Takashi Yoshiki

Association between HLA and Japanese patients with rheumatoid arthritis.

Japanese patients with rheumatoid arthritis (RA) were observed to have a statistical association with HLA-DR4, MT3. Strong association between the clinical severity of RA and HLA was also observed. Male patients had a stronger association with HLA than female patients. Males are more resistant to RA than females. This suggested that the threshold of liability for RA is higher in males than in females. Japanese patients with RA with systemic vasculitis were negative for HLA-Bw44 and had antilymphocytotoxic autoantibody, indicating that RA with systemic vasculitis is different in etiology from RA without systemic vasculitis.

Gastrointestinal hepatoid adenocarcinoma: venous permeation and mimicry of hepatocellular carcinoma, a report of four cases.

Aims: Four cases of hepatoid adenocarcinoma, three in the stomach, and one in the sigmoid colon, are presented to emphasize venous permeation and mimicry of hepatocellular carcinoma by metastatic liver nodules. Methods and results: Tumour cells in all cases extensively invaded veins, and intravenous tumour thrombi in two cases were grossly observed as anastomosing, worm‐like cords up to 10 mm in diameter in the lesser omentum and mesentery in continuity with the primary mucosal lesions. The cytological features and trabecular architecture of the metastatic liver nodules in these subjects mimicked primary hepatocellular carcinoma. In a third case the tumour contained grossly visible bile in a metastatic lung nodule, but there was no evidence of bile production in the primary gastric or metastatic liver lesions. In the fourth case, detailed histopathological study revealed a gastric origin of the hepatoid adenocarcinoma, rather than primary hepatocellular carcinoma metastatic to the stomach, the initial diagnosis. Conclusions: These cases are reported here to draw attention to this rare variant of gastrointestinal adenocarcinoma, its mimicry of hepatocellular carcinoma when metastatic to the liver and other sites, and its propensity for venous permeation.

Cytokine regulation of ICAM-1 expression on human renal tubular epithelial cells in vitro.

Regulation of the intercellular adhesion molecule-1 (ICAM-1) expression on human renal tubular epithelial cells in culture (hKEC-1) was investigated. A large proportion of hKEC-1 cells from the primary cultures expressed the ICAM-1 antigen. Supernatants from mixed lymphocyte reaction (MLR) of both specific and third-party combinations augmented the expression of the ICAM-1 antigen, in a dose-dependent manner. A kinetic study revealed maximal augmentation by MLR supernatant on the first day, with a gradual decrease thereafter. Among several recombinant human cytokines tested, i.e., interferon-gamma, tumor necrosis factor-alpha, interleukin 1 alpha and beta, and IL-4, IFN-γ, TNF-α, and IL-1α/β were shown to augment the expression of ICAM-1. MLR supernatants and IFN-γ were more effective in augmenting ICAM expression than TNF-α and IL-1α/β. IFN-γ upregulated ICAM-1 expression in a dose-dependent manner, and maximal augmentation was achieved on the first day. The MLR supernatants were shown to contain IFN-γ and TNF-α, and the activity of the MLR supernatant was partially inhibited by neutralizing antibody against IFN-γ. These data suggest that cytokines, especially IFN-γ, TNF-α, and IL-1α/β, released by T cells and antigen-presenting cells upon recognition of alloantigens upregulate ICAM-1 expression on renal tubular epithelial cells. This may result in an increase in the attachment of graft-infiltrating T cells to the renal tubular cells, by the ICAM-1-LFA-1 interaction.

Hepatoid adenocarcinoma of the renal pelvis producing alpha-fetoprotein of hepatic type and bile pigment

A right renal pelvic mass in a 72‐year‐old man was resected. The histologic appearance of the tumor was a mixture of tubular adenocarcinoma cells and hepatoid neoplastic cells, and there was a resemblance to hepatoid adenocarcinoma. The intraoperative level of serum alpha‐fetoprotein (AFP) was calculated to be 2246 ng/ml, and the postoperative level ranges from 183.6 to 285.6 ng/ml. Lectin binding assays showed that the serum AFP was the hepatic carcinoma type. In a hepatoid portion, an iron‐negative, brown to green pigment was positive for bile. Alpha‐fetoprotein was immunohistochemically evident in the neoplastic cells. In addition to the hepatic differentiation, the tumor had differentiated into intestinal absorptive or pancreatobiliary tract cells, as deduced from the frequent presence of spicular bodies, a unique light microscopic feature equivalent to microvilli with an actin core. The hepatoid adenocarcinoma is a distinct type of AFP‐producing carcinoma present in the organs with epithelium of endodermal origin. Hepatoid adenocarcinoma in the renal pelvis may arise from a metaplasia of neoplastic mesonephric cells into endodermal cells.

Gene-expression profile changes correlated with tumor progression and lymph node metastasis in esophageal cancer

Purpose: The purpose of this research was to identify molecular clues to tumor progression and lymph node metastasis in esophageal cancer and to test their value as predictive markers. Experimental Design: We explored the gene expression profiles in cDNA array data of a 36-tissue training set of esophageal squamous cell carcinoma (ESCC) by using generalized linear model-based regression analysis and a feature subset selection algorithm. By applying the identified optimal feature sets (predictive gene sets), we trained and developed ensemble classifiers consisting of multiple probabilistic neural networks combined with AdaBoosting to predict tumor stages and lymph node metastasis. We validated the classifier abilities with 18 independent cases of ESCC. Results: We identified 71 genes of 1289 cancer-related genes of which the expression correlated with tumor stages. Of the 71 genes, 47 significantly differed between the Tumor-Node-Metastasis pT1/2 and pT3/4 stages. Cell cycle regulators and transcriptional factors possibly promoting the growth of tumor cells were highly expressed in the early stages of ESCC, whereas adhesion molecules and extracellular matrix-related molecules possibly promoting invasiveness increased in the later stages. For lymph node metastasis, we identified 44 genes with predictive values, which included cell adhesion molecules and cell membrane receptors showing higher expression in node-positive cases and cell cycle regulators and intracellular signaling molecules showing higher expression in node-negative cases. The ensemble classifiers trained with the selected features predicted tumor stage and lymph node metastasis in the 18 validation cases with respective accuracies of 94.4% and 88.9%. This demonstrated the reproducibility and predictive value of the identified features. Conclusion: We suggest that these characteristic genes will provide useful information for understanding the malignant nature of ESCC as well as information useful for personalizing the treatments.

