New evaluation of the tumor immune microenvironment of non-small cell lung cancer and its association with prognosis.

BACKGROUND: A better understanding of the tumor immune microenvironment (TIME) will facilitate the development of prognostic biomarkers and more effective therapeutic strategies in patients with lung cancer. However, little has been reported on the comprehensive evaluation of complex interactions among cancer cells, immune cells, and local immunosuppressive elements in the TIME. METHODS: Whole-exome sequencing and RNA sequencing were carried out on 113 lung cancers. We performed single sample gene set enrichment analysis on TIME-related gene sets to develop a new scoring system (TIME score), consisting of T-score (tumor proliferation), I-score (antitumor immunity) and S-score (immunosuppression). Lung cancers were classified according to a combination of high or low T-score, I-score, and S-scores (eight groups; G1-8). Clinical and genomic features, and immune landscape were investigated among eight groups. The external data sets of 990 lung cancers from The Cancer Genome Atlas and 76 melanomas treated with immune checkpoint inhibitors (ICI) were utilized to evaluate TIME scoring and explore prognostic and predictive accuracy. RESULTS: The representative histological type including adenocarcinoma and squamous cell carcinoma, and driver mutations such as epidermal growth factor receptor and TP53 mutations were different according to the T-score. The numbers of somatic mutations and predicted neoantigens were higher in Thi (G5-8) than Tlo (G1-4) tumors. Immune selection pressure against neoantigen expression occurred only in Thi and was dampened in Thi/Ilo (G5-6), possibly due to a reduced number of T cells with a high proportion of tumor specific but exhausted cells. Thi/Ilo/Shi (G5) displayed the lowest immune responses by additional immune suppressive mechanisms. The T-score, I-score and S-scores were independent prognostic factors, with survival curves well separated into eight groups with G5 displaying the worst overall survival, while the opposite group Tlo/Ihi/Slo (G4) had the best prognosis. Several oncogenic signaling pathways influenced on T-score and I-scores but not S-score, and PI3K pathway alteration correlated with poor prognosis in accordance with higher T-score and lower I-score. Moreover, the TIME score predicted the efficacy of ICI in patients with melanoma. CONCLUSION: The TIME score capturing complex interactions among tumor proliferation, antitumor immunity and immunosuppression could be useful for prognostic predictions or selection of treatment strategies in patients with lung cancer.

Cardiac tamponade due to rupture of a giant coronary artery aneurysm with a coronary arteriovenous fistula: a case report.

BACKGROUND: Coronary artery aneurysm (CAA) is defined as dilatation exceeding 1.5 times the width of the normal adjacent coronary artery segments. CAA usually causes few symptoms, and rupture is rare, but can be lethal due to cardiac tamponade when it does occur. CASE PRESENTATION: A 79-year-old woman presented with presyncope and back pain. Emergency surgery was performed based on a diagnosis of cardiac tamponade due to either rupture of coronary arteriovenous fistula or CAA. At surgery, a rupture site was located on the wall of the giant CAA, with a diameter of 55 mm, originating from the ostium of the right coronary artery. Suture closure of the inflow and outflow of the aneurysm was performed, and the aneurysmal cavity was obliterated by multiple sutures. The patient made an uneventful recovery and was discharged from hospital on postoperative day 13. CONCLUSION: On the basis of this case, we propose considering rupture of a CAA as one of the causes of cardiac tamponade.

Neuroprotective effect of pressure-oriented flow regulation and pH-stat management in selective antegrade brain perfusion during total aortic arch repair.

OBJECTIVES: The aim of this study was to assess the safety and effectiveness of our selective antegrade brain perfusion (SABP) strategy, which is characterized by moderate hypothermic and low-pressure management under pH-stat using a completely closed cardiopulmonary bypass circuit with a single centrifugal pump. METHODS: Forty-nine consecutive patients (median age, 74) underwent total aortic arch replacement using a 4-branched graft. SABP was conducted with individual cannulation in all arch vessels. The SABP flow rate was monitored, and the flow rates of each arch vessel were also measured in patients with available data. RESULTS: One patient died of cerebral infarction, and 7 had transient neurological deficits without apparent findings on postoperative imaging studies and without residual sequels at hospital discharge. The operation, cardiopulmonary bypass, cardiac arrest, circulatory arrest and SABP times were 327 min (interquartile range, 292-381), 211 (184-247), 107 (84.8-138.3), 54.0 (48-68) and 137 (114-158), respectively. The total flow of the SABP was 18.1 ml/kg/min (15.7-20.9). The flow rates of the brachiocephalic, the left carotid and the left subclavian arteries were 9.5 ml/kg/min (7.7-11.5), 4.2 (2.8-5.7) and 4.5 (3.7-5.5), respectively. Only the flow rate of the brachiocephalic artery was significantly correlated with the total SABP flow rate (Spearman rank correlation coefficient, r = 0.58, P < 0.01). CONCLUSIONS: The moderate hypothermic, high-flow, low-pressure SABP strategy with pH-stat management can be applied in adult aortic surgery; however, the feasibility and effectiveness of this concept need further evaluation in a prospective controlled study.

