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Background: Substernal thyrotoxic multinodular goiter (MNG) shows signs and symptoms as a result of compression of adjacent organs and thyrotoxicosis. However, acute airway obstruction is rarely caused by substernal thyrotoxic MNG., Case Report: We have described a 56-year-old Japanese woman who demonstrated acute airway obstruction because of compression of the airway by substernal thyrotoxic MNG. She had been diagnosed with substernal thyrotoxic MNG 6 years back. However, because she was unwilling to undergo surgery to remove substernal thyrotoxic MNG, she was treated with methimazole. The patient maintained normal thyroid function with this therapy for 6 years. However, after 6 years the patient was admitted to our hospital because of severe dyspnea. Physical examination revealed inspiratory stridor, which indicated an airway obstruction caused by substernal thyrotoxic MNG. Airway intubation and subtotal thyroidectomy were performed. After the surgery, the dyspnea ameliorated. The general condition of the patient remained good 6 months after the surgery., Conclusion: This case clearly demonstrates the need for careful monitoring of substernal thyrotoxic MNG, because it may lead to an airway obstruction.

Appropriate use of multiple reliable molecular biomarkers in the right context will play a role in tailormade medicine of clear cell renal cell carcinoma (RCC) patients in the future. A total of 11,056 patients from 53 studies were included in this review. The article numbers of the each evidence levels, using the grading system defined by the Oxford Centre for Evidence-based Medicine, in 1b, 2a, 2b, and 3b were 5 (9%), 18 (34%), 29 (55%), and 1 (2%), respectively. The main goal of using biomarkers is to refine predictions of tumor progression, pharmacotherapy responsiveness, and cancer-specific and/or overall survival. Currently, carbonic anhydrase (CA9) and vascular endothelial growth factor (VEGF) in peripheral blood and p53 in tumor tissues are measured to predict metastasis, while VEGF-related proteins in peripheral blood are used to assess pharmacotherapy responsiveness with sunitinib. Furthermore, interleukin 8, osteopontin, hepatocyte growth factor, and tissue inhibitors of metalloproteinases-1 in peripheral blood enable assessment of responsiveness to pazopanib treatment. Other reliable molecular biomarkers include von Hippel–Lindau gene alteration, hypoxia-inducible factor-1a, CA9, and survivin in tumor tissues and VEGF in peripheral blood for predicting cancer-specific survival. In the future, studies should undergo external validation for developing tailored management of clear cell RCC with molecular biomarkers, since individual institutional studies lack the generalization and consistency required to maintain accuracy among different patient series.

Background: Recent advances in information technology have allowed the development of a telepathology system involving high-speed transfer of high-volume histological figures via fiber optic landlines. However, at present there are geographical limits to landlines. The Japan Aerospace Exploration Agency (JAXA) has developed the "Kizuna" ultra-high speed internet satellite and has pursued its various applications. In this study we experimented with telepathology in collaboration with JAXA using Kizuna. To measure the functionality of the Wideband InterNet working engineering test and Demonstration Satellite (WINDS) ultra-high speed internet satellite in remote pathological diagnosis and consultation, we examined the adequate data transfer speed and stability to conduct telepathology (both diagnosis and conferencing) with functionality, and ease similar or equal to telepathology using fiber-optic landlines., Materials and Methods: We performed experiments for 2 years. In year 1, we tested the usability of the WINDS for telepathology with real-time video and virtual slide systems. These are state-of-the-art technologies requiring massive volumes of data transfer. In year 2, we tested the usability of the WINDS for three-way teleconferencing with virtual slides. Facilities in Iwate (northern Japan), Tokyo, and Okinawa were connected via the WINDS and voice conferenced while remotely examining and manipulating virtual slides., Results: Network function parameters measured using ping and Iperf were within acceptable limits. However; stage movement, zoom, and conversation suffered a lag of approximately 0.8 s when using real-time video, and a delay of 60-90 s was experienced when accessing the first virtual slide in a session. No significant lag or inconvenience was experienced during diagnosis and conferencing, and the results were satisfactory. Our hypothesis was confirmed for both remote diagnosis using real-time video and virtual slide systems, and also for teleconferencing using virtual slide systems with voice functionality., Conclusions: Our results demonstrate the feasibility of ultra-high-speed internet satellite networks for use in telepathology. Because communications satellites have less geographical and infrastructural requirements than landlines, ultra-high-speed internet satellite telepathology represents a major step toward alleviating regional disparity in the quality of medical care.

