Genomic and expression analysis of microdissected inflammatory breast cancer

Inflammatory breast cancer (IBC) is a unique clinical entity characterized by rapid onset of erythema and swelling of the breast often without an obvious breast mass. Many studies have examined and compared gene expression between IBC and non-IBC (nIBC), repeatedly finding clusters associated with receptor subtype, but no consistent gene signature associated with IBC has been validated. Here we compared microdissected IBC tumor cells to microdissected nIBC tumor cells matched based on estrogen and HER-2/neu receptor status. Gene expression analysis and comparative genomic hybridization were performed. An IBC gene set and genomic set were identified using a training set and validated on the remaining data. The IBC gene set was further tested using data from IBC consortium samples and publicly available data. Receptor driven clusters were identified in IBC; however, no IBC-specific gene signature was identified. Fifteen genes were correlated between increased genomic copy number and gene overexpression data. An expression-guided gene set upregulated in the IBC training set clustered the validation set into two clusters independent of receptor subtype but segregated only 75 % of samples in each group into IBC or nIBC. In a larger consortium cohort and in published data, the gene set failed to optimally enrich for IBC samples. However, this gene set had a high negative predictive value for excluding the diagnosis of IBC in publicly available data (100 %). An IBC enriched genomic data set accurately identified 10/16 cases in the validation data set. Even with microdissection, no IBC-specific gene signature distinguishes IBC from nIBC. Using microdissected data, a validated gene set was identified that is associated with IBC tumor cells. Inflammatory breast cancer comparative genomic hybridization data are presented, but a validated genomic data set that identifies IBC is not demonstrated.     

Extended survival of a porcine mitral bioprosthesis for 23 years: Report of a case

(Received for publication on Feb. 26, 1998; accepted on Nov. 6, 1998)     

Early gastric cancer in the young: clinicopathological study.

BACKGROUND: Thirty-four cases of early gastric carcinoma in patients under 50 years of age treated in the period from 1985 to 1995 were reviewed. METHODS: These constituted 3.7% of 923 cases of gastric cancer in patients of all ages that were treated at Sendai National Hospital during the same 10-year period. Data were compared with those of 194 patients 50 years of age or older. RESULTS: The incidence of gastric cancer in men and women was almost the same in both groups. Tumours tended to be located distally in the stomach. Macroscopically, depressed lesions were more common in younger patients. Significant differences were observed in depth of invasion, histological type and histological growth patterns. CONCLUSIONS: The distinctive histological features of early gastric cancer in younger patients were a diffuse type of cancer with infiltrative tumours in the mucosal layer. The prognosis of younger patients was similar to that of older patients.     

Anti-insulin receptor autoantibodies in a patient with type B insulin resistance and fasting hypoglycemia

We studied a patient with systemic lupus erythematosus and type B insulin resistance who showed almost complete normalization of postprandial plasma glucose in 3 months and a transient coccurrence of fasting hypoglycemia from day 35 (i. e. the 35th day of hospitalization) to day 77. To determine the clinical relevance of the biological ability of anti-insulin receptor antibodies (anti-IRAb), we made multiple preparations of the patient's dialyzed serum and IgG. Dialyzed serum prepared on day 1 showed 95% inhibition of insulin binding. The binding inhibition was, however, decreased parallel to the normalization of insulin sensitivity. For 2DG uptake, 6.2 μM IgG purified on 3 different days (day 7, 35 and 78, designated IgG-NOV, -JAN, and -FEB, respectively) stimulated 2DG uptake into CHO-hIR at 3.4-, 3.1-, and 1.5-fold, respectively. Phosphotyrosine immunoblotting revealed that apparent insulin receptor autophosphorylation was visible only with IgG-NOV, not with the IgG-JAN or -FEB. Mutation of tyrosine-960 or lysine-1018 of the insulin receptor failed to transduce the IgG's stimulatory effect. IgG-NOV was not able to stimulate the autophosphorylation of the human IGF-I receptor. In the present study, the insulin binding inhibitory activities of the dialyzed sera prepared at different time points were shown to be altered parallel to insulin sensitivity in vivo. Stimulatory activities of the patient's IgG were, however, discordant for the occurrence of fasting hypoglycemia observed in vivo. Other pathogenic factors or mechanisms in addition to the insulin-like action of the anti-IRAb may be also required to fully understant the development of fasting hypoglycemia in type B insulin resistance. Received: 2 May 2000 / Accepted in revised form: 24 November 2000     

Inhibition of glycogen synthase kinase-3 enhances the expression of alkaline phosphatase and insulin-like growth factor-1 in human primary dermal papilla cell culture and maintains mouse hair bulbs in organ culture

Dermal papilla (DP) at the hair follicle base is important for hair growth. Recent studies demonstrated that mouse vibrissa DP cells can be cultured in the presence of fibroblast growth factor-2 (FGF-2), but lose expression of versican and their follicle-inducing activity during the culture, and that activation of the Wnt signal, which is inhibited by glycogen synthase kinase-3 (GSK-3), in the DP cells promotes hair growth activity. We therefore investigated the influence of a GSK-3 inhibitor, (2′Z,3′E)-6-bromoindirubin-3′-oxime (BIO), on the growth of human DP cells and mouse vibrissa follicles in culture. We first demonstrated that, similarly to mouse DP cells, human DP cells were able to be cultured up to 15 passages in the presence of FGF-2, and lost the expression of alkaline phosphatase (ALP). When human DP cells later than ten passages were treated with BIO, the expression of ALP as well as insulin-like growth factor-1 (IGF-1), another DP marker, was significantly elevated. Nuclear and perinuclear translocation of β-catenin was also observed. We then cultured mouse vibrissa follicles. In the presence of BIO, the follicles could be maintained for at least 3 days without detectable regression of the hair bulbs. The morphology and ALP expression were well preserved. BIO successfully retrieved the expression of DP marker molecules, such as ALP and IGF-1 in cultured human DP cells, and maintained mouse hair bulbs. Thus, treatment with BIO may be useful to prepare DP cells with hair follicle-inducing activity.