Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice.

The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing with the growing epidemics of obesity and diabetes. NAFLD encompasses a clinicopathologic spectrum of disease ranging from isolated hepatic steatosis to NASH, which is a more aggressive form of fatty liver disease, to cirrhosis and, finally, hepatocellular carcinoma (HCC). The exact mechanism behind the development of HCC in NASH remains unclear; however, it has been established that hepatic steatosis is the important risk factor in the development of HCC. Metformin has recently drawn attention because of its potential antitumor effect. Here, we investigated the effects of metformin on high-fat diet (HFD)-induced liver tumorigenesis, using a mouse model of NASH and liver tumor. Metformin prevented long-term HFD-induced liver tumorigenesis in C57Bl/6 mice. Of note, metformin failed to protect against liver tumorigenesis in mice that had already begun to develop NAFLD. Metformin improved short-term HFD-induced fat accumulation in the liver, associated with the suppression of adipose tissue inflammation. Collectively, these results suggest that metformin may prevent liver tumorigenesis via suppression of liver fat accumulation in the early stage, before the onset of NAFLD, which seems to be associated with a delay in the development of inflammation of the adipose tissue.

Phase I/II study of intraperitoneal docetaxel plus S-1 for the gastric cancer patients with peritoneal carcinomatosis.

PURPOSE: We designed a phase I/II trial of intraperitoneal (IP) docetaxel plus S-1 to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate its efficacy and safety in gastric cancer patients with peritoneal carcinomatosis (PC). METHODS: Patients with PC confirmed by laparoscopy or laparotomy received IP docetaxel on days 1 and 15 and S-1 (80 mg/m(2)) on days 1-14 every 4 weeks. RESULTS: In the phase I part (n = 12), each cohort received escalating doses of docetaxel (35-50 mg/m(2)); the MTD was determined to be 50 mg/m(2) and the RD was determined to be 45 mg/m(2). Dose-limiting toxicities included grade 3 febrile neutropenia and grade 3 diarrhea. In the phase II part (n = 27), the median number of courses was 4 (range 2-11). The 1-year overall survival (OS) rate was 70 % (95 % confidence interval 53-87 %). The overall response rate was 22 % and peritoneal cytology turned negative in 18 of 22 (81 %) patients. The most frequent grade 3/4 toxicities included anorexia (19 %), neutropenia (7 %), and leukopenia (7 %). CONCLUSION: IP docetaxel plus S-1 is active and safety in gastric cancer patients with PC.

[Clinicopathological characteristics of pulmonary cryptococcosis].

Pulmonary cryptococcosis is a fungal infection caused by the inhalation of Cryptococcus neoformans, and may progress to disseminated disease, particularly in immunocompromised host such as acquired immunodeficiency syndrome. We reported a retrospective review of the 8 patients who had undergone surgical resection for pulmonary cryptococcosis during recent 12 years. There were 5 men and 3 women with a mean age of 49 years. The number of lesions was solitary in 4 patients and multiple in 4 patients. All patients had neither symptom from the lesion nor human immunodeficiency virus infection. The most common computed tomography finding was well-defined solid nodules (<2 cm) of the lung. The lesion size ranged from 0.8 to 2.0 cm with a mean of 1.3 cm. Pathologically, the resected specimen revealed Cryptococcus fungal bodies in all cases. After surgery, 4 patients were treated with systemic antifungal therapy (fluconazole), and the others had no treatment. In all patients, no sign of relapse was found during the postoperative follow-up period. Although the prognosis of present cases was excellent regardless of the treatment after the surgery, the recommendation for the treatment in patients with pulmonary cryptococcosis is oral or intravenous fluconazole therapy because of the possible development of subclinical systemic disseminated disease.

[Lipoma of the diaphragm; report of a case].

A 50-year-old man was referred to our hospital with an abnormal shadow on chest roentgenogram taken on a health examination in September, 1999. His past history was an operation for scoliosis at the age of 39 years. His family history was unremarkable. Chest roentgenogram showed a smooth rounded bulging nodule in continuity with the left diaphragm. Chest computed tomography (CT) revealed a well-defined and homogeneous nodular lesion with a low attenuation value of -100 Hounsfield unit, corresponding with a fat density, on the base of the left hemithorax. For making diagnosis and treatment, videothoracoscopic surgery was performed in January, 2000. The tumor was removed with combined resection of diaphragm, using stapling device, because the lesion partially adhered to the diaphragm. The postoperative course was uneventful. The pathological diagnosis was lipoma About 2 years later. he was again found to have a similar abnormal shadow on a routine chest roentgenogram in August, 2003. Chest CT showed a nodular lesion involving a previous operative staple line on the base of the left hemithorax. We considered this lesion to be a locally recurrent tumor and performed surgical resection of the lesion with a wide margin of normal diaphragm and partial retroperitoneal fat tissue. The pathological diagnosis of the resected specimen was again lipoma. Since then, he has been in good health without recurrence for about 4 years.

