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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]

Recently we have developed new sustained release system of basic fibroblast growth factor (bFGF) using gelatin hydrogel as a carrier. Using this system, we examined the effect of topical sustained release of bFGF on angiogenesis and tissue blood perfusion in a rabbit model of hind limb ischemia. Thirty-two rabbits underwent excision of right femoral artery under general anesthesia. Two weeks later the rabbits were randomized into four groups ( n = 8 each): no treatment, intramuscular injection of gelatin hydrogel alone, and intramuscular injection of gelatin hydrogel incorporating 30 µg and 100 µg of bFGF. Four weeks after each treatment, selective angiography, tissue blood flowmetry using laser Doppler perfusion imaging, and histological examination of thigh muscle were performed. In groups treated with bFGF incorporating gelatin hydrogel, tissue blood flow, number of arterioles, and vascular density were significantly increased in a dose-dependent manner 4 weeks after the treatment. Serum concentrations of bFGF and vascular endothelial growth factor were not elevated 4 weeks after the treatment. In conclusion, sustained release of bFGF using gelatin hydrogel augmented angiogenesis and improved tissue blood flow after excision of the femoral artery. [ABSTRACT FROM AUTHOR]

Abstract: Background: Increasing age of breast cancer patients was reported to cause not only failure of sentinel lymph node (SLN) identification but also false negative results. Methods: A retrospective review was conducted of breast cancer patients who underwent sentinel lymph node biopsy (SLNB) using small-sized technetium-99m–labeled tin colloid (particle size: 200–400 nm in diameter). A comparison between 82 patients who were less than 60 years and 40 patients who were ≥60 years of age was performed to evaluate the efficacy of SLNB using the small-sized tin colloid in older patients. Results: One hundred twenty-two clinically node-negative breast cancer patients underwent SLNB. Apart from age, there were no statistically significant differences between the younger patients and the older patients in terms of the clinicopathologic characteristics. Successful mapping rates, false negative rates, and accuracy were comparable between the 2 groups. Conclusions: SLNB using the small-sized tin colloid was not affected by increasing age. [Copyright &y& Elsevier]

Living-donor lobar lung transplantation (LDLLT) remains a life-saving option for pediatric patients with respiratory failure. However, the long-term survival and post-transplant quality of adult lobar grafts transplanted into children are unknown. Therefore, this study aimed to evaluate the outcomes of pediatric LDLLT and post-transplant graft growth. We retrospectively reviewed the prospectively collected clinical data of 25 living-donor lung transplantations performed in 24 pediatric recipients aged ≤17 years. The annual pulmonary function test data and computed tomography scans of 12 recipients, followed up for >5 years without significant complications, were used to evaluate growth in height, graft function, and radiological changes. The Kaplan–Meier method and simple linear regression were performed for analysis. Bilateral lower lobe transplantation was performed in 12 patients, unilateral lower lobe transplantation in 12, and bilateral middle lobe transplantation in 1. The median volumetric size matching at transplantation was 142% (range, 54%-457%). The 5- and 10-year overall survival rates were 87.7% and 75.1༅, respectively. Chronic lung allograft dysfunction occurred in 2 patients. During a median follow-up of 6 years, the median increases in height and vital capacity were 14.4% (range, 0.80%-43.5%) and 58.5% (range, 6.7%-322%), respectively. Graft weight was positively correlated with graft volume (r2=0.622, p <0.001) after the graft volume exceeded the original lobar volume in the donor. This study shows that pediatric LDLLT offers satisfactory long-term survival, with the growth of mature adult lobes transplanted into growing children. [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]

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.

