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Objective: To evaluate the efficacy of pleurodesis using OK-432 after cardiac surgery in the neonatal period or early infancy. Methods: We retrospectively reviewed the data of 11 consecutive patients who underwent cardiac surgery in the neonatal period or early infancy and pleurodesis using OK-432 for persistent postoperative pleural effusion in two institutions. Results: The median age at surgery was 8 days (interquartile range [IR], 2–18) with a body weight of 2.84 kg (IR, 2.30–3.07). The maximum amount of pleural drainage before pleurodesis was 94.7 (IR, 60.2–107.7) ml/kg/day. Pleurodesis was initiated at postoperative day 20 (IR, 17–22) and performed in bilateral pleural spaces in seven patients and unilateral in four. The median numbers of injection were 4 (IR, 3–6) times per patient and 3 (IR, 2–3) times per pleural space. In 10 patients, pleural effusion was decreased effectively, and drainage tubes were removed without reaccumulation within 15 (IR, 12–28) days after initial pleurodesis. However, in one patient, with severe lymphedema, pleural effusion was uncontrollable, resulting in death due to sepsis. Adverse events were observed in nine patients; temporal deterioration of lung compliance and arterial blood gas occurred in two, insufficient drainage requiring new chest tube(s) in five, temporal atrial tachyarrhythmia in one, and lymphedema in four. Conclusions: Pleurodesis using OK-432 is effective and reliable for persistent postoperative pleural effusion in neonates and early infants. Most of the complications, which derived from inflammatory reactions, were temporary and controllable. However, severe lymphedema is difficult to control. [ABSTRACT FROM AUTHOR]

A five-year-old boy was diagnosed with the ventricular septal rupture and ventricular aneurysm after blunt chest trauma in child abuse. Because of the intractable heart failure, he underwent operation in subacute period. Postoperative course was uneventful. The blunt cardiac injury in children can be caused by mild trauma and can be lethal. Surgical intervention should be considered when the clinical condition is unstable. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Living-donor lobar lung transplantation (LDLLT) is a life-saving procedure for critically ill patients with various lung diseases, including pulmonary hypertension (PH). However, there are concerns regarding the development of heart failure with pulmonary oedema after LDLLT in which only 1 or 2 lobes are implanted. This study aimed to compare the preoperative conditions and postoperative outcomes of LDLLT with those of cadaveric lung transplantation (CLT) in PH patients. METHODS: Between 2008 and 2021, 34 lung transplants for PH, including 12 LDLLTs (5 single and 7 bilateral) and 22 bilateral CLTs, were performed. Preoperative variables and postoperative outcomes were retrospectively compared between the 2 procedures. RESULTS: Based on the preoperative variables of less ambulatory ability (41.7% vs 100%, P < 0.001), a higher proportion of World Health Organization class 4 (83.3% vs 18.2%, P < 0.001) and higher mean pulmonary artery pressure (74.4 vs 57.3 mmHg, P = 0.040), LDLLT patients were more debilitated than CLT patients. Nevertheless, hospital death was similar between the 2 groups (8.3% vs 9.1%, P > 0.99, respectively). Furthermore, the 5-year overall survival rate was similar between the 2 groups (90.0% vs 76.3%, P = 0.489). CONCLUSIONS: Although LDLLT patients with PH had worse preoperative conditions and received smaller grafts than CLT patients, LDLLT patients demonstrated similar perioperative outcomes and prognoses as CLT patients. LDLLT is a viable treatment option for patients with PH. Lung transplantation (LTx) has been performed as the final option for saving the lives of patients with end-stage pulmonary diseases with satisfactory outcomes, and the number of LTx procedures performed has been gradually increasing [1]. [ABSTRACT FROM AUTHOR]

Background: Breast-conserving surgery with radiotherapy is one of standard treatments for early breast cancer. However, it is regarded as an option to treat elderly patients with small hormone receptor-positive breast cancer with breast-conserving surgery and hormone therapy without radiotherapy. We conducted two sequential prospective studies to examine the feasibility of breast-conserving surgery without radiotherapy since 2002 and present the results. Patients and methods: Primary female breast cancer patients who fulfilled the strict eligibility criteria were prospectively enrolled in two sequential studies named WORTH 1 and 2. The surgical materials were sliced in 5-mm intervals and all slices were examined microscopically. Postoperative radiotherapy was not allowed, but tamoxifen or anastrozole was administered for 5 years. Ipsilateral breast tumor recurrence (IBTR)-free survival was the primary outcome. Results: The data of the two studies were combined (N = 321). The median follow-up period for IBTR was 94 months (4–192 months). Only three patients were treated with adjuvant chemotherapy. The 5- and 10-year IBTR-free rates were 97.0% and 90.5%, respectively. The age at operation and PR status affected IBTR rates independently. When we calculated IBTR-free rates of patients who were 65 years of age or older at the time of surgery and had PR-positive tumors, the 5- and 10-year IBTR rates were both 98.4%. Conclusions: Our "5-mm-thick slice and 5-mm free-margin" method may be effective to select patients who can be treated by breast-conserving surgery and hormone therapy without radiotherapy. [ABSTRACT FROM AUTHOR]

Decellularized xenogeneic vascular grafts can be used in revascularization surgeries. We have developed decellularization methods using high hydrostatic pressure (HHP), which preserves the extracellular structure. Here, we attempted ex vivo endothelialization of HHP-decellularized xenogeneic tissues using human endothelial cells (ECs) to prevent clot formation against human blood. Slices of porcine aortic endothelium were decellularized using HHP and coated with gelatin. Human umbilical vein ECs were directly seeded and cultured under dynamic flow or static conditions for 14 days. Dynamic flow cultures tend to demonstrate higher cell coverage. We then coated the tissues with the E8 fragment of human laminin-411 (hL411), which has high affinity for ECs, and found that Dynamic/hL411showed high area coverage, almost reaching 100% (Dynamic/Gelatin vs Dynamic/hL411; 58.7 ± 11.4 vs 97.5 ± 1.9%, P = 0.0017). Immunostaining revealed sufficient endothelial cell coverage as a single cell layer in Dynamic/hL411. A clot formation assay using human whole blood showed low clot formation in Dynamic/hL411, almost similar to that in the negative control, polytetrafluoroethylene. Surface modification of HHP-decellularized xenogeneic endothelial tissues combined with dynamic culture achieved sufficient ex vivo endothelialization along with prevention of clot formation, indicating their potential for clinical use as vascular grafts in the future. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Excessive and chronic inflammation after a myocardial infarction (MI) is associated with left ventricular remodelling and impaired cardiac function. Among inflammatory cells, macrophages play a critical role in polarizing proinflammatory M1 or the reparative M2 subtype. Pioglitazone (PGZ) is reported to regulate macrophage polarization to the M2 subtype. Our goal was to validate the therapeutic effects and the mechanisms of PGZ utilizing a drug delivery system. METHODS Poly L-lactic-co-glycolic acid microspheres (MS) incorporating PGZ were prepared. To validate the therapeutic potential of PGZ-MS, Sprague-Dawley rats were subjected to permanent left coronary artery ligation to induce an MI. Placebo-MS (100 μg) or PGZ-MS (100 μg) was injected to the infarct region just after induction. Cardiac function and size were assessed by echocardiography. At 28 days after surgery, the rats were sacrificed, and the excised hearts were evaluated histologically. RESULTS Sustained release of PGZ from the PGZ-MS was confirmed in vitro. PGZ-MS significantly rehabilitated cardiac dysfunction after an MI (fractional shortening: MI vs MI+placebo-MS vs MI+PGZ-MS, 24.4 ± 1.1 vs 24.3 ± 1.6 vs 32.2 ± 1.4%; P = 0.0035) with reverse remodelling. Immunohistochemical analyses revealed that PGZ-MS enhanced macrophage polarization (ratio of M2 subtype: 0.39 ± 0.03 vs 0.42 ± 0.02 vs 0.54 ± 0.02; P = 0.0004) and attenuated apoptosis of cardiomyocytes in the ischaemic border zone. CONCLUSIONS We confirmed macrophage polarization by sustained release of PGZ, which resulted in amelioration of adverse left ventricular remodelling and cardiac dysfunction. Drug delivery system-based macrophage polarization might serve as a promising strategy in cardiac regenerative therapy for ischaemic heart disease. (241 words) [ABSTRACT FROM AUTHOR]