11C-acetate PET in the evaluation of brain glioma: comparison with 11C-methionine and 18F-FDG-PET.

PURPOSE: The aim of the study is to retrospectively investigate the usefulness of 11C-acetate (ACE)-positron emission tomography (PET) for evaluation of brain glioma, in comparison with 11C-methionine (MET) and 2-deoxy-2-18F-fluoro-D-glucose (FDG). PROCEDURES: Fifteen patients with brain glioma referred to initial diagnosis were examined with ACE, MET, and FDG-PET. Five patients had low-grade gliomas (grade II), three had anaplastic astrocytomas (grade III), and seven had glioblastomas (grade IV). PET results were evaluated by visual and semiquantitative analysis. For semiquantitative analysis, the standardized uptake value (SUV) and tumor to contralateral normal gray matter (T/N) ratio were calculated. The sensitivity for detection of high-grade gliomas was calculated using visual analysis. RESULTS: Sensitivities of ACE, MET, and FDG were 90%, 100%, and 40%, respectively. ACE and MET T/N ratios were significantly higher than that of FDG. ACE and FDG SUV in high-grade gliomas were significantly higher than that in low-grade gliomas. No significant differences were observed using MET. CONCLUSIONS: ACE PET is a potentially useful radiotracer for detecting brain gliomas and differentiating high-grade gliomas.

Analysis of donor-type chimerism in lineage-specific cell populations after allogeneic myeloablative and non-myeloablative stem cell transplantation.

We analyzed donor-type chimerism in CD3+, CD14.15+ and CD56+ cells from 36 patients who had undergone conventional-intensity allogeneic stem cell transplantation (CST) and 34 patients who had undergone non-myeloablative allogeneic stem cell transplantation (NST) for hematological malignancies. On day 28 after transplantation, all fractions in NST patients and CD3+ cells in CST patients who received a non-total body irradiation (TBI) regimen showed more frequent mixed chimerism (<90% donor cells) than those in patients who had received TBI. NST patients with acute graft-versus-host disease (grade II-IV) frequently showed more than 50% donor-type chimerism in CD3+ cells on day 14 (P=0.029). NST patients with <50% donor-type chimerism on day 14 and with <90% donor-type chimerism on day 28 in CD56+ cells had significantly poor 1-year overall survival (0 vs 91%, P<0.001 and 20 vs 74%, P=0.002, respectively). Both NST and CST patients with <90% donor-type chimerism in CD14.15+ cells on day 28 had significantly poor 1-year overall survival (14 vs 70%, P=0.005 and 0 vs 66%, P=0.002, respectively). Our data show that the extent of donor-type chimerism in lineage-specific cells appears to have an impact on outcome after allogeneic stem cell transplantation.

[Carney triad; report of a case].

We report a case of Carney triad which is very rare disease composed of gastrointestinal stromal tumor (GIST), pulmonary chondroma and paraganglioma. A 15-year-old girl was reffered for treatment with multiple tumors in the left lung. At the age of 13, she underwent total gastrestomy for GIST. At that time multiple pulmonary tumors have already developed and made a diagnosis of chondroma. Progressive enlargement of their size and persistent bloody sputum made her received operation. Finally she underwent left pneumonectomy. In general all 3 tumors have manifested for a long time. Gastric tumors and paragangliomas are often lethal. This shows the necessity of intensive and long-term follow-up.

[Aortic valve replacement presence of anti-Jr(a) antibody].

A 65-year-old female with a heart murmur developed progressive symptom of chest oppression. She was diagnosed severe aortic valve stenosis with echocardiogram. Antibody screening revealed anti-Jr(a) antibody. Preoperatively, erythropoietin was administered. Over 14 days, a total 1,000 ml of her blood was drawn and stored for autologous transfusion. The aortic valve was replaced with ATS mechanical valve [18 mm advanced performance (AP)]. Following surgery, her stored blood was administered to him. But her HCT was 17% on the 1st postoperative day. Frozen thawed red cells were transferred 7th postoperative day.

