[Epithelioid Hemangioendothelioma of the Upper Mediastinum:Report of a Case].

A 81-year-old woman was referred to our hospital for neck discomfort. Chest computed tomography (CT) showed a tumor in the upper mediastinum. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed the mild accumulation in the tumor. Percutaneous biopsy was performed and epithelioid hemangioendothelioma was suspected, and the surgical treatment was performed. The histological study showed polygonal and irregular cells with nuclear atypia in myxoma-like substrate compatible with epithelioid hemangioendothelioma.

[Primary Pericardial Malignant Mesothelioma:Report of a Case].

A 67-year-old woman was referred to our hospital for cough and fever. Chest computed tomography (CT) showed some masses showing slightly enhanced effect in the pericardium. FDG-PET showed the accumulation of FDG in the masses. Thoracoscopic surgical biopsy was performed to establish the diagnosis. The histological study showed proliferation of short spindle-shaped cells surrounded by lymphocyte, and the spindle cells were immunohistochemically positive for cytokeratin AE1/AE3, WT-1, D2-40, CAM5.2, intelectin-1 and negative for CEA, TTF-1, napsin A, claudin-4, calretinin, MUC4, PAX8, CD30. These findings were compatible with epithelial pericardial malignant mesothelioma.

Total synthesis and biological evaluation of oscillatoxins D, E, and F.

Oscillatoxins (OTXs) and aplysiatoxins are biosynthetically related polyketides produced by marine cyanobacteria. We previously developed a synthetic route to phenolic O-methyl analogs of OTX-D and 30-methyl-OTX-D during collective synthesis of these natural products. According to our synthetic strategy, we achieved total synthesis of OTX-D, 30-methyl-OTX-D, OTX-E, and OTX-F by deprotecting the O-methyl group in an earlier intermediate, and determined their biological activities. Although OTX-D and 30-methyl-OTX-D have been reported to show antileukemic activity against L1210 cell line, we found that their cytotoxicity in vitro against this cell line is relatively weak (IC50: 29-52 µm). In contrast, OTX-F demonstrated cell line-selective antiproliferative activity against DMS-114 lung cancer cells, which implies that OTXs target as yet unknown target molecules as part of this unique activity.

[Solitary Pulmonary Metastasis from Follicular Thyroid Carcinoma Resected 28 Years Earlier Coexisting with Early Lung Cancer;Report of a Case].

A 71-year-old woman was referred to our hospital for a round mass shadow in the right lower lung field in mass screening chest X-ray. Computed tomography (CT) of the chest showed a well-defined lobulating mass shadow measuring 2.2 cm in diameter in the lower lobe of the right lung and a ground glass opacity ( GGO) in the upper lobe of the left lung. She underwent video-assisted partial resection of right lower lobe of the lung. The pathological examinations indicated a pulmonary metastasis of follicular thyroid carcinoma. Three months later, video-assisted partial resection of left upper lobe of the lung was performed. Microscopically, 2 lesions of adenocarcinoma in situ were revealed.

Histological features of endomyocardial biopsies in patients undergoing hemodialysis: Comparison with dilated cardiomyopathy and hypertensive heart disease.

BACKGROUND: Heart failure is a frequently occurring complication in patients on maintenance hemodialysis (HD). However, the histological features of right ventricular endomyocardial biopsy (RVEMB) samples remain unclear. METHODS: The clinical characteristics and histological findings of consecutive patients undergoing HD with available RVEMB samples (HD group; n=28) were retrospectively compared with those of patients with dilated cardiomyopathy (n=56) and hypertensive heart disease (n=15). RESULTS: The mean myocyte diameter was significantly larger in the HD group than in the other groups (P<.001), whereas the mean percent area of fibrosis did not differ among the three groups. Immunohistochemical analysis revealed that the capillary density was significantly lower in the HD group compared with the other groups (P<.001), and it was positively associated with left ventricular ejection fraction (P=.014). The number of CD68-positive macrophages, which was significantly higher in the HD group compared with the other two groups (P<.001), was associated with cardiovascular mortality (P=.020; log-rank test). CONCLUSIONS: Myocyte hypertrophy, macrophage infiltration, and reduced capillary density were characteristic histological features of the RVEMB samples in patients undergoing HD, which may be related to the pathogenesis of cardiac dysfunction.

