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Objective@#Maternal embryonic leucine zipper kinase (MELK) is receiving an attention as a therapeutic target in various types of cancers. In this study, we aimed to evaluate the prognostic significance of MELK expression in ovarian cancer using clinical samples, and assessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derived ovarian cancer cells as well as cell lines. @*Methods@#Expression levels of MELK in 11 ovarian cancer cell lines were confirmed by western blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay.MELK messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients by quantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluated using freshly-isolated primary ovarian cancer cells including spheroid formation condition. @*Results@#MELK mRNA expression was significantly higher in ovarian cancer than in normal ovaries (p<0.001), and high MELK mRNA expression was observed in patients with advanced stage, positive ascites cytology and residual tumor size. Patients with high MELK mRNA expression showed shorter progression-free survival (p=0.001). Expression of MELK was also confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitory concentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167 showed significant growth inhibitory effect against patient-derived ovarian cancer cells, regardless of their tumor locations, histologic subtypes and stages. @*Conclusions@#We demonstrated MELK as both a prognostic marker and a therapeutic target for ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may be an effective approach to treat ovarian cancer patients.
ABSTRACT
Objective@#Maternal embryonic leucine zipper kinase (MELK) is receiving an attention as a therapeutic target in various types of cancers. In this study, we aimed to evaluate the prognostic significance of MELK expression in ovarian cancer using clinical samples, and assessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derived ovarian cancer cells as well as cell lines. @*Methods@#Expression levels of MELK in 11 ovarian cancer cell lines were confirmed by western blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay.MELK messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients by quantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluated using freshly-isolated primary ovarian cancer cells including spheroid formation condition. @*Results@#MELK mRNA expression was significantly higher in ovarian cancer than in normal ovaries (p<0.001), and high MELK mRNA expression was observed in patients with advanced stage, positive ascites cytology and residual tumor size. Patients with high MELK mRNA expression showed shorter progression-free survival (p=0.001). Expression of MELK was also confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitory concentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167 showed significant growth inhibitory effect against patient-derived ovarian cancer cells, regardless of their tumor locations, histologic subtypes and stages. @*Conclusions@#We demonstrated MELK as both a prognostic marker and a therapeutic target for ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may be an effective approach to treat ovarian cancer patients.
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<b>Background</b> : Perioperative care in congenital heart surgery has evolved in recent years, and it was considered a contributive factor to improve surgical outcome and prognosis. <b>Objective</b> : To extract perioperative clinical protocols that have been applied in our hospital, then assess their usefulness for better clinical outcome. <b>Methods</b> : We retrospectively reviewed our patients' records to analyze representative perioperative protocols that might have contributed to surgical outcome, such as intraoperative transesophageal echocardiography (ITEE), extubation in the operating room on patients of atrial septal defect (ASD), ventricular septal defect (VSD), tetralogy of Fallot (TOF), Glenn procedure and Fontan procedure. We also assessed clinical pathway of ASD and VSD, and each protocol was individually explored to calculate achievement ratio in order to show its adequacy. <b>Results</b> : This study included 482 of on-pump surgery patients and 146 of off-pump surgery patients from June 2007 to June 2014. ITEE was performed in 474 of on-pump surgery patients and 102 of off-pump surgery patients. No case had a residual lesion immediately after operation. Extubation in the operating room was performed in cases without severe pulmonary hypertension (PH). The extubation ratio was 94.7% (ASD repair), 60.0% (VSD repair), 50.0% (TOF repair), 42.5% (Glenn procedure), and 45.2% (Fontan procedure), respectively. Clinical pathways of ASD and VSD included patients without severe PH. Achievement ratio of the clinical pathway was 98.2% in ASD and 94.2% in VSD patients, respectively. Four patients were excluded because of high c-reactive protein (CRP), and one patient because of familial circumstance. <b>Conclusion</b> : ITEE was useful in evaluation of cardiac function, residual issue and residual air at weaning of cardiopulmonary bypass. Reintubation did not occur in any clinical course of extubation in the operating room, but the extubation rate was not high because of safety concerns. Achievement ratio of the clinical pathways of both ASD and VSD was more than 90%, therefore, application of the clinical pathway was considered appropriate.
