Tohru Asai

IgG4-related inflammatory aneurysm of the aortic arch

IgG4‐related sclerosing disease can occur in the cardiovascular system and some inflammatory abdominal aortic aneurysms have been shown to belong to IgG4‐related sclerosing disease. Herein is reported a case of IgG4‐related inflammatory aortic aneurysm of the aortic arch. A 71‐year‐old Japanese man was found to have an aneurysm of the aortic arch with maximum dimension of 5.5 cm. The surgically resected aneurysm wall had conspicuous fibrosclerotic changes, dense lymphoplasmacytic infiltration and occasional obliterative phlebitis in the adventitia; the thickness of the adventitia was 6.5 mm. Immunohistochemistry indicated numerous IgG4‐positive plasma cell infiltrates; 84% of the IgG‐bearing cells were IgG4 positive. The diagnosis of IgG4‐related inflammatory aortic aneurysm of the aortic arch was made. Although previously reported IgG4‐related inflammatory aortic aneurysms were confined to the abdominal aorta, the present case report demonstrates that IgG4‐related inflammatory aortic aneurysm can occur in the aortic arch, thereby extending the spectrum of IgG4‐related periaortitis. Further studies are needed to clarify the spectrum of IgG4‐related sclerosing disease in the cardiovascular system.

Off-pump Bilateral Skeletonized Internal Thoracic Artery Grafting in Elderly Patients

BACKGROUND The purpose of the present study was to compare outcome in propensity score-matched patients, aged 70 years or greater, undergoing isolated off-pump coronary bypass surgery using a bilateral (BITA) or single (SITA) skeletonized internal thoracic artery. METHODS Of 912 consecutive patients undergoing isolated coronary bypass grafting (906 using the off-pump technique without emergent conversion to cardiopulmonary bypass), the 491 aged 70 years or greater undergoing off-pump skeletonized single (n=247) or bilateral (n=244) skeletonized internal thoracic artery grafting were retrospectively analyzed after excluding the 6 who were transferred to our hospital after receiving percutaneous cardiopulmonary bypass, the 72 who had only 1 target in the left coronary area, and the 343 aged less than 70 years. A total of 217 pairs were matched using propensity scores calculated from 9 preoperative factors (0.69). RESULTS The rate of postoperative complications was similar between the groups. The 5-year estimated survival free from overall death and cardiac event, respectively, in the BITA group versus the SITA group were 86.4%±3.2% versus 73.5%±3.9% (p=0.01) and 93.2%±2.7% versus 87.5%±3.0% (p=0.01). In multivariate Cox models, bilateral internal thoracic artery grafting was significantly associated with a lower risk of overall death (hazard ratio 0.56; 95% confidence interval 0.31 to 0.99; p=0.04) and cardiac event (hazard ratio 0.36; 95% confidence interval 0.15 to 0.88; p=0.03). CONCLUSIONS In elderly patients, off-pump in situ left-sided bilateral skeletonized internal thoracic artery grafting is associated with lower risk of overall death and cardiac event than single internal thoracic artery grafting and carries no increased operative risk.

In Off-Pump Surgery, Skeletonized Gastroepiploic Artery is Superior to Saphenous Vein in Patients With Bilateral Internal Thoracic Arterial Grafts

BACKGROUND When the bilateral internal thoracic arteries are grafted to the left coronary arteries, it remains controversial whether the better conduit is provided by grafting the saphenous vein graft (SVG) or the gastroepiploic artery (GEA) to the right coronary artery territory. From the beginning of the present study, we consistently used the GEA in a skeletonized fashion using ultrasound scissors. METHODS From January 2002 to December 2009, 320 consecutive patients with triple-vessel disease underwent in situ bilateral internal thoracic artery grafting to the left coronary arteries. Among the 320 patients, of whom 229 underwent GEA grafting to the right coronary artery and 91 SVG grafting, 85 propensity score-matched pairs were identified (C statistic, 0.68 [p < 0.001]). RESULTS The mean follow-up duration was 5.1 ± 2.2 years. Seven-year freedom from death from all causes was 96.0% in the GEA group and 82.2% in the SVG group (p = 0.03); the rate of freedom from cardiac events (cardiac death, myocardial infarction, angina pectoris, repeat intervention, and heart failure) was 89.3% in the GEA group and 77.5% in the SVG group (p = 0.048). Multivariate Cox proportional hazard regression analysis showed that SVG use (without GEA) (p = 0.04; hazard ratio, 0.31; 95% confidence interval, 0.11 to 0.94) and smoking history (p = 0.02; hazard ratio, 0.22; 95% confidence interval, 0.07 to 0.81) were independent predictors of late cardiac event. CONCLUSIONS Skeletonized GEA grafting to the right coronary artery system is better than SVG grafting in patients with left-sided bilateral internal thoracic arterial grafts.