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]

: PurposeWe have previously reported that entire axillary lymph node regions could be irradiated by the modified tangential irradiation technique (MTIT). In this study, MTIT was compared with a conventional irradiation technique (CTIT) using dose–volume histograms to verify how adequately MTIT covers the breast and axillary lymph node region and the extent to which it involves the lung and heart.: Methods and materialsForty-four patients with early-stage breast cancer were treated by lumpectomy, axillary dissection, and postoperative radiotherapy. Twenty-two patients were treated with MTIT and 22 with CTIT. In 25 patients, the breast tumor was on the left and in 19 on the right. During axillary dissection, surgical clips were left as markers at the border of the axillary lymph node region. MTIT was planned by setting the dorsal edge of the radiation field on a lateral-view simulator film at the dorsal edge of the humeral head and the cranial edge of the radiation field at the caudal edge of the humeral head. CTIT was planned to ensure radiation of the breast tissue without considering the axillary region. In this study, all patients underwent computed tomography, and the CT data were transmitted on-line to a radiotherapy planning system, in which the dose-distribution computed tomography images and dose–volume histograms were calculated by defining the breast, axillary region (levels I, II, and III), lung, and heart region.: ResultsDose–volume histogram analysis demonstrated that breast tissue was radiated with an 86.5–100% volume (median 96.5%) by MTIT and an 83–100% volume (median, 95%) by CTIT at >95% of the isocenter dose. The axillary lymph node regions at Levels I, II, and III were irradiated with 84–100% (median, 94.5%), 59–100% (median, 89%), and 70–100% (median, 89.5%) volumes, respectively, by MTIT and with 2–84% (median, 38%), 0–53% (median, 15%), and 0–31% (median, 0%) volumes, respectively, by CTIT at >70% of the isocenter dose. The ipsilateral lung was irradiated with a 5–22% volume (median, 11.5%) by MTIT and 5–15% volume (median 9%) by CTIT at >90% of the isocenter dose. In all 25 left-sided breast cancer patients, the volumes irradiated with an 80% isocenter dose were <30 cm3.: ConclusionThe results of our study demonstrated that the breast tissue was sufficiently irradiated with both CTIT and MTIT planning, the axillary lymph node areas irradiated by MTIT were much wider than those irradiated by CTIT at all levels, and the lung and heart volumes irradiated by MTIT were small. [Copyright &y& Elsevier]

Chordal-sparing mitral valve replacement (CSMVR) has been proven to be beneficial for postoperative left ventricular (LV) function. In patients with mitral stenosis, however, diseased chordae tendineae (CT) often have to be replaced using artificial CT to achieve CSMVR. Previously, we reported that resusupension of artificial CT in an oblique direction enhances systolic LV function. Among 40 consecutive patients with mitral valve replacement (MVR), 17 (4 men and 13 women; mean age 66.5 years) with rheumatic mitral stenosis underwent CSMVR with oblique resuspension. Echocardiography was done before the operation, early (mean 25 days) after the operation, and at a late stage (mean 14 months). There was no mortality or major morbidity. LV ejection fraction late after the operation (68 ± 8%) was better than that in the early period (61 ± 8%, p < 0.01), and comparable to the preoperative level (65 ± 9%). The oblique method may help to improve the results of MVR. [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]

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]

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]

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]

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]

An 8-year-old girl became ventilator-dependent due to severe bronchiolitis obliterans/interstitial pneumonia caused by cord-blood cell transplantation for neuroblastoma. Her mother''s right lower lobe was twice as large as her right chest cavity. She successfully underwent living-donor, right, single-lobe lung transplantation and simultaneous left pneumonectomy under conditions of cardiopulmonary bypass. At 18 months after transplantation, the patient returned to school life and is currently able to carry out daily activities without supplemental oxygen. [Copyright &y& Elsevier]

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]