Various surgical techniques have been reported for Scimitar syndrome, because of the heterogenous anatomy of the disease. We developed a novel surgical method to repair Scimitar syndrome, in which, a new pulmonary venous route is constructed behind the inferior vena cava using autologous flaps of the inferior vena cava and the interatrial septum. An adult case of Scimitar syndrome was repaired by this method with good results. [ABSTRACT FROM AUTHOR]

Objective: The perioperative outcome of lung transplantation (LTx) for patients with severe pulmonary hypertension (PH) remains poor due to the occurrence of primary graft dysfunction (PGD) from left ventricular failure. We hypothesized that tapering pretransplant use of epoprostenol rather than abrupt discontinuation after transplantation might improve perioperative outcomes. Methods: We performed 23 LTxs for patients with severe PH who received epoprostenol therapy from 2008 until 2021. In the discontinued group (n = 6), epoprostenol was discontinued after the establishment of extracorporeal circulation. In the tapered group (n = 17), epoprostenol was discontinued and resumed after reperfusion, and then gradually tapered over the following 2 weeks. We assessed survival, bleeding, blood transfusion, re-opening of the chest, oxygenation, PGD score, extracorporeal membrane oxygenation (ECMO) requirement for recovery after transplantation, and duration of mechanical ventilation. Results: The PGD score was significantly lower in the tapered group than in the discontinued group at 0 h, 24 h, and 48 h after LTx. In addition, the discontinued group required longer mechanical ventilation than the tapered group. Delayed chest closure and post-transplant ECMO use for recovery occurred significantly more frequently in the discontinued group. Conclusions: To resume and taper epoprostenol administration after reperfusion in patients with severe PH may be a valuable new strategy associated with better perioperative outcomes. [ABSTRACT FROM AUTHOR]

Incorporation of surrounding tissues after implantation of synthetic vascular prostheses potentially varies in accordance with implanted prostheses. To evaluate post-implant tissue incorporation, we examined surgical, histological and ultrastructural findings after implantation in animal models. Three types of commercially available prostheses were tested (Gelweave™; Group G, J Graft SHIELD NEO®; Group J and Triplex®; Group T). Prostheses were implanted into Sprague–Dawley rats subcutaneously or sutured on abdominal aorta of Japanese white rabbits. The tissues were surgically examined for adhesion and were subjected to histological evaluations for cellular and tissue infiltration and ultrastructural observations by scanning electron microscopy (SEM). Group G exhibited less tendency in adhesion formation in early phase (rat: G vs J, P < 0.0001; G vs T, P < 0.0001/rabbit: G vs J, P < 0.0001; G vs T, P = 0.059). In late phase, Group J showed highest adhesion (rat: G vs J, P = 0.0004; J vs T, P = 0.015/rabbit: G vs J, P = 0.0015; J vs T, P = 0.0044). In group G, a gap was observed between implants and surrounding tissues forming capsulation, whereas other groups exhibited tissue infiltration inside of the implants wall which were also confirmed by SEM. The tissue permeation toward the implants and adhesion was positively correlated (P < 0.0001). Surrounding tissue conformation varied in accordance with the type of prostheses. It is desirable to elucidate characteristics of each prosthesis to select suitable grafts for each patient to achieve a better surgical outcome. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES To investigate risk factors for mortality after systemic-to-pulmonary (SP) shunt procedures in patients with a functionally univentricular heart using the Japan Cardiovascular Surgery Database registry. METHODS Clinical data from 75 domestic institutions were collected. Overall, 812 patients with a functionally univentricular heart who underwent initial SP shunt palliation were eligible for analysis. Patients with pulmonary atresia with an intact ventricular septum and patients with a SP shunt as part of the Norwood procedure were excluded. Risk factors for 30- and 90-day mortalities were analysed using a logistic regression model. RESULTS Median age and body weight at SP shunt placement were 41 days and 3.6 kg, respectively. Modified Blalock–Taussig shunt, central shunt and other types of SP shunts were applied in 689 (84.9%), 94 (11.8%) and 30 (3.7%) patients, respectively. Cardiopulmonary bypass was utilized in 410 patients (51%) for 128 min (median, 19–561). There were 411 isolated SP shunt procedures. Median hospital stay was 27 days, and 742 (91.4%) patients were discharged. The 30- and 90-day mortality rates were 3.4% and 6.0%, respectively. Placement of a central shunt was identified as a risk factor for 30-day mortality, while lower body weight, preoperative ventilator support, right atrial isomerism and coexistence of major aortopulmonary collateral arteries and an unbalanced atrioventricular septal defect were identified as risk factors for 90-day mortality. CONCLUSIONS SP shunt carries a high mortality rate in patients with a functionally univentricular heart when it is performed in smaller patients with complex cardiac anomalies. [ABSTRACT FROM AUTHOR]

Autologous vascular grafts are widely used in revascularization surgeries for small caliber targets. However, the availability of autologous conduits might be limited due to prior surgeries or the quality of vessels. Xenogeneic decellularized vascular grafts from animals can potentially be a substitute of autologous vascular grafts. Decellularization with high hydrostatic pressure (HHP) is reported to highly preserve extracellular matrix (ECM), creating feasible conditions for recellularization and vascular remodeling after implantation. In the present study, we conducted xenogeneic implantation of HHP-decellularized bovine vascular grafts from dorsalis pedis arteries to porcine carotid arteries and posteriorly evaluated graft patency, ECM preservation and recellularization. Avoiding damage of the luminal surface of the grafts from drying significantly during the surgical procedure increased the graft patency at 4 weeks after implantation (P = 0.0079). After the technical improvement, all grafts (N = 5) were patent with mild stenosis due to intimal hyperplasia at 4 weeks after implantation. Neither aneurysmal change nor massive thrombosis was observed, even without administration of anticoagulants nor anti-platelet agents. Elastica van Gieson and Sirius-red stainings revealed fair preservation of ECM proteins including elastin and collagen after implantation. The luminal surface of the grafts were thoroughly covered with von Willebrand factor-positive endothelium. Scanning electron microscopy of the luminal surface of implanted grafts exhibited a cobblestone-like endothelial cell layer which is similar to native vascular endothelium. Recellularization of the tunica media with alpha-smooth muscle actin-positive smooth muscle cells was partly observed. Thus, we confirmed that HHP-decellularized grafts are feasible for xenogeneic implantation accompanied by recellularization by recipient cells. [ABSTRACT FROM AUTHOR]

