A Case of Preserved Blood Flow to the Portal Vein Due to the Concurrent Reconstruction of the Superior Mesenteric Vein and the Splenic Vein Using an Artificial Blood Vessel.

Pancreatic cancer is often advanced and invades the major blood vessels around the pancreas. Portal vein (PV) and/or superior mesenteric vein (SMV) resection is performed for radical resection. In such cases, end-to-end anastomosis is best if the remnant vein is sufficiently long. However, when the excision distance is long, reconstruction requires an artificial blood vessel. In contrast, there is no consensus concerning the need for splenic vein (SV) reconstruction. We herein report a case in which portal vein thrombus and congestion of the bowel that occurred after PV-SMV reconstruction were improved by additional anastomosis of the PV-SV.

Successful Pre-Operative Local Control of Skin Invasion of Breast Cancer Using a Combination of Systemic Chemotherapy and Mohs Paste.

Locally advanced breast cancer (tumor > 5 cm, widespread infiltration of the skin and muscle, or metastases to lymph nodes) is difficult to resect by surgery, and even when it is resectable, there is a high probability of local recurrence and distant metastasis. Therefore, systemic therapy should be administered first. However, as cutaneous infiltration progresses, the patient's quality of life is impaired by pain, bleeding, presence of exudates, and a foul-smelling odor. Treatment with Mohs paste with systemic therapy can control symptoms associated with skin infiltration and can also be expected to decrease tumor volume. Herein, we report a case in which a tumor was resected following Mohs paste and systemic chemotherapy administration, and the skin defect was reconstructed with a latissimus dorsi myocutaneous flap. We also review the literature for previously reported cases of breast cancer involving Mohs paste.

Effect of Venous Superdrainage on Colon Interposition for Esophageal Reconstruction.

When performing esophageal reconstruction, a colonic pedicle graft is chosen as the next candidate to the stomach because of complications arising from the operation time and vascular anastomosis. Vascular anastomosis is not necessarily required for pedicle grafts, but it is necessary to perform additional vascular anastomosis in some cases. We herein report a case of superdrainage in which anastomosis of the colonic vein and the right internal thoracic vein was effective against congestion. A 68-year-old man with thoracic esophageal cancer and pyloric antrum gastric cancer was referred to our hospital. Complete resection was performed with subtotal esophageal resection and total gastrectomy. We added superdrainage (right internal thoracic vein - ileocolic vein) to the colonic pedicle graft, which showed congestion, and performed esophageal reconstruction. Venous superdrainage using a colonic pedicle graft is effective for esophageal reconstruction.

The Lymphocyte-to-monocyte Ratio Is an Independent Prognostic Indicator in Pancreatic Head Cancer that Correlates With Obstructive Jaundice.

BACKGROUND/AIM: Several indicators of systemic inflammation have been reported to predict the outcomes of patients with malignant tumors but have not been fully investigated. The aim of this study was to evaluate whether the preoperative lymphocyte-to-monocyte ratio (LMR) can predict the outcomes of patients with pancreatic head cancer. PATIENTS AND METHODS: We studied 32 patients who underwent curative surgery for pancreatic head cancer in our hospital between 2006 and 2016. Patients were classified into high and low groups according to their LMR. RESULTS: The low LMR group had a significantly lower survival rate than the high LMR group (p=0.0313). A multivariate analysis showed that the pretreatment LMR (p=0.01) was an independent risk factor for cancer-related death. The LMR was correlated with obstructive jaundice (p=0.001). CONCLUSION: Preoperative LMR is a significant predictor of the outcome after pancreaticoduodenectomy in patients with pancreatic head cancer.

