Characteristic differences in the abundance of tumor-infiltrating lymphocytes and intratumoral developing T cells in thymoma, with special reference to PD-1 expression.

PURPOSE: Though programmed cell death-1 (PD-1) inhibitors mainly target tumor-infiltrating lymphocytes (TILs) expressing PD-1, developing T cells in thymus also express PD-1 in their process of maturation. To predict the therapeutic effect of PD-1 inhibitors for thymoma, it is necessary to clarify the proportions of TILs and intratumoral developing T cells. METHODS: The expressions of CD4, CD8, and PD-1 on T cells were analyzed by flow cytometry in 31 thymomas. The amount of T cell receptor excision circles (TRECs), which can be detected in newly formed naïve T cells in the thymus, was evaluated using sorted lymphocytes from thymomas by quantitative PCR. The expressions of granzyme B (GZMB) and lymphocyte activation gene-3 (LAG-3) in PD-1 + CD8 T cells were analyzed by image cytometry using multiplex immunohistochemistry. RESULTS: The PD-1 + rate in both CD4 and CD8 T cells was significantly higher in type AB/B1/B2 than in type A/B3 thymomas. The amounts of TRECs in CD4 and CD8 T cells were significantly higher in type AB/B1/B2 than in type A/B3 thymomas and comparable to normal thymus. PD-1 expression at each stage of T cell development of type AB/B1/B2 thymomas was comparable to that of normal thymus. Both the percentages and cell densities of PD-1 + CD8 T cells expressing GZMB or LAG-3, which are known to contain tumor-reactive T cells, were significantly lower in type AB/B1/B2 thymomas. CONCLUSION: Most PD-1 + T cells in type AB/B1/B2 thymomas are intratumoral developing T cells and are not TILs.

Effectiveness of cardiac palliative surgery for trisomy 18 patients with increased pulmonary blood flow.

Congenital heart disease (CHD) is common among patients with trisomy 18 (T18), but cardiac surgery has been rarely indicated for T18 patients due to their short life span. Although the therapeutic effects of aggressive interventions were recently demonstrated for T18 patients, the subjects and factors examined varied, resulting in inconsistent findings. Therefore, the effects of cardiac surgery for T18 remain unclear. We herein investigated the outcomes of cardiac palliative surgery for CHD with increased pulmonary blood flow in T18 patients. 27 patients were examined: 13 (48.1%) underwent cardiac palliative surgery and 14 (51.9%) did not. Median survival times in the no-surgery and surgery groups were 223.0 days (95% confidence interval [CI]: 46-361 days) and 723.0 days (95% CI: 360-1447 days), respectively. The number of patients with pulmonary hypertension significantly differed between the two groups (5 of 14 in the no-surgery group and 0 in the surgery group). Five of 14 patients in the no-surgery group and 10 of 13 in the surgery group were discharged to home care (odds ratio: 10.8 [95% CI: 1.07-110.0]). Therefore, cardiac palliative surgery may be used to treat CHD with increased pulmonary blood flow in T18 patients.

Histological finding of maternal antibody-associated congenital heart block accompanied by large atrial septal defect and severe cardiac dysfunction.

Cardiac dysfunction commonly occurs in congenital heart block associated with maternal anti-SSA antibodies, especially after pacemaker implantation. We report the case of a 4-year-old girl with antibody-associated congenital heart block and a large secundum atrial septal defect who presented with significant cardiac dysfunction 4 years after pacemaker implantation. Histological findings were useful for determining the course of treatment and perioperative risk of intracardiac repair.

Partnership Between Japan and the United States for Early Development of Pediatric Medical Devices　- Harmonization By Doing for Children.