IgA Nephropathy: Clinicopathology and Immunopathology

In a total of 283 biopsies, 100 (35%) were found to be IgA nephropathy. The incidence reached 40% among primary glomerulonephropathies. On the basis of histopathologic changes in glomeruli, these biopsies were classified into 3 groups. The criteria employed correlated well with clinical, laboratory and immunofluorescent findings. Immune complex pathogenesis was discussed in relation to our findings.

Genotyping of Human Papillomaviruses by a Novel One-Step Typing Method with Multiplex PCR and Clinical Applications

ABSTRACT We describe here a rapid, high-throughput genotyping procedure that allows the simultaneous detection of 16 high- and low-risk genital human papillomavirus (HPV) types by multiplex PCR in a single reaction tube. Multiplex PCR is based on the amplification of HPV DNA by sets of HPV genotype-specific primers, and the genotypes of HPV are visually identified by the sizes of amplicons after they are separated by capillary electrophoresis. The procedure does not include a hybridization step with HPV-specific probes and is rapid and labor-saving. We detected all 16 HPV genotypes (types 16, 58, 52, 51, 56, 31, 18, 39, 66, 59, 6, 33, 30, 35, 45, and 11) with a high sensitivity and a high degree of reproducibility. By using this newly developed method, we conducted a pilot study to examine the correlation between the prevalence and genotype distributions of HPV and the cytological group classifications for 547 cervical samples. Compared with the group of samples considered normal (14.7%), there was a significant increase in the prevalence of HPV in women with atypical squamous cells of unknown significance (61.3%), low-grade intraepithelial lesions (75.8%), and high-grade intraepithelial lesions (HSILs) (82.2%). The prevalence and distribution of type 58 were correlated with cytological malignancies, with the highest prevalence in women with HSILs. In conclusion, the novel multiplex PCR method described appears to be highly suitable not only for the screening of cervical cancer precursor lesions but also for the characterization of genotype distributions in large-scale epidemiological studies and HPV vaccination trials.

Phenotypes correlating to metastatic properties of pancreas adenocarcinoma in vivo : The importance of surface Sialyl Lewisa antigen

Metastasis to the liver often occurs in patients during the natural course of pancreatic cancer. Using carcinoma cell lines established from 9 such patients, we examined phenotypes of cell lines to search for correlations with their potential to metastasize to the liver. Anti‐asialo GMI‐treated nude mice were used. PCI‐43, ‐55, ‐24 and ‐6, in this order, had frequent metastases, while PCI‐10, ‐19, ‐35, ‐64, and ‐66 did not. In vitro doubling time, surface expression of sialyl Lewis a (SLe a), VLA‐4/6, LFA‐1/3, CEA, E‐selectin, VCAM‐I, NCAM, Mac‐I, HLA‐ABC/DR/DQ, ICAM‐1/2, production of interleukin‐1α, tumor necrosis factor‐α, and matrix metalloproteinase, as well as susceptibility to cytotoxicity by natural killer cells, were all examined. Expression of surface SLea was significantly associated with metastasis; numbers of metastatic colonies of SLe a‐positive and ‐negative cell lines were 21.6 ± 33.9 and 6.5 ± 14.3 (p < 0.01), respectively. Moreover, the intensity of surface SLe a expression of each PCI line correlated with the number of metastatic colonies in the liver. When anti‐SLea monoclonal antibody (MAb) was administered, the development of liver metastasis by PCI‐43 cells was significantly repressed, as compared with a control MAb. Although a reverse correlation between surface ICAM‐1 expression and liver metastasis was noted, the species‐restricted function of ICAM‐1 makes interpretation difficult. Collective evidence indicates that expression of SLe a is an important positive mediator in the hematogenous metastasis of pancreas carcinoma.

Effect of FK-506, a novel immunosuppressive drug on murine systemic lupus erythematosus

A novel immunosuppressive compound extracted from the fermentation broth of Streptomyces tsukubaensis belongs to the macrolide family. We gave this drug (FK-506) to MRL/lpr and NZB X NZW F1 (B/W F1) mice, an animal model of human systemic lupus erythematosus (SLE), to investigate its effect on the course of the disease. This drug showed potential to prolong the lifespan, to reduce proteinuria, and to prevent the progression of nephropathy. Appreciable differences in the levels of anti-dsDNA antibodies between treated and control animals were nil.

Ectopic thyroid follicles in the submucosa of the duodenum

Ectopic microscopic thyroid follicles were encountered fortuitously in the submucosa of the duodenum in a 63-year-old man undergoing pancreaticoduodenectomy for pancreatic carcinoma. The follicles, filled with a colloid-like substance, were intermingled with Brunners glands of the duodenum. There were no signs or symptoms of a thyroid tumour. The epithelial cells and colloid-like substance were both immunoreactive for thyroglobulin but no cells stained for calcitonin. The possibility of a metastatic origin for the follicles from an occult thyroid carcinoma was excluded by the clinical and histopathological findings. These ectopic thyroid follicles cannot be explained by developmental inclusions or metastasis and may be metaplastic in nature.