Determinants of recurrent tricuspid regurgitation following tricuspid valve annuloplasty during mitral valve surgery.

BACKGROUND: The purpose of this study was to determine risk predictors for recurrent tricuspid regurgitation (TR) following tricuspid valve annuloplasty during mitral valve surgery. METHODS: Ninety-eight consecutive patients underwent tricuspid valve annuloplasty concomitant with mitral valve repair (71 patients), replacement (16 patients), or other procedures over a 10-year period. Fifty-seven patients underwent surgery with a flexible band and 41 with a rigid ring. RESULTS: Late TR progression (≥2/4) occurred in eight (14.0%) of flexible band patients, and in nine (22.0%) rigid ring patients. Multivariate analysis did not identify the superiority of one annuloplasty device over the other to prevent recurrent TR. Multivariate risk predictors of late TR progression were late atrial fibrillation (hazard ratio [HR]: 3.78; 95% confidence interval [CI]: 1.19-12.0), and recurrent mitral regurgitation; HR; 4.46; 95%CI; 1.52-13.1). Freedom from TR progression at 5 years was 89.2% in atrial fibrillation-free patients compared to 56.8% in those with atrial fibrillation (log-rank, P = 0.018), and 89.8% in mitral regurgitation-free patients compared to 55.3% in those with recurrent mitral regurgitation (log-rank, P = 0.003). CONCLUSIONS: A durable mitral valve repair and preservation of sinus rhythm are the keys to preventing late TR progression.

Efficacy of Tolvaptan on Fluid Management After Cardiovascular Surgery Using Cardiopulmonary Bypass.

OBJECTIVE: To investigate the efficacy of the selective vasopressin V2-receptor antagonist tolvaptan in postoperative fluid management after cardiovascular surgery using cardiopulmonary bypass. DESIGN: A retrospective cohort study. SETTING: A tertiary care center. PARTICIPANTS: The study comprised 99 patients undergoing cardiovascular surgery using cardiopulmonary bypass. INTERVENTIONS: Oral tolvaptan was administered after surgery. MEASUREMENTS AND MAIN RESULTS: Fifty-one patients treated with tolvaptan were compared with 48 patients treated with intravenous diuretics. Urine volume, the time interval until the patients' body weight returned to the preoperative value, and the length of oxygen dependency after extubation were assessed as surrogate markers for resolution of fluid overload. Urine output on postoperative days 1 and 2 was significantly higher in the tolvaptan-treated patients (29.2 v 20.1 mL/kg/day, p = 0.001; 43.0 v 27.4 mL/kg/day, p<0.001, respectively). Postoperative body weight returned to baseline in 49 tolvaptan-treated patients compared with 33 patients treated with intravenous diuretics (96.1% v 68.8%, p<0.001). Among those with successful body weight reduction, the time interval was shorter in the tolvaptan-treated patients (5 v 7 days, p = 0.006). The length of oxygen dependency after extubation also was shorter in the tolvaptan-treated patients (2 v 3 days, p = 0.006). The urine osmolarity reduction rate before and 4 hours after the first dose of tolvaptan emerged as a significant predictor of its efficacy with a cutoff point of 33.7%, sensitivity of 0.73, and specificity of 0.67 (p = 0.030). CONCLUSION: Tolvaptan facilitated early improvement of postoperative fluid overload after cardiovascular surgery.

Emergency Off-Pump Coronary Artery Bypass Graft Surgery for Patients on Preoperative Intraaortic Balloon Pump.