BACKGROUND: The Harmonization By Doing (HBD) program was established in 2003 as a partnership among stakeholders of academia, industry and regulatory agencies in Japan and the United States, with a primary focus on streamlining processes of global medical device development for cardiovascular medical devices. While HBD has traditionally focused on development of devices intended to treat conditions prevalent in adults, in 2016, HBD established the "HBD-for-Children" program, which focuses on the development of pediatric devices as the development of medical devices for pediatric use lags behind that of medical devices for adults in both countries.Methods and Results:Activities of the program have included: (1) conducting a survey with industry to better understand the challenges that constrain the development of pediatric medical devices; (2) categorizing pediatric medical devices into five categories based on global availability and exploring concrete solutions for the early application and regulatory approval in both geographies; and (3) facilitating global clinical trials of pediatric medical devices in both countries. CONCLUSIONS: The establishment of the HBD-for-Children program is significant because it represents a global initiative for the introduction of pediatric medical devices for patients in a timely manner. Through the program, academia, industry and regulatory agencies can work together to facilitate innovative pediatric device development from a multi-stakeholder perspective. This activity could also encourage industry partners to pursue the development of pediatric medical devices.

[Adult Congenital Heart Surgery as a Novel Specialty in Thoracic Surgery; Perioperative Patient Management and Surgical Procedures].

Recently, number of adult congenital heart disease(ACHD) patients are rapidly increasing, but statistical evidences in adult congenital heart surgery are not sufficient because of its short history in addition to the complicated pathophysiology of ACHD. Therefore, a "heart team" including surgeons, pediatricians, and cardiologists are required, and blood flow imaging and 4-dimensional (4D) imaging plays an essential role in perioperative patient management. Enhanced 3-dimensional computed tomography( 3D-CT) scan is useful to determine cardiopulmonary bypass strategies in reoperation, and 4D flow magnetic resonance imaging( MRI) is useful in assessment of complicated hemodynamics. Diastolic function of systemic ventricle is very important in right side heart valve surgery or univentricular heart surgery, echocardiography is essential to examine the valve structure, and electrophysiological mapping is useful in concomitant arrhythmia surgery. This article describes the indications, procedures, and perioperative managements of surgery in the right ventricular outflow tract, tricuspid valve, aortic root, Fontan circulation, and systemic right ventricle.

Energetic performance analysis of staged palliative surgery in tricuspid atresia using vector flow mapping.

BACKGROUND: Staged palliative surgery markedly shifts the balance of volume load on a single ventricle and pulmonary vascular bed. Blalock-Taussig shunt necessitates a single ventricle eject blood to both the systemic and pulmonary circulation. On the contrary, bidirectional cavopulmonary shunt release the single ventricle from pulmonary circulation. CASE PRESENTATION: We report a case of tricuspid atresia patient who underwent first palliative surgery and second palliative surgery. Volume loading condition was assessed by energetic parameters (energy loss, kinetic energy) intraoperatively using vector flow mapping. These energetic parameters can simply indicate the volume loading condition. CONCLUSION: Vector flow mapping was useful tool for monitoring volume loading condition in congenital heart disease surgery.

Successful replacement of the systemic tricuspid valve with a mechanical valve in a 3-month-old boy with congenitally corrected transposition of the great arteries having a dysplastic tricuspid valve.

There are a few reports of successful replacement of the left-sided systemic tricuspid valve with a mechanical valve in small infants with congenitally corrected transposition of the great arteries having Ebstein's anomaly. Tricuspid valve replacement is the preferred option when pulmonary artery banding, performed as a prelude to performing the double-switch operation, is not feasible because of severe heart failure caused by tricuspid regurgitation.

Development of a thermodynamic control system for the Fontan circulation pulsation device using shape memory alloy fibers.