We encountered a unique pattern of cardiac dyssynchrony in a patient with complex congenital heart disease (heterotaxy syndrome) with a biventricular physiology and systemic left ventricle (LV). On speckle tracking echocardiography, dyssynchrony was not detected within the LV, but was noted in an interventricular fashion between the LV and right ventricle (RV). An electrophysiologic study revealed a conduction delay in the subpulmonary RV. Cardiac resynchronization therapy provided reverse cardiac remodeling and an excellent result in our patient by placing the pacing leads around the dyssynchronous lesion. [ABSTRACT FROM AUTHOR]

Objective: Retrosternal adhesion after median sternotomy possibly raises the risk of cardiac injury at resternotomy. A biodegradable glue "Lydex" is composed of food additives, dextran and ε-poly (l-lysine), and the degradation speed can be controlled by the composition. In the present study, we evaluated the preventative effect of Lydex on retrosternal adhesion and the relationship between degradation speed and the progression of retrosternal fibrosis. Methods: Japanese white rabbits are subjected to median sternotomy. Lydex 1, 2 and 3 were loaded at the retrosternal space of rabbits in allocated groups before sternal closure, respectively (n = 11 for each group). Retrosternal adhesion was macroscopically evaluated after surgery. Retainment of Lydex, retrosternal fibrosis and the infiltration of macrophages are histologically evaluated, respectively. Results: All Lydex groups exhibited less retrosternal adhesion at 4 weeks after loading compared to unloaded control. The degradation speed of Lydex varied according to the compositions. Lydex with faster degradation (Lydex 2 or Lydex 3) showed lower progression of retrosternal fibrosis compared to that with slower degradation (Lydex 1) [fibrosis ratio: control vs Lydex 1 vs Lydex 2 vs Lydex 3: 0.60 ± 0.15 vs 0.18 ± 0.17 vs 0.00 ± 0.00 vs 0.00 ± 0.00, P = 0.0005 (Lydex 1 vs Lydex 2), P = 0.0005 (Lydex 1 vs Lydex 3)]. Retrosternal infiltrations of macrophages in Lydex 1 and Lydex 3 groups are not higher compared to that in unloaded control. Conclusions: The degradation speed of Lydex could be controlled according to the compositions. The degradation speed affected the progression of retrosternal fibrosis. [ABSTRACT FROM AUTHOR]

Objectives: Systemic inflammation evoked by cardiopulmonary bypass (CPB) leads to acute lung injury (ALI) and respiratory failure. Although recombinant human soluble thrombomodulin (rTM) consists of three domains (D1–3), is reported to attenuate systemic inflammation through the N-terminal lectin-like domain (D1), anticoagulant domain (D2) may exacerbate coagulopathy after CPB. We investigated the potential of selective D1 against CPB-mediated ALI free from anticoagulant effects using a rat CPB model. Methods: Rats were divided into three groups: control (CPB alone, n = 5), D1 (CPB + D1, n = 4), and D123 (CPB + D123, n = 6). D1 or D123 was administrated to the rats of each group before CPB establishment. Blood samples are collected before, during and after CPB. Blood coagulability was assessed by a coagulation analyzer. Lung samples are collected at 1 h after the termination of CPB for histological analyses. Results: D123 group exhibited significantly prolonged glass beads-activated clotting time with heparinase after CPB compared to that in control group, whereas no significant prolongation in control and D1 group (control vs. D1 vs. D123: 65.4 ± 9.2 vs. 65.3 ± 10.9 vs. 83.5 ± 4.6 s, p = 0.036 [control vs. D123], 0.99 [control vs. D1]) indicating the absence of anticoagulant activities of D1. Histological studies revealed less congestion, edema, inflammation, and hemorrhage in both D1 and D123 groups compared to those in control group indicating protective effects of both D1 and D123 against ALI mediated by CPB. Conclusions: N-terminal lectin-like domain of rTM may reduce the risk of ALI without anticoagulant effects. [ABSTRACT FROM AUTHOR]

Objective: Although surgical ventricular restoration for ischemic cardiomyopathy is expected as an alternative or bridge to heart transplantation, post-operative remodeling of left ventricle (LV) needs to be addressed. This study aimed to examine the effect of basic fibroblast growth factor (bFGF), which induces angiogenesis and tissue regeneration in ischemic myocardium, to prevent remodeling after surgical ventricular restoration (SVR) using a rat ischemic cardiomyopathy model. Methods: Four weeks after coronary artery ligation, rats were divided into two groups: rats treated with SVR alone (SVR; n = 21), and rats treated with SVR and local sustained release of bFGF using gelatin hydrogel sheet (SVR + bFGF; n = 22). Cardiac function was assessed by serial echocardiography and cardiac catheterization. Cardiac tissue sections were histologically examined for vascular density and fibrosis. Results: Higher systolic function and lower LV end-diastolic pressure (LVEDP) were observed in rats treated with SVR + bFGF (SVR vs SVR + bFGF; Ees: 0.22 ± 0.11 vs 0.33 ± 0.22 mmHg/μL, p = 0.0328; LVEDP: 12.7 ± 7.0 vs 8.5 ± 4.3 mmHg, p = 0.0230). LV area tended to be lower in rats treated with SVR + bFGF compared to rats treated with SVR alone (left-ventricular end-diastolic area: 0.66 ± 0.07 vs 0.62 ± 0.07 cm2, p = 0.071). Vascular density tended to be higher in rats treated with SVR + bFGF than those without bFGF (23.3 ± 8.1 vs 28.8 ± 9.5/mm2, p = 0.0509). Conclusions: BFGF induced angiogenesis and attenuated remodeling after SVR which secured the efficacy of SVR in a rat ischemic cardiomyopathy model. [ABSTRACT FROM AUTHOR]

Objective: Chronic myocardial infarction (CMI) tends to be resistant to treatments possibly due to extensive solid fibrotic scar, hypoxia mediated by poorly vascularized environment, and/or inflammation and apoptosis. Here we aimed to testify the therapeutic effects of sustained release of basic fibroblast growth factor (bFGF) using gelatin hydrogel (GH) in a rat chronic MI model and to elucidate the therapeutic mechanism including the alteration of extracellular matrix component.Methods: CMI model rats are prepared by the permanent ligation of proximal left anterior descending coronary artery. After 4 weeks, GH sheets (GHSs) with bFGF (100 µg) (bFGF group) or with phosphate-buffered saline (Vehicle group) were implanted to the CMI models to evaluate the effect of bFGF-GHS on chronic scar tissue. Sham operation group was also prepared (n = 5 for each).Results: 4 weeks after implantation, bFGF-GHS significantly improved cardiac contractile function (fractional shortening: 21.8 ± 1.1 vs 21.5 ± 1.3 vs 29.7 ± 1.8%; P < 0.001/fractional area change: 33.0 ± 1.4 vs 34.1 ± 2.3 vs 40.6 ± 1.8%; P < 0.001) (Sham vs Vehicle vs bFGF) accompanied with neovascularization. Immunohistochemical studies revealed that bFGF-GHS increased collagen III/I ratio indicating the alteration of solid scar tissue. Quantitative RT-PCR results showed a decrease of collagen I mRNA expression within border MI zone.Conclusions: The implantation of bFGF-GHS altered the collagen subtype of the fibrotic scar more suitable for tissue repair. The treatment of sustained-release bFGF may be promising for ischemic heart disease through chronic pathology. [ABSTRACT FROM AUTHOR]