BACKGROUND: The aim of this study was to investigate early and long-term outcomes of patients with acute coronary syndrome preoperatively requiring intraaortic balloon pump support who underwent emergency off-pump coronary artery bypass graft surgery. METHODS: One hundred and fifteen patients on preoperative intraaortic balloon pump receiving emergency off-pump coronary artery bypass graft surgery over an 11-year period were evaluated. The median age was 71 years (range, 33 to 87). Acute myocardial infarction and unstable angina were present in 54 patients (47.0%) and 61 patients (53.0%), respectively. Left main disease and triple-vessel disease without left main involvement were present in 74 patients (64.3%) and 33 patients (28.7%), respectively. RESULTS: There were 3 perioperative deaths. Complete surgical revascularization was accomplished in 82 patients (71.3%), and in situ internal thoracic artery graft was used in 96 (83.5%). Late survival, freedom from major adverse cardiac and cerebrovascular events, and freedom from repeat revascularization rates at 5 years were 83.3%, 73.5%, and 84.2%, respectively. The Cox multivariate prognostic predictors of total mortality were preoperative renal impairment (hazard ratio [HR] 7.90; 95% confidence interval [CI]: 3.06 to 20.4) and low ejection fraction (HR 0.94, 95% CI: 0.88 to 0.99). The multivariate risk predictors of major adverse cardiac and cerebrovascular events were preoperative renal impairment (HR 2.68, 95% CI: 1.00 to 7.19) and peripheral vascular disease (HR 2.81, 95% CI: 1.05 to 7.51), and complete revascularization was protective (HR 0.39, 95% CI: 0.19 to 0.81). The multivariate risk factor of repeat revascularization was previous percutaneous coronary intervention (HR 3.26, 95% CI: 1.14 to 9.33), and complete surgical revascularization was also protective (HR 0.30, 95% CI: 0.11 to 0.85). CONCLUSIONS: Off-pump coronary artery bypass graft surgery is a feasible option for patients requiring preoperative intraaortic balloon pump support.

[Pulmonary Arterioplasty with Autologous Pericardial Patch for Lung Cancer].

Three patients underwent left upper lobectomy with arterioplasty of left pulmonary artery trunk for lung cancer. For pulmonary arterioplasty, wide wedge resection and patch plasty with autologous pericardium was performed. No in-hospital death or no postoperative complications due to arterioplasty was encountered. The mean follow-up period was 3.6 years and long-term patency of the reconstructed pulmonary artery was confirmed by computed tomography in all patients.

[A patient with descending necrotizing mediastinitis successfully treated by cervical, transthoracic, and mediastinoscopic drainage].

A 62-year-old man was admitted to a local hospital for cervical abscess. He was given an antibiotic, but his symptoms worsened. Computed tomographic cervical and chest scan 6 days after hospitalization revealed that left cervical abscess extended to the mediastinum. He was transferred to our hospital following a diagnosis of descending necrotizing mediastinitis. Cervical and left transthoracic drainage through a left cervical incision and a left antero-axillary thoracotomy were performed on hospital day 1. On hospital day 2, chest radiograph revealed enlargement of the superior mediastinal shadow. Mediastinoscopic drainage was performed for the abscess in the paratracheal space on hospital day 3. Two mediastinal drainage tubes were placed in the upper and middle mediastinal space using mediastioscopy. Postoperatively, he required additional right transthoracic drainage by chest tube for pleural effusion on hospital day 5. Then his clinical and radiological findings gradually improved, and he was discharged from hospital day 37.

[Recurrent mediastinal desmoid tumor treated by surgical resection ; report of a case].

We report a rare case of mediastinal desmoid tumor in a 17-year-old man. The patient was a 17-year old man who had underwent surgery for mediastinal tumor at our hospital 2 years before. The tumor was diagnosed as a solitary fibrous tumor of the mediastinum. After 2 years, chest computed tomography(CT) and magnetic resonance imaging( MRI) showed a mass at the previously resected site. Surgery was performed again under the diagnosis of recurrent tumor. The tumor densely adhered to the superior vena cava, right innominate vein, pericardium, and the right lung. The tumor was completely resected with the aid of the partial extracorporeal circulation. Finally, both previously resected tumor and the recurrent tumor were diagnosed pathologically as desmoid tumors.

Hemodynamic performance of the Edwards Prima Plus stentless valve at 1 year.