The Fontan procedure is one of the common surgical treatments for circulatory reconstruction in pediatric patients with congenital heart disease. In Fontan circulation, low pulsatility may induce localized lung ischemia and may impair the development of pulmonary peripheral endothelial cells. To promote pulmonary circulation in Fontan circulation, we have been developing a pediatric pulmonary circulatory pulsation device using shape memory alloy fibers attached from the outside of total cavopulmonary connection. In this study, we developed a new thermal control system for the device and examined its functions. We mounted on the device 16 fibers connected in parallel around an ePTFE graft circumferentially. To provide optimized contraction, we designed the new thermal control system. The system consisted of a thermistor, a pressure sensor, and a regulator that was controlled by the adaptive thermodynamic transfer functions. We monitored the parameters and calculated heat transfer function as well as pressure distribution on the graft surface. Then we examined and compared the dynamic contractile pressure and changes in surface temperature. As a result, by the application of the control based on the new feedback system analysis, the circumferential contractile pressure increased by 35%. The adaptive thermodynamic regulation was useful for the selection of alternative thresholds of the surface temperature of the graft. The system could achieve effective contraction for the pulsatile flow generation by the device.

Postoperative mitral leaflet rupture in an infant with Loeys-Dietz syndrome.

This report describes an infantile case of Loeys-Dietz syndrome (LDS) with spontaneous mitral leaflet rupture. The patient was diagnosed with a type B interruption of the aortic arch. Bilateral pulmonary artery banding was performed 5 days after birth. On the 53rd day, intra-cardiac repair was performed without valvuloplasty. Although the operation was successful, mitral regurgitation deteriorated at 4 weeks after operation. On the 88th day, a mitral valvuloplasty was performed and a severely ruptured anterior leaflet was observed. Seven days after valvuloplasty, the mitral valve insufficiency again worsened and a fourth operation was performed. Two tears were observed in the anterior and posterior mitral valve leaflets, and a mitral valve replacement was required. Subsequently, the patient was diagnosed with LDS according to gene mutational status. LDS is known to have a poor prognosis with cardiovascular complications, but valve rupture has not been previously reported in other cases.

[Right ventricular outflow tract reconstruction].

With the increase of adult patients who need repeated surgery long after definitive repair of congenital heart defects in their childhood, right ventricular outflow tract reconstruction (RVOTR) is gaining more importance. From the viewpoint of timing and indication of surgical intervention, early primary repair and annulus preserving procedure have been the 2 current standards of RVOTR;however, long term outcome of both procedures has to be determined by further study. Although a wide variety for materials are used for pulmonary valve replacement in RVOTR, deficient longevity is one of the most common problems, especially when used for young patients mainly due to immunological rejection. In our institute, we originally developed and manufactured expanded polytetrafluoroethylene (ePTFE) valved patches/conduits, which showed excellent clinical results in a former multicenter study in Japan. This improved outcome may partly be attributable to the biocompatibility and low antigenicity of ePTFE and also to the fluid dynamical properties arising from the 2 characteristic structures:bulging sinus and fan-shaped valve. However, to achieve better patients prognosis with good quality of life,there still remains a lot of problems to be solved concerning RVOTR, such as indication and timing of definitive repair and choice of materials for pulmonary valve replacement. This review describes recent surgical strategies and remaining problems of RVOTR.

[The treatment strategy for hypoplastic left heart syndrome].

In the recent years, the outcomes of treatment for hypoplastic left heart syndrome (HLHS) is improved because of perioperative management and procedure. We adopt a strategy of the primary Norwood procedure basically for neonates with HLHS, however bilateral pulmonary artery banding precede in patients with risk factors. In the Norwood procedure, aortic arch is reconstructed without artificial prostheses and pulmonary blood flow is supplied from the Blalock-Taussig shunt or the right ventricle-pulmonary artery shunt by case. We administer high dose vasodilators and nitric oxide gas with low resistance strategy after the Norwood procedure. The survival rate of patients with HLHS after 2005 is 84.2% in this strategy.

Configuration of the neoaortic root after chimney reconstruction in the Norwood procedure.