This study investigated the safety and efficacy of a sustained release of basic fibroblast growth factor (bFGF) with biodegradable gelatin hydrogel sheets as therapeutic angiogenesis in canine chronic myocardial infarction (MI) models. Canine chronic MI model was induced by ligating the left anterior descending coronary artery and its diagonal branches. At 4 week post-induction, we applied either saline (Control group, n = 5) or 200 μg of bFGF (Treatment group, n = 6) soaked gelatin hydrogel sheets on the ischemic area of the left ventricular (LV) wall. At 6 weeks after the procedure, we evaluated the efficacy by echocardiography and immunohistochemical study. There were no procedure-related adverse events or deaths. The serum bFGF level was under detectable levels in all animals at any sampling points. In terms of efficacy, echocardiographic evaluation demonstrated that fractional shortening was significantly improved in the treatment group. In addition, immunohistochemical study showed that the capillary density in the border zone of the MI area, as well as the MI area, significantly increased in the treatment group. Therapeutic angiogenesis by bFGF using biodegradable gelatin hydrogel sheets was safe, increased the capillary density, and improved LV function in canine chronic MI models. [ABSTRACT FROM AUTHOR]

To realize human induced pluripotent stem cell (hiPSC)-based cardiac regenerative therapy, evidence of therapeutic advantages in human-sized diseased hearts are indispensable. In combination with an efficient and simultaneous differentiation of various cardiac lineages from hiPSCs and cell sheet technology, we aimed to generate clinical-sized large cardiac tissue sheets (L-CTSs) and to evaluate the therapeutic potential in porcine infarct heart. We simultaneously induced cardiomyocytes (CMs) and vascular cells [vascular endothelial cells (ECs) and vascular mural cells (MCs)] from hiPSCs. We generated L-CTSs using 10cm-sized temperature-responsive culture dishes. We induced myocardial infarction (MI) in micromini-pigs (15–25 kg) and transplanted the L-CTSs (Tx) 2 weeks after MI induction (4 sheets/recipient) under immunosuppression (Tx: n = 5, Sham: n = 5). Self-pulsating L-CTSs were approximately 3.5cm in diameter with 6.8×106±0.8 of cells containing cTnT+-CMs (45.6±13.2%), VE-cadherin+-ECs (5.3±4.4%) and PDGFRβ+-MCs (14.4±20.7%), respectively (n = 5). In Tx group, echocardiogram indicated a significantly higher systolic function of the left ventricle (LV) compared to that in sham control (Sham vs Tx: fractional shortening: 24.2±8.6 vs 40.5±9.7%; p<0.05). Ejection fraction evaluated by left ventriculogram was significantly higher in Tx group (25.3±6.2% vs 39.8±4.2%; p<0.01). Speckle tracking echocardiogram showed a significant increase of circumference strain in infarct and border regions after transplantation. Fibrotic area was significantly lower in Tx group (23.8±4.5 vs 15.9±3.8%; P<0.001). Capillary density in the border region was significantly higher in Tx group (75.9±42.6/mm2 vs 137.4±44.8/mm2, p<0.001). These data indicate that the L-CTS transplantation attenuated LV remodeling. L-CTSs potentially restore cardiac dysfunction of human-sized infarct heart. [ABSTRACT FROM AUTHOR]

China has become one of the most desired locations in which to do R&D. However, it has little innovation of its own, and intellectual property protection is weak. This raises questions: Is China R&D more hype than reality? Do cost advantages really outweigh the risk of losing technology to Chinese competitors? Lessons learned from managing R&D in China show that in order to avoid the typical pitfalls of managing R&D in a developing country, any China-based R&D must be part of an overall China strategy and must also be part of a global R&D effort. [ABSTRACT FROM AUTHOR]

A prospective randomized phase II trial was conducted to evaluate the time course effects of toremifene (TOR) and letrozole (LET), as adjuvant hormone therapy, on serum lipid profiles and bone metabolism in estrogen receptor (ER)-positive, postmenopausal breast cancer patients.Fifty-four postmenopausal breast cancer patients [ER positive, HER2 negative, T1-2, node metastases ( n = 0-3), M0] who had undergone curative resection were enrolled. They were randomized to receive either TOR 40 mg/day or LET 2.5 mg/day as adjuvant hormone therapy. Serum lipids and bone markers were measured prior to, and again at 6, 12, and 24 months after initiation of treatment. Changes in serum lipids and bone markers were compared. Serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were decreased compared with the baseline values at 6 months in 6.5 and 14.0% of patients, respectively, receiving TOR. Lipid levels did not change in patients administered LET. Significant differences were observed in TC and LDL-C between the two groups at 12 and 24 months. In the TOR group, serum bone-specific alkaline phosphatase (BAP) was decreased by 25.0% at 12 months, and serum cross-linked N-telopeptide of type-I collagen (NTx) was decreased by 13.6% at 6 months, and these reductions were maintained for at least 24 months. In contrast, in the LET group, serum BAP did not change and NTx was increased by 16.0% at 6 months and by 18.6% at 24 months, as compared with the baseline.TOR and LET exert different effects on serum lipid profiles and bone metabolism markers. The effects of TOR, as adjuvant hormone therapy, on both lipids and bone metabolism in postmenopausal breast cancer patients are superior to those of LET. [ABSTRACT FROM AUTHOR]

Blood vessels are essential components for many tissues and organs. Thus, efficient induction of endothelial cells (ECs) from human pluripotent stem cells is a key method for generating higher tissue structures entirely from stem cells. We previously established an EC differentiation system with mouse pluripotent stem cells to show that vascular endothelial growth factor (VEGF) is essential to induce ECs and that cyclic adenosine monophosphate (cAMP) synergistically enhances VEGF effects. Here we report an efficient and robust EC differentiation method from human pluripotent stem cell lines based on a 2D monolayer, serum-free culture. We controlled the direction of differentiation from mesoderm to ECs using stage-specific stimulation with VEGF and cAMP combined with the elimination of non-responder cells at early EC stage. This “stimulation-elimination” method robustly achieved very high efficiency (>99%) and yield (>10 ECs from 1 hiPSC input) of EC differentiation, with no purification of ECs after differentiation. We believe this method will be a valuable technological basis broadly for regenerative medicine and 3D tissue engineering. [ABSTRACT FROM AUTHOR]

Examines the bubble material of (BiSmLu)[sub3](FeSc)[sub5]O[sub12] grown from PbO-Bi[sub2]O[sub3]-V[sub2]O[sub5] flux. Procedure to be used in order to increase the uniaxial anisotropy energy in the films; Anisotropy energy of 0.3-μm-diam bubble material of (BiSmLu)[sub3](FeSc)[sub5]O[sub12; Factor attributed to the increase in the anisotropy energy.