A novel diagnostic method for evaluation of vascular lesions in the digestive tract using infrared fluorescence endoscopy.

BACKGROUND AND STUDY AIMS: We have developed an infrared fluorescence endoscope to evaluate gastrointestinal vascular lesions. Infrared endoscopy (IRE) after intravenous administration of indocyanine green (ICG) is used at present to examine vascular lesions such as esophageal varices. However, no previous study has compared the sensitivity of infrared fluorescence endoscopy (IRFE) with that of IRE. In this study, we compared the usefulness of IRFE and IRE. PATIENTS AND METHODS: For IRFE we used an infrared endoscope equipped with excitation and barrier filters and an intensified charge-coupled device camera. In preliminary experiments, the observable tissue depth was assessed by wrapping increasing numbers of layers of commercially available pork around a syringe containing a uniform concentration of ICG or by changing the concentration of ICG in a syringe covered by a piece of pork of uniform thickness. In the clinical part of the study, ICG was administered intravenously at different concentrations to patients with esophageal varices and the resulting infrared fluorescent images were evaluated. RESULTS: The preliminary experiments revealed that the depth of tissue that could be visualized was significantly greater in IRFE than it was in IRE (11.2 mm in IRFE vs. approximately 3.2 mm in IRE). Clear infrared fluorescence was obtained by IRFE at lower concentrations of ICG than the concentrations required to obtain clear images using IRE. In the clinical part of the study, clear infrared fluorescence was observed in a region where esophageal varices had been detected by conventional endoscopy when ICG was administered in doses of 0.005 mg/kg to 0.01 mg/kg, which was lower than the doses used in IRE. CONCLUSIONS: Compared with conventional IRE, IRFE facilitated the observation of deeper layers, and esophageal varices were observed by IRFE following the intravenous administration of a markedly reduced dose of ICG. IRFE, in combining the characteristics of reflected infrared light and fluorescence, may be a useful novel procedure in the diagnosis of vascular lesions in the gastrointestinal tract.

Assessment of synthetic peptides of severe acute respiratory syndrome coronavirus recognized by long-lasting immunity.

In order to determine highly immunogenic severe acute respiratory syndrome coronavirus (SARS-CoV) epitope peptides capable of inducing long-lasting immunity, we first screened immunoglobulin-G (IgG) antibodies reactive to 197 different overlapping 15-mers from the SARS-CoV proteins in the sera of three infected patients. Forty-two peptides among them were reactive to the sera from all three patients. Consequently, we tested for the reactivity of these 42 peptides to patients' sera (n = 45) at 6-month post-infection. The significantly higher levels of IgG antibodies specific to three (S791, M207 and N161) of 42 peptides were detectable in the post-infection sera from 23 (51%), 27 (60%) and 19 (42%) of 45 patients, respectively. These three peptides, recognized by their long-lasting immunity, may provide a better understanding of the immunogenicity of SARS-CoV.

[Surgical treatment for left ventricular false aneurysm caused by infective endocarditis; report of a case].

A 24-year-old man who had left ventricular (LV) false aneurysm, which is caused by mitral valve infective endocarditis, underwent aneurysmectomy, direct closure of aneurysmal mouth and concomitant mitral valve replacement. Post-operative course was uneventful. It has been reported that the etiology of this false aneurysm was due to the vegetations' friction, which could have caused an initial endocardial ulceration that progressively expanded into the myocardium. The false aneurysmal wall should be completely removed in order to eliminate the possibility of recurrence of the infective endocarditis. We believe that the surgical treatment should be carried out as soon as possible after completion of diagnosis because the aneurysmal wall is usually quite thin and could rupture easily.

Angioarrestin mRNA expression in early-stage lung cancers.