[Primary Pulmonary Synovial Sarcoma;Report of a Case].

A 66-year-old man was referred to our hospital for an abnormal shadow. Chest computed tomography (CT)showed a heterogeneous mass with well-defined border in the right S10and ipsilateral pleural effusion. Fluorodeoxyglucose-positron emission tomography(FDG-PET)showed the accumulation in the mass and pleural effusion. Right lower lobectomy with lymphnode dissection was performed for diagnosis and treatment. Histologically,the tumor was mainly composed of complicated spindle-shaped cells with extensive necrosis, showing a large number of nuclear fission images. Immunohistochemistry showed the tumor cells to be positive for cytokeratin AE1/AE3, Bcl-2, EMA, vimentin and negative for TTF-1, S-100, calretinin, CD34, being compatible with monophasic fibrous synovial sarcoma.

Semi-synthesis and Structure-Activity Relationship of Neuritogenic Oleanene Derivatives.

(3S,4R)-23,28-Dihydroxyolean-12-en-3-yl (2E)-3-(3,4-dihydroxyphenyl)acrylate (1 a), which possesses significant neuritogenic activity, was isolated from the traditional Chinese medicine (TCM) plant, Desmodium sambuense. To confirm the structure and to assess biological activity, we semi-synthesized 1 a from commercially available oleanolic acid. A series of novel 1 a derivatives was then designed and synthesized for a structure-activity relationship (SAR) study. All synthetic derivatives were characterized by analysis of spectral data, and their neuritogenic activities were evaluated in assays with PC12 cells. The SAR results indicate that the number and position of the hydroxy groups on the phenyl ring and the triterpene moiety, as well as the length of the (saturated or unsaturated) alkyl chain that links the phenyl ring with the triterpene critically influence neuritogenic activity. Among all the tested compounds, 1 e [(3S,4R)-23,28-dihydroxyolean-12-en-3-yl (2E)-3-(3,4,5-trihydroxyphenyl)acrylate] was found to be the most potent, inducing significant neurite outgrowth at 1 µm.

More than 50 Years after Konno's Development of the Endomyocardial Biopsy.

The endomyocardial biopsy (EMB) method was first developed by Japan's Dr. Souji Konno in 1962. Since then, this technique has been used worldwide in clinical cardiology for the recognition and diagnosis of cardiomyopathies, arrhythmias, and other heart conditions. Many studies relating to the EMB have been published at the global level, including a large review by Cooper, et al.,1) wherein a limited selection of Japanese papers were cited despite considerable pioneering work on the EMB having been done in Japan. Following this, the Cardiac Biopsy Conference (CABIC) organization, which was founded in Japan in 1979, conducted a nationwide survey of the English language literature on the EMB. Among the collection of 500 studies compiled, approximately 40 abstracts have been selected by the co-editors in CABIC for further discussion. This report aims to supplement Cooper's work and bring to light other prominent contributions of Japanese researchers on the EMB.

Solitary splenic metastasis of pulmonary carcinoid: A rare case report and literature review.

We herein report a rare case of solitary splenic metastasis of a pulmonary carcinoid, for which hand-assisted laparoscopic splenectomy was performed. A 73-year-old man was admitted to the Inoue Hospital (Fukuyama, Japan) in March 2015 with an abnormal shadow of the spleen. The patient had a history of right upper lobectomy with lymph node dissection for a pulmonary typical carcinoid (pT1N0M0 stage IA) 7 years earlier. Plain abdominal computed tomography (CT) revealed a low-density area in the spleen. Enhanced abdominal CT revealed a mass in the spleen measuring 3×3 cm. Blood tests and tumor marker analysis revealed no abnormalities. Abdominal magnetic resonance imaging revealed a mass that was low-intensity on T1- and high-intensity on T2-weighted images, and positron emission tomography revealed abnormal fluorodeoxyglucose accumulation in the mass. Hand-assisted laparoscopic splenectomy was performed for diagnosis and treatment. The resected specimen included a reddish-brown mass. On immunohistochemistry, the mass was positive for chromogranin A, synaptophysin and CD56, which was similar to the resected pulmonary carcinoid tumor; thus, splenic metastasis of pulmonary carcinoid was diagnosed. The postoperative course was uneventful and the patient is currently under observation and remains recurrence-free, with no adjuvant chemotherapy.