Off-Pump Bilateral Versus Single Skeletonized Internal Thoracic Artery Grafting in Patients With Diabetes

BACKGROUND We compared the outcomes in propensity score-matched patients with diabetes undergoing off-pump coronary artery bypass grafting using skeletonized bilateral or single internal thoracic artery (ITA) and assessed any benefit of bilateral ITA grafting for outcomes. METHODS Among 770 consecutive patients undergoing isolated coronary artery bypass graft surgery (99.2% by off-pump technique without conversion to cardiopulmonary bypass), 423 patients had diabetes mellitus. After excluding patients who were older than 85 years of age (n = 10) or had only one target vessel at the left coronary area (n = 9), 170 pairs were matched using propensity scores created on the basis of 12 preoperative factors. RESULTS Except for 1 patient, bilateral ITA was anastomosed to the left coronary system. Postoperative serum glucose was well controlled in both groups. The rate of deep sternal infection was similar between the groups. The mean observation period was 3.2 years. The 5-year survival free from overall death in bilateral versus single ITA grafting was 87.5% versus 70.8% (log-rank test p = 0.01). For freedom from cardiac death, the respective rate was 92.1% versus 78.7% (p = 0.01). For freedom from cardiac event, the respective rate was 91.0% versus 72.6% (p = 0.01). In multivariate Cox models, bilateral ITA grafting was significantly associated with a lower risk for overall death (hazard ratio, 0.45; 95% confidence interval, 0.22 to 0.89; p = 0.02), cardiac death (hazard ratio, 0.43; 95% confidence interval, 0.21 to 0.87; p = 0.02), and cardiac event (hazard ratio, 0.42; 95% confidence interval, 0.20 to 0.85; p = 0.02). CONCLUSIONS Off-pump skeletonized left-sided bilateral ITA grafting is associated with better mid-term outcomes than single ITA grafting, without increasing the risk of deep sternal infection.

Inhibition of Transforming Growth Factor-β–Mediated Immunosuppression in Tumor-Draining Lymph Nodes Augments Antitumor Responses by Various Immunologic Cell Types

Tumor-draining lymph nodes (DLN) are the most important priming sites for generation of antitumor immune responses. They are also the location where an immunosuppressive cytokine, transforming growth factor-beta (TGF-beta), plays a critical role in suppressing these antitumor immune responses. We focused on TGF-beta-mediated immunosuppression in DLNs and examined whether local inhibition of TGF-beta augmented antitumor immune responses systemically in tumor-bearing mice models. For inhibition of TGF-beta-mediated immunosuppression in DLNs, C57BL/6 mice subcutaneously bearing E.G7 tumors were administered plasmid DNA encoding the extracellular domain of TGF-beta type II receptor fused to the human IgG heavy chain (TGFR DNA) i.m. near the established tumor. In DLNs, inhibition of TGF-beta suppressed the proliferation of regulatory T cells and increased the number of tumor antigen-specific CD4(+) or CD8(+) cells producing IFN-gamma. Enhancement of antitumor immune responses in DLNs were associated with augmented tumor antigen-specific cytotoxic and natural killer activity in spleen as well as elevated levels of tumor-specific antibody in sera. The growth of the established metastatic as well as primary tumors was effectively suppressed via augmented antitumor immune responses. Inhibition of TGF-beta-mediated immunosuppression in DLNs is significantly associated with augmented antitumor responses by various immunocompetent cell types. This animal model provides a novel rationale for molecular cancer therapeutics targeting TGF-beta.