Background Tricuspid valve regurgitation due to pacemaker leads is a well-known complication. Although some reports have suggested that pacemaker leads should be surgically explanted, strongly adhered leads cannot always be removed. The aim of this study was to describe our tricuspid valve repair techniques with pacemaker leads left in situ. Methods Our retrospective study investigated 6 consecutive patients who required tricuspid valve surgery for severe regurgitation induced by pacemaker leads. Results From the operative findings, we identified 3 patterns of tricuspid valve and pacemaker lead involvement. In 3 patients, the leads were caught in the chordae, in 2 patients, tricuspid regurgitation was caused by lead impingement on the septal leaflet, and in 3 patients, tricuspid valve leaflets had been perforated by the pacemaker leads. During surgery, all leads were left in situ after being separated from the leaflet or valvular apparatus. In addition, suture annuloplasty was performed for annular dilatation in all cases. In one patient, the lead was reaffixed to the annulus after the posterior leaflet was cut back towards the annulus, and the leaflet was then closed. There was one hospital death due to sepsis. The degree of tricuspid regurgitation was trivial in all surviving patients at discharge. During a mean follow-up of 21 months, one patient died from pneumonia 20 months after tricuspid valve repair. Conclusion In patients undergoing tricuspid valve surgery due to severe tricuspid regurgitation caused by pacemaker leads, the leads can be left in situ after proper repair with annuloplasty. [ABSTRACT FROM AUTHOR]

There is no consensus regarding the strategy for managing the regional lymph nodes in patients with local breast cancer recurrence. This paper reviews the updated data on re-sentinel lymph node biopsy (re-SLNB) after previous surgery. The identification rate of re-SLNB varied from 29 to 100 % (mean 67 %). The success rate of re-SLNB depends on the method used for the previous axillary surgery and the number of lymph nodes harvested. Re-SLNB may be feasible even after mastectomy. A relationship between post-operative radiotherapy and identification of re-SLNB was not seen. A longer disease-free interval may correlate with a lower identification rate, but this finding is not definitive. Based on data regarding back-up dissection after re-SLNB, the accuracy of re-SLNB may be as good as SLNB in primary cases. Altered lymphatic drainage was reported in 2-89 % (mean 32 %) of cases. Because the altered lymphatic drainage can be detected only by lymphoscintigraphy, the radioisotope method, followed by lymphoscintigraphy, should be used. There are not many reported cases of axillary recurrence after re-SLNB, and the follow-up periods have been short. Because re-SLNB cases have a wide variety of backgrounds, it is necessary to accumulate a larger number of cases and to obtain data from longer follow-up period in order to make clear recommendations. [ABSTRACT FROM AUTHOR]

We present the case of a 19-day-old girl with incomplete atrioventricular septal defect, muscular ventricular septal defect, and severe left atrioventricular valve regurgitation. We attempted biventricular repair with left atrioventricular valve repair; however, we could not control the regurgitation. Moreover, the commercially available prosthetic valve was too large to implant. Thus we switched intraoperatively to a univentricular repair. We successfully performed patch closure of the left atrioventricular valve (Starnes procedure), Damus-Kaye-Stansel anastomosis, and a systemic-to-pulmonary artery shunt. [ABSTRACT FROM AUTHOR]

To realize cardiac regeneration using human induced pluripotent stem cells (hiPSCs), strategies for cell preparation, tissue engineering and transplantation must be explored. Here we report a new protocol for the simultaneous induction of cardiomyocytes (CMs) and vascular cells [endothelial cells (ECs)/vascular mural cells (MCs)], and generate entirely hiPSC-engineered cardiovascular cell sheets, which showed advantageous therapeutic effects in infarcted hearts. The protocol adds to a previous differentiation protocol of CMs by using stage-specific supplementation of vascular endothelial cell growth factor for the additional induction of vascular cells. Using this cell sheet technology, we successfully generated physically integrated cardiac tissue sheets (hiPSC-CTSs). HiPSC-CTS transplantation to rat infarcted hearts significantly improved cardiac function. In addition to neovascularization, we confirmed that engrafted human cells mainly consisted of CMs in >40% of transplanted rats four weeks after transplantation. Thus, our HiPSC-CTSs show promise for cardiac regenerative therapy. [ABSTRACT FROM AUTHOR]

A 5-day-old girl who had pulmonary atresia with ventricular septal defect, patent ductus arteriosus, intralobar pulmonary sequestration of the right lower lobe, and retroesophageal innominate vein, was referred to our institution. We successfully performed a systemic-to-pulmonary shunt. During cardiopulmonary bypass, the arteries supplying the sequestrated lung were ligated above the diaphragm through the median sternotomy, without a thoracotomy. The postoperative course was uneventful, and we avoided the potential complications of lung infection and ventricular overload. [ABSTRACT FROM PUBLISHER]

Background: The outcome in patients with human epidermal growth factor receptor-2 (HER-2)-positive locally advanced breast cancer may be improved by integrating trastuzumab with primary systemic therapy (PST). Methods: The efficacy and safety of PST comprising EC (epirubicin 90 mg/m and cyclophosphamide 600 mg/m, four cycles every 3 weeks) followed by docetaxel (75 mg/m, four cycles every 3 weeks) and concurrent trastuzumab (loading dose 4 mg/kg followed by 2 mg/kg, 12 cycles every week) was investigated in a multicenter, prospective, phase II study in patients with HER-2-positive stage IIIB/IIIC/IV breast cancer. The primary endpoint was pathologic complete response (pCR) including the tumor intraductal component confirmed by central pathologic review. Results: In total, 38 patients were enrolled (stage IIIB, 63.2 %; IIIC, 23.7 %; IV, 13.2 %; estrogen receptor- and/or progesterone receptor-positive, 47.4 %). The pCR rate was 16.2 % in the primary tumor (six of 37 patients in the Full Analysis Set) and 56.8 % (21/37) in the ipsilateral axillary lymph nodes. Treatment was given according to protocol in 28 of 37 patients; six of 28 in the Per-Protocol Set achieved pCR (21.4 %). The clinical response rate was 67.6 % (25/37 patients; complete response, 13.5 %; partial response, 54.1 %). No patients developed congestive heart failure; however, three patients had a non-symptomatic decrease of >10 % of left ventricular ejection fraction. Conclusions: PST including concurrent use of trastuzumab combined with docetaxel is effective and well-tolerated in HER-2-positive advanced breast cancer patients, including those patients requiring mastectomy for local control. [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose) polymerase (PARP)-1 inhibitor has been suggested to attenuate the ischemia-reperfusion injury. We investigated the protective effect of the cardioplegia with a PARP-1 inhibitor, 4-hydoxyquinazoline (4-HQ), against myocardial ischemia-reperfusion injury. Isolated rat hearts were perfused on a Langendorff apparatus and cardioplegically arrested for 90 min by perfusion with St. Thomas' Hospital solution (ST-solution). In the Group ST ( n = 8), the hearts were arrested with the ST-solution alone. The Group HQ ( n = 8) were treated with the ST-solution containing 4-HQ (10 µM) for cardioplegia. During reperfusion, the Group HQ showed significantly greater functional recovery of +dp/dtmax ( p = 0.005) and lower enzymatic leakage ( p < 0.01). NAD+ levels were also preserved higher in the Group HQ ( p < 0.01). Immunohistochemical study revealed lesser extents of oxidative stress and apoptosis, in the Group HQ. Thus, addition of 4-HQ in the cardioplegia may provide a new intervention for myocardial protection against ischemia-reperfusion injury by decreasing NAD+ consumption and suppressing oxidative stress. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is a heterogeneous disease with a diversity of clinical behaviors. The purpose of this study was to evaluate the utility of breast cancer intrinsic subtypes in the prediction of pathological complete response (pCR) in a cohort of breast cancer patients receiving preoperative chemotherapy. Methods: Patients with stage II/III breast cancer received 4 cycles of XT (capecitabine and docetaxel) followed by 4 cycles of FEC (fluorouracil, epirubicin, and cyclophosphamide) as preoperative chemotherapy. Tumors were classified as luminal A, luminal B, luminal/HER2, HER2, basal-like, or non-basal-like triple negative by immunohistochemical analysis in core needle biopsy samples at baseline. Results: The overall pCR rate was 11.9% (12/101). Multivariate analysis showed that intrinsic subtype was an independent factor to predict pCR. With luminal A patients as the reference group, luminal B (OR = 16.39; 95% CI 1.44-185.88; p = 0.024), HER2 (OR = 14.73; 95% CI 1.19-180.84; p = 0.035), and basal-like (OR = 13.27; 95% CI 1.27-138.79; p = 0.031) patients had a significantly higher likelihood of pCR. Conclusion: The present data indicate that intrinsic subtypes may be useful predictive biomarkers of pCR in breast cancer patients treated with preoperative chemotherapy. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Data reviewed at the Kyoto Breast Cancer Consensus Conference (KBCCC) showed that preoperative systemic therapy (PST) could optimize surgery through the utilization of information relating to pre- and post-PST tumor stage, therapeutic sensitivity, and treatment-induced changes in the biological characteristics of the tumor. As such, it was noted that the biological characteristics of the tumor, such as hormone receptors, human epidermal growth factor receptor-2, histological grade, cell proliferative activity, mainly defined by the Ki67 labeling index, and the tumor's multi-gene signature, should be considered in the planning of both systemic and local therapy. Furthermore, the timing of axillary sentinel lymph node diagnosis (i.e., before or after the PST) was also noted to be critical in that it may influence the likelihood of axillary preservation, even in node positive cases. In addition, axillary diagnosis with ultrasound and concomitant fine needle aspiration cytology or core needle biopsy (CNB) was reported to contribute to the construction of a treatment algorithm for patient-specific or individualized axillary surgery. Following PST, planning for breast surgery should therefore be based on tumor subtype, tumor volume and extent, therapeutic response to PST, and patient preference. Nomograms for predicting nodal status and drug sensitivity were also recognized as a tool to support decision-making in the selection of surgical treatment. Overall, review of data at the KBCCC showed that PST increases the likelihood of patients receiving localized surgery and individualized treatment regimens. [ABSTRACT FROM AUTHOR]