PURPOSE: The Edwards Prima Plus stentless valve bioprosthesis (EPPSV) is a porcine aortic root cylinder with resected coronary ostia, fixed in glutaraldehyde at low pressure, and chemically treated to prevent calcification. Utilization of this valve was approved in January 2005 in Japan. The purpose of this study was to evaluate the early hemodynamic performance of EPPSVs in our experience. MATERIALS AND METHODS: From April 2005 to January 2006, a total of 21 patients underwent aortic valve replacement with EPPSVs. The hemodynamic performance of EPPSVs was evaluated at the time of discharge (2 weeks) and at 1 year by transthoracic two-dimensional Doppler echocardiography. RESULTS: There was one non-valve-related early death and one non-valve-related late death. Hemodynamic data were available for comparison from the time of discharge and at 1 year postoperatively in 19 patients (mean valve size 22 +/- 1 mm). Hemodynamic follow-up showed a significant decrease in the peak and mean transvalvular pressure gradients at discharge (37 +/- 16 and 18 +/- 8 mmHg, respectively) and 1 year postoperatively (25 +/- 7 and 12 +/- 4 mmHg, respectively) (P < 0.01). The effective orifice area increased significantly between the time of discharge (1.31 +/- 0.31 cm2) and 1 year (1.57 +/- 0.37 cm2) (P < 0.05) postoperatively. The left ventricular mass index was significantly reduced from the time of discharge (167 +/- 49 g/m2) to 1 year postoperatively (126 +/- 47 g/m2) (P < 0.001). CONCLUSION: EPPSVs have been associated with high early transprosthetic gradients. Such gradients tend to regress, with significant improvement at 1 year and concomitant regression of left ventricular hypertrophy.

Locally applied cilostazol suppresses neointimal hyperplasia and medial thickening in a vein graft model.

BACKGROUND: Pathological changes in vein grafts begin immediately after arterial circulation is applied to the grafts. Chemical mediator stimulation and mechanical strain induce neointimal hyperplasia and medial thickening of the vein grafts, resulting in their failure. We investigated the inhibitory effect of locally applied cilostazol, an inhibitor of cyclic adenosine monophosphate phosphodiesterase III, on neointimal hyperplasia and medial thickening of the grafts. METHODS AND RESULTS: We established a distal anastomotic stricture model of femoral vein-abdominal aorta interposition grafting in rats. In this model, neointimal hyperplasia was observed not only at the distal anastomotic sites, but also in the graft body at postoperative day 14 and was markedly progressed at day 28. A strong expression of tenascin-C was found in the media and neointima of the graft body. In the grafts around which cilostazol was administered locally using Pluronic gel, neointimal hyperplasia was significantly suppressed compared with control grafts treated with the gel alone, with the mean neointimal cross-sectional area reduced by 87.1% for the graft body and by 78.9% for the distal anastomotic sites and mean medial cross-sectional area of the graft body reduced by 54.2% at day 28 versus the control. Cilostazol treatment decreased cell proliferation and the number of tenascin-C-producing cells seen by in situ hybridization, but the expression of tenascin-C protein was not suppressed. CONCLUSION: We concluded that a single perivascular application of cilostazol inhibits neointimal hyperplasia and medial thickening of vein grafts in a rat model.

A case of isolated tricuspid valve infective endocarditis caused by Abiotrophia defectiva.

A 17-year-old man with a history of dental caries was admitted to our hospital because of 1-week high fever. There was no history of previous cardiac disease. He denied drug abuse. Blood culture was positive for Abiotrophia defectiva. Echocardiography demonstrated large vegetation attached to the anterior cusp of the tricuspid valve with moderate regurgitation. Although he was treated with antibiotics for more than 3 weeks, he had chest pain due to septic pulmonary emboli on chest computed tomography. Surgical resection of the vegetation was performed. The postoperative course was uneventful and he is doing well at the time of follow-up.

Method of cell transplantation promoting the organization of intraarterial thrombus.

BACKGROUND: Endovascular aortic repairs have been developed as less invasive treatments for aortic aneurysms. Some aneurismal cavities, however, remain without organization, causing a re-expansion of the aneurysms. We studied cell transplantation into the aneurismal sac to promote the organization of thrombus for the complete healing of aneurysms. METHODS AND RESULTS: Skin fibroblasts and skeletal myoblasts were isolated from rats for cell transplantation. An intraarterial thrombus model was made by ligation of the carotid artery. Culture medium (medium group, n=11), collagen gel (gel group, n=11), fibroblasts with collagen gel (F group, n=15), myoblasts with collagen gel (M group, n=12), or mixture of fibroblasts and myoblasts with collagen gel (F+M group, n=14) were injected into the thrombus. After 28 days, histologically, the arterial lumens of the F and M groups were partly filled with fibrous tissues, whereas in the F+M group organization was almost completed and luminal sizes diminished. Immunohistochemical staining demonstrated that alpha-smooth muscle actin-positive cells were more abundantly contained in the organized area of the F+M group than in the other groups. We also analyzed cellular function in vitro with immunofluorescence; coculture of fibroblasts and myoblasts showed that the fraction of alpha-smooth muscle actin-positive fibroblasts increased. This phenomenon accounts for the rapid organization of thrombus in the F+M group in vivo. CONCLUSIONS: Cell transplantation accelerated thrombus organization. Especially, myoblasts enhanced differentiation of fibroblasts into myofibroblasts, contributing to rapid thrombus organization. Cell transplantation into unorganized spaces seems applicable to endovascular treatment of aneurysms.