OBJECTIVES: After staged reconstruction for hypoplastic left heart syndrome, the neoaortic root tends to dilate, and the incidence of significant neoaortic valve insufficiency increases with time. This study aimed to evaluate the mid-term outcomes of the neoaortic root geometries and valve function after chimney reconstruction in the Norwood procedure. METHODS: Between 2013 and 2021, 20 consecutive patients who underwent chimney reconstruction during the Norwood procedure for hypoplastic left heart syndrome and its variants in our institution were enrolled. The actual diameters of the following points were measured, and Z-scores were calculated based on the normal aortic root geometries using the long axis view of echocardiography at the pre-Norwood stage and the lateral view of angiography at pre-Glenn, pre-Fontan, post-Fontan and follow-up (age 5-6 years) stages: neoaortic valve annulus; sinus of Valsalva; sinotubular junction; and ascending aorta just proximal to the anastomosis to the aortic arch. The degree of neoaortic valve regurgitation was evaluated by echocardiography at each stage. RESULTS: The median follow-up period was 3.9 years. Neoaortic roots after chimney reconstruction were spared from progressive dilation over time. With growth, the conical configuration of the neoaortic roots was preserved without geometrical distortion. The Z-scores of the annulus, sinus of Valsalva, sinotubular junction and ascending aorta ranged roughly from 4 to 6, 4 to 6, 2 to 4 and 0 to 2, respectively. All neoaortic valves at each stage had mild or no regurgitation. CONCLUSIONS: Chimney reconstruction prevented neoaortic root dilation and avoided significant neoaortic valve regurgitation in the mid-term. These neoaortic dimensions with smooth flow profiles in the neoaorta after chimney reconstruction may have contributed to the current results. Further studies are needed to clarify the long-term outcomes.

[Re-right ventricular outflow reconstruction].

The timing and indication of re-right ventricular outflow tract reconstruction (reRVOTR) remains controversial. The main cause for reRVOTR is pulmonary stenosis and pulmonary regurgitation. A pressure gradient of more than 50 mmHg between right ventricle and pulmonary artery or a right ventricular systolic pressure/left ventricular systolic pressure ratio higher than 0.7~0.8 is the threshold for recommending reoperation. Pulmonary regurgitation is difficult to quantify and is not an indication for reoperation until there was evidence of increasing right ventricular dilatation. That is, reoperation is recommended when there are mild to moderate pulmonary regurgitation with mild to moderate right ventricular dilatation and severe pulmonary regurgitation with or without right ventricular dilatation. ReRVOTR should be undertaken in maintaining normal right ventricular function, that is,under remaining free of symptoms. Therefore the right ventricular function needs to be assessed over time.

Multiple Pulmonary Artery Plasty With Tissue-Engineered Vascular Grafts.

In pediatric cardiovascular surgery, the autologous pericardium is useful for pulmonary artery augmentation. However, in some cases, the autologous pericardium may not be available for various reasons. Since 2014, we have developed tissue-engineered vascular grafts (TEVGs) and obtained good results. We report a successful case of multiple pulmonary artery plasty with TEVGs for pulmonary atresia/ventricular septal defect with major aortopulmonary collateral arteries. TEVGs are useful alternatives to autologous pericardium in pediatric cardiovascular operations that often require multistage procedures.

A new predictor of the optimal pulmonary artery reconstruction method during the arterial switch operation.

OBJECTIVES: The aim of this study was to more accurately predict the optimal pulmonary artery (PA) reconstruction procedure (Lecompte manoeuvre or original Jatene procedure) during the arterial switch operation, we focused on the horizontal sectioning (HS) angle between the left hilum PA and the great arteries using preoperative computed tomography imaging. METHODS: We defined the HS angle α (ß) as the angle between the tangential line from the posterior (anterior) wall of the left PA at the hilum to the left anterior (right posterior) surface of the main PA and the tangential line from the left surface of the ascending aorta to the left anterior (right posterior) surface of the main PA. We identified 14 consecutive patients diagnosed with transposition of the great arteries or transposition of the great artery-type double-outlet right ventricle who underwent preoperative computed tomography imaging. The original Jatene or Lecompte procedure was used for 9 (OJ group) and 5 (L group) patients. Relationships of the great arteries of the OJ and L groups were side by side in 8 and 2 patients, oblique in 1 and 1 patient and anteroposterior in 0 and 2 patients, respectively. RESULTS: In the OJ group, ß was greater than α in all patients. The median α/ß value was 0.618. In group L, α was greater than ß in all patients. The median α/ß was 1.307. Left PA stenosis caused by stretching was not observed in the L group. Coronary obstruction was not identified in the OJ group. Left PA stenosis behind the neo-ascending aorta was observed in 1 patient in the OJ group and required reoperation. CONCLUSIONS: The HS angle may be a useful predictor of optimal intraoperative PA reconstruction during arterial switch operation, especially for side-by-side or oblique relationships.