KISS-1 is a metastasis-suppressor gene of human melanoma, and encodes metastin, which was identified as the ligand of a G-protein-coupled receptor (metastin receptor). The precursor protein is cleaved to 54 amino acids, which may be further truncated into carboxy-terminal fragments. Previous studies showed that lack of metastin receptor in clear cell renal cell carcinoma (RCC) is associated with tumor progression, but the prediction of metastasis in patients with pT1 clear cell RCC after radical nephrectomy is difficult. The objective of this study was to evaluate the usefulness of metastin receptor immunohistochemistry in predicting metastasis after nephrectomy for pT1 clear cell RCC. After verification of the correlation between immunostaining and mRNA expression, we evaluated the clinical value of metastin receptor immunohistochemistry. Fifty-four patients were enrolled in this study; following radical nephrectomy, seven patients were found to have lung metastasis. The sensitivity, specificity, positive predictive value, and negative predictive value with negative immunostaining of metastin receptor were 85.7, 97.6, 46.2, and 97.6 %, respectively. Metastasis-free survival rates were significantly higher in patients with positive staining (97.6 %) than in patients with negative staining (53.8 %) (P < 0.001). In univariate analysis for metastasis-free survival, negative immunostaining of metastin receptor was a significant risk factor for metastasis (P = 0.001). Furthermore, negative immunostaining of metastin receptor was an independent predictor for metastasis in multivariate analysis (hazard ratio, 3.735; 95 % CI 0.629-22.174; P = 0.002). In conclusion, our study suggests that negative expression of metastin receptor in clear cell RCC is significantly related to metastasis.

The purpose of the present study is to identify genes that contribute to cell proliferation or differentiation of breast cancers independent of signalling through the oestrogen receptor (ER) or human epidermal growth factor receptor 2 (HER2). An oligonucleotide microarray assayed 40 tumour samples from ER(+)/HER2(-), ER(+)/HER2(+), ER(-)/HER2(+), and ER(-)/HER2(-) breast cancer tissues. Quantitative reverse transcriptase PCR detected overexpression of a cell cycle-related transcription factor, E2F-5, in ER-negative breast cancers, and fluorescence in situ hybridisation detected gene amplification of E2F-5 in 5 out of 57 (8.8%) breast cancer samples. No point mutations were found in the DNA-binding or DNA-dimerisation domain of E2F-5. Immunohistochemically, E2F-5-positive cancers correlated with a higher Ki-67 labelling index (59.5%, P=0.001) and higher histological grades (P=0.049). E2F-5-positive cancers were found more frequently in ER(-)/progesterone receptor (PgR)(-)/HER2(-) cancer samples (51.9%, P=0.0049) and in breast cancer samples exhibiting a basal phenotype (56.0%, P=0.0012). Disease-free survival in node-negative patients with E2F-5-positive cancers was shorter than for patients with E2F-5-negative cancers. In conclusion, we identify, for the first time, a population of breast cancer cells that overexpress the cell cycle-related transcription factor, E2F-5. This E2F-5-positive breast cancer subtype was associated with an ER(-)/PgR(-)/HER2(-) status, a basal phenotype, and a worse clinical outcome.