Inhibition of veratridine-induced delayed inactivation of the voltage-sensitive sodium channel by synthetic analogs of crambescin B.

Crambescin B carboxylic acid, a synthetic analog of crambescin B, was recently found to inhibit the voltage-sensitive sodium channels (VSSC) in a cell-based assay using neuroblastoma Neuro 2A cells. In the present study, whole-cell patch-clamp recordings were conducted with three heterologously expressed VSSC subtypes, Nav1.2, Nav1.6 and Nav1.7, in a human embryonic kidney cell line HEK293T to further characterize the inhibition of VSSC by crambescin B carboxylic acid. Contrary to the previous observation, crambescin B carboxylic acid did not inhibit peak current evoked by depolarization from the holding potential of -100mV to the test potential of -10mV in the absence or presence of veratridine (VTD). In the presence of VTD, however, crambescin B carboxylic acid diminished VTD-induced sustained and tail currents through the three VSSC subtypes in a dose-dependent manner, whereas TTX inhibited both the peak current and the VTD-induced sustained and tail currents through all subtypes of VSSC tested. We thus concluded that crambescin B carboxylic acid does not block VSSC in a similar manner to TTX but modulate the action of VTD, thereby causing an apparent block of VSSC in the cell-based assay.

[Deciduoid Mesothelioma].

A 64-year-old man consulted for an abnormal shadow in November 2012. Chest computed tomography showed a thicking and small nodules of the left pleura and pleural effusion with mediastinal and supracravicular lymphnodes swelling. The cytological study of the pleural effusion showed individual atypical cells surrounded by many lymphocyte. The atypical cells are large, round or ovoid and had welldefined borders, abundant eosinophilic, glassy cytoplasm, and round or elliptic nuclei with clear eosinophilic nucleoli resembling decidua cells. According to immunohistochemistry study, cells were positive for calretinin, EMA, cytokeratinAE1/AE3, WT-1, D2-40 and negative for CEA, desmin, TTF-1, Ber-EP4, synaptophysin, S-100 compatible with deciduoid mesothelioma. The cytological features are important and useful for diagnosis of deciduoid mesothelioma.

One-pot non-enzymatic formation of firefly luciferin in a neutral buffer from p-benzoquinone and cysteine.

Firefly luciferin, the substrate for the bioluminescence reaction of luminous beetles, possesses a benzothiazole ring, which is rare in nature. Here, we demonstrate a novel one-pot reaction to give firefly luciferin in a neutral buffer from p-benzoquinone and cysteine without any synthetic reagents or enzymes. The formation of firefly luciferin was low in yield in various neutral buffers, whereas it was inhibited or completely prevented in acidic or basic buffers, in organic solvents, or under a nitrogen atmosphere. Labelling analysis of the firefly luciferin using stable isotopic cysteines showed that the benzothiazole ring was formed via the decarboxylation and carbon-sulfur bond rearrangement of cysteine. These findings imply that the biosynthesis of firefly luciferin can be developed/evolved from the non-enzymatic production of firefly luciferin using common primary biosynthetic units, p-benzoquinone and cysteine.

Risk factors and serological markers of liver cirrhosis after Fontan procedure.

Liver cirrhosis (LC), which may result in hepatic failure or cancer, has been reported in patients after Fontan procedure. The purpose of this study was to clarify the frequency and histological characteristics of LC, and to evaluate the risk factors and serological markers of LC with Fontan circulation. Retrospective review of contrast-enhanced CT scans (CT) of the liver was carried out in 57 patients after Fontan procedure. Patients were divided into two groups: LC group (n = 31) and no LC group (n = 26). Age at Fontan procedure, duration after Fontan procedure, catheterization data, and history of failing Fontan circulation were compared between groups. Serological data including γ-GTP and hyaluronic acid were compared. Histology of autopsy specimens was assessed when available. Duration after Fontan procedure was significantly longer in LC group than no LC group. History of failing Fontan circulation was more frequent in LC group than in no LC group. There was no correlation between type of procedure (APC/Bjork/lateral tunnel/TCPC) and LC in this series. Serum hyaluronic acid, γ-GTP, and Forns index were significantly higher in LC group. Significant risk factors for LC were duration after Fontan procedure (>20 years). In autopsy specimens, histopathological changes of LC were observed predominantly in the central venous area. LC diagnosed with CT is frequent in patients long after Fontan procedure, especially after 20 years. Hyaluronic acid and γ-GTP could be useful markers to monitor the progression of liver fibrosis in Fontan patients.

