Yasunobu Funamoto

Rare sugar D-psicose improves insulin sensitivity and glucose tolerance in type 2 diabetes Otsuka Long-Evans Tokushima Fatty (OLETF) rats

A rare sugar, D-psicose has progressively been evaluated as a unique metabolic regulator of glucose and lipid metabolism, and thus represents a promising compound for the treatment of type 2 diabetes mellitus (T2DM). The present study was undertaken to examine the underlying effector organs of D-psicose in lowering blood glucose and abdominal fat by exploiting a T2DM rat model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Rats were fed 5% D-psicose or 5% D-glucose supplemented in drinking water, and only water in the control for 13 weeks and the protective effects were compared. A non-diabetic Long-Evans Tokushima Otsuka (LETO), fed with water served as a counter control of OLETF. After 13 weeks feeding, D-psicose treatment significantly reduced the increase in body weight and abdominal fat mass. Oral glucose tolerance test (OGTT) showed the reduced blood glucose and insulin levels suggesting the improvement of insulin resistance in OLETF rats. Oil-red-O staining elucidated that D-psicose significantly reduced lipid accumulation in the liver. Immunohistochemical analysis showed D-psicose induced glucokinase translocation from nucleus to cytoplasm of the liver which enhances glucokinase activity and subsequent synthesis of glycogen in the liver. D-psicose also protected the pathological change of the β-cells of pancreatic islets. These data demonstrate that D-psicose controls blood glucose levels by reducing lipotoxicity in liver and by preserving pancreatic β-cell function.

Secondary myeloid/natural killer cell precursor acute leukemia following essential thrombocythemia

The de novo leukemic transformation of essential thrombocythemia is a rare event, and usually associated with previous treatments. We describe a patient who received treatments with nitrosourea for long-standing essential thrombocythemia and subsequently developed extramedullary tumors, tentatively diagnosed as lymphoblastic lymphoma. Combination chemotherapy was initially successful, but relapsed with marked bone marrow involvement. Surface marker analysis revealed that the tumor cells had CD5, CD7, CD33, CD34, and CD56 antigens but lacked other T-cell, and B-cell markers. Immunogenotypical studies revealed germline configurations for both T-cell receptors and immunoglobulin genes. These clinical and phenotypical features are consistent with a myeloid/natural killer cell precursor leukemia, a recently proposed distinct clinical entity. To our knowledge, this is the first report of secondary leukemia of myeloid/ natural killer cell precursor origin, and suggest that myeloid/natural killer cell precursor might be a potent target of therapy-related leukemia.

Establishment and characterization of a Kaposi's sarcoma- associated herpesvirus- and Epstein-Barr virus-negative malignant lymphoma cell line (OHK) with primary effusion lymphoma immunophenotype

Summary. A novel cell line, designated OHK, was established from ascites of a 59‐year‐old Japanese woman with diffuse large B‐cell lymphoma showing a peculiar serosal tropism, as seen in primary effusion lymphomas (PEL). OHK exhibited a large pleomorphic morphology with irregular nuclei and distinct nucleoli, and included immunoblastic and Reed–Sternberg‐like giant cells. On ultrastructural examination, rich intermediate filaments, and well‐developed Golgi apparati and rough endoplasmic reticulum, were seen. Immunophenotypically, OHK lacked T and B cell‐associated antigens, and had CD10, CD30, CD33 and CD138 antigens. Although OHK cells did not express immunoglobulin (Ig) protein, Southern blot analysis demonstrated clonal rearrangements of Ig heavy and light chain genes. These observations suggest that OHK cells are derived from preterminally differentiated B cells, and that they have features of PEL. Kaposis sarcoma‐associated herpesvirus and Epstein–Barr virus were not detected. OHK displayed hyperploid karyotypes with multiple structural abnormalities, and produced some cytokines such as macrophage‐colony‐stimulating factor (M‐CSF), granulocyte‐CSF, interleukin 6 and transforming growth factor β1. In particular, vascular endothelial growth factor (VEGF), whose stimulation of vascular permeability is thought to be critical to the pathogenesis of PEL, was also produced in large quantities. These results indicate that OHK may be a useful tool for the investigation of PEL.

