal cardiac function, whereas advanced cardiomyopathy modified the blood flow pattern post-MV replacement.

Overview of the 82nd Annual Scientific Meeting of the Japanese Circulation Society　- Futurability: Pioneering the Future of Circulatory Medicine.

The 82nd Annual Scientific Meeting of the Japanese Circulation Society was held in Osaka, Japan, on March 23-25, 2018, when the cherry blossoms were just opening everywhere around the venue. This was the 5th Annual Scientific Meeting of JCS in which a cardiovascular surgeon served as Congress Chairperson. The main theme of this meeting was "Futurability: Pioneering the Future of Circulatory Medicine". The word, futurability, is a neologism of future ability, because we now have to contemplate what constitutes the essence of cardiovascular medicine, how it should develop as medicine for future generations, and how its ability should be displayed. The meeting was favored by splendid weather and the number of participants was recorded as being higher than 18,700. There were heated and profound discussions about the "futurability" of cardiology, cardiovascular surgery, and heart team medical care as well, in every session. The meeting was successfully completed and we sincerely appreciate the great cooperation and support from all affiliates.