Current Status and Perspectives on Pharmacologic Therapy for Abdominal Aortic Aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA), a common disease involving the segmental expansion and rupture of the aorta, has a high mortality rate. Therapeutic options for AAA are currently limited to surgical repair to prevent catastrophic rupture. Non-surgical approaches, particularly pharmacotherapy, are lacking for the treatment of AAA. OBJECTIVE: We review both basic and clinical studies and discuss the current challenges to developing medical therapy that reduces AAA progression. RESULTS: Studies using animal models of AAA progression and human AAA explant cultures have identified several potential targets for preventing AAA growth. However, no clinical studies have convincingly confirmed the efficacy of any pharmacologic treatment against the growth of AAA. Thus, there is as yet no strong recommendation regarding pharmacotherapy to reduce the risk of AAA progression and rupture. CONCLUSION: This review identifies concerns that need to be addressed for the field to progress and discusses the challenges that must be overcome in order to develop effective pharmacotherapy to reduce AAA progression in the future.

Inhibitory effect of statins on inflammation-related pathways in human abdominal aortic aneurysm tissue.

HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors (statins) have been suggested to attenuate abdominal aortic aneurysm (AAA) growth. However, the effects of statins in human AAA tissues are not fully elucidated. The aim of this study was to investigate the direct effects of statins on proinflammatory molecules in human AAA walls in ex vivo culture. Simvastatin strongly inhibited the activation of nuclear factor (NF)-κB induced by tumor necrosis factor (TNF)-α in human AAA walls, but showed little effect on c-jun N-terminal kinase (JNK) activation. Simvastatin, as well as pitavastatin significantly reduced the secretion of matrix metalloproteinase (MMP)-9, monocyte chemoattractant protein (MCP)-2 and epithelial neutrophil-activating peptide (CXCL5) under both basal and TNF-α-stimulated conditions. Similar to statins, the Rac1 inhibitor NSC23766 significantly inhibited the activation of NF-κB, accompanied by a decreased secretion of MMP-9, MCP-2 and CXCL5. Moreover, the effect of simvastatin and the JNK inhibitor SP600125 was additive in inhibiting the secretion of MMP-9, MCP-2 and CXCL5. These findings indicate that statins preferentially inhibit the Rac1/NF-κB pathway to suppress MMP-9 and chemokine secretion in human AAA, suggesting a mechanism for the potential effect of statins in attenuating AAA progression.

Use of the continuous suture technique in dunking pancreatojejunostomy without stenting.

PURPOSE: To evaluate the newly developed continuous suture technique in dunking pancreatojejunostomy without pancreatic duct stenting after pancreatoduodenectomy (PD). METHODS: Thirty-four consecutive pancreaticojejunostomies (patient age 73 ± 11, 41-88) with continuous sutures without stenting after PD were performed from 2006 to 2011. This study evaluated the operation time, intraoperative blood loss, initial postoperative day of oral feeding, postoperative hospital stay, postoperative early complications, and late complications. The indications for surgery included bile duct cancer (n = 12), pancreatic cancer (n = 11), intraductal papillary mucinous neoplasm (n = 3), cancer of the papilla (n = 3), duodenal cancer (n = 2), and others (n = 3). Portal vein or superior mesenteric vein resections and reconstructions were performed in 7 patients, and another organ was resected in 3. RESULTS: No operative or in-hospital deaths occurred. The operation time (minutes) was 315 ± 68 and, postoperative hospital stay (days) was 27 ± 16. Pancreatic fistula, wound infection, and delayed gastric emptying were observed in 15, 15, and 9 %, respectively. Grade C pancreatic fistula was seen in 2 patients. Both recovered after laparotomy and drainage and were successfully discharged. Worsening diabetes mellitus was seen in 2 of 34 patients, and dilatation of the pancreatic duct was seen in 3 of 28 patients. CONCLUSION: The newly developed continuous suture technique in dunking pancreatojejunostomy without stenting may therefore produce favorable results in PD.

Hypoxic preconditioning enhances angiogenic potential of bone marrow cells with aging-related functional impairment.

