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Background Although Helicobacter pylori eradication is a first-line treatment of gastric MALT lymphoma, roughly 25% of patients do not respond to treatment. CD4+ FOXP3+ regulatory T ( Treg) cells regulate immune responses in physiological conditions and various inflammatory conditions, including H. pylori-associated diseases. Our goal was to determine how Treg cells affect responsiveness to H. pylori eradication therapy. Materials and methods We performed dual immunohistochemistry for CD4 and FOXP3 to evaluate the prevalence of FOXP3+ Treg cells in the stomach of 63 patients with MALT lymphoma and 55 patients with chronic active gastritis. Receiver operating characteristic analysis was carried out to determine the best cut-off point in differentiating H. pylori eradication responders from nonresponders. Results Both the FOXP3+/ CD4+ cell ratio and the absolute number of FOXP3+ cells per high-power field in MALT lymphoma were significantly greater in H. pylori eradication responders compared with nonresponders, suggesting that Treg cells function in regression mechanisms of MALT lymphomas. Cut-off points with good sensitivities and specificities were obtained to predict eradication outcome. Conclusions A high number of Treg cells or a high ratio of Treg cells to the total number of CD4+ T cells in gastric MALT lymphoma could predict responsiveness to eradication therapy. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to clarify the prognostic significance of tumor-infiltrating lymphocytes (TILs) in oral squamous cell carcinoma (OSCC); the present study analyzed various TIL-related parameters. Study design: Immunohistochemistry was performed in 87 patients with OSCC for the following TIL-related parameters: nest-CD8+ T cells, stromal CD8+ T cells, CD4+ T cells, total regulatory T cells (Tregs), CCR4+ Tregs, ratio of nest CD8+ T cells/CCR4+ Tregs, and ratio of stromal CD8+ T cells/CCR4+ Tregs. Results: In univariate analyses, the following parameters were associated with decreased survival: few nest- and stromal CD8+ T cells and more stromal CCR4+ Tregs, but not total Tregs. Low ratios of nest and stromal CD8+ T cell/CCR4+ Treg were associated with worse survival. In multivariate analysis, the stromal CD8+ T cell/CCR4+ Treg ratio was an independent prognostic factor. Conclusion: Host immune responses in the stroma of OSCC affect the survival of the patients. The in situ balance between effector T cells and regulatory T cells is the most important factor predicting survival. [Copyright &y& Elsevier]

Hepatocellular necrosis may be complicated in the clinical course of T-cell lymphoma. Herein are reported two cases of peripheral T-cell lymphoma associated with a rapid increase of serum transaminases in their final course. The final diagnoses were enteropathy-type T-cell lymphoma of the jejunum (patient 1) and hepatosplenic T-cell lymphoma (patient 2). The livers of both patients had non-zonal, well-demarcated coagulation necrosis (approximately 70% in patient 1 and 40% in patient 2) that was infiltrated by lymphoma cells bearing a cytolytic granule content (granzyme B). Hepatocytes in the necrotic areas in patient 2 showed immunoreactivity for human simplex virus type 1. Although the mechanism of the hepatocyte necrosis is unclear, it is suggested that the hepatocyte submassive necrosis may be related to an infection complicated in the final course of lymphoma or by certain direct effects of the tumor cells. [ABSTRACT FROM AUTHOR]