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<b>Introduction</b> : We initiated an ambulatory care training program at five community hospitals in Nagasaki, including hospitals on remote islands, for the residents of Nagasaki University Hospital. We examined the educational effect of the ambulatory care training program in meeting the achievement targets for clinical training.<br><b>Methods</b> : The study included all residents (n=49) working in Nagasaki University Hospital in 2012. Following completion of the ambulatory care training program, the residents answered a questionnaire on the number of patients and their symptoms, inaddition to a self-assessment, and assessment by their supervisor.<br><b>Results</b> : The mean number of patients seen was 3.29 persons / training session. The number of symptoms to be encountered, which are established by Ministry of Health, Labour and Welfare, was positively correlated with the total number of patients seen. Although residents initially had a low rating of self-assessment on diagnosis or treatment, this rating tended to increase with time. The gap in levels on assessment of history taking, diagnosis, or treatment by residents versus those by the supervisors reduced with time in the program.<br><b>Conclusion</b> : Our ambulatory care training program is an effective program for meeting the achievement targets in clinical training for residents.
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1）We instituted the “CHANGE Nagasaki University Hospital” project to improve both management and medical education and to boost the number of physicians recruited to this hospital.<br>2）We first identified the physicians’ problems and complaints via a questionnaire. Next, focusing on the most common complaints, we reduced secondary duties and methodically improved the educational environment by employing the a– b–c–d–strategy, which is based on the principles of medical education.<br>3）As a result, both, the hospital’s economic growth and the recruitment figures for resident physicians have increased continuously over the past 4 years.
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Of 225 patients who underwent surgery for abdominal aortic aneurysm from April 1995 to June 2002, 8 patients. or 3.6%, aged 90 years or more (mean age 90.8±1.4. range 90 to 94, 7 men and 1 woman) were the subjects of this study. Four of these patients (50%) underwent emergency surgery. Of these 4 patients, preoperative shock was found in 1 patient. Preoperative complications were hypertension in 4 (50%), ischemic heart disease in 1 (13%), disseminated intravascular coagulation syndrome in 1 (13%), and pleuritis in 1 (13%). The maximum diameter of AAA was 69.5±16.6mm (range 48 to 100mm). The surgical procedure was median laparotomy. Long-term follow-up by the attending physician, or questionnaire by phone was completed for all patients and range to 6.3 years (median, 2.4 years). There were no hospital deaths. Postoperative complications were delirium in 2 (25%), atelectasis in 1 (13%), and ileus in 1 (13%). There were 5 (63%) late deaths. The causes of death were pneumonia in 2, senescence in 1, cardiac failure in 1, and rupture of a pseudoaneurysm at the anastmotic site in 1. Long-term survivals at 1 year, 2 years, and 3 years were 88±12%, 63±17%, and 20±18%, respectively, whereas expected survivals at 1, 2, and 3 years were 82%, 65%, and 51%, respectively. Longterm survivals were not good, but no significant difference was found between long-term and expected survivals. Therefore, this surgical and long-term treatment can achieve satisfactory results. This result led us to recommend performing the operation for patients aged 90 years or more, except if they were bedridden, had severe dementia, or were at the end stage of a malignant disease.
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Recently we reported that the inhibitor of <i>p</i>38 mitogen-activated protein kinase, FR-167653 (Fujisawa Pharm. Co., Ltd., Osaka) may suppress postoperative intimal hyperplasia. In this study we evaluated the best dosage and phase for administration of FR-167653, in order to clarify its mechanism in the postoperative treatment of intimal hyperplasia. Twenty-one Lewis male rats (484±5g) were studied. The epigastric vein graft was interposed into the common femoral artery. The rats were divided into four groups according to the dosage and phase of administration of FR-167653: group I (<i>n</i>=5) with 2.0μg/g of FR-167653 immediately before bypass, group T (<i>n</i>=5) with 2.0μg/g immediately before bypass and 2 weeks after bypass, group D (<i>n</i>=5) with 4.0μg/g immediately before bypass, and the control group (<i>n</i>=6) with the same dose of saline. The intimal areas of vein grafts were measured at 4 weeks postoperatively. The mean intimal areas in group I, T and D were significantly decreased compared with the control group, especially in group D (0.05±0.02mm<sup>2</sup> vs. 0.43±0.05mm<sup>2</sup>, <i>p</i><0.001). These results suggest that FR-167653 can suppress the postoperative intimal hyperplasia that occurs with interposition of vein grafts in rats.