Early and Long-Term Patency of In Situ Skeletonized Gastroepiploic Artery After Off-Pump Coronary Artery Bypass Graft Surgery

BACKGROUND There is at present no accurate figure for the long-term patency rate of the skeletonized gastroepiploic artery (GEA). METHODS From January 2002 to July 2012, 956 consecutive patients underwent isolated off-pump coronary artery bypass graft (OPCABG) surgery at our institution. Of these, the 424 who underwent GEA grafting and postoperative GEA graft evaluation were the subjects of the present study. Of these 424 subjects, 155 (36.6%) underwent long-term outpatient evaluation using multidetector computed tomography angiography. RESULTS No patient was converted from off pump to on pump surgery. Overall 30-day mortality was 0.5% (2 of 424). The overall early (4 to 21 days after surgery) patency rate of the skeletonized GEA was 98.2% (599 of 610 anastomoses). A total of 215 GEA anastomoses, including 55 sequential bypasses, were followed for long-term evaluation, of which 12, including three sequential bypasses, were found to be occluded. The overall patency rate in skeletonized GEA grafting over a mean follow-up period of 73 months was 94.4% (203 of 215). The cumulative patency rate of the skeletonized GEA was 97.8% at 30 days, 96.7% at 1 year, 96.0% at 3 years, 94.7% at 5 years, and 90.2% at 8 years after surgery. Multivariate Cox proportional hazard regression analysis showed that target vessel stenosis (p = 0.008, hazard ratio 0.086, 95% confidence interval: 0.014 to 0.53) was the only independent predictor of late graft occlusion. CONCLUSIONS We demonstrated an accurate long-term patency rate for the skeletonized GEA superior to that for pedicled GEA or saphenous vein graft. A low-grade degree of target vessel stenosis was the only risk factor for late GEA occlusion.

Preoperative hemoglobin A1c predicts atrial fibrillation after off-pump coronary bypass surgery.

OBJECTIVE Diabetes mellitus has been recognized as a risk factor for mortality and morbidity after coronary bypass grafting, but a significant association between diabetes mellitus and postoperative atrial fibrillation (AF) has not been found. Although a recent study demonstrated a potential link between preoperative hemoglobin A1c level and risk of postoperative AF, there has not been sufficient examination of this relationship. We aimed to investigate the association between preoperative hemoglobin A1c and AF after isolated off-pump coronary bypass grafting. METHODS Of 912 consecutive patients undergoing isolated coronary bypass surgery, 805 were retrospectively analyzed for AF after excluding the following 107 cases: emergency (n=81), chronic AF (n=18), and pacemaker rhythm (n=8). We performed a group analysis with hemoglobin A1c levels categorized into tertiles of the baseline distribution and a continuous analysis based on 1% increments in hemoglobin A1c levels. The cutoff points for the tertiles were as follows: lower, 3.8-5.6% (n=283); middle, 5.7-6.7% (n=282); upper, 6.8-11.4% (n=240). RESULTS AF occurred in 159 patients (19.8%) after surgery. The median value (25th-75th percentile) of preoperative hemoglobin A1c was significantly lower in patients who developed AF than in those who did not (5.8 (5.4-6.3) vs 6.1 (5.5-7.2), p=0.01). The incidence of postoperative AF was 28.3% (80/283) in the lower tertile, 17.4% (49/282) in the middle tertile, and 12.5% (30/240) in the upper tertile (p for trend=0.01). The unadjusted odds ratio (95% confidence interval) for the association between hemoglobin A1c and postoperative AF was 0.70 (0.61-0.83) per 1% increase and 0.42 (0.29-0.70) for the upper versus the lower tertile. This association persisted after adjustment for the univariate predictors (0.74 (0.60-0.92) per 1% increase; 0.54 (0.31-0.90) for upper vs lower tertile) and the known risk factors (0.78 (0.63-0.95) per 1% increase; 0.55 (0.35-0.88) for upper vs lower tertile). The area under the receiver operator characteristic curve (95% confidence interval) for preoperative hemoglobin A1c as a predictor of postoperative AF was 0.70 (0.65-0.75) (p=0.01). CONCLUSIONS Preoperative hemoglobin A1c independently predicts the occurrence of AF after isolated off-pump coronary bypass grafting.