OBJECTIVES: In the colonic mucosa with ulcerative colitis (UC), it has been suggested that L-selectin-peripheral lymph node addressin (PNAd) interaction plays a role in lymphocyte recruitment, which requires PNAd induction on high endothelial venule (HEV)-like vessels. The present study was undertaken to elucidate how these HEV-like vessels participate in the pathogenesis of UC and also to determine whether the presence of such vessels is correlated with clinical outcomes. METHODS: Biopsy specimens composed of active (N = 32) and remission (N = 12) phases of UC were subjected to immunohistochemistry for CD34, MECA-79, and HECA-452, and the immunostained sections were quantitatively analyzed. An in vitro binding assay with L-selectin•IgM chimeric protein was carried out to determine whether PNAd on HEV-like vessels formed in UC functions as an L-selectin ligand. RT-PCR was carried out to determine which enzyme is upregulated for PNAd biosynthesis on HEV-like vessels induced in the active phase of UC. Triple immunostaining for MECA-79 together with CD3 and CD20/CD79α, CD4 and CD8, or CXCR3 and ST2L was carried out to determine which lymphocyte population closely associates with these vessels. RESULTS: PNAd-expressing HEV-like vessels were preferentially induced in the active phase of UC with increased transcription of the gene encoding N-acetylglucosamine-6- O-sulfotransferase (GlcNAc6ST)-1, which directs expression of the MECA-79 epitope. Moreover, T cells, particularly CD4+ T cells, were more closely associated with these HEV-like vessels than B cells. CONCLUSIONS: T-cell recruitment via PNAd-expressing HEV-like vessels induced by expression of GlcNAc6ST-1 may play a role in UC pathogenesis. [ABSTRACT FROM AUTHOR]

Primary breast lymphoma, particularly primary mucosa-associated lymphoid tissue (MALT) lymphoma, is a rare disease. We report here a case of a MALT lymphoma of the breast with high-grade transformation. An 84-year-old woman presented with a Pagetoid mass in her right breast. After a clinical diagnosis of breast cancer, T2N1M0, stage IIB, she underwent mastectomy with axillary lymph node dissection. She had no history of autoimmune disease such as Hashimoto thyroiditis or Sjogren disease. Pathologically the tumor tissue was composed of small to large lymphoid cells. The large cells contained a considerable number of centroblasts, forming a sheet-like proliferation centrally. Among the small cells many small cleaved cells were present, which were more predominant in the peripheral areas. Immunohistochemistry revealed that these cells were positive for CD20 and CD79a. The tumor cells infiltrated the ductular epithelial cells, distorting the duct structures, to form lymphoepithelial lesions. Immunohistochemistry for cytokeratin and CD20 was helpful for identification. No germinal centers were formed. MALT lymphoma with high-grade transformation was diagnosed. Rituximab (anti-CD20 antibody) was prescribed as systemic treatment without chemotherapy or irradiation. After 18 months, no tumor recurrence was observed. We emphasize the importance of lymphoepithelial lesions for the diagnosis of MALT lymphoma of the breast. [ABSTRACT FROM AUTHOR]

We report on a 49-year-old woman with osteosarcoma arising in the breast. She had undergone two consecutive excision biopsies for right breast tumors at ages 40 and 42 years. The tumors were diagnosed as a fibroadenoma and a benign phyllodes tumor, respectively. At age 46 years, she noticed a gradually enlarging mass in the same breast. After 3 years, at age 49 years, total mastectomy was performed. The tumor occupied the entire breast and measured 12×9×8.5 cm. The tumor cells were spindle-shaped and pleomorphic, with large, irregular nuclei and distinct nucleoli. Many tumor cells had characteristics of osteoblastic and chondroblastic elements producing osteoid, osseous, and cartilaginous intracellular substances. Pathologic mitoses and apoptotic cells were frequent. Neoplastic cells had infiltrated the skin. Blood and lymph vessel invasion was present. Tumor cells expressed vimentin, osteopontin, vascular endothelial growth factor, CD10, and alkaline phosphatase, but did not express keratin. Chemotherapy was not effective. The patient died of multiple pulmonary metastases 9 months after mastectomy. [ABSTRACT FROM AUTHOR]