Abstract: Objective: Surgical ventricular restoration (SVR) can be effective to treat ischaemic cardiomyopathy or left ventricular (LV) aneurysm. However, the initial improvement in LV function does not always last long because of LV remodelling. Beta-blockers prevent LV remodelling of failing hearts; however, their effects following SVR have not been elucidated. Thus, we sought to investigate the effects of a potent β-blocker, carvedilol, on LV remodelling and function following SVR in rats with myocardial infarction. Methods: Rats, which developed LV aneurysm 4 weeks after coronary artery ligation, underwent SVR. They were orally administered a vehicle (vehicle group), and low or high dose of carvedilol (20 or 50mgkg−1 day−1 for C20 or C50 group) for 4 weeks following SVR (n =7 in each group). Results: Four weeks following SVR, late cardiac remodelling was alleviated only in the C50 group (LV end-diastolic area: 65±4mm2 vs 74±11mm2 and 76±11mm2 for C50, C20 and vehicle groups; p =0.039 and p =0.013, respectively). There was no difference in LV systolic function (end-systolic elastance) among the three groups; however, LV diastolic functions (LV end-diastolic pressure and the time constant of isovolumic relaxation) were significantly better in the C20 and C50 groups. Histologically, the percentage of myocardial fibrosis in the C50 group (4.1±0.2%) was lower than those in the C20 (6.7±0.4%, p <0.0001) and vehicle (7.5±0.6%, p <0.0001) groups. The mRNA expression of transforming growth factor-β1 and brain natriuretic peptide in the C50 group were lower than those in the C20 and the vehicle groups. Conclusions: High-dose carvedilol alleviated LV remodelling and diastolic dysfunction following SVR accompanying with reduction in myocardial fibrosis. Blockade of β-adrenergic receptor may be a promising adjuvant therapy in patients following SVR. [Copyright &y& Elsevier]

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]

Abstract: Though cardiac progenitor cells should be a suitable material for cardiac regeneration, efficient ways to induce cardiac progenitors from embryonic stem (ES) cells have not been established. Extending our systematic cardiovascular differentiation method of ES cells, here we show efficient and specific expansion of cardiomyocytes and highly cardiogenic progenitors from ES cells. An immunosuppressant, cyclosporin-A (CSA), showed a novel effect specifically acting on mesoderm cells to drastically increase cardiac progenitors as well as cardiomyocytes by 10–20 times. Approximately 200 cardiomyocytes could be induced from one mouse ES cell using this method. Expanded progenitors successfully integrated into scar tissue of infracted heart as cardiomyocytes after cell transplantation to rat myocardial infarction model. CSA elicited specific induction of cardiac lineage from mesoderm in a novel mesoderm-specific, NFAT independent fashion. This simple but efficient differentiation technology would be extended to induce pluripotent stem (iPS) cells and broadly contribute to cardiac regeneration. [Copyright &y& Elsevier]

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]

Abstract: Objective: Saline injection test performed during mitral valvuloplasty is popular; however, discrepancies are sometimes noticed between the ‘naked eye’ findings of regurgitation during the saline injection test and the echocardiographic findings after surgery. These discrepancies may arise due to the geometric differences in the mitral valve-left ventricular complex between the saline-injected left ventricle (LV) and the beating LV. Therefore, to elucidate these differences, we compared the three-dimensional geometries between these two conditions. Methods: Sonomicrometry crystal markers were implanted in seven mongrel dogs at the mitral annulus, edge of the mitral leaflets between scallops, tips of papillary muscles, and LV apex under cardiopulmonary bypass. Geometric data of the LV were acquired during the saline injection test and in the beating heart. Results: The commissural width was greater and the annular height was lesser during the saline injection test than in the beating heart (20.5±5.1mm vs 17.2±2.2mm, p <0.01 and 5.5±1.8mm vs 7.3±2.2mm, p <0.05, respectively), indicating that the saddle-shaped mitral annulus was flattened during the test. Additionally, the middle scallop width and the distance between the papillary tips were greater during the test (14.0±4.2mm vs 11.3±3.6mm, p <0.05 and 22.9±5.9mm vs 11.6±5.0mm, p <0.01, respectively), implying that the middle scallop was stretched by the traction of the chordae. The distance between the papillary tips and the mitral annular plane remained constant in both the conditions (19.3±2.6mm vs 18.6±6.2mm, not significant). Conclusions: The saline injection test could aid in determining the length of the reconstructed chordae. However, the test may provide inaccurate data of the mitral-LV dimensions due to the flattened annulus and overstretched leaflets. [Copyright &y& Elsevier]

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]