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Recently we reported that tumor necrosis factor-α (TNF-α) mRNA expression and the development of postoperative intimal hyperplasia (IH) is different in rat epigastric vein interposition graft, compared to femoral artery re-anastomosis. We evaluated whether a TNF-α suppressive agent, FR-167653 (Fujisawa Pharm. Co., Ltd., Osaka) could suppress IH or not. Eleven Lewis male rats (480±8g) were studied. The epigastric vein graft was interposed into the common femoral artery. They were divided into two groups: group FR (<i>n</i>=5) with 2.0μg/g of FR-167653, and group C (<i>n</i>=6) with same dose of saline instead of FR-167653. The intimal areas of vein grafts were measured at 4 weeks postoperatively. The mean intimal area in group FR was significantly decreased, compared with group C (0.160±0.057mm<sup>2</sup> vs. 0.434±0.045mm<sup>2</sup>, <i>p</i><0.01). These results suggest that the TNF-α suppressive agent FR-167653 may suppress the postoperative intimal hyperplasia that occurs on the interposition vein graft in rats.
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Several substitutes have been utilized for pericardial closure after open heart surgery. A 55-year-old man was admitted to our hospital with a diagnosis of constrictive pericarditis 13 years after open mitral commissurotomy. At reoperation, the thickened pericardium was peeled off and the epicardium was covered with 0.1mm expanded polytetrafluoroethylene surgical membrane (Gore-tex<sup>®</sup>, sheet thickness 0.1mm). At the 7th postoperative day, he complained of fatigue and dyspnea. Physical examination revealed jugular venous distension, hepatomegaly, ascites and peripheral edema. Cardiac catheterization suggested the suspicion of pericardial or epicardial constriction. On the 3rd-operation, the Gore-tex<sup>®</sup> sheet was removed and multiple longitudinal and transverse incisions were made in the thickened epicardium, that is the waffle procedure, while protecting the myocardium and the coronary arteries. Perioperative hemodynamics improved remarkably. His cardiac index increased from 3.0 to 4.5<i>l</i>/min/m<sup>2</sup>. The postoperative course was uneventful.
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A 65-year-old woman underwent abdominal aortic replacement using a woven Dacron tube graft for abdominal aortic aneurysm on April 2nd, 1996. She had pyrexia on the 6th postoperative day and abdominal enhanced CT scan showed periprosthetic bubble formations. She underwent relaparotomy 14 days after the initial procedure due to large retroperitoneal abcess bacterial culture of which revealed methicillin resistant <i>staphylococcus aureus</i>. She underwent debridement and local irrigation by an electrolyzed strong acid solution. Her pyrexia diminished immediately after relaparotomy and bacterial culture of the drain of the left retroperitoneal space became negative 82 days later. She was discharged and has had no active inflammatory signs for 3 years. She is doing well at present.
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A 72-year-old woman underwent simultaneous combined surgical treatment for descending aortic aneurysm, coronary artery disease and left common iliac artery stenoses. The operation was performed through the left posterolateral thoracotomy via the 6th intercostal space and a left retroperitoneal approach. At first, 10mm woven Dacron graft was anastomosed to the abdominal aorta as an inlet of the cardiopulmonary bypass and the left femoral vein was used for venous drainage. A saphenous vein graft was anastomosed to the left anterior descending artery during partial cardiopulmonary bypass with the heart beating. Secondly, the aneurysm was replaced with 24mm woven Dacron graft. Thirdly, the proximal end of the vein graft was anastomosed to the Dacron graft of the descending aorta. Finally after cardiopulmonary bypass was terminated, the distal end of the woven Dacron graft for arterial perfusion was anastomosed to the left external iliac artery in end-to-side fashion. The postoperative course was uneventful. We conclude that simultaneous operation for descending aortic aneurysm and coronary artery bypass grafting through left thoracotomy with the heart beating is useful in these combined diseases.