In a recent report, [Zhang et al. (2003) N. Engl. i. Med. 348,203-213], the presence of CD3+ tumor-infiltrating lymphocytes (TILs) was found to correlate with improved survival in epithelial ovarian cancer. We performed immunohistochemical analysis for TILs and cancer testis antigens in 117 cases of epithelial ovarian cancer. The interrelationship between subpopulations of TILs and expression of cancer testis antigens was investigated, as well as between TILs and overall survival. The median follow-up of the patients was 31 months. Patients with higher frequencies of intraepithelial CD8+ T cells demonstrated improved survival compared with patients with lower frequencies [median = 55 versus 26 months; hazard ratio = 0.33; confidence interval (C.I.) = 0.18-0.60; p = 0.0003]. No association was found for CD3+ TILs or other subtypes of intraepithelial or stromal TILs. However, the subgroups with high versus low intraepithelial CD8+/CD4+ TIL ratios had median survival of 74 and 25 months, respectively (hazard ratio = 0.30; C.I. = 0.16-0.55; P = 0.0001). These results indicate that CD4+ TILs influence the beneficial effects of CD8+ TIL. This unfavorable effect of CD4+ T cells on prognosis was found to be due to CD25+ forkhead box P3 (FOXP3)+ regulatory T cells (Treg; suppressor T cells), as indicated by survival of patients with high versus low CD8+/Treg ratios (median = 58 versus 23 months; hazard ratio = 0.31; C.I. = 0.17-0.58; P = 0.0002). The favorable prognostic effect of intraepithelial CD8+ TILs did not correlate with concurrent expression of NY-ESO-1 or MAGE antigens. We conclude that intraepithelial CD8+ TILs and a high CD8+/Treg ratio are associated with favorable prognosis in epithelial ovarian cancer. [ABSTRACT FROM AUTHOR]

Herein is presented a case of cytokeratin (CK) 20-positive large cell neuroendocrine carcinoma of the colon, in which the tumor was clinically at stage IV and located in the ascending colon. Pathological examination of the resected tumor revealed nested and solid proliferation of large undifferentiated cells with vesicular nucleus and prominent nucleoli. No areas showed differentiation toward adenocarcinoma or squamous cell carcinoma. Tumor cells were immunohistochemically positive for chromogranin A, synaptophysin, CD 56 (focal), and bore electron-dense granules. With these features, the tumor was diagnosed as a large cell neuroendocrine carcinoma of the colon. Liver metastasis and local recurrence progressed, and the patient died of the primary disease 7 months after operation. The autopsy confirmed this diagnosis without detectable tumors in the lungs. Interestingly, more than half of the tumor cells were positive for CK 20, while CK 7 was not expressed. Most neuroendocrine carcinomas do not express CK 20, with the exception of Merkel cell carcinomas, and most colorectal adenocarcinomas express CK 20. To the best of the authors’ knowledge, the present case is the first CK 20-positive, CK 7-negative colorectal neuroendocrine carcinoma to be described, suggesting a link between colorectal neuroendocrine carcinoma and conventional adenocarcinoma. [ABSTRACT FROM AUTHOR]

The gene coding for microphthalmia-associated transcription factor (Mitf) contains many promoters that could generate multiple Mitf isoforms with distinct amino-termini, such as ubiquitously expressed Mitf-A and Mitf-H. To gain further insight into Mitf isoform multiplicity and the regulation of the promoter usage of the Mitf gene, we have analyzed the function of the amino-terminal domains of Mitf isoforms and the expression of Mitf mRNA in mouse postnatal testis, which is characterized by spermatogenesis and by a cool temperature because of its unique location. Here we show that the amino-terminal domain of Mitf-A possesses a transactivation activity, as judged by yeast expression analysis. We also show the expression of Mitf-A and Mitf-D mRNAs in testis by PCR-based methods. Moreover, in situ hybridization analysis revealed that an Mitf mRNA, probably representing Mitf-A and/or Mitf-D, is expressed in germ cells, including spermatogonia, spermatocytes that undergo meiosis, and round spermatids with the haploid genome, but is undetectable in elongated spermatids with remodeled and condensed chromatin. Notably , Mitf mRNA is undetectable in somatic Leydig cells and peritubular cells. Therefore, multiple promoters may direct differential expression of the Mitf gene in the testis and contribute to functional diversity of Mitf isoforms. [ABSTRACT FROM AUTHOR]

