Postoperative Complications and Cancer Recurrence: Impact on Poor Prognosis of Lower Lobe Cancer.

BACKGROUND: Previous reports suggest that lung cancer in the lower lobe is associated with a poorer prognosis than upper lobe disease. However, the reason remains controversial. We evaluated the relationship among the affected lobe, postoperative infectious complications, and cancer recurrence in patients who underwent lobectomy for clinical stage I lung cancer. METHODS: We retrospectively reviewed 422 cases of resected lung cancer. We recorded the postoperative complications that developed within 30 days after surgery. The covariates included in the outcome analysis were patient demographic variables, surgical approach, laterality, affected lobe, tumor size, histologic type, tumor grade, pleural lavage cytology, pleural invasion, lymphovascular invasion, and lymph node metastasis. RESULTS: Lower lobectomy was associated with significantly poorer recurrence-free (excluding nonspecific death) and overall survival than upper lobectomy. According to a stepwise multiple Cox proportional hazards analysis, lower lobectomy, lymph node metastasis, tumor grade, and pleural invasion were independent predictors of recurrence. The following postoperative complications were significantly associated with cancer recurrence and predominantly developed after lower lobectomy: any grade ≥3 complications (n = 61), space/organ surgical site infection of any grade (n = 55), and any infection requiring antibiotics (n = 61). CONCLUSIONS: The current study revealed a significant relationship among the site of resection (upper or lower lobe), cancer recurrence, and occurrence of infectious complications. We must clarify the role of preventing infectious complications in improving the early- and long-term outcomes of lower lobe cancer.

Impact of acute kidney injury on prognosis of chronic kidney disease after aortic arch surgery.

OBJECTIVES: Postoperative acute kidney injury (AKI) is a common complication associated with increased long-term mortality after cardiothoracic surgery. However, AKI after total aortic arch replacement (TAR) is not well studied. This study aimed to investigate the prognosis and impact of AKI on the long-term outcomes of chronic kidney disease (CKD) patients undergoing TAR. METHODS: We included 208 patients who underwent TAR between September 2003 and December 2014. Patients were divided into a CKD (n = 83, 40%) and non-CKD (n = 125, 60%) group. The definition of AKI followed the Risk, Injury, Failure, Loss of kidney function and End-stage kidney disease (RIFLE) criteria. Independent risk factors for all-cause death and AKI were identified with multivariable analysis. RESULTS: Postoperative AKI was observed in 24 patients (29%) and 39 patients (31%) of CKD and non-CKD groups, respectively. The survival rate of CKD patients was significantly lower than that of non-CKD patients (P = 0.02). Among CKD patients, the 5-year survival rate was 57% in those with AKI group and 92% in those without AKI; prognosis was significantly poorer in patients with AKI (P = 0.001). In the non-CKD group, there was no difference in prognosis between patients with or without AKI (P = 0.77). Multivariable logistic regression analysis revealed that intraoperative blood loss of ≥600 ml was the only predictor of AKI in the CKD group (odds ratio 4.32, P = 0.04). CONCLUSIONS: CKD is associated with reduced long-term survival after TAR. Postoperative AKI strongly influences long-term survival in CKD patients only.

Midterm Outcomes of Endovascular Aortic Aneurysm Repair with Carbon Dioxide-Guided Angiography.

BACKGROUND: Although iodinated contrast (IC) agents are commonly used in endovascular aneurysm repair (EVAR), perioperative use in patients with renal dysfunction or IC allergies is avoided. Carbon dioxide (CO2)-guided angiography is a promising alternative. We aimed to evaluate short-term and midterm outcomes of EVAR using CO2-guided angiography. METHODS: Three hundred eighty-one patients who underwent EVAR from January 2012 to September 2016 were retrospectively reviewed and divided into an IC-EVAR group (n = 351) and CO2-EVAR group (n = 30). Subjects in the CO2-EVAR group had severe renal dysfunction (n = 27) and IC allergy (n = 4). Intraoperative, postoperative, and follow-up variables were compared. RESULTS: Compared with the IC-EVAR group, preoperative serum creatinine level was significantly higher (2.0 vs. 0.92 mg/dL, P < 0.0001) and mean IC dose was significantly lower (18 vs. 55 mL, P < 0.0001) in the CO2-EVAR group. The fluoroscopy time, operative time, number of stent grafts placed, and technical success rates of the groups were similar; no type I and/or type III endoleaks were detected on completion angiography. There was no acute kidney injury and one case of intestinal necrosis in the CO2-EVAR group, potentially due to cholesterol embolism. Postoperative endoleak, enlargement of aneurysms, survival, freedom from secondary intervention, and renal function change up to 3 months, postoperatively, were similar between the groups. CONCLUSIONS: CO2-EVAR is technically feasible and exhibits prominent renal protection. However, consideration of the aortic lumen status remains an important challenge.