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Between March 1976 and February 1996, 17 patients underwent surgical treatment for cardiac myxomas. There were 5 men and 12 women with a mean age of 55 years (range: 22 to 78 years). The location was the left atrium in 13, right atrium in 2, right ventricle in 1 and multiple locations in 1. Since 1978 the standard operative method to treat left atrial myxoma has been a biatrial approach with complete removal of cardiac myxoma and partial resection of the atrial septum. There were no perioperative deaths, but 1 patient had a permanent pace-maker implantation, 2 had transient atrial fibrillation during the early postoperative period, and 1 had acute pulmonary edema after resection of a right ventricular myxoma. There were two late deaths, not related to cardiac event and one recurrence with multiple myxomas. Overall with long term follow-up, the actual survival rate at 10 years was 75% (<i>n</i>=6), with a mean follow-up of 7.1 years, with a 100% follow-up ratio (17 patients). We conclude that the biatrial approach with complete removal of the left atrial myxomas and partial resection of the atrial septum is one of the best procedures for surgical treatment.
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We evaluated 13 patients (4 men & 9 women, mean age: 61 years-old) who required steroid treatment for more than 1 month before open heart surgery. The subjects included 3 patients with collagen diseases, 3 with dermatopathy, 2 with bronchial asthma, one each with Takayasu's disease, autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, brain tumor and post-renal transplantation. Surgical procedures were performed with an AC bypass in 9 cases, one each with AVR, MVR, reMVR and ASD patch closure. The steroid treatment before open heart surgery had been continued for a mean of 4 years and 11 months at a mean dose of 9.4mg/day equivalent of prednisolone. We evaluated the adrenocortical function on the rapid ACTH test and found hypoadrenalism in 5 of 8 cases (63%). In these cases we gave either 100mg of hydrocortisone or 1, 000mg of methylprednisolone before open heart surgery. The total perioperative dosage of steroid was a mean of 2, 488mg equivalent of prednisolone, including 4mg/kg of betamethasone during the extra corporeal circulation. Postoperatively we lost one case due to ventricular rupture after MVR. Other major complications were seen in one case each, cardiac tamponade, temporary clamp, wound infection and lumbar vertebral fracture. For steroid treated patients, it is important to select the patient who really need steroid by the rapid ACTH test, and to use the minimum dosage of steroids in open heart surgery.
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A 31-year-old woman complained of dizziness. Preoperative aortogram revealed a saccular type of aneurysm of the aortic arch and abnormal origin of the left subclavian artery. She underwent reconstruction of the aortic arch through 4th intercostal thoracotomy on August 10th, 1996. The aneurysm originated distally to the left common carotid artery and its wall was very thin. Aortic arch replacement with woven Dacron prosthesis was performed between the left common carotid artery and the left subclavian artery using the inclusion method under hypothermic circulatory arrest. The post operative course was uneventful. Cystic medial necrosis of the aneurysmal wall, and normal arterial findings of the left femoral artery were recognized by the pathohistological examinations. Kinking of the aorta is a congenital disease due to abnormal embryonal development. The aortic arch elongates between the left common carotid artery and the left subclavian artery, and arch aneurysm originates in this portion, because the aneurysmal wall is very thin and fragile when accompanied with cystic medial necrosis. Therefore, it is important that the left subclavian artery originating distally to the arch aneurysm in this category of the aortic arch aneurysm be recognized. There are 11 cases which were successfully operated for aortic arch aneurysm associated with congenital kinking of the aorta in Japan.
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A 66-year-old man suddenly fell into a state of shock on his way back to his room after emergency coronary angiography and intracoronary thrombolysis for acute myocardial infarction. Both echocardiography and pericardiocentesis suggeted a diagnosis of cardiac rupture. The patient was transferred to an operating room with a percutaneous cardiopulmonary support system (PCPS) and intraaortic balloon pumping. Following thoracotomy and release of cardiac tamponade, blow out rupture of the left ventricular free wall was detected. The rupture was repaired using triple mattress sutures by reinforcing with felt pledgets. An infarctectomy was not added and cardiopulmonary bypass was not used. Postoperative recovery of cardiac function was satisfactory and the left ventricular ejection fraction after 2 months was 35%. PCPS and consecutive surgical therapy are effective for the treatment of blow out rupture of the left ventricular free wall.