Antigen-presenting cells (APCs) participate in the initiation of the inflammatory process in various immune-mediated dermatoses through the activation of antigen-specific T lymphocytes. The skin contains several different subsets of APCs. To investigate the role of these APCs in T-cell immune-mediated inflammation, we examined the distribution and numbers of epidermal and dermal CD1a+ dendritic cells (DCs), factor XIIIa+ dermal DCs, and CD68+ macrophages in five T-cell-mediated inflammatory skin diseases. Immunohistochemistry of CD1a, factor XIIIa, and CD68 was performed using paraffin-embedded tissue obtained from a total of 51 patients with eczematous dermatitis (histologically spongiotic dermatitis), psoriasis, lichen planus, acute graft-versus-host disease (GVHD), and chronic GVHD. The numbers of positive cells for each staining were compared with those in site-matched normal skin control specimens from aged-matched subjects. In spongiotic dermatitis and lichen planus, the numbers of epidermal and dermal CD1a+ cells and factor XIIIa+ cells were significantly greater than in normal control skin, while in psoriasis only factor XIIIa+ cells were significantly increased in number. Acute and chronic GVHD showed a reduced number of dermal CD1a+ cells. Interestingly, factor XIIIa+ cells were decreased in acute GVHD while they were increased in chronic GVHD. There was a significant reduction in epidermal CD1a+ cells in acute GVHD, but not in chronic GVHD. The differences in the numbers of APCs in lesional skin appeared to reflect differences in the pathophysiology of these inflammatory skin diseases. [ABSTRACT FROM AUTHOR]

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is selectively expressed in the endothelial cells of intestinal mucosa and gut-associated lymphoid tissue (GALT). Engagement of MAdCAM-1 to its ligand, integrin α4 β7 , on lymphocytes is associated with the homing of gut-associated lymphocytes to normal gastrointestinal tract and inflammation sites. The present study was designed to elucidate differences between Crohn's disease (CrD) and ulcerative colitis (UC) from the expression patterns of MAdCAM-1. Samples were taken from 40 patients with CrD and 24 patients with UC at surgical resection. Using frozen sections, immunohistochemistry was performed for MAdCAM-1, E-selectin and CD34. MAdCAM-1+ venules were abundant in inflamed mucosa in both UC and CrD. In contrast, clear differences were noted between UC and CrD in the inflammatory area in the ulcer base, that is, MAdCAM-1+ venules were more abundant in CrD than in UC (P < 0.001), while E-selectin was expressed equally in these venules in both diseases. Furthermore, CrD was characterized by the occurrence of MAdCAM-1+ venules in deeper layers of the intestinal tissue, mainly in lymphoid aggregates. Our data indicated more extensive expression of MAdCAM-1 in CrD, which could contribute not only to mucosal inflammation, but also to transmural inflammation in CrD. [ABSTRACT FROM AUTHOR]

We encountered two unique cases of papillary carcinoma of the thyroid gland forming fibroma-like nodular tumors. The two cases showed well-defined nodules composed largely of fibromatosis-like stroma with small foci of papillary carcinoma. This type of tumor is relatively rare and has been reported with the name of ‘papillary carcinoma of the thyroid with fibromatosis-like stroma or nodular fasciitis-like stroma’. The stromal cells have had myofibroblastic features in all reported cases, including the present cases. The pathogenesis of this tumor is still unknown. We must be careful to differentiate this type of thyroid tumor from fibrosarcomatous anaplastic carcinoma, particularly in the intraoperative consultation. We speculate that this unique tumor is an autonomous proliferation of stromal cells, based on the immunohistochemical analyses of early stromal changes in usual-type papillary carcinoma of the thyroid. The present names of this disease may not represent the proper features of this tumor because all the reported cases formed fibroma-like nodules. We propose the name ‘papillary carcinoma forming myofibroblastic nodular tumors’. [ABSTRACT FROM AUTHOR]