Pituitary carcinomas are exceedingly rare. At present, the sole diagnostic criterion is metastatic spread, either craniospinal or systemic. There is no agreement on a histologic, immunohistochemical, and/or ultrastructural definition. We report a clinically and morphologically well-documented example of pituitary thyrotropin cell carcinoma in a man with multiple endocrine neoplasia type 1 syndrome. The tumor produced thyrotropin, alpha-subunit, and prolactin and, through electron microscopy, was found to consist solely of Thyrotroph cells. Over a protracted course, craniospinal and systemic metastases were noted. The primary and metastatic deposits of this aggressive tumor were studied. To our knowledge, this tumor is the first reported case of thyrotropin cell carcinoma occurring in association with the multiple endocrine neoplasia type 1 syndrome. The literature regarding thyrotropin carcinomas is reviewed. Based on the study of several biopsies during disease progression, we believe that the carcinoma originated de novo without an intermediary adenoma phase.

Androgen receptor (AR) mediates diverse androgen actions, particularly reproductive processes in males and females. AR-mediated androgen signaling is considered to also control metabolic processes; however, the molecular basis remains elusive. In the present study, we explored the molecular mechanism of late-onset obesity in male AR null mutant (ARKO) mice. We determined that the obesity was caused by a hypercorticoid state. The negative feedback system regulating glucocorticoid production was impaired in ARKO mice. Male and female ARKO mice exhibited hypertrophic adrenal glands and glucocorticoid overproduction, presumably due to high levels of adrenal corticotropic hormone. The pituitary glands of the ARKO males had increased expression of proopiomelanocortin and decreased expression of the glucocorticoid receptor (GR). There were no overt structural abnormalities and no alteration in the distribution of cell types in the pituitaries of male ARKO mice. Additionally, there was normal production of the other hormones within the glucocorticoid feedback system in both the pituitary and hypothalamus. In a cell line derived from pituitary glands, GR expression was under the positive control of the activated AR. Thus, this study suggests that the activated AR supports the negative feedback regulation of glucocorticoid production via up-regulation of GR expression in the pituitary gland.

Background: We conducted a nationwide survey to estimate the incidence of neuroendocrine gastrointestinal tumors (NETs) newly diagnosed in Japan from 2002 through 2004., Methods: Data on 1541 patients, 514 pancreatic endocrine tumors (PETs) and 1027 gastrointestinal carcinoids (GICs), were collected and analyzed., Results: Nonfunctioning tumors (NF-PET) constituted 47.7% of PETs. Next in frequency were insulinoma (31.7%) and gastrinoma (8.6%). Malignancy was frequent in NF-PETs (46.1%) and gastrinomas (45.5%), but only 7.4% of insulinomas were malignant. The incidence of multiple endocrine neoplasia type-1 associated with PETs was 7.4%. The incidence of GICs was 28.8%, 5.2%, and 66.0% in foregut, midgut, and hindgut, respectively. Carcinoid syndrome and metastases were observed in only 1.7% and 5.6% of GICs, respectively., Conclusions: The incidence of NETs in Japan was clarified by this preliminary study. Comparatively large differences in GICs between Japan and Western nations were present with regard to the location, symptomatic status, and prevalence of malignancy.

Aim: To review five ovarian carcinomas with varying degrees of neuroendocrine differentiation (ND) using an immunohistochemical study focused on the relationship with morphological features., Methods: ND was immunohistochemically analyzed using 21 antibodies by an indirect immunoperoxidase method, and ploidy pattern was analyzed using paraffin sections., Results: The tumors were divided according to tumor cell size into 'small-sized' for case 1, 'intermediate-sized' for cases 2 and 3, and 'large-sized' for cases 4 and 5. Expressions of neuroendocrine markers and argyrophil reaction tended to be strengthened as tumor cell size increased. Cases 1, 2 and 3 showed diploid pattern and cases 4 and 5 showed aneuploid pattern., Conclusion: ND of ovarian carcinomas is closely related to morphological features represented by the cell size. Therefore, ovarian carcinomas with ND should be defined because the disease entity