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Recently several papers have been published on the use of vancomycin (VCM) to prevent perioperative infection during open-heart surgery, but there have been few papers from Japan. In this study, we evaluated the pharmacokinetics of VCM in the serum and right atrial tissues of eight patients (4 men and 4 women) who underwent open-heart surgery, to prevent perioperative infection. Preoperatively all patients had neither hearing disorder nor renal dysfunction. A total of 1, 000mg of VCM was given intravenously over 40-50 minutes before a skin incision. The serum levels of VCM were measured every 20 minutes during open-heart surgery with enzyme-immunoassay. VCM levels in the right atrial tissues were also assayed before the start of extracorporeal circulation (ECC). The peak serum levels of VCM were 55.3±10.1μg/ml and decreased gradually to 10μg/ml prior to the ECC. During the ECC, the serum levels of VCM remained between 7.6 and 9.9μg/ml, while VCM levels in the right atrial tissues were 18.9±6.9μg/ml (serum/tissue ratio: 0.34). Staphylococcal infection is generally inhibited by VCM levels of 2.0-6.5μg/ml. This study suggests that 1, 000mg of VCM given intravenously before a skin incision may be effective to prevent perioperative infection during open-heart surgery.
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A 71-year-old woman underwent mitral valve replacement with Carpentier-Edwards Pericardial Xenograft for mitral regurgitation on January 8, 1987. She had nocturnal hematuria and paroxysmal nocturnal hemoglobinuria was diagnosed in November, 1992. She had congestive heart failure in February, 1993. Cineradiographical analysis revealed a fracture of the wireform in three locations of the Xenograft and the stent was distorted inward. A second mitral valve replacement was successfully performed on March 16, 1993. She was discharged 45 days after operation after an uneventful course.
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A 65-year-old woman was admitted with a diagnosis of unstable angina after PTCA. She was diagnosed with acromegaly 8 years ago. She underwent an emergency coronary artery bypass grafting (LITA-LAD, SVG-HL-Cx). Serum growth hormone (GH) levels were 65.5ng/ml (normal limit<5ng/ml) before the operation. During a cardiopulmonary bypass GH levels elevated to 92.7ng/ml, but decreased to 15.9ng/ml after the operation. After 3 postoperative days GH levels increased gradually again and blood sugar levels became unstable. Finally it was necessary to increase the dose of bromocriptine. To our knowledge, there are only a few patients who have undergone coronary artery bypass grafting associated with acromegaly. This case suggests it is important to control GH levels at the operation and during the postoperative period.
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The patient was a 61-year-old male, who underwent thoracoabdominal aortic aneurysm repair with Gelseal Triaxial prosthetic graft 2 years previously. False-aneurysm due to prosthetic graft dilatation was diagnosed. The direct closure of the ostium of the disruption of the anastomosis was successfully performed by an emergency operation. The postoperative course was uneventful. This case suggests that prosthetic graft dilatation may cause false-aneurysm at the site of end-to-side anastomosis.
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A 58-year-old man was admitted with pulsatile abdominal mass with fever and dull pain. Abdominal aortic aneurysm with left hydronephrosis due to obstruction of the left ureter was diagnosed by CT scanning. Aortic valve replacement was performed ten years previously for aortic regurgitation and recently his cardiac function deteriorated. On the 5th day after admission he suddenly suffered from hemorrhagic shock with massive melena. Emergency laparotomy was performed and ruptured abdominal aortic aneurysm was observed penetrating to the sigmoid colon with perianeurysmal abscess. The abdominal aorta was excluded and closed using two-layer sutures just below the renal artery, and bilateral common iliac arteries were also closed. The aneurysmal sac and the sigmoid colon were removed as a whole, and colostomy was made according to Hartmann's procedure. Permanent right axillo-bifemoral bypass graftiny was made to avoid infectious complications of the vascular graft. A successful vascular reconstruction was done without any complication of graft infection, however he died of cardiac failure due to dilated cardiomyopathy after 4 months postoperatively. We reported a successfully treated abdominal aortic aneurysm extending to the sigmoid colon with hemorrhagic schok.