Mikiko Kobayashi

Bio: Mikiko Kobayashi is an academic researcher from Shinshu University. The author has contributed to research in topics: Adenocarcinoma & Medicine. The author has an hindex of 6, co-authored 27 publications receiving 134 citations.

Intrahepatic cholangiocarcinoma with predominant "ductal plate malformation" pattern: a new subtype.

Abstract: Ten cases of intrahepatic cholangiocarcinoma showing a highly differentiated adenocarcinoma mimicking ductal plate malformation (DPM) are reported. The patients included 7 males and 3 females with an average age of 69.5 years. Six cases were associated with chronic liver disease and the remaining 4 cases showed mild fatty change in the parenchyma and/or minimal to mild portal inflammation. Grossly, the tumor was a single nodule 1.5 to 6.6 cm in diameter, and was whitish and solid without a fibrous capsule. Microscopically, the tumor was composed of many vague, small nodular carcinomatous areas with desmoplastic reactions, and neoplastic glands had an irregularly dilated lumen lined with a single layer of cuboidal or low columnar carcinoma cells and irregular protrusions and bulges, resembling DPM. At its border, the carcinoma seemed to replace the non-neoplastic hepatic lobules or regenerative nodules. The central parts of the tumor were variably hypocellular and fibrotic. Although these carcinomas were negative for mucin and HepParI, they were frequently positive for CK19, epithelial cell adhesion molecule, and epithelial membrane antigen. Neural cell adhesion molecule was also expressed variably. The Ki-67 labeling index was <10% and p53 was scarcely expressed. In conclusion, a new subtype of intrahepatic cholangiocarcinoma with predominant DPM pattern was identified.

Reappraisal of the Immunophenotype of Pancreatic Intraductal Papillary Mucinous Neoplasms (IPMNs)—Gastric Pyloric and Small Intestinal Immunophenotype Expression in Gastric and Intestinal Type IPMNs—

Abstract: Pancreatic intraductal papillary mucinous neoplasms (IPMNs) are mucin-producing neoplasms of the main and/or branch pancreatic ducts. To assess differences between various IPMN subtypes, immunohistochemical markers of gastric surface mucous cells (MUC5AC), gastric gland mucous cells (MUC6 and GlcNAcα1→4Galβ→R), gastric pyloric and duodenal epithelial cells (PDX1), intestinal cells (MUC2 and CDX2), small intestinal cells (CPS1) and large intestinal cells (SATB2) were evaluated in 33 surgically treated IPMNs. MUC2 expression classified IPMNs into gastric (n=17), intestinal (n=8) and mixed gastric and intestinal type (collision=7, composite=1). No differences in age or sex were observed among these types. MUC5AC and PDX1 were expressed in all IPMNs. MUC6 expression was higher in gastric and mixed types than in intestinal type. GlcNAcα1→4Galβ→R was detected in gastric and mixed type, but not in intestinal type. MUC2 and CDX2 expression were higher in intestinal type than gastric and mixed type. CPS1 expression was higher in intestinal type than gastric type. SATB2 was not observed in any IPMNs. Frequent abrupt transition between the two IPMN types in mixed-type IPMNs was observed. Gastric pyloric and small intestinal differentiation are characteristic of gastric and intestinal type IPMN, respectively, and these two IPMN types may have distinct pathogenesis.

Histologic and Immunohistochemical Evaluation of Infiltrating Inflammatory Cells in Kawasaki Disease Arteritis Lesions.