To elucidate the pathogenesis of T cell-mediated inflammatory skin diseases, we examined the exact sites where CD8(+) T cells proliferate, correlating them with the localization of antigen-presenting dendritic cells. We performed CD8/Ki-67 double immunohistochemical staining and single staining for CD1a, CD68, and factor XIIIa on sections of paraffin-embedded tissue samples of inflammatory dermatoses in which T lymphocytes are thought to play a crucial role. The dermatoses were lichen planus (12 samples), acute graft-versus host disease (GVHD) (12 samples), chronic GVHD (10 samples), spongiotic dermatitis (8 samples) and psoriasis (7 samples). Labelling for Ki-67 among CD8(+) T cells was predominantly observed in the subepidermal lymphoid infiltrate, and was scanty in the epidermis. This suggested that proliferation of CD8(+) T cells occurred preferentially in the dermis. The labelling index for Ki-67 among dermal and epidermal CD8(+) cells was quite different among the different diseases studied (P < 0.05). They were rich in the subepidermal portion of the dermis of spongiotic dermatitis, acute GVHD and chronic GVHD, but rare in the dermis of psoriasis and lichen planus. A moderate infiltrate was also observed in lesional epidermis of spongiotic dermatitis, acute GVHD and chronic GVHD, whereas they was almost none in the epidermis of psoriasis and lichen planus. CD1a(+) dermal dendritic cells were densely distributed within the lymphoid infiltrate in the affected dermis of spongiotic dermatitis, psoriasis and lichen planus, whereas they were minimal in GVHD. These dermal dendritic cells are candidates as stimulators on T cells in the dermis. In conclusion, the proliferative status of T cells could be an important clue in the elucidation of the pathophysiology of T cell-mediated inflammatory dermatoses. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate how rat hyaline cartilagesat various sites in vivo express the gene and protein of type I collagen using in situ hybridization and immunohistochemistry. The gene of pro alpha1(I) collagen was expressed by chondrocytes in articular cartilage, and theprotein of type I collagen was identified in the cartilage matrix. In contrast,growth plate cartilage expressed the gene of pro alpha 1(I) collagen, butno protein of type I collagen. Neither gene nor protein of type I collagenwas expressed in cartilages of trachea and nasal septum. The present studysuggested that expression of type I collagen in hyaline cartilages may beregulated tissue-specifically at gene and/or protein levels. [ABSTRACT FROM AUTHOR]

Human Sim2 is a product of one of the genes located on human chromosome 21q22 and is a homolog of Drosophila single-minded (sim) which is a critical player in midline development of the central nervous system of the fly. Since Sim2 mRNA is expressed in facial, skull, palate and vertebra primordia in human and rodent embryos, features that are associated with phenotypes of Down's syndrome (DS), its trisomic state is suspected to contribute to the symptoms of DS. Here we describe that mSim2 mRNA is expressed in hippocampus and amygdala of adult mice, and that while mice overexpressing mSim2 under the control of the β-actin promoter are viable and fertile and have superficially normal skeletal, brain and heart structures, they exhibit a moderate defect in context-dependent fear conditioning and a mild defect in the Morris water maze test. Taken together, our data show that overdosage of Sim2 may be important for the pathogenesis of Down's syndrome, especially mental retardation. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate whether or not chondrocytes in articular cartilage express type I collagen in vivo under physiological conditions. Expressions of the gene and the phenotype of type I collagen were examined in rat tibial articular cartilage in the knee joint during development. Knee joints of Wistar rats at 1, 5, and 11 weeks postnatal were fixed in 4% paraformaldehyde with or without 0.5% glutaraldehyde and decalcified in 10% EDTA. After the specimens were embedded in paraffin and serial sections made, adjacent sections were processed for immunohistochemistry and in situ hybridization for type I collagen. The epiphysis of the tibia was composed of cartilage in week-1 rats. Formation of articular cartilage was in progress in week 5 as endochondral ossification proceeded and was completed in week 11. Anti-type I collagen antibody stained only the superficial area of the epiphysis in week 1, but the immunoreactivity was expanded into the deeper region of the articular cartilage with development in weeks 5 and 11. Hybridization signals for pro-alpha 1 (I) collagen were seen in some of chondrocytes in the epiphysis of the week-1 tibia. The most intense signals were identified in chondrocytes in week 5 and the signals appeared weaker in week 11. The present study demonstrated that chondrocytes synthesize type I collagen and accumulate the protein in the matrix during development of the articular cartilage. [ABSTRACT FROM AUTHOR]