AIMS: Angioarrestin is a recently isolated gene, which has a novel function as an angiogenesis inhibitor. Angiogenesis plays an important role in tumorigenesis. It has been reported that the angioarrestin expression was decreased in lung cancer. We attempted to determine the influence of angioarrestin expression on clinicopathological features in patients with lung cancer who had undergone surgery. METHODS: Expression of angioarrestin messenger RNA was evaluated by a quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 93 lung carcinomas and adjacent histological normal lung samples using LightCycler. RESULTS: Angioarrestin/GAPDH mRNA expression was significantly decreased in the tumor of lung cancer tissue (86.676+/-123.505) than in the normal lung tissue (1154.218+/-2003.508, p<0.0001), although only four lung cancer tissues had more than one tumor/normal ratio of angioarrestin/GAPDH mRNA expression. There was no relationship between angioarrestin gene expression and age, gender or T-status. However, decreased angioarrestin/GAPDH expression was especially seen at stage I lung cancer (54.156+/-62.783) when compared to stage II-IV lung cancer (110.315+/-151.359, p=0.0316). Decreased angioarrestin/GAPDH expression was especially seen at N0 lung cancer (56.396+/-69.941) when compared to N2 lung cancer (137.522+/-180.489, p=0.0362). CONCLUSIONS: The decreased expression of angioarrestin mRNA was the early phase phenomena for tumor progression from lung cancer. Alternatively, loss of antianiogenesis might play a role in oncogenesis for lung cancer.

[Prosthetic valve endocarditis after aortic valve replacement with freestyle stentless xenograft].

A 52-year-old man underwent aortic valve replacement with freestyle stentless xenograft, using subcoronary technique for active infective endocarditis in June, 2001. Eighteen month later he had late prosthetic valve endocarditis associated with aortic annular abscess due to Staphylococcus epidermidis infection. The abscess was debrided and gelatin-resorcin-formalin glue (GRF glue) was injected into the abscess cavity. Abscess cavity was closed with continuous running suture of 3-0 polypropylene stitches. Finally the aortic valve was replaced with ATS mechanical valve (20 mmAP). After administration of vancomycin and gentamicin for 4 weeks, he discharged on 57th postoperative day in good condition. We strongly suggest that GRF glue is essential to close the aortic annular abscess of combined with aortic regurgitation due to active infective endocarditis.

Clinical significance of tissue inhibitor of metalloproteinase and matrix metalloproteinase mRNA expression in thymoma.

BACKGROUND: Matrix metalloproteinases (MMPs) are proteolytic enzymes which degrade extracellular matrix and basement membrane. There is much evidence that their increased expression is correlated with tumor aggressiveness in various carcinomas. Tissue inhibitor of metalloproteinases (TIMPs) are the specific inhibitors of MMPs. MMPs and TIMPs are considered to play an important role in carcinoma invasion and metastasis. We hypothesized that MMPs and TIMPs also play an important role in thymoma. MATERIALS AND METHODS: This study included 34 thymoma cases. The mRNA levels of MMP-1, -7, and -9, TIMP-1 and -2, and GAPDH were quantified by real-time polymerase chain reaction using LightCycler. We also performed immunohistochemistry for TIMP-1. RESULTS: The TIMP-1/GAPDH mRNA expression level was significantly higher in invasive (stage II-IV) thymomas (means +/- SE, 81.4 +/- 28.1) than in noninvasive (stage I) thymomas (30.9 +/- 8.3, P = 0.026). The MMP-1/GAPDH mRNA expression level was also higher in invasive thymomas (19.7 +/- 7.5) than in non invasive thymomas (2.26 +/- 1.72, P = 0.020). Immunopositivity of TIMP-1 was localized in stromal cells adjacent to the advancing margin of the tumor. CONCLUSIONS: These findings suggest that TIMPs and MMPs play an important role in the invasion of thymoma.

Video-assisted anatomic mediobasal segmentectomy of lung.

Although video-assisted thoracic surgery (VATS) is now widely accepted, pulmonary segmentectomy is rarely performed. We present a case series of patients undergoing this procedure. The first patient had multiple arteriovenous malformations of the right mediobasal segment and a leiomyoma in the bronchus of the mediobasal segment. The second patient had multiple pulmonary metastases from colon cancer, including one in the right mediobasal segment. The third patient had metastases in the right ventrobasal and mediobasal segments from a solitary fibrous tumor that originated in the contralateral diaphragm. In the first two patients, a solitary mediobasal segmentectomy was done. In the third patient, a combined ventrobasal and mediobasal bisegmentectomy was performed. There were no complications, and visualization was excellent. Because VATS provides such excellent exposure, mediobasal segmentectomy of the lung is feasible, even though this operation is not done as an open procedure.

An extrapleural approach to the anterior mediastinum using video-assisted thoracic surgery (VATS).

A lateral extrapleural approach via video-assisted thoracic surgery (VATS) was used in a patient suspected of having a benign tumor of right lobe of the thymus. The patient previously had undergone lung resection for pulmonary tuberculosis, and the ipsilateral thorax had contracted and dense pleural adhesions were likely to exist. Lateral extrapleural approach by VATS was performed successfully and is an alternative to open surgery in highly selected patients with anterior mediastinal lesions.