Abstract: Kawasaki disease (KD) is a systemic vasculitis of unknown etiology which predominantly affects medium- and small-sized muscular arteries. Histopathologic studies of KD vasculitis lesions have demonstrated characteristic T cell infiltration and an abundance of CD8 T cells; however, the contribution of cytotoxic lymphocytes to KD vasculitis lesions has not been identified. Here, we histopathologically and immunohistochemically examined infiltrating inflammatory cells, particularly cytotoxic protein-positive cells, such as granzyme B cells and TIA-1 cells, in KD vasculitis lesions. Three autopsy specimens with acute-phase KD were observed and contained 24 vasculitis lesions affecting medium-sized muscular arteries, excluding pulmonary arteries. Infiltrating neutrophils in vasculitis lesions were evaluated by hematoxylin and eosin staining, and monocytes/macrophages and lymphocytes were evaluated by immunohistochemistry. The predominant cells were CD163 monocytes/macrophages and CD3 T cells. CD8 T cells, granzyme B cells, and TIA-1 cells were also observed, but CD56 natural killer cells were rare. To the best of our knowledge, the current study is the first histopathologic report confirming the infiltration of inflammatory cells with cytotoxic proteins in vasculitis lesions in patients with KD. Cytotoxic T cells may play a role in the development of vasculitis lesions in KD patients.

Food allergy after cord blood transplantation in children.

Abstract: Delbini, P., Vaja, V., Graziadei, G., Duca, L., Nava, I., Refaldi, C. & Cappellini, M.D. (2010) Genetic variability of TMPRSS6 and its association with iron deficiency anaemia. British Journal of Haematology, 151, 281–284. Desmet, F.O., Hamroun, D., Lalande, M., CollodBeroud, G., Claustres, M. & Beroud, C. (2009) Human Splicing Finder: an online bioinformatics tool to predict splicing signals. Nucleic Acid Research, 37, e67. De Falco, L., Totaro, F., Nai, A., Pagani, A., Girelli, D., Silvestri, L., Piscopo, C., Campostrini, N., Dufour, C., Al Manjomi, F., Minkov, M., Van Vuurden, D.G., Feliu, A., Kattamis, A., Camaschella, C. & Iolascon, A. (2010) Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA). Human Mutation, 31, E1390–E1405. Finberg, K.E. (2009) Iron-refractory iron deficiency anemia. Seminars in Hematology, 46, 378–386. Finberg, K.E., Heeney, M.M., Campagna, D.R., Aydinok, Y., Pearson, H.A., Hartman, K.R., Mayo, M.M., Samuel, S.M., Strouse, J.J., Markianos, K., Andrews, N.C. & Fleming, M.D. (2008) Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nature Genetics, 40, 569–571. Nai, A., Pagani, A., Silvestri, L. & Camaschella, C. (2010) Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice. Blood, 116 (5), 851–852.

In vasculitis of small muscular arteries, activation of vessel-infiltrating CD8 T cells seems to be antigen-independent.

Abstract: The etiology of polyarteritis nodosa (PAN) and localized PAN is still unknown, although a T cell-mediated immune mechanism has been considered. CD8 T cells participate not only in the antigen-dependent adaptive immune system, but also in the antigen-independent innate immune system. Non-antigen-activated CD8 T cells express a unique phenotype: granzyme B (GrB) positive /CD25 negative /programmed death-1 (PD-1) negative. The aims of this study were to assess the participation of T cells, especially innate CD8 T cells, in the development of vasculitis. Twenty-eight consecutive cases of skin biopsy specimens with cutaneous vasculitis of small muscular arteries (CVSMA) were retrieved. The series comprises of 21 cases of cutaneous arteritis, three cases of PAN, and four cases of rheumatoid vasculitis. Cases of antineutrophil cytoplasmic antibody-associated vasculitis were excluded. The phenotypes of infiltrating lymphocytes in vasculitis lesions were evaluated by immunohistochemistry. In most cases of CVSMA, the number of CD8 T cells infiltrating the intima was higher than that of CD4 T cells, and significant numbers of GrB-positive cells, which represent activated CD8 T cells, were observed. However, GrB/CD25-double-positive cells, which correspond to antigen-activated T cells, were very few in a small number of cases. Cells positive for PD-1, which is also expressed on antigen-activated CD8 T cells, were not detected. We conclude that a T cell-mediated immune mechanism, involving cytotoxic CD8 T cells, may play a role in the development of CVSMA. Low expression of CD25 in activated CD8 T cells suggests that activation was antigen-independent.