BACKGROUND: Hypoxic preconditioning of bone marrow cells (BMCs) from young healthy individuals can enhance the cells' therapeutic potential. Considering that the response to hypoxia may differ according to the quality of the cells, we assessed the effect of hypoxic preconditioning on BMCs from aged mice and compared the difference in response between BMCs from aged and young mice. METHODS AND RESULTS: BMCs from young (3 months) and aged (20-22 months) mice were subjected to hypoxic preconditioning by culture for 24 h in 2% O2. Compared with BMCs from young mice, those from aged mice showed significantly fewer CD34- or c-kit-positive stem cells, higher expression of p53, and lower telomerase activity. Adhesion, survival and angiogenic potency were also lower in BMCs from aged mice, indicating an aging-related impairment. Hypoxia-preconditioned BMCs from aged mice showed enhanced adhesion, survival, and angiogenic potency with the in vitro assessments, as well as the in vivo implantation into ischemic hindlimbs. All the enhancements by hypoxic preconditioning were comparable between BMCs from aged and young mice, although the angiogenic potential of BMCs with and without hypoxic preconditioning was lower in old mice compared with young mice. CONCLUSIONS: Similar responses to hypoxia by BMCs from both aged and young mice suggest that hypoxic preconditioning could be a useful method of enhancing the angiogenic potential of BMCs.

Routine diagnostic venous ultrasound and las for leg edema of unknown cause.

OBJECTIVE: To verify the diagnostic efficiency of venous duplex ultrasound and lymphangioscintigraphy (LAS) in establishing the cause of leg edema and to clarify the pathology of these leg edemas. MATERIALS AND METHODS: Between April 2009, and March 2010, 62 patients with leg edema of unknown origin were referred to the Edema Clinic of the Yamaguchi University Graduate School of Medicine. All patients underwent a venous duplex ultrasound scan and LAS. RESULTS: Of 62 patients, lymphatic insufficiency, venous insufficiency or both was diagnosed in 42 (68%), and lymphedema, in 29 (47%). Venous duplex ultrasound detected obvious venous disorders in only 13 (21%), and for 20 patients, the ultrasound and LAS did not reveal any abnormalities; however, for 15 of the 20 (24% of all patients), venous edema was attributed to functional causes. CONCLUSION: Venous duplex ultrasound and LAS assisted in the diagnosis of leg edema of unknown origin and also proved useful in establishing treatment strategies.

Lysyl oxidase resolves inflammation by reducing monocyte chemoattractant protein-1 in abdominal aortic aneurysm.

Lysyl oxidase (LOX) is an enzyme critical for the stability of extracellular matrix and also known to have diverse biological functions. Little is known, however, about the role of LOX in regulating inflammation. Here we demonstrate that LOX suppresses secretion of monocyte chemoattractant protein-1 (MCP-1) in cultured vascular smooth muscle cells. Furthermore, enhancement of LOX activity reduces MCP-1 in a mouse model of abdominal aortic aneurysm (AAA), thereby preventing macrophage infiltration and AAA progression. These findings suggest that LOX has a novel function in resolving inflammation by reducing MCP-1 in AAA.

Impact of intraoperative transesophageal echocardiography in cardiac and thoracic aortic surgery: experience in 1011 cases.

BACKGROUND: Although intraoperative transesophageal echocardiography (IOTEE) has been widely used in cardiovascular surgery, the exact incidence of abnormalities detected by IOTEE in each type of surgical procedure is still unclear. The aim of this study was to review our experiences of IOTEE, in patients who underwent different types of cardiovascular surgery and to evaluate the clinical usefulness of IOTEE. METHODS AND RESULTS: Our database of 1011 consecutive patients, who underwent cardiovascular surgery and IOTEE monitoring was reviewed. The incidence of abnormal findings was 115 of 1011 patients (11.4%), and the highest incidence was the appearance of new wall motion abnormalities after cardiopulmonary bypass. These findings influenced surgical decision-making in 59 of the evaluated 1011 patients (5.8%). CONCLUSIONS: IOTEE provides important intraoperative and postoperative information that may influence surgical decision-making in various cardiovascular surgeries.

[The outcomes of program based on complex decongestive physiotherapy for a patient with secondary lymphedema caused by infection on the leg].