Etanercept-induced sarcoidosis in rheumatoid arthritis: FDG PET findings.

We report the F-FDG PET/CT findings of an etanercept-induced sarcoidosis in a patient with rheumatoid arthritis. A 68-year-old woman with rheumatoid arthritis who had been treated with etanercept and methotrexate showed multiple lung nodules and hilar lymph node swellings on CT. She underwent FDG PET/CT for cancer screening. Intense FDG uptakes were found in the multiple lung nodules, bilateral hilar lymph nodes, a periurethral masslike lesion, and cranial meningeal nodules. A histopathological examination revealed epithelioid granuloma with multinucleated giant cells, which was compatible with sarcoidosis.

HER2-positive gastric cancer with paraaortic nodal metastasis successfully resected after chemotherapy with trastuzumab: a case report.

We report on a case of human epidermal growth factor receptor-2 (HER2)-positive gastric cancer with paraaortic lymph node metastasis. The patient (a 49-year-old female) received chemotherapy (capecitabine and cisplatin) plus molecular-targeted therapy (trastuzumab), followed by curative resection. Interestingly, the resected residual cancer was HER2-negative. Intra-tumor heterogeneity hinders molecular-targeted therapy for gastric cancer. In our case, continued trastuzumab administration presented few benefits since the residual cancer cells were HER2-negative. No consensus exists regarding the appropriate therapy for unresectable gastric cancers whose non-curative factors disappear following trastuzumab chemotherapy. The principal options are treatment with surgery or continued chemotherapy with trastuzumab. In our case, resection treated the HER2-negative residual cancer effectively, resulting in curative therapy. This is the first case of positive-to-negative change in the HER2 expression of residual tumor cells following trastuzumab therapy. It suggests that, due to intra-tumor heterogeneity, the risks presented by remnant HER2-negative cancer cells persist despite trastuzumab therapy.

Blood vessel invasion and other variables as predictors of long-term survival in Japanese and British patients with primary invasive breast cancer.

This study was undertaken to investigate the associations of blood vessel invasion (BVI), lymphatic vessel invasion (LVI) or other variables and long-term survival in 173 Japanese and 184 British patients with primary invasive breast cancer, and whether they are associated with survival differences between Japanese and British patients. BVI was detected by objective methods, using both factor VIII-related antigen (F-VIII) staining and elastica van Gieson (E v G) staining. BVI was classified into three subtypes. 1) BVI e, BVI detected by E v G staining alone, 2) BVI f, BVI detected by F-VIII staining alone, 3) BVIef, BVI evaluated by combining BVIf and BVIe. LVI was also detected by objective methods, using lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) staining alone. There was a borderline significance between the frequencies for BVIef of British patients and those of Japanese patients (8.2% vs 3.5%; P = 0.06) but not for LVI (P = 0.36). British patients had a significantly worse relapse-free survival (RFS) and overall survival (OS) than Japanese patients (P < 0.01, P < 0.01, respectively) even though their tumors were smaller and more ER-positive with a similar prevalence of lymph-node involvement. LVI was not significantly associated with RFS and OS, however, BVIef positive tumors had a significantly worse RFS and OS compared with BVIef negative patients, after statistical adjustment for the other variables (P = 0.02, P = 0.01, respectively). The present study shows that BVIef variability might contribute to the Japanese and British disparities in breast cancer outcomes.

The relevance of the intrinsic subtype to the clinicopathological features and biomarkers in Japanese breast cancer patients.