Tenascin-C is an essential factor for neointimal hyperplasia after aortotomy in mice.

OBJECTIVE: Neointimal hyperplasia at the arterial anastomotic site is a critical problem during cardiovascular surgery. It has been suggested that tenascin-C (TN-C), an extracellular matrix (ECM) glycoprotein, might play an important role in neointimal hyperplasia. In this study, the direct contribution of tenascin-C to neointimal hyperplasia after aortotomy was examined using tenascin-C-deficient (TNKO) mice. METHODS AND RESULTS: A simple aortotomy model was constructed in mice. In wild-type (WT) mice, neointimal hyperplasia was observed at the suture sites at days 14 and 28. Immunohistochemical staining showed strong expression of tenascin-C in both neointima and media around the suture line at day 14. At day 28, tenascin-C staining was detected in neointima, but not in media. In tenascin-C-deficient mice, much less neointimal hyperplasia was seen compared to that in wild-type mice, and the mean neointima/media area ratio decreased to 52.8% and 34.3% at days 14 and 28, respectively. The proliferating cell nuclear antigen indices in wild-type mice were twice those in tenascin-C-deficient mice at day 14. There were fewer Alcian blue-positive proteoglycans deposited in the neointima of tenascin-C-deficient mice than in wild-type mice. These results suggest that tenascin-C promotes neointimal cell migration and proliferation, and the deposition of proteoglycans. CONCLUSIONS: We have presented direct evidence that tenascin-C is a crucial molecule in neointimal hyperplasia at anastomotic sites.

Locally applied cilostazol suppresses neointimal hyperplasia by inhibiting tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts.

OBJECTIVE: Accumulation of smooth muscle cells and extracellular matrix in the intima of artery bypass grafts induces neointimal hyperplasia, resulting in graft failure. We investigated the inhibitory effect of locally applied cilostazol, an inhibitor of cyclic adenosine monophosphate phosphodiesterase III, on neointimal hyperplasia and the role of tenascin-C synthesis and smooth muscle cell proliferation in free artery grafts. Methods and results We established a distal anastomotic stricture model of free artery graft stenosis using rat abdominal aorta. In this model, neointimal hyperplasia was observed not only in the distal anastomotic site but also in the graft body at postoperative day 14 and was markedly progressed at day 28. Strong expression of tenascin-C was found in the media and neointima of the graft body. When cilostazol was locally administered around the graft using Pluronic gel, neointimal hyperplasia of the graft was significantly suppressed in comparison with gel-treated control graft. The mean neointima/media area ratio was reduced by 86.6% for the graft body and by 75.8% for the distal anastomotic site versus the control. Cilostazol treatment decreased cell proliferation and tenascin-C expression in the neointima. In an in vitro experiment using cultured smooth muscle cells isolated from rat aorta, cilostazol completely suppressed the tenascin-C mRNA expression induced by platelet-derived growth factor-BB. CONCLUSION: A single topical administration of cilostazol may suppress neointimal hyperplasia by inhibiting cell proliferation and tenascin-C synthesis in free artery grafts, presenting the potential for clinical use in vascular surgery.

Use of a new venous cannula for minimally invasive cardiac surgery.

Interest in minimally invasive cardiac surgery (MICS) for cardiac disease continues to increase, because it causes less surgical trauma and produces a better cosmetic appearance. We introduced the transxiphoid approach without sternotomy for correction of congenital heart defects. To improve exposure of the cardiac lesion during MICS, we developed a new venous cannula that is made of wire reinforced silicone, with an inflatable balloon attached at the tip. The advantages of this cannula are its extreme flexibility and that a tape does not need to be placed around the vena cava. During a period of 12 months, eight children underwent closure of atrial septal defects. The approach consisted of a 4 to 5 cm low midline incision with division of the xiphoid only. The new venous cannula was used as the superior vena cava cannula, all the patients survived the operation. This new venous cannula provided better exposure during cardiac surgery through a limited incision and is beneficial for minimally invasive cardiac surgery.