Age-related increase in Wnt inhibitor causes a senescence-like phenotype in human cardiac stem cells.

Aging of cardiac stem/progenitor cells (CSCs) impairs heart regeneration and leads to unsatisfactory outcomes of cell-based therapies. As the precise mechanisms underlying CSC aging remain unclear, the use of therapeutic strategies for elderly patients with heart failure is severely delayed. In this study, we used human cardiosphere-derived cells (CDCs), a subtype of CSC found in the postnatal heart, to identify secreted factor(s) associated with CSC aging. Human CDCs were isolated from heart failure patients of various ages (2-83 years old). Gene expression of key soluble factors was compared between CDCs derived from young and elderly patients. Among these factors, SFRP1, a gene encoding a Wnt antagonist, was significantly up-regulated in CDCs from elderly patients (≥65 years old). sFRP1 levels was increased significantly also in CDCs, whose senescent phenotype was induced by anti-cancer drug treatment. These results suggest the participation of sFRP1 in CSC aging. We show that the administration of recombinant sFRP1 induced cellular senescence in CDCs derived from young patients, as indicated by increased levels of markers such as p16, and a senescence-associated secretory phenotype. In addition, co-administration of recombinant sFRP1 could abrogate the accelerated CDC proliferation induced by Wnt3A. Taken together, our results suggest that canonical Wnt signaling and its antagonist, sFRP1, regulate proliferation of human CSCs. Furthermore, excess sFRP1 in elderly patients causes CSC aging.

Short- and long-term outcomes of intramyocardial implantation of autologous bone marrow-derived cells for the treatment of ischaemic heart disease.

Objectives: Ischaemic heart disease remains a major cause of death in Japan. We have implanted autologous bone marrow-derived cells locally into the ischaemic region as a therapy in addition to coronary artery bypass grafting since 1999. We describe the outcomes of our cell therapy for ischaemic heart disease. Methods: Eleven patients underwent local implantation of bone marrow-derived cells into the ischaemic region during coronary artery bypass grafting. Clinical outcomes during the acute and chronic phases were recorded. Results: In the acute phase, no adverse effects were observed. Left ventricular ejection fraction values were not significantly different before and after treatment. Seven of the 11 patients showed improved blood perfusion in the area of cell therapy 1 month after treatment. In the chronic phase, 5 of 11 patients exhibited improved regional blood flow 1 year after treatment. Overall survival at 1, 5 and 10 years was 100%, 83.3% and 83.3%, respectively. Freedom from major adverse cardiac and cerebrovascular events at 1, 5 and 10 years was 100%, 80.8% and 80.8%, respectively. Death from all causes or freedom from major adverse cardiac and cerebrovascular events at 1, 5 and 10 years was 100%, 64.6% and 64.6%, respectively. Conclusions: Local implantation of bone marrow-derived cells in patients with ischaemic heart disease is safe and feasible. Cell therapy is a therapeutic option for otherwise untreatable ischaemic heart disease.

Increased plasma VEGF levels following ischemic preconditioning are associated with downregulation of miRNA-762 and miR-3072-5p.

Ischemic preconditioning (IPC) has protective effects against ischemia-perfusion injury of organs. In the present study, we investigated the associated mechanisms after performing remote IPC (rIPC) of lower limbs by clamping abdominal aorta in mice. Subsequent experiments showed decreased damage and paralysis of lower limbs following spinal cord injury (SCI). Concomitantly, plasma vascular endothelial growth factor (VEGF) levels were increased 24 h after rIPC compared with those in sham-operated animals. In subsequent microRNA analyses, thirteen microRNAs were downregulated in exosomes 24 h after rIPC. Further studies of femoral CD34-positive bone marrow (BM) cells confirmed downregulation of these seven microRNAs 24 h after rIPC compared with those in sham-operated controls. Subsequent algorithm-based database searches suggested that two of the seven microRNAs bind to the 3' UTR of VEGF mRNA, and following transfection into CD34-positive BM cells, anti-miR-762, and anti-miR-3072-5p inhibitors led to increased VEGF concentrations. The present data suggest that rIPC transiently increases plasma VEGF levels by downregulating miR-762 and miR-3072-5p in CD34-positive BM cells, leading to protection against organ ischemia.

Treatment of refractory cutaneous ulcers with mixed sheets consisting of peripheral blood mononuclear cells and fibroblasts.