This randomized phase II study was intended to identify the optimal dose of TAS-108, a novel steroidal antiestrogen, for the treatment of breast cancer in postmenopausal Japanese women. The potential clinical effects of TAS-108 on the uterus, bone, serum lipids, and hormones were also investigated. Postmenopausal women with hormone receptor-positive metastatic breast cancer who had previously received one or two endocrine therapies were randomly assigned to one of the three possible dose levels of TAS-108 (40, 80 or 120 mg/day). Oral TAS-108 was given daily, and the efficacy and safety of the three doses were evaluated. A total of 97 patients (33, 32, and 32 in the 40-, 80-, and 120-mg groups, respectively) were treated with TAS-108. The clinical benefit rate was 30.3% for the 40-mg, 25.0% for the 80-mg, and 25.0% for the 120-mg group. The 40-mg group achieved the prespecified target threshold. TAS-108 at all dose levels was well tolerated and appeared to have no harmful effects in terms of the variables examined in this study. We conclude that the optimal dose of TAS-108 among the three doses is 40 mg, once daily, for further studies. JAPIC Clinical Trials Information number: Japic CTI - 121754. [ABSTRACT FROM AUTHOR]

Although stem cell therapy is a promising strategy for cardiac restoration, the heterogeneity of transplanted cells has been hampering the precise understanding of the cellular and molecular mechanisms. Previously, we established a cardiovascular cell differentiation system from mouse pluripotent stem cells, in which cardiomyocytes (CMs), endothelial cells (ECs), and mural cells (MCs) can be systematically induced and purified. Combining this with cell sheet technology, we generated cardiac tissue sheets reassembled with defined cardiovascular populations. Here, we show the potentials and mechanisms of cardiac tissue sheet transplantation in cardiac function after myocardial infarction (MI). Transplantation of the cardiac tissue sheet to a rat MI model showed significant and sustained improvement of systolic function accompanied by neovascularization. Reduction of the infarct wall thinning and fibrotic length indicated the attenuation of left ventricular remodeling. Cell tracing with species-specific fluorescent in situ hybridization after transplantation revealed a relatively early loss of transplanted cells and an increase in endogenous neovascularization in the proximity of the graft, suggesting an indirect angiogenic effect of cardiac tissue sheets rather than direct CM contributions. We prospectively dissected the functional mechanisms with cell type-controlled sheet analyses. Sheet CMs were the main source of vascular endothelial growth factor. Transplantation of sheets lacking CMs resulted in the disappearance of neovascularization and subsequent functional improvement, indicating that the beneficial effects of the sheet were achieved by sheet CMs. ECs and MCs enhanced the sheet functions and structural integration. Supplying CMs to ischemic regions with cellular interaction could be a strategic key in future cardiac cell therapy. S TEM C ELLS 2012;30:1196-1205 [ABSTRACT FROM AUTHOR]

We report the case of a 68-year-old man with progressive heart failure due to effusive-constrictive pericarditis. During approximately 1 month, echocardiography revealed rapid progression from pericarditis with effusion without tamponade to pericardial thickening and diastolic dysfunction. Cardiac catheterization revealed that the pressure in the right heart chambers remained high after pericardiocentesis. The patient was rescued by aggressive pericardiectomy and sharp dissection of the epicardium into small fragments. This on-pump beating-heart surgery is known as the waffle procedure. [ABSTRACT FROM AUTHOR]

The present study examined long-term efficacy outcomes in a subgroup of postmenopausal, estrogen receptor-positive Japanese breast cancer patients from the Pre-Operative 'Arimidex' Compared with Tamoxifen trial, following pre-operative (3 months) and post-operative (5 years) adjuvant treatment with either anastrozole or tamoxifen. Patients with large, potentially operable, locally-advanced breast cancer were randomized to receive anastrozole (1 mg/day) plus tamoxifen placebo or tamoxifen (20 mg/day) plus anastrozole placebo pre-operatively. After surgery at 3 months, patients continued on the same study medication as adjuvant therapy for up to 5 years or until recurrence, intolerable toxicity or withdrawal of patient consent. Recurrence-free survival and overall survival were measured from the date of randomization to the date of recurrence or death, whichever occurred first. Patients were monitored for adverse events throughout the study period and up to 30 days following administration of the last study medication. During post-operative adjuvant therapy, 4/48 (8%) anastrozole and 25/49 (51%) tamoxifen patients experienced recurrence. There was a significant difference in recurrence-free survival between the two groups (hazard ratio 0.14; 95% confidence interval 0.05-0.41; P = 0.0003). There was a significant increase in overall survival with anastrozole (0.21; 0.05-0.96; P = 0.0436) and there were 2/48 (4%) and 10/49 (20%) deaths with anastrozole and tamoxifen, respectively. Most patients responding to pre-operative therapy remained recurrence-free. Sequential pre-operative/post-operative treatment with anastrozole resulted in lower recurrence and death rates, compared with tamoxifen. ( Cancer Sci 2012; 103: 491-496) [ABSTRACT FROM AUTHOR]