BACKGROUND: Breast cancer is a disease rich in diversity, and it can be categorized into the immunohistochemical intrinsic subtypes : ER/PR + and HER2-, ER/PR + and HER2+, HER2 type, basal-like and unclassified. METHODS: In this study, in addition to the clinicopathological features potentially associated with the intrinsic subtypes, protein expression and genetic mutations of key molecules associated with breast cancer prognosis and treatment sensitivity were analyzed. The distribution of subtypes in the patient population and the differences in marker distribution across the subtypes were investigated. RESULTS: The immunohistochemical features of 471 consecutive surgical cases of women with primary breast cancer, treated in a single institution, were examined. There were 306 patients who were ER/PR + HER2- (65%); 41 who were ER/PR + HER2+ (8.7%); 59 with HER2 type (12.5%); 37 with basal-like (7.9%); and 28 patients whose breast cancer was unclassified (5.9%). There were no significant differences between the subtypes regarding age, menopausal status, disease stage, lymphatic invasion, blood vessel invasion and lymph node metastasis. Statistically significant differences were found for histological type and grade. Regarding protein expression and genetic mutation, significant differences were found in the distribution within each subtype for six out of 12 molecules investigated. CONCLUSIONS: This study revealed that subtypes differ not only in their clinical pathological profiles, such as histological types and histological grades, but also in molecular expression. The molecular expression patterns observed for each intrinsic subtype may help the selection of an optimal treatment strategy.

Antiproliferative effect of a novel mTOR inhibitor temsirolimus contributes to the prolonged survival of orthotopic esophageal cancer-bearing mice.

Esophageal squamous cell carcinoma (ESCC) remains one of the most aggressive cancers with poor prognosis regardless of a several reports that indicate a better therapeutic efficacy using some new chemotherapeutic agents. Recent drug development has contributed to an improved specificity to suppress mTOR activity by which many types of malignancies can be explosively progressed. Temsirolimus (CCI-779, TricelTM) is one of recently synthesized analogs of rapamycin and has provided better outcomes for patients with renal cell carcinoma. In this study, we experimentally evaluated an efficacy of targeting mTOR by temsirolimus for ESCC treatment, with an assessment of its survival advantage using an advanced ESCC animal model. First, we confirmed that the expression of phosphorylated mTOR was increased in 46 of 58 clinical ESCC tumor tissues (79.3%) and appeared to get strengthened with tumor progression. All of ESCC cell lines used in this study revealed an increase of mTOR phosphorylation, accompanied with the upregulation of hypoxia inducible factor-I α (HIF-1α), one of the critical effectors regulated by mTOR. Temsirolimus treatment apparently suppressed the activation of mTOR and its downstream effectors, resulting in the reduced ability of ESCC cell proliferation. Finally, the weekly administration of temsirolimus significantly diminished the size of subcutaneous tumors (vehicle, 3261.6 ± 722.0; temsirolimus, 599.2 ± 122.9; p = 0.007) in nude mice and effectively prolonged orthotopic esophageal cancer-bearing mice (median survival periods: control, 31 d; temsirolimus, 43 d; p = 0.0024). These data suggests that targeting mTOR by temsirolimus may become a therapeutic alternative for esophageal cancer, with a contribution to a better outcome.

Brefeldin A is an estrogenic, Erk1/2-activating component in the extract of Agaricus blazei mycelia.

We purified an Erk1/2-activating component in Agaricus blazei and identified it as brefeldin A (BFA). The extract of A. blazei mycelia (ABE) previously showed an estrogenic gene-expression profile and positive effects in patients with cardiovascular symptoms. Here, we demonstrate that BFA has estrogenic activity in reporter gene assays and stimulates an estrogen-receptor pathway revealed by activation of Erk1/2, although BFA had no growth-stimulating activity in breast cancer MCF-7 cells. The presence of estrogenic activity without any explicit growth-stimulating effect is unique to BFA, and such components are termed here "silent estrogens". To test this hypothesis, we examined the target-gene transcription and signaling pathways induced by BFA. Furthermore, BFA was found in the mycelium but not fruiting body of A. blazei, suggesting the potential use of ABE for therapeutics and its supplementary use in traditional medicines and functional foods.