The purpose of this study was to confirm the therapeutic effects of mixed sheets consisting of peripheral blood mononuclear cells (PBMNCs) and fibroblasts on cutaneous skin ulcers. Vascular endothelial growth factor (VEGF) secretion in mixed cell sheets was much higher than in PBMNCs and fibroblasts. Concerning the mechanism, transforming growth factor beta 1 and platelet-derived growth factor BB secreted from PBMNCs enhanced VEGF production in fibroblasts. In wounds created on the backs of diabetic mice, the therapeutic effect of mixed cell sheets was similar to that of daily treatment with trafermin, a recombinant human basic fibroblast growth factor. Although abnormal granulation tissue and inflammatory cell infiltration were observed in trafermin-treated wounds, the transplantation of mixed cell sheets resulted in the natural anatomy of subcutaneous tissues. The expression patterns of identical wound-healing factors in wounds were different between mixed sheet-transfected and trafermin-treated animals. Because mixed cell sheets transplanted into full-thickness skin defects were eliminated in hosts by day 21 in syngeneic transplantation models, allogeneic transplantation was performed using mice with different genetic backgrounds. The wound-healing rates were similar between the mixed cell sheet and trafermin groups. Our data indicated that mixed cell sheets represent a promising therapeutic material for cutaneous ulcers.

Autologous preconditioned mesenchymal stem cell sheets improve left ventricular function in a rabbit old myocardial infarction model.

Mesenchymal stem cells (MSCs) constitute one of the most powerful tools for therapeutic angiogenesis in infarcted hearts. However, conventional MSC transplantation approaches result in insufficient therapeutic effects due to poor retention of graft cells in severe ischemic diseases. Cell sheet technology has been developed as a new method to prolong graft cell retention even in ischemic tissue. Recently, we demonstrated that hypoxic pretreatment enhances the therapeutic efficacy of cell sheet implantation in infarcted mouse hearts. In this study, we investigated whether hypoxic pretreatment activates the therapeutic functions of bone marrow-derived MSC (BM-MSC) sheets and improves cardiac function in rabbit infarcted hearts following autologous transplantation. Production of vascular endothelial growth factor (VEGF) was increased in BM-MSC monolayer sheets and it peaked at 48 h under hypoxic culture conditions (2% O2). To examine in vivo effects, preconditioned autologous BM-MSC sheets were implanted into a rabbit old myocardial infarction model. Implantation of preconditioned BM-MSC sheets accelerated angiogenesis in the peri-infarcted area and decreased the infarcted area, leading to improvement of the left ventricular function of the infarcted heart. Importantly, the therapeutic efficacy of the preconditioned BM-MSC sheets was higher than that of standardly cultured sheets. Thus, implantation of autologous preconditioned BM-MSC sheets is a feasible approach for enhancing therapeutic angiogenesis in chronically infarcted hearts.

Influence of aging on the quantity and quality of human cardiac stem cells.

Advanced age affects various tissue-specific stem cells and decreases their regenerative ability. We therefore examined whether aging affected the quantity and quality of cardiac stem cells using cells obtained from 26 patients of various ages (from 2 to 83 years old). We collected fresh right atria and cultured cardiosphere-derived cells (CDCs), which are a type of cardiac stem cell. Then we investigated growth rate, senescence, DNA damage, and the growth factor production of CDCs. All samples yielded a sufficient number of CDCs for experiments and the cellular growth rate was not obviously associated with age. The expression of senescence-associated b-galactosidase and the DNA damage marker, gH2AX, showed a slightly higher trend in CDCs from older patients (≥ 65 years). The expression of VEGF, HGF, IGF-1, SDF-1, and TGF-b varied among samples, and the expression of these beneficial factors did not decrease with age. An in vitro angiogenesis assay also showed that the angiogenic potency of CDCs was not impaired, even in those from older patients. Our data suggest that the impact of age on the quantity and quality of CDCs is quite limited. These findings have important clinical implications for autologous stem cell transplantation in elderly patients.

Combinatorial Treatment with Apelin-13 Enhances the Therapeutic Efficacy of a Preconditioned Cell-Based Therapy for Peripheral Ischemia.

Hypoxic pretreatment of peripheral blood mononuclear cells (PBMNCs) enhances therapeutic angiogenesis in ischemic tissues after cell transplantation. However, newly formed vessels generated using this approach are immature and insufficient for promoting functional recovery from severe ischemia. In this study, we examined whether apelin-13, a regulator of vessel maturation, could be an effective promoter of therapeutic angiogenesis, following severe limb ischemia. Combinatorial treatment of hypoxic preconditioned PBMNCs with apelin-13 resulted in increased blood perfusion and vascular reactivity in ischemic mouse hindlimbs compared with a monotherapy comprising each factor. Apelin-13 upregulated expression of PDGF-BB and TGF-ß1 in hypoxic PBMNCs, as well as that of PDGFR-ß in vascular smooth muscle cells (VSMCs). Proliferation and migration of VSMCs treated with apelin-13 was accelerated in the presence of PDGF-BB. Interestingly, expression of an apelin receptor, APJ, in PBMNC was increased under hypoxia but not under normoxia. In addition, an in vitro angiogenesis assay using a co-culture model comprising mouse thoracic aorta, hypoxic PBMNCs, and apelin-13 demonstrated that combinatorial treatment recruited mural cells to sprouted vessel outgrowths from the aortic ring, thereby promoting neovessel maturation. Thus, combinatorial injection of hypoxic PBMNCs and apelin-13 could be an effective therapeutic strategy for patients with severe ischemic diseases.