Abstract: Objective: Although left ventricular repair (LVR) has been widely performed, the initial improvement of LV function does not last because of LV remodeling. Recent studies have demonstrated that chymase, a local enzyme in the heart, promotes angiotensin II formation as well as activation of transforming growth factor (TGF)-β, both of which facilitate myocardial fibrosis. Therefore, chymase blockade may play an important role in the prevention of cardiac remodeling after LVR. In this study, the effects of chronic chymase inhibition (Chy-I) after LVR were evaluated in a rat LV aneurysm model. Methods: Rats that developed LV aneurysms 4 weeks after coronary artery ligation underwent LVR by plicating the LV aneurysm, and were randomized into two groups, the LVR group and the LVR+Chy-I group that received an oral chymase inhibitor (10mg/kg/day) for 4 weeks. Results: Echocardiography revealed better LV function in the LVR+Chy-I group than in the LVR group at 4 weeks. Four weeks after LVR, LV end-diastolic pressure and the time constant of LV isovolumic pressure decay, were significantly lower in the LVR+Chy-I group. The end-systolic pressure–volume relationship was higher in the LVR+Chy-I group. In the LVR+Chy-I group, mRNA expressions of TGF-β1 and BNP significantly decreased in the LV myocardium. Histology showed reduced interstitial fibrosis in the LVR+Chy-I group. Conclusions: Chronic chymase inhibition prevented myocardial fibrosis and preserved cardiac function after LVR. A chymase inhibition could be an important strategy for management after LV repair surgery. [Copyright &y& Elsevier]

Abstract: Objective: Left atrial (LA) volume reduction surgery concomitant with the maze procedure has been reported to facilitate sinus rhythm recovery even in patients with refractory atrial fibrillation (AF) with an enlarged LA. However, it is unknown whether the procedures can also restore effective atrial function of the enlarged LA with over-stretched myocardium. Methods: The maze procedures in association with mitral valve surgery were performed to 57 AF patients with an enlarged LA (LA diameter ≥60mm). Among them, 32 patients had concomitant LA volume reduction surgery (VR group). Another 25 patients did not have the volume reduction (control group). Results: Three months postoperatively LA end-diastolic volume (LAEDV, ml) assessed by magnetic resonance (MR) imaging was larger in the VR group than that in the control group (291±117 vs 223±81ml, p <0.05). Postoperatively, sinus rhythm recovery rate was better (84 vs 68%, p <0.05) and LAEDV was drastically smaller (118±48 vs 203±76ml, p <0.001) in the VR group than those in the control group. Among the patients with sinus rhythm recovery in both groups, LA contraction ejection fraction (%) improved in the VR group but not in the control group (22.3±7.8 vs 10.3±4.7%, p <0.001). Conclusions: The LA volume reduction surgery concomitant with the maze procedure restored contraction of the enlarged LA; however, the maze procedure alone did not restore LA contraction in spite of successful sinus rhythm recovery. LA volume reduction surgery may be desirable to the patients with refractory AF with over-stretched LA. [Copyright &y& Elsevier]

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]

Background: Mechanical unloading (MU) of a failing heart using a left ventricular assist device (LVAD) can lead to “bridge to recovery” in some patients. However, it is still unknown how to determine when to withdraw assistance. We sought to determine the optimal duration of MU by investigating its short- and long-term effects using a rat model of heterotopic heart transplantation. Methods: Heart failure (HF) was induced in Lewis rats by ligating the left anterior descending artery. In the MU-HF groups, failing hearts were harvested and heterotopically transplanted. In the non-unloaded HF groups and the control group, hearts were not transplanted. After 2, 4 and 8 weeks, we evaluated papillary muscle function, histologic change and cardiac gene expression. Normal hearts served as the control group. Results: In the MU-HF groups, papillary muscle function improved significantly in the early period of unloading. It peaked and normalized at 4 weeks of unloading, but decreased to 50% the level of a normal heart at 8 weeks. In parallel with papillary muscle function, expression of brain natriuretic peptide (BNP) mRNA and SERCA2a mRNA normalized at 2 and 4 weeks of unloading, respectively, but deteriorated after 4 weeks. Cardiomyocyte hypertrophy was normalized at 2 weeks of unloading, but extended unloading induced cardiac atrophy. Myocardial fibrosis increased after unloading. Conclusions: Mechanical unloading of the failing heart can help normalize cardiac function, cardiomyocyte hypertrophy and cardiac gene expression for an optimal duration (<4 weeks), but this normalization deteriorates with prolonged support. [Copyright &y& Elsevier]