Lymphedema is a chronic problem causing distress and loss of functions throughout the lifespan. Complex decongestive physiotherapy (CDP) is in common use in developed countries but has only recently been used in Japan for people in outpatient settings. CDP is a representative conservative treatment for lymphedema, conducted by combining four kinds of physical therapies: skin care, manual lymph drainage (MLD), bandage and exercise. This research project lead by a nurse is underway using CDP in an outpatient department. We report a case of secondary lymphedema caused by infection successfully treated by CDP. A 22-year-old man suffered from cellulitis of unknown origin when he was a high school student. After this event, he had been repeatedly admitted to hospital with infections as a result of the lymphedema. He underwent MLD once or twice monthly and received health education for skin care, self-massage and exercise, and was advised to wear compression stockings. Within 7 months the leg swelling had significantly reduced and his feelings of malaise and pain disappeared. Fourteen months later the circumferences of his knee and ankle had kept the sizes, and he has not re-entered hospital for infections. For this man, CDP had a positive outcome, as it has for many others around the world. Our experience has found it very important to establish adequate support systems for such people in outpatient and community settings. However, more research and knowledge sharing are required to understand the usefulness and effectiveness about this program as a primary treatment combined with health education in community settings in Japan.

Transient increase of cytokines in the acute ischemic tissue is beneficial to cell-based therapeutic angiogenesis.

BACKGROUND: Implantation of bone marrow cells (BMCs) is a treatment of ischemic disease. It is well known that many inflammatory cytokines are released in ischemic tissue, especially in the acute phase, so in the present study it was investigated if the transient increase of cytokines in the acute ischemic tissue influences cell-based therapeutic angiogenesis. METHODS AND RESULTS: Ischemic limb models were created in C57BL/6 mice as 24 h (acute) or 2 weeks (chronic) after ischemia. BMCs were cultured with total tissue protein, which was extracted from the acute and chronic ischemic muscles. The survival, adhesion, and migration of BMCs were significantly better after culture with 1 mg/ml total tissue protein extracted from the acute ischemic limbs than from the chronic ischemic limbs (p<0.001). For the in-vivo study, 8 x 10(6) BMCs, collected from green fluorescent protein (GFP) transgenic mice, were implanted into the acute or chronic ischemic limbs of the mice. The survival of implanted cells and blood flow were significantly better when BMCs were implanted into the acute ischemic limbs than into the chronic ischemic limbs (p<0.001). CONCLUSIONS: A transient increase of cytokines in the acute ischemic tissue is beneficial for cell-based therapeutic angiogenesis.

Infected aneurysms of bilateral deep femoral arteries due to Campylobacter fetus subspecies fetus.

Infected aneurysms due to Campylobacter fetus subspecies fetus have rarely been reported. Here, we describe the first case of infected aneurysm of bilateral deep femoral arteries due to C. fetus fetus. We successfully treated this case by administration of antibiotics effective for C. fetus fetus and bilateral obturator bypass with complete resection of the infected aneurysms. The aneurysmal wall culture disclosed the presence of C. fetus fetus in a microaerobic atmosphere after the operation. A distinctive culture condition was necessary to detect C. fetus fetus. In the case of infected aneurysms, we should be aware of the possibility of infection with C. fetus fetus, and an appropriate culture for this organism may be needed.

Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase in mice.