[Therapeutic options which potentially cure patients with thymoma].

This study reports clinicopathologic features, treatment, and outcome of 107 thymomas, especially focusing on a combined modality program using hemithorax irradiation (HI) and restaging surgery using corticosteroid for advanced thymoma showing disseminative lesions. The use of HI after presumably total resection of the dissemination under posterolateral thoracotomy had no effect on reducing the incidence of relapsing. On the other hand, our own experience revealed that corticosteroid caused degenerative changes in the epithelial cells and lymphocytes of thymomas. The fact led us administer corticosteroid not only in preoperative setting but during postoperative HI. A better prognosis may be anticipated, although the follow up period is short and the number of patients involved is small.

Availability of lobe-selective bronchial blockade for video-assisted thoracic surgery: an initial experience with three cases.

BACKGROUND: Stable oxygenation and sufficient collapse of the lung are essential for video-assisted thoracic surgery (VATS). We performed the lobe-selective lung collapse technique with VATS for patients who had deteriorated lung function. METHODS AND RESULTS: CASE 1: A 75-year-old man who had undergone thoracoplasty showed spontaneous pneumothoraces in the contralateral side. Bullae were stapled successfully under complete isolation and collapse of diseased lobe. CASE 2: A 57-year-old woman who had undergone left lower lobectomy for lung cancer presented with another lung cancer in the right lower lobe. The right lower lobe bronchus was closed selectively, and basal segmentectomy was performed. CASE 3: A 60-year-old woman who had lost left lung function presented with right-side spontaneous pneumothoraces. The right upper lobe was collapsed selectively, and bullectomy was performed. CONCLUSION: Lobe-selective bronchial blockade may be beneficial when VATS is performed for selected patients with deteriorated lung function.

[Surgery for multiple primary lung cancers].

Thirty-eight patients (3.4%) of multiple primary lung cancers were treated among 1,106 patients of lung cancer at Nagoya City University Hospital. Twenty-eight patients had multiple lung lesions at the same time. Ten had the second primary lung cancer from 5 to 12 years after the first operation. Thirty-six patients had the second operation, and two had adjuvant therapy for lung cancer. Their 5 year survival rate was 36%. Especially of the patients with stage I lung cancer, 5 year survival rate was 65%. Radical but less invasive operation like VATS should be chosen for their treatment.

Clinical significance of matrix metalloproteinase-7 and Ets-1 gene expression in patients with lung cancer.

BACKGROUND: Matrix metalloproteinase-7 (MMP-7) is a member of the MMP family and has a wide variety of substrate spectra. Ets domain transcription factors are reported to play an important role in carcinoma invasion and metastasis. The regulatory role of Ets-1 has been shown in several MMPs. We have hypothesized that MMP-7 and Ets-1 mRNA levels could be predictors of the development and invasion of lung cancer. METHODS: The study included 73 lung cancer cases. The mRNA levels were quantified by real-time reverse transcription-polymerase chain reaction (RT-PCR) using a LightCycler. RESULTS: No significant difference in MMP-7 and Ets-1 mRNA levels was found among gender, age, and pathological subtype. The MMP-7 mRNA levels were elevated in tumor tissues from stage II-IV lung cancer (1.629 +/- 2.267) compared to those from stage I lung cancer (0.762 +/- 1.463) (P = 0.0290). There was a tendency toward higher MMP-7 mRNA expression levels in tumors with lymph node metastasis (1.728 +/- 2.432) compared to those without lymph node metastasis (1.141 +/- 1.838) (P = 0.1076). Thus, MMP-7 mRNA levels may serve as a marker of higher stages in lung cancer. No significant difference in Ets-1 mRNA levels was found among clinical stages and T-status. The Ets-1 mRNA levels were elevated in tumors from N2 patients (7.512 +/- 13.306) compared to those from N0 patients (2.525 +/- 4.719) (P = 0.0209). Ets-1 mRNA levels showed a positive correlation with MMP-7 expression (P = 0.0042). CONCLUSIONS: Using the LightCycler RT-PCR assay, the determination of MMP-7 and Ets-1 mRNA levels might provide a potential marker for advanced lung cancer. However, further studies and a longer follow-up are needed to confirm the impact of MMP-7 in the biological behavior of the tumor.