Off-Pump Bilateral Versus Single Skeletonized Internal Thoracic Artery Grafting in High-Risk Patients

Background— We compared the outcomes in propensity score-matched high-risk patients (European System for Cardiac Operative Risk Evaluation [EuroSCORE] ≥5) undergoing off-pump coronary artery bypass graft surgery using bilateral or single skeletonized internal thoracic artery (ITA). Methods and Results— Of 794 consecutive patients undergoing isolated coronary artery bypass graft surgery (788 by the off-pump technique without emergent conversion to cardiopulmonary bypass), the 536 who had a EuroSCORE ≥5 and underwent off-pump skeletonized single (n=236) or bilateral (n=300) ITA were retrospectively analyzed after excluding the 6 who were transferred to our hospital after receiving percutaneous cardiopulmonary support, the 45 who had only 1 target in the left-side coronary area, and the 207 with EuroSCORE <5. A total of 235 pairs were matched using propensity scores calculated from 7 preoperative factors (C statistic, 0.65). The rate of postoperative complications was similar between the groups. The mean observation period was 3.2 years. The 5-year estimated survival rate free from overall death and cardiac event in patients receiving bilateral versus single ITA grafting was 85.8±5.5% versus 74.8±4.9% (P=0.002) and 87.4±4.6% versus 66.1±5.7% (P=0.001), respectively. In multivariate Cox proportional hazard models, bilateral ITA grafting was significantly associated with a lower risk of overall death (hazard ratio, 0.56; 95% CI, 0.32 to 0.87; P=0.009) and cardiac event (hazard ratio, 0.40; 95% CI, 0.24 to 0.69; P=0.001). Conclusions— In high-risk patients, off-pump skeletonized left-sided bilateral in situ ITA grafting is associated with lower risk of overall death and cardiac event than single ITA grafting without increased operative risk.

Safety and efficacy of central cannulation through ascending aorta for type A aortic dissection

The femoral and axillary arteries are common arterial cannulation sites for repair of type A dissection. However, these peripheral approaches involve certain problems. From January 2002 to August 2009, a total of 77 patients underwent emergency surgery for acute type A dissection. Central cannulation was applied in 26 patients and peripheral cannulation in 51. The arterial cannulation site was decided according to preoperative computed tomography findings, the patients condition, and intraoperative epiaortic ultrasonography findings. Central cannulation was avoided in cases of cardiac tamponade with shock. A cannula was inserted under ultrasound guidance using the Seldinger technique. Preoperative patient comorbidities and dissection-related complications were equally distributed between the two groups. Central cannulation was successfully performed in all 26 cases without incident. Operation time, cardiopulmonary bypass time, mean intubation time and mean intensive care unit stay duration were significant shorter in the central group. One patient (4%) died in the central group compared with four patients (8%) in the peripheral group (P=0.45). Direct central cannulation was successful for repair of type A dissection in selected patients and produced equal or superior surgical data to peripheral cannulation, thus providing one option in the approach to this condition.

Cancer‐associated fibroblast‐targeted strategy enhances antitumor immune responses in dendritic cell‐based vaccine

Given the close interaction between tumor cells and stromal cells in the tumor microenvironment (TME), TME‐targeted strategies would be promising for developing integrated cancer immunotherapy. Cancer‐associated fibroblasts (CAFs) are the dominant stromal component, playing critical roles in generation of the pro‐tumorigenic TME. We focused on the immunosuppressive trait of CAFs, and systematically explored the alteration of tumor‐associated immune responses by CAF‐targeted therapy. C57BL/6 mice s.c. bearing syngeneic E.G7 lymphoma, LLC1 Lewis lung cancer, or B16F1 melanoma were treated with an anti‐fibrotic agent, tranilast, to inhibit CAF function. The infiltration of immune suppressor cell types, including regulatory T cells and myeloid‐derived suppressor cells, in the TME was effectively decreased through reduction of stromal cell‐derived factor‐1, prostaglandin E2, and transforming growth factor‐β. In tumor‐draining lymph nodes, these immune suppressor cell types were significantly decreased, leading to activation of tumor‐associated antigen‐specific CD8+ T cells. In addition, CAF‐targeted therapy synergistically enhanced multiple types of systemic antitumor immune responses such as the cytotoxic CD8+ T cell response, natural killer activity, and antitumor humoral immunity in combination with dendritic cell‐based vaccines; however, the suppressive effect on tumor growth was not observed in tumor‐bearing SCID mice. These data indicate that systemic antitumor immune responses by various immunologic cell types are required to bring out the efficacy of CAF‐targeted therapy, and these effects are enhanced when combined with effector‐stimulatory immunotherapy such as dendritic cell‐based vaccines. Our mouse model provides a novel rationale with TME‐targeted strategy for the development of cell‐based cancer immunotherapy.