In the pediatric population, the concomitant presentation of end-stage liver disease and congenital cardiac malformation occurs rarely. Determining the surgical priority in these cases is a challenge due to the presence of hemodynamic alterations that increase surgical risks. We examined five cases that received living-donor liver transplantation. In four patients that had congenital heart disease with a left to right shunt, two had cardiac surgery first, one had both heart and liver surgery simultaneously, and one underwent liver transplantation first. Both of the patients that received heart surgery before liver transplantation needed emergency liver transplantation because of post-operative liver failure. All five patients had a good outcome. Meticulous surgery, close monitoring, and adequate volume management, in addition to tailoring management decisions to the patient's specific condition, make it possible to correct both the liver and the heart abnormalities with satisfactory results. [ABSTRACT FROM AUTHOR]

Objective: To evaluate structure-oriented left ventricular volume reduction surgery (LVVRS). The purpose of this study was to report the early and mid-term results of left volume reduction surgery for dilated cardiomyopathy (DCM). Methods: We performed LVVRS on 29 patients with DCM. The age of the patient ranged from 8 to 73 years (mean 58 ± 18 years). There were 19 male patients (63%). Twenty-three patients were ischemic, 5 were non-ischemic, and 1 had salcoidosis. Twenty-three patients were in New York Heart Association class III or IV. Fourteen patients underwent the Dor operation, 11 underwent a septal anterior ventricular exclusion operation, and 6 underwent a modified Batista operation. Fifteen patients underwent mitral annuloplasty and 2 patients had mitral valve replacement. All patients were divided into two groups, a Dor group (n = 14) and non-Dor group (n = 15). Postoperative early results and mid-term survival rate were compared between the two groups. Results: Hospital mortality was 13.8% (4/29). The causes of death were low-output syndrome (n = 3) and septic shock (n = 1). Survival rate was 80% at 1 year and 72% at 3 years. Two-year survival rate of Dor and non-Dor groups were 69.8% and 93.8%, respectively (p = 0.099). Conclusions: Early and mid-term results of LVVRS were satisfied, and the non-Dor operation tended to be superior in mid-term survival to the Dor operation. Long-term follow-up is warranted. [ABSTRACT FROM AUTHOR]

Taurine (2-aminoethanesulfonic acid) is a potent antioxidant and inhibits cell apoptosis in ischemic reperfusion injury. In this study we evaluated whether addition of taurine to St. Thomas' cardioplegic solution enhances its myocardial protective effects in prolonged hypothermic heart preservation in rats. Hearts isolated from male Sprague–Dawley rats were mounted on a Langendorff apparatus to estimate baseline cardiac function, then arrested and stored in St. Thomas' cardioplegic solution, with taurine (10 mM; taurine group, n = 8) or without taurine (control group, n = 8), for 6 h at 4°C. After storage, the hearts were reperfused and heart rate (HR), coronary flow (CF), left ventricular developed pressure (LVP), and positive maximum left ventricular developing pressure (max LV d p/d t) were measured. The LV tissue was examined immunohistochemically for determining DNA oxidative stress and cell apoptosis. Compared with control groups, recovery of LVP ( P < 0.001), max LV d p/d t ( P < 0.001), and coronary flow ( P < 0.001) were significantly enhanced, whereas glutamic oxaloacetic transaminase ( P < 0.01), lactate dehydrogenase ( P < 0.05), creatine phosphate kinase ( P < 0.01), 8-hydroxy-2′-deoxyguanosine index ( P < 0.01), caspase-3 mRNA expression ( P < 0.05), and percentage of TUNEL-positive cardiomyocytes ( P < 0.05) were reduced in the taurine group. Addition of taurine to St. Thomas' cardioplegic solution improved cardiac function recovery for prolonged hypothermic rat heart preservation by suppressing DNA oxidative stress and cell apoptosis. [ABSTRACT FROM AUTHOR]