Rapidly progressing left atrial hemangiopericytoma.

Cardiac hemangiopericytoma is a rare soft tissue tumor. We describe a case of hemangiopericytoma in the left atrium, which was diagnosed as myxoma preoperatively. A 70-year-old woman was admitted with heart failure. An echocardiogram showed a large myxoma-like mass in the left atrium, herniating into the left ventricle; therefore, an emergency operation was performed. Histological examination revealed a malignant hemangiopericytoma. The patient's postoperative course was uneventful, but she died due to a local recurrence 4 months after the operation.

[Video-assisted thoracoscopic implantation of left ventricular pacing lead;usefulness of CARTO system;report of a case].

A 70-year-old man, with a history of broad anterior myocardial infarction and repeated several hospitalizations due to heart failure, was referred to our institution for cardiac resynchronization therapy. However, as intravenous implantation of the left ventricular pacemaker lead was not possible, the patient underwent video-assisted thoracoscopic (VAT) implantation. We noted broad myocardial scarring and patent grafts, along with previously bypassed left internal thoracic artery( LITA)-left anterior descending artery (LAD) and right internal thoracic artery (RITA)-D1;thus, the area suitable for implantation of the left ventricule (LV) pacemaker was believed to be restricted. Therefore, we decided to determine the viable myocardial area by using CARTO system and identify the appropriate access port positions for the subsequent VAT surgery. After the LV pacemaker lead was implanted, the recorded pacing threshold was found to be <1.2 V at 0.5 ms. Thus, the CARTO system might be useful to preoperatively identify an area suitable for surgical implantation of a LV pacemaker lead in patients with ischemic cardiomyopathy.

Heat shock transcription factor 1 inhibits expression of IL-6 through activating transcription factor 3.

The febrile response is a complex physiological reaction to disease, including a cytokine-mediated increase in body temperature and the activation of inflammatory systems. Fever has beneficial roles in terms of disease prognosis, partly by suppressing the expression of inflammatory cytokines. However, the molecular mechanisms underlining the fever-mediated suppression of inflammatory gene expression have not been clarified. In this study, we showed that heat shock suppresses LPS-induced expression of IL-6, a major pyrogenic cytokine, in mouse embryonic fibroblasts and macrophages. Heat shock transcription factor 1 (HSF1) activated by heat shock induced the expression of activating transcription factor (ATF) 3, a negative regulator of IL-6, and ATF3 was necessary for heat-mediated suppression of IL-6, indicating a fever-mediated feedback loop consisting of HSF1 and ATF3. A comprehensive analysis of inflammatory gene expression revealed that heat pretreatment suppresses LPS-induced expression of most genes (86%), in part (67%) via ATF3. When HSF1-null and ATF3-null mice were injected with LPS, they expressed much higher levels of IL-6 than wild-type mice, resulting in an exaggerated febrile response. These results demonstrate a novel inhibitory pathway for inflammatory cytokines.

Heat shock transcription factor 1 opens chromatin structure of interleukin-6 promoter to facilitate binding of an activator or a repressor.

Heat shock transcription factor 1 (HSF1) not only regulates expression of heat shock genes in response to elevated temperature, but is also involved in developmental processes by regulating genes such as cytokine genes. However, we did not know how HSF1 regulates non-heat shock genes. Here, we show that constitutive HSF1 binding to the interleukin (IL)-6 promoter is necessary for its maximal induction by lipopolysaccharide (LPS) stimulation in mouse embryo fibroblasts and peritoneal macrophages. Lack of HSF1 inhibited LPS-induced in vivo binding of an activator NF-kappaB and a repressor ATF3 to IL-6 promoter. Neither NF-kappaB nor ATF3 binds to the IL-6 promoter in unstimulated HSF1-null cells even if they were overexpressed. Treatment with histone deacetylase inhibitor or a DNA methylation inhibitor restored LPS-induced IL-6 expression in HSF1-null cells, and histone modification enzymes were recruited on the IL-6 promoter in the presence of HSF1. Consistently, chromatin structure of the IL-6 promoter in the presence of HSF1 was more open than that in its absence. These results indicate that HSF1 partially opens the chromatin structure of the IL-6 promoter for an activator or a repressor to bind to it, and provides a novel mechanism of gene regulation by HSF1.