The potential long-term adverse effects on quality of life have to be considered when selecting agents for adjuvant hormonal treatment for postmenopausal patients with estrogen receptor-positive breast cancer. We performed a 2-year multicenter randomized study to assess the differences in the time course effects between toremifene (TOR) and anastrozole (ANA) on serum lipid profiles and bone metabolism. This study assessed the serum levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A1), and apolipoprotein B (Apo B) as lipid profiles and bone-specific alkaline phosphatase (BAP) and the N-telopeptide of type-I collagen (NTX) as bone turnover markers in patients who received daily doses of 40 mg and 1 mg for TOR and ANA, respectively. A decreased serum level of TC, LDL-C, and Apo B was, respectively, observed at 6 months in 6.2, 12.9, and 13.8% of the patients who received TOR compared with the baseline. These decreases were maintained for at least 24 months. These lipid levels were not changed in those who received ANA. In the TOR patients, there was an increase in the serum level of HDL-C and Apo A1 at 6 months in 17.1 and 16.3%, respectively, which was maintained for at least 24 months, whereas these levels were almost stable in the patients who received ANA. Serum BAP decreased by 12.1% at 12 months and further decreased at 24 months and the serum NTX decreased by 22.0% at 6 months, which was maintained for at least 24 months in the patients who received TOR. In contrast, the serum BAP was increased by 26.0% at 6 months and by 29.2% at 12 months and the serum NTX increased by 21.3% at 24 months compared with baseline in those received ANA. However, the serum BAP increase was not significant at 24 months. TOR provides better effects than ANA in terms of lipid profiles and bone metabolism in postmenopausal females with early breast cancer. [ABSTRACT FROM AUTHOR]

Objective: The objective of this investigation was to establish the effectiveness of sustained-release platelet-rich plasma (PRP) on perfusion and neovascularization in diabetic murine hind limb ischemia. Methods: After surgery in streptozotocin-induced diabetic mice, the mice were randomly assigned to the following 4 experimental groups: control (C), 100 μl of the sustained-release form of platelet-poor plasma (PPP), 100 μl of the solution form of PRP (PRP-sol), and 100 μl of the sustained-release form of PRP (PRP-sr). Endpoint evaluations were: blood perfusion by laser Doppler perfusion imaging (LDPI), vascular density by anti-vWF, and mature vessel density by anti-smooth muscle actin antibody. Results: This study demonstrated that a sustained release of PRP increases the perfusion of ischemic tissue as measured by LDPI (57 ± 12; 56 ± 9; 72 ± 7, and 98 ± 4 for the C, PPP, PRP-sol, and PRP-sr groups, respectively; p < 0.05), capillary density (151 ± 16; 158 ± 12; 189 ± 39, and 276 ± 39 for groups C, PPP, PRP-sol, and PRP-sr, respectively; p < 0.05), and mature vessel density (28 ± 2; 31 ± 3; 52 ± 10, and 85 ± 13 for the C, PPP, PRP-sol, and PRP-sr groups, respectively; p < 0.05). Conclusion: A sustained release of PRP containing potent angiogenic growth factors restores blood perfusion by stimulating angiogenesis and arteriogenesis. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cells (iPSCs) are novel stem cells derived from adult mouse and human tissues by reprogramming. Elucidation of mechanisms and exploration of efficient methods for their differentiation to functional cardiomyocytes are essential for developing cardiac cell models and future regenerative therapies. We previously established a novel mouse embryonic stem cell (ESC) and iPSC differentiation system in which cardiovascular cells can be systematically induced from Flk1+ common progenitor cells, and identified highly cardiogenic progenitors as Flk1+/CXCR4+/VE-cadherin- (FCV) cells. We have also reported that cyclosporin-A (CSA) drastically increases FCV progenitor and cardiomyocyte induction from mouse ESCs. Here, we combined these technologies and extended them to mouse and human iPSCs. Co-culture of purified mouse iPSC-derived Flk1+ cells with OP9 stroma cells induced cardiomyocyte differentiation whilst addition of CSA to Flk1+ cells dramatically increased both cardiomyocyte and FCV progenitor cell differentiation. Spontaneously beating colonies were obtained from human iPSCs by co-culture with END-2 visceral endoderm-like cells. Appearance of beating colonies from human iPSCs was increased approximately 4.3 times by addition of CSA at mesoderm stage. CSA-expanded human iPSC-derived cardiomyocytes showed various cardiac marker expressions, synchronized calcium transients, cardiomyocyte-like action potentials, pharmacological reactions, and ultra-structural features as cardiomyocytes. These results provide a technological basis to obtain functional cardiomyocytes from iPSCs. [ABSTRACT FROM AUTHOR]

Cardioplegic arrest has been the main mechanism of myocardial protection during open-heart surgery; however, it causes myocardial injury during ischemia-reperfusion. Free radical scavengers are widely known to attenuate ischemia-reperfusion injury in various settings. We investigated the effects of edaravone, a novel free radical scavenger that was originally used for cerebral protection, on myocardial function during ischemia-reperfusion after cardioplegic arrest. Rat hearts were excised and perfused using Langendorff apparatus. The hearts were cardioplegically arrested for 90 min using St. Thomas’ Hospital cardioplegic solution (ST solution) at 4°C every 45 min and then reperfused for 20 min. The hearts were divided into 4 groups ( n = 13 in each group). In Group ST, the hearts were arrested using the ST solution alone. In Groups L, M, and H, the hearts were arrested using the ST solution supplemented with a low-dose (1 μM), moderate dose (10 μM), and high dose (100 μM) of edaravone, respectively. Left ventricular function (+d p/d tmax) and the levels of the cardiac enzymes released were measured before and after cardioplegic arrest. At the end of the study, the water content and the tissue oxidative stress (8-hydroxy-2′-deoxyguanosine) of the heart were measured. During reperfusion, the edaravone-treated groups showed a greater functional recovery with regard to the +d p/d tmax ( P < 0.05). The lactate level was the lowest ( P < 0.01) in Group M. The water content of the hearts in the edaravone-treated groups was significantly lower ( P < 0.05) than that in Group ST. Oxidative stress was significantly lower ( P < 0.01) in the edaravone-treated hearts than in Group ST, and it was the lowest in Group M. The addition of edaravone to the cardioplegic solution ameliorates the impairment in myocardial function by reducing the oxidative stress after cardioplegic arrest. In this study, the maximum improvement in the myocardial function was achieved by addition of a moderate dose (10 μM) of edaravone. [ABSTRACT FROM AUTHOR]

The next step of sentinel lymph node biopsy (SLNB) in breast cancer is to determine which patients need axillary lymph node dissection (ALND) following a positive SLNB. A prospective database of 239 patients who underwent SLNB followed by complete ALND at Keio University Hospital from January 2001 to June 2005 was reviewed. A total of 131 patients with one or more positive sentinel lymph nodes (SLNs) were further analyzed. A univariate analysis showed a significant correlation between non-SLN involvement and lymphatic invasion, vascular invasion, number of tumor-involved SLNs, radioactivity of SLNs, and size of SLN metastasis (p = 0.0002, p = 0.004, p = 0.006, p = 0.04, p = 0.03, respectively). By multivariate analysis, lymphatic invasion and the number of tumor-involved SLNs remained significant predictors of non-SLN involvement. In breast cancer patients with a positive SLN, lymphatic invasion and the number of tumor-involved SLNs were both independent predictors of non-SLN involvement. [ABSTRACT FROM AUTHOR]