Abstract. When an arterial graft is used, reversible perfusion defects on single-photon emission tomography (SPET) perfusion images are occasionally observed early after coronary artery bypass graft surgery (CABG), owing to the restricted flow capacity. The purpose of this study was to determine whether the functional information obtained with electrocardiography (ECG)-gated perfusion SPET could be helpful in evaluating the effect of revascularization early after CABG. Twenty-three patients (18 men and 5 women, mean age 65 +/- 9 years) underwent stress/re-injection thallium-201 ECG-gated SPET before and 4 weeks after CABG (13 with exercise and 10 with dipyridamole). Patency of all grafts was confirmed by coronary angiography I month after CABG. Cardiac functional data including the left ventricular ejection fraction (LVEF) and the transient ischaemic dilatation (TID) ratio were analysed using a commercially available automated program. The conventional stress and re-injection tomograms were interpreted by means of a five-point scoring system in a nine-segment model. Stress-induced reversible [sup 201]Tl perfusion defects were present in 64% of the myocardial segments bypassed by patent arterial grafts, in contrast to 42% of the myocardial segments bypassed by patent venous grafts (chi[sup 2]=7.8, P=0.005). Of the 23 patients, 12 showed improvement... [ABSTRACT FROM AUTHOR]

We report a patient with cardiogenic shock due to severely dilated cardiomyopathy who underwent complex, but comprehensive left ventricle (LV) repair. Preoperative investigation showed marked LV dilatation, poor LV function, severe mitral and tricuspid regurgitation, and total occlusion of two coronary arteries. We urgently performed (1) modified Batista operation which preserves the LV apex, (2) septal anterior ventricular exclusion (SAVE) operation, (3) mitral annuloplasty, (4) tricuspid annuloplasty, and (5) coronary bypass. Postoperative evaluation revealed good graft flow, reduced LV dimension preserving the elliptical shape, improved LV function, and minimal MR. Twenty-six months postoperatively, the patient has minimum clinical symptoms (NYHA: I). [ABSTRACT FROM AUTHOR]

Backgrounds: Human induced pluripotent stem cell (hiPSC)-derived cardiac tissue sheets (CTSs) hold potentials in cardiac functional recovery. Here we investigated the effects of hiPSC-derived cardiac tissues (HiCTs) transplantation to an ischemic heart under unloading condition induced by heterotopic heart transplantation mimicking left ventricular assist device implantation. Methods: We generated 5-layered HiCTs by inserting gelatin hydrogel microspheres between CTSs (HiCT-5). Myocardial infarction was induced in male athymic nude rats by a permanent ligation of left anterior descending artery. One week later, the infarcted heart and lung were harvested and ectopically transplanted into the abdominal aorta of a recipient nude rat. Infarcted hearts were divided into 3 groups: heterotopic heart transplantation group (HTx), heterotopic heart transplantation with HiCT-5 transplantation group (HTx+CTS) and sham operation group as a control (MI). Four weeks later, we histologically evaluated the grafted hearts. Results: Transplanted HiCT-5 formed myocardial region in 5 out of 6 rats of HTx+CTS group (83.3%). cTnT/Ki67 double positive cells were observed in the myocardial region indicating the proliferative potential of engrafted hiPSC-derived cardiomyocytes 4 weeks after transplantation. Infarcted area in HTx+CTS was significantly lower compared to those in HTx group and MI group (MI vs HTx vs HTx+CTS :33.6±6.2 vs 34.5±8.4 vs 22.4±5.5 %; P=0.01). HTx+CTS group showed higher number of capillaries in border zone than those of HTx group and MI group (MI vs HTx vs HTx+CTS:12.7±4.7 vs 16.0±1.6 vs 70.5±58/mm2; P=0.0025). HiCT-5 transplantation suppressed the atrophy of cardiomyocytes caused by the unloading (cross section area of cardiomyocyte: MI vs HTx vs HTx+CTS: 819.0±158.9 vs 335.6±72.2 vs 622.3±139.0 um2, P=0.001). Conclusion: HiCT transplantation is a potentially effective method for the treatment of ischemic hearts under the left ventricular assist device through the attenuation of ventricular remodeling, promotion of angiogenesis and cardiomyocyte proliferation, and the attenuation of cardiomyocyte atrophy, which may serve as a therapeutic strategy in the "bridge to recovery" of ventricular assist devices in the future. [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]