Abdominal aortic aneurysm (AAA) is a common disease that, when surgical treatment is inapplicable, results in rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is eagerly awaited, the destruction of the aortic walls in AAA has been considered an irreversible process. We found that c-Jun N-terminal kinase (JNK) is highly activated in human AAA walls. We also found that JNK activity is essential for the expression of matrix metalloproteinase (MMP)-9 and, concurrently, suppression of the extracellular matrix (ECM) biosynthesis. We therefore investigated the role of JNK in the pathogenesis of AAA in vivo. We created a mouse AAA model by periaortic application of CaCl(2), which was accompanied by activation of JNK and MMPs, and suppression of lysyl oxidase (LOX), which is an essential biosynthetic enzyme for collagen and elastin fibers. Our data indicate that, in addition to MMP activities, suppression of ECM biosynthesis may contribute to the AAA pathogenesis because local LOX gene delivery prevented AAA formation. Treatment of mice with SP600125, a specific JNK inhibitor, completely abrogated the formation of CaCl(2)-induced AAA. Furthermore, SP600125 treatment after the establishment of AAA caused a reduction in the aortic diameters with normalized tissue architecture. SP600125 treatment also caused significant regression of angiotensin II-induced AAA in ApoE-null mice after its establishment, as demonstrated by serial ultrasonographic studies in live animals. These data demonstrate that JNK dictates the abnormal ECM metabolism in AAA pathogenesis by enhancing tissue degradation and suppressing tissue repair. Therefore, inhibition of JNK may provide a novel therapeutic option for AAA.

Identification of c-Jun N-terminal kinase as a therapeutic target for abdominal aortic aneurysm.

Despite the advances in molecular cell biology, identification of a therapeutic target in a given disease still poses a significant challenge. Here we report a strategy for identification of the therapeutic target in abdominal aortic aneurysm (AAA). We screened for various signaling molecules in human AAA samples and identified c-Jun N-terminal kinase (JNK) as a prominently activated molecule. The JNK pathway-oriented transcriptome analyses revealed that activation of JNK leads to enhancement of the activity of matrix metalloproteinases and, concurrently, suppression of the extracellular matrix biosynthesis, suggesting that JNK may represent a novel therapeutic target in AAA.

Impaired potency of bone marrow mononuclear cells for inducing therapeutic angiogenesis in obese diabetic rats.

Using Zucker fatty rats, a strain characterized by diabetes and hyperlipidemia, we investigated the diabetes- and hyperlipidemia-related impairment of bone marrow mononuclear cells (BMCs) for inducing therapeutic angiogenesis. BMCs from Zucker fatty and normal Zucker lean rats were collected and cultured. Although the characterization and cell survival of BMCs did not differ, the VEGF production, endothelial differentiation, and endothelial cell colony-forming potential of BMCs from Zucker fatty rats were significantly lower than those of BMCs from lean rats. By using an ischemic hindlimb model, we found that the native recovery of induced limb ischemia in the Zucker fatty rats was also significantly worse than that in the lean rats. Furthermore, the expression of 5-hydroxytryptamine (5-HT(2A)) receptors was obviously higher in the Zucker fatty rats than that in the lean rats and was enhanced after limb ischemia. Although the therapeutic potency was lower than with the implantation of BMCs from normal lean rats, the implantation of BMCs from fatty rats could also induce angiogenesis and increase blood flow significantly in the ischemic hindlimbs of Zucker fatty rats. Furthermore, the blood flow in the ischemic hindlimbs was increased by the administration of sarpogrelate, a selective 5-HT(2A)-receptor antagonist. Our results clearly show diabetes- and hyperlipidemia-related dysfunction and impaired potency for inducing angiogenesis of BMCs. However, the implantation of autologous BMCs into ischemic limbs of diabetic and hyperlipidemic rats has induced therapeutic angiogenesis effectively, and blood flow would be enhanced by the administration of a 5-HT(2A)-receptor antagonist.

Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase.

Abdominal aortic aneurysm (AAA) is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is much awaited, few options are available because its molecular pathogenesis remains elusive. Here, we identify JNK as a proximal signaling molecule in the pathogenesis of AAA. Human AAA tissue showed a high level of phosphorylated JNK. We show that JNK programs a gene expression pattern in different cell types that cooperatively enhances the degradation of the extracellular matrix while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in two mouse models. Thus, JNK promotes abnormal extracellular matrix metabolism in the tissue of AAA and may represent a therapeutic target.

Regeneration of infarcted myocardium by intramyocardial implantation of ex vivo transforming growth factor-beta-preprogrammed bone marrow stem cells.