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi-institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross-sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty-five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non-Ashkenazi individuals. Statistical analysis using the Mantel-Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non-Ashkenazi individuals ( P = 0.005, odds ratio 1.87, 95% confidence interval 1.22–2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives ( P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165–7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives ( P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25–6.64). ( Cancer Sci 2008; 99: 1967–1976) [ABSTRACT FROM AUTHOR]

Background: Anthracyclines and taxanes are major cytotoxic drugs against breast cancer. To develop a combination of epirubicin (EPI) and docetaxel (DTX) in Japan, dose escalation and pharmacokinetic studies were performed in patients with advanced or recurrent breast cancer. Methods: Twenty patients received EPI (40, 50 or 60 mg/m2) as 5-min intravenous infusion, followed by DTX infusion (50 or 60 mg/m2) over 1 h in cohorts of 3–6 patients. The maximum tolerated dose (MTD) was defined during the first cycle when more than 2 of 3 or 3 of 6 patients suffered a dose-limiting toxicity (DLT). The DLT was based on febrile neutropenia (FN), prolonged neutropenia, thrombocytopenia and grade 3–4 nonhematological toxicity during the first cycle. Plasma sampling was performed to assess the pharmacokinetic study of these drugs. Results: The second level (EPI/DTX 50/50 mg/m2) was found to be a maximum tolerated dose because of a short duration of FN with no distress. Subsequently, the protocol was modified to permit a new DLT definition including FN lasting for more than 72 h. At the following levels of EPI/DTX 50/50, 50/60 or 60/60 mg/m2, the dose escalation study revealed a high incidence of grade 4 neutropenia (100%) and FN (67%), which did not reach DLT. However, the safety committee decided not to go further because of too high an incidence of FN lasting 3 days, although a little less than 72 h. The pharmacokinetic study with a combination of EPI and DTX showed comparable blood levels of DTX and EPI in relation to those seen when given alone. Conclusion: For further evaluation, the recommended dose and schedule of this combination is EPI 60 mg/m2 and DTX 60 mg/m2, given every 3 weeks to patients without prior chemotherapy and EPI 50 mg/m2 and DTX 50 mg/m2 given to patients with prior chemotherapy, respectively. The pharmacokinetic study indicates no interaction between EPI and DTX. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The PReOperative ‘Arimidex’® Compared with Tamoxifen (PROACT) trial compared neoadjuvant anastrozole and tamoxifen in postmenopausal women with large, operable or potentially operable, locally advanced hormone receptor-positive breast cancer. Here, we compare objective clinical responses with histopathological tumor responses to therapy in a cohort of 97 Japanese patients, in order to investigate the consistency of assessment methods and the change in estrogen-receptor (ER) and progesterone-receptor (PgR) status. Histopathological response and the change in ER and PgR status were assessed by comparing pathological specimens collected at baseline (via needle biopsy) with those collected at 3 months (from excised tumors). The response was evaluated using Pathological Response Criteria for Breast Cancer as defined by the Japanese Breast Cancer Society. The patients were randomized to receive anastrozole ( n = 48) or tamoxifen ( n = 49). A numerically greater histopathological response rate was observed when neoadjuvant anastrozole compared with neoadjuvant tamoxifen (35.4 and 12.2%, respectively). The histopathological and clinical objective response rates agreed in 63/97 patients. The ER status of 5/40 patients changed from positive at baseline to negative at 3 months in the anastrozole group compared with 20/37 patients in the tamoxifen group. The PgR status of 16/17 patients in the anastrozole group and of 1/11 patients in the tamoxifen group changed from positive to negative. These data support the findings of the main PROACT trial, which confirmed that anastrozole, as compared with tamoxifen, is an effective neoadjuvant endocrine treatment in objective response rates for postmenopausal women with large operable hormone-receptor positive breast cancer. Further follow-up is required to confirm whether histopathological responses to therapy correlate with an overall improvement in survival. [ABSTRACT FROM AUTHOR]

Catheter-related infection is one of the most serious complications. Microbes migrate along the catheter (the foreign material) from the wound at the insertion-site, leading to catheter-related infection. Basic fibroblast growth factor (bFGF) is a potent mitogen that promotes the growth and regeneration of organs and tissues in vivo. Catheter-related bacterial invasion was simulated by the invasion of inoculated bacteria into a transplanted foreign material. Sterile Dacron sheets (foreign materials) were implanted on the subcutis of 96 male mice (C57BL/6) randomized into four groups ( n = 24 per group). Group A: Dacron sheets only; Group B: Dacron sheets treated with a plain gelatin hydrogel sheet; Group C: Dacron sheets treated with free bFGF (50 µg); Group D: Dacron sheets treated with sustained-release bFGF (50 µg). On day 7, “detachment test” (to measure the force needed to pull out the Dacron sheet) and microscopic evaluations were performed, and the tissue immediately above the Dacron sheet was inoculated with methicillin-resistant Staphylococcus aureus (MRSA) 1 × 106 colony-forming units. The total energy needed for pulling out the implanted Dacron sheet in Group D was significantly higher than other three groups ( P < 0.01). Group D had a large granulation tissue area containing a large amount of collagen tissue and vessels microscopically. Two days after the MRSA inoculation, the number of MRSA in the Dacron sheet of Group D was smallest. Pretreatment with sustained-release form of bFGF promoted tissue regeneration and reduced catheter-related bacterial invasion, indicating a useful adjuvant for reducing catheter-related infection. [ABSTRACT FROM AUTHOR]

Objective: Chymase, a serine protease, is released from mast cells, which is closely associated with adhesion formation. Chymase activates transforming growth factor-β1 (TGF-β1), which promotes tissue fibrosis. Recently we have found that chymase may play an important role in adhesion formation in hamsters. Accordingly, this study was designed to confirm that a chymase inhibitor prevents postoperative cardiac adhesions in large animals. Methods: In 14 dogs, the epicardium was abraded 200 times with gauze and the mid-portion of the left anterior descending coronary artery (LAD) was exposed with No. 15 blade. Either chymase inhibitor (CI group, n = 7) or placebo (P group, n = 7) was sprayed into the pericardial cavity, then the pericardium was closed. Cardiac chymase activity, the level of TGF-β1 in the pericardial fluid, the density of epicardial mast cells, the adhesion area between the heart and the pericardium, and the presence of adhesion between the mid-LAD and the pericardium were evaluated 1 and 2 months after surgery. Five nonsurgical dogs were used as a control for cardiac chymase activity. Results: Cardiac chymase activity and TGF-β1 level were lower in CI group than in P group (53.7 ± 35.0 vs. 93.4 ± 20.4 μU/mg protein, p = 0.01, 3.2 ± 0.9 vs. 4.3 ± 1.1 μg/mL, p = 0.06, respectively). In CI group, the density of mast cells (19 ± 5 vs. 32 ± 8 cells/cm, p < 0.01), the adhesion area (2.2 ± 0.8 vs. 7.5 ± 1.5 cm2, p < 0.01), and adhesions between the heart and the mid-LAD (0% vs. 57%) were all reduced. Conclusion: Chymase inhibitor suppresses cardiac chymase activity and reduces the TGF-β1 level, resulting in a reduction of cardiac adhesion in a large animal. [ABSTRACT FROM AUTHOR]