A microfluidics-based in vitro model of the gastrointestinal human-microbe interface.

Abstract: We thank the scientists and technical staff of the Luxembourg Centre for Systems Biomedicine and Center for Applied Nanobioscience and Medicine, particularly Matthew Barrett and Brett Duane for their excellent technical assistance and engineering support We are grateful to Francois Bernardin, Nathalie Nicot and Laurent Vallar for the microarray analysis; Aidos Baumuratov for imaging support; Linda Wampach for HuMiX illustrations; and Anna Heintz-Buschart for fruitful discussions This work was supported by an ATTRACT programme grant (ATTRACT/A09/03), a CORE programme grant (CORE/11/BM/1186762), a European Union Joint Programming in Neurodegenerative Diseases grant (INTER/JPND/12/01) and a Proof-of-Concept grant (PoC-15/11014639) to PW, Accompany Measures mobility grant (12/AM2c/05) to PW and PS, an INTER mobility grant to PS (INTER/14/7516918), and an Aide a la Formation Recherche (AFR) postdoctoral grant (AFR/PDR 2013-1/BM/5821107) as well as a CORE programme grant (CORE/14/BM/8066232) to JVF, all funded by the Luxembourg National Research Fund (FNR) This work was further supported by a grant attributed to CS-D by the 'Fondation Recherche sur le SIDA du Luxembourg' Bioinformatics analyses presented in this paper were carried out in part using the HPC facilities of the University of Luxembourg (http://hpcunilu)

Pathologic classification of cholangiocarcinoma: New concepts

Abstract: Herein, we propose a new pathologic classification of cholangiocarcinoma (CCA) based on recent progress in studies of preinvasive CCA lesions and the relationship of CCA to hepatic progenitor cells, as well as a new concept with respect to the pathologic similarities between biliary and pancreatic neoplasms. Depending on anatomical location, CCA is classifiable as intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). iCCA is classifiable as the conventional type and the bile ductular type, whereas pCCA and dCCA mainly present as conventional adenocarcinoma. In addition, these three CCAs may present as the intraductal neoplasm type or rare variants. Bile ductular CCA resembles proliferating bile ductules and expressing hepatic progenitor cell phenotypes. Four types of preinvasive lesions are proposed: flat, papillary, tubular lesion, and cystic lesion. These lesions are eventually followed by invasive CCA. Interestingly, these preinvasive lesions have pancreatic counterparts. This CCA classification may introduce a new field of CCA research.

Pathology of intrahepatic cholangiocarcinoma

Abstract: Intrahepatic cholangiocarcinoma (iCC) is a primary carcinoma of the liver with increasing significance and major pathogenic, clinical and therapeutic challenges. Classically, it arises from malignant transformation of cholangiocytes bordering small portal bile duct (BD) to second-order segmental large BDs. It has three major macroscopic growth pattern [mass-forming (MF), periductal infiltrative (PI), and intraductal growth (IG)] and histologically is a desmoplastic stroma-rich adenocarcinoma with cholangiocyte differentiation. Recent data pointed out noteworthy degree of heterogeneity in regards of their epidemiology and risk factors, pathological and molecular features, pathogenesis, clinical behaviors and treatment. Notably, several histological variants are described and can coexist within the same tumor. Several different cells of origin have also been depicted in a fraction of iCCs, amongst which malignant transformation of ductules, of hepatic stem/progenitor cells, of periductal glands or through oncogenic reprogramming of adult hepatocytes. A degree of pathological overlap with hepatocellular carcinoma (HCC) may be observed in a portion of iCC. A series of precursor lesions are today characterized and emphasize the existence of a multistep carcinogenesis process. Overall, these new data have brought up in proposal of new histological or molecular classifications, which could soon replace current anatomic-based classification and could have major impact on establishment of prognosis and on development of novel target treatment approaches.