BACKGROUND: Recent studies have shown that bone marrow-derived stem cells differentiate into the phenotype of cardiomyocytes in vivo and in vitro. We tried to regenerate infarcted myocardium by implanting ex vivo transforming growth factor (TGF)-beta-preprogrammed CD117 (c-kit)-positive (CD117+) stem cells intramyocardially. METHODS AND RESULTS: CD117+ cells were isolated from the bone marrow mononuclear cells of GFP-transgenic or normal C57/BL6 mice. The myogenic differentiation of CD117+ cells was achieved by cultivation with TGF-beta. Using an acute myocardial infarction model, we also tried to regenerate infarcted myocardium by implanting untreated (newly isolated) or preprogrammed (24 hours of cultivation with 5 ng/mL TGF-beta1) CD117+ cells intramyocardially. TGF-beta increased the cellular expression of myosin, troponins, connexin-43, GATA-4, and NKx-2.5, which suggested that it induced the myogenic differentiation of CD117+ cells. Compared with the effects of PBS injection only, the microvessel density in the infarcted myocardium was increased significantly 3 months after the implantation of either TGF-beta-preprogrammed or untreated CD117+ cells. Moreover, many of the TGF-beta-preprogrammed CD117+ cells were stained positively for myosin, whereas few of the untreated CD117+ cells were. Histological analysis revealed newly regenerated myocardium in the left ventricular anterior wall after the implantation of TGF-beta-preprogrammed cells but not untreated cells. Furthermore, the left ventricular percent fraction shortening was significantly higher after the implantation of TGF-beta-preprogrammed cells than after the implantation of untreated CD117+ cells. CONCLUSIONS: TGF-beta conducted the myogenic differentiation of CD117+ stem cells by upregulating GATA-4 and NKx-2.5 expression. Therefore, the intramyocardial implantation of TGF-beta-preprogrammed CD117+ cells effectively assisted the myocardial regeneration and induced therapeutic angiogenesis, contributing to functional cardiac regeneration.

Cellular expression of integrin-beta 1 is of critical importance for inducing therapeutic angiogenesis by cell implantation.

OBJECTIVES: Using cell-based therapy to induce therapeutic angiogenesis has been the focus of much recent attention. We used freshly collected CD117-positive stem cells (CD117(+) cells) and ex vivo expanded CD117(+) cells to investigate the role of cellular expression of several adhesion molecules in this therapeutic regimen. METHODS: CD117(+) cells were separated from the bone marrow mononuclear cells of C57/BL6 mice and cell expansion was done by 2 weeks of cultivation. The cellular expression of integrin-beta(1), integrin-beta(3) and VE-cadherin was analyzed by Western blot and real-time PCR. Three-dimensional culture was performed to observe the capillary-like tube formation. We also implanted cells into the ischemic limbs of mice and evaluated the survival and incorporation of these implanted cells and measured the blood flow and microvessel density of the ischemic limbs 2 weeks after treatment. RESULTS: The expression of integrin-beta(1) in the expanded cells decreased significantly, to about 30% of the freshly unexpanded CD117(+) cells. However, the expression of integrin-beta(3) did not change significantly and the VE-cadherin increased after ex vivo expansion of the CD117(+) cells. Antibody perturbation to integrin-beta(1) significantly inhibited the adhesion, growth and tube formation of cultured CD117(+) cells. Furthermore, the freshly unexpanded CD117(+) cells survived well and were incorporated in microvessels after implantation into the ischemic limbs of mice, resulting in a significant increase in blood flow and microvessel density. The cell survival and incorporation decreased, and the angiogenic potency was deprived by antibody perturbation to integrin-beta(1) before implantation. Conversely, these expanded cells had weak angiogenic potency because of the poor cell survival and incorporation after implantation, but the increase in integrin-beta(1) expression by subjecting them to 24-h hypoxia prestimulation increased cell survival and angiogenic potency significantly after implantation into the ischemic limbs. CONCLUSION: These data clearly show that integrin-beta(1) is a critical adhesion molecule for inducing therapeutic angiogenesis in cell-based therapy, by regulating cell survival and differentiation after implantation into ischemic tissue.