Effect of procedural volume on the outcomes of congenital heart surgery in Japan.

OBJECTIVES: The present study developed a new risk model for congenital heart surgery in Japan and determined the relationship between hospital procedural volume and mortality using the developed model. METHODS: We analyzed 47,164 operations performed between 2013 and 2018 registered in the Japan Cardiovascular Surgery Database-Congenital and created a new risk model to predict the 90-day/in-hospital mortality using the Japanese congenital heart surgery mortality categories and patient characteristics. The observed/expected ratios of mortality were compared among 4 groups based on annual hospital procedural volume (group A [5539 procedures performed in 90 hospitals]: ≤50, group B [9322 procedures in 24 hospitals]: 51-100, group C [13,331 procedures in 21 hospitals]: 101-150, group D [18,972 procedures in 15 hospitals]: ≥151). RESULTS: The overall mortality rate was 2.64%. The new risk model using the surgical mortality category, age-weight categories, urgency, and preoperative mechanical ventilation and inotropic use achieved a c-index of 0.81. The observed/expected ratios based on the new risk model were 1.37 (95% confidence interval, 1.18-1.58), 1.21 (1.08-1.33), 1.04 (0.94-1.14), and 0.78 (0.71-0.86) in groups A, B, C, and D, respectively. In the per-procedure analysis, the observed/expected ratios of the Rastelli, coarctation complex repair, and arterial switch procedures in group A were all more than 3.0. CONCLUSIONS: The risk-adjusted mortality rate for low-volume hospitals was high for not only high-risk but also medium-risk procedures. Although the overall mortality rate for congenital heart surgeries is low in Japan, the observed volume-mortality relationship suggests potential for improvement in surgical outcomes.

Engineering analysis of the effects of bulging sinuses in a newly designed pediatric pulmonary heart valve on hemodynamic function.

The purpose of this study was to examine the hemodynamic characteristics of expanded polytetrafluoroethylene (ePTFE) pulmonary valves with bulging sinuses quantitatively in a pediatric pulmonary mechanical circulatory system designed by us, in order to propose the optimal design for clinical applications. In this study, we developed a pediatric pulmonary mock circulation system, which consisted of a pneumatic right ventricular model, a pulmonary heart valve chamber, and a pulmonary elastic compliance tubing with resistive units. The hemodynamic characteristics of four different types of ePTFE valves and a monoleaflet mechanical heart valve were examined. Relationships between the leaflet movements and fluid characteristics were evaluated based on engineering analyses using echocardiography and a high-speed video camera under the pediatric circulatory conditions of the mock system. We successfully performed hemodynamic simulations in our pediatric pulmonary circulatory system that could be useful for quantitatively evaluating the pediatric heart valves. In the simulation study, the ePTFE valve with bulging sinuses exhibited a large eddy in the vicinity of the leaflets, whereas the straight tubing exhibited turbulent flow. The Reynolds number obtained in the valve with bulging sinuses was calculated to be 1667, which was smaller than that in the straight tubing (R (e) = 2454).The hemodynamic characteristics of ePTFE pediatric pulmonary heart valves were examined in our mock circulatory system. The presence of the bulging sinuses in the pulmonary heart valve decreased the hydrodynamic energy loss and increased the systolic opening area. Based on an in vitro experiment, we were able to propose an optimal selection of pulmonary valve design parameters that could yield a more sophisticated pediatric ePTFE valve shape.