Poor engraftment of cells after transplantation to the heart is a common and unresolved problem in the cardiac cell therapies. We previously generated cardiovascular cell sheets entirely from pluripotent stem cells with cardiomyocytes, endothelial cells and vascular mural cells. Though sheet transplantation showed a better engraftment and improved cardiac function after myocardial infarction, stacking limitation (up to 3 sheets) by hypoxia hampered larger structure formation and long-term survival of the grafts. Here we report an efficient method to overcome the stacking limitation. Insertion of gelatin hydrogel microspheres (GHMs) between each cardiovascular cell sheet broke the viable limitation via appropriate spacing and fluid impregnation with GHMs. Fifteen sheets with GHMs (15-GHM construct; >1 mm thickness) were stacked within several hours and viable after 1 week in vitro. Transplantation of 5-GHM constructs (≈2 × 106 of total cells) to a rat myocardial infarction model showed rapid and sustained functional improvements. The grafts were efficiently engrafted as multiple layered cardiovascular cells accompanied by functional capillary networks. Large engrafted cardiac tissues (0.8 mm thickness with 40 cell layers) successfully survived 3 months after TX. We developed an efficient method to generate thicker viable tissue structures and achieve long-term survival of the cell graft to the heart. [ABSTRACT FROM AUTHOR]

Background: Chemoradiation therapy (CRT) has been widely used for unresectable esophageal squamous cell carcinoma (ESCC) patients. However, many patients develop local recurrence after CRT. In this study, we hypothesized that the immunotherapy by peptide vaccine may be effective for the eradication of minimal residual cancer cells after CRT. This study was conducted as a phase I clinical trial of multiple-peptide vaccine therapy combined with CRT on patients with unresectable ESCC.Patients and Methods: HLA-A*2402 positive 11 unresectable chemo-naïve ESCC patients were treated by HLA-A*2402-restricted multi-peptide vaccine combined with CRT. The peptide vaccine included the 5 peptides as follows; TTK protein kinase (TTK), up-regulated lung cancer 10 (URLC10), insulin-like growth factor-II mRNA binding protein 3 (KOC1), vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2). CRT consisted of radiotherapy (60 Gy) with concurrent cisplatin (40 mg/m²) and 5-fluorouracil (400 mg/m²). Peptide vaccines mixed with incomplete Freund's adjuvant were injected subcutaneously once a week on at least 8 occasions combined with CRT.Results: Vaccination with CRT therapy was well-tolerated, and no severe adverse effects were observed. In the case of grade 3 toxicities, leucopenia, neutropenia, anemia and thrombocutopenia occurred in 54.5%, 27.3%, 27.3% and 9.1% of patients, respectively. Grade 1 local skin reactions in the injection sites of vaccination were observed in 81.8% of patients. The expressions of HLA class I, URLC10, TTK, KOC1, VEGFR1 and VEGFR2 antigens were observed in the tumor tissues of all patients. All patients showed peptide-specific cytotoxic T lymphocytes responses in at least one of the 5 kinds of peptide antigens during the vaccination. Six cases of complete response (CR) and 5 cases of progressive disease (PD) were observed after the 8th vaccination. The 4 CR patients who continued the peptide vaccination experienced long consistent CR for 2.0, 2.9 4.5 and 4.6 years.Conclusions: A combination therapy of multi-peptide vaccine with CRT can successfully be performed with satisfactory levels of safety, and application of this combination therapy may be an effective treatment for patients with unresectable ESCC.Trial Registration: ClinicalTrial.gov, number NCT00632333. [ABSTRACT FROM AUTHOR]