Cytopathologic features of orbital intraosseous chordoid meningioma: Report of a case and distinction from other myxoid/mucoid tumors

Chordoid meningioma (CM) is characterized by a striking histologic resemblance to chordoma and propensity for aggressive behavior or recurrence (WHO grade II designation). Orbital intraosseous CM is extremely uncommon and only one case report has been documented. A case is presented here in which squash smears of a left orbital tumor in a 53‐year‐old male revealed small clusters or cord‐like structures of bland tumor cells embedded in a myxoid or mucinous background. Whorl‐like structures were also identified. The tumor cells possessed uniformly round nuclei with a smooth nuclear outline, fine granular chromatin, and small nucleoli. Occasional intranuclear inclusions, coarse collageneous cytoplasmic filaments were observed. Many spindle‐shaped cells with similar nuclear findings were also seen. A cytologic diagnosis of a chordoid meningioma was suggested and histochemical and immunohistochemical studies were conducted on formalin‐fixed, paraffin‐embedded material. Immunohistochemically, the tumor cells showed diffuse and strong membranous and cytoplasmic staining for vimentin, epithelial membrane antigen (EMA) and faintly reactive with S‐100 protein but negative for pan‐neuroendocrine markers (i.e., NSE, chromogranin A, synaptophysin), cytokeratin AE1/AE3, smooth muscle actin, D2‐40, brachyury or class III beta‐tubulin. The proliferative index with MIB‐1 was less than 1%. The diagnosis of orbital intraosseous CM was confirmed based on cytopathologic, histopathological, immunohistochemical results, location of the tumor, and the lack connection to the duramater. We demonstrated here for the first time the cytopathological features of intraosseous CM with emphasis on differential diagnostic considerations. Diagn. Cytopathol. 2010; 38:818–821.

Hyaluronan synthesis by anaplastic large cell lymphoma with massive lymphomatous effusion. A case report.

BACKGROUND Hyaluronan (HA) synthesis is frequently observed in malignant mesothelioma cells, whereas it is rarely found in lymphoma cells. Previous studies have reported that a high HA concentration in the serum was related to poor prognosis in lymphomas, although the mechanism was not elucidated. We recently encountered a case of anaplastic large cell lymphoma with an HA-rich, massive, lymphomatous effusion. Several studies were performed to clarify the character of this unusual lymphoma and to observe whether the lymphoma cells synthesized HA. CASE A 59-year-old female was admitted with abdominal pain. Radiologic studies revealed a pleural effusion and paraaortic lymph node swelling. A biopsied specimen was compatible with anaplastic large cell lymphoma. Detailed cytologic observations revealed that the lymphoma cells in the pleural effusion had alcian blue-positive, productive material in the prominent Golgi area and microvillous structures on the surface. Further studies found that most of the lymphoma cells had HA-binding protein and expressed CD44 antigen, a receptor for HA. In addition, the HA concentration in the supernatant of the primary culture cells was extremely high and increased time dependently. CONCLUSION These observations suggest that the lymphoma cells synthesized and released HA. Interactions of the released HA and CD44 on the surface might play an important role in the peculiar serosal growth of lymphoma cells.

Cytopatholologic features of gliosarcoma with areas of primitive neuroepithelial differentiation of the brain in squash smears

Gliosarcoma with areas of primitive neuroepithelial differentiation (GSPNED) is an extremely rare neoplasm. A case is presented here in which squash smears of a left temporal lobe tumor in a 76‐year‐old male demonstrated two distinct and easily recognizable cellular populations, i.e., densely hyperchromatic cells of a primitive nature in a fibrillary background and pleomorphic spindle‐shaped cells. Occasional pseudo‐rosette formations and nuclear cannibalism suggestive of neuroendocrine differentiation were also found. A cytologic diagnosis of a malignant tumor was suggested, and histochemical and immunohistochemical studies were conducted on formalin‐fixed, paraffin‐embedded material. Reticulin stain highlighted increased intercellular collagen and reticulin deposition within the spindled regions, whereas nodules with primitive cells were reticulin‐poor. There was a diffuse and strong reactivity to neuron specific enolase, synaptophysin and CD56 immunostains. A stain for glial fibrillary acidic protein and S‐100 protein demonstrated a subset of tumor cells including elongated cytoplasmic processes. The spindled component was positive for vimentin and smooth muscle actin, whereas the primitive‐appearing tumor cells were negative. The diagnosis of GSPNED was confirmed based on cytopathologic, histopathological and immunohistochemical results. The cytomorphologic features of this distinctive tumor are illustrated, and the adjunctival value of squash smears for frozen‐section diagnosis is also discussed. This is the first presentation of a cytopathologic analysis that provides an important clue to an accurate diagnosis of GSPNED. Diagn. Cytopathol. 2009.

Medico-legal investigation of chicken fat clot in forensic cases: Immunohistochemical and retrospective studies

Chicken fat clot (CFC), a fibrin-like substance, is sometimes found in the heart and large blood vessels in some autopsy cases. Reports of detailed histological findings of CFC are scant. We therefore examined CFC histologically in 53 autopsy cases and its correlation with ante-mortem or post-mortem evidence. We found three microscopic patterns of CFC: (1) wavelike fibrin fibers (WFF), (2) short fibrin fibers (SFF), and (3) short fibrin fibers mixed with wavelike fibrin fibers (SFF+WFF). WFF were found in the cases that survived less than 3 h after poisoning, burns, asphyxia, intracerebral hemorrhage, etc. SFF were found in the cases that survived more than 1 day after malignant neoplasms and acute or chronic inflammatory diseases, etc. SFF+WFF were found in the cases that died of inflammatory diseases, chronic heart failure, hemorrhagic shock, drowning, etc. About two-thirds of the SFF+WFF cases survived more than 1 day, with the rest surviving less than that. Our study confirmed three CFC patterns and their relation with survival interval. Therefore, these findings can be used as an index of the survival interval of a few acute and most chronic medico-legal death cases.

Cytopathological features of warty (condylomatous) carcinoma of the penis: a case report and distinction from other verruciform penile tumors.

Warty (condylomatous) carcinoma (WC) is a rare specific variant of invasive squamous cell carcinoma that shows hybrid features of condyloma with invasive cell carcinoma. As compared with conventional squamous cell carcinoma, WC tends to run a less aggressive clinical course. A case is presented here in which squash smears of a penile foreskin tumor in a 65‐year‐old male revealed small cohesive clusters and sheets of tumor cells in papillary configurations. The neoplastic cells were polygonal to elongated and contained oval nuclei, coarse chromatin pattern, and distinct nucleoli. Nuclear pleomorphism and loss of nuclear polarity were observed. Characteristically, there were also many koilocytes demonstrating mild to moderate nuclear atypia and perinuclear cytoplasmic halos. A cytologic diagnosis of a verruciform penile tumor was suggested. Histologic examination of the tumor showed a hyper‐parakeratotic arborizing papillomatous growth with thin fibrovascular cores and the tips were variably rounded or tapered. Obvious koilocytic cytopathic change, nuclear pleomorphism, and focal stromal invasion were observed. Immunohistochemically, the tumor cells showed diffuse and strong membranous staining for cytokeratin (AE1/AE3) while the MIB‐1 and p53 immunoreactive cells were confined to the basal areas of the papillae. No lymphovascular invasion was detected in D2‐40 or elastic Van‐Gieson stains. On the basis of the overall features, we confirmed a final diagnosis of penile WC. We demonstrated here for the first time the cytopathological features of penile WC with emphasis on differential diagnostic considerations. Diagn. Cytopathol. 2010;38:841–845.

Cytologic studies of cerebrospinal fluid in invasive lobular carcinoma of the bilateral breasts accompanied with carcinomatous meningitis.

浸潤性小葉癌の髄膜転移例を経験したので, その髄液細胞所見を中心に報告した. 患者は32歳の女性で29歳時, 右側乳房腫瘤を指摘されたが放置していた. 1991年2月腹部膨満感を自覚し, 当院を受診する. 両側乳房に不整形の硬い腫瘤を認め, 右側では大胸筋と固定しており皮膚への浸潤を認めた. また, 著明な腹水とともに両側卵巣の腫大がみられ, 4月両側卵巣摘出術を行い, 同時に両側乳房の生検を行った. 両側乳房は浸潤性小葉癌で, 両側卵巣および大綱に転移を認めた. 1991年11月頃より, 頭痛, 嘔吐などの髄膜刺激症状を認めたため, 髄液細胞診を行った. シート状にならぶ小型の腫瘍細胞および対細胞を呈する腫瘍細胞を認めた. またマクロファージ, 悪性細胞ともに風船状, 樹枝状の突起を有していた. 剖検では腫瘍細胞は脊髄くも膜下腔血管周囲に認められた. 下垂体には腫瘍細胞の浸潤を認めたが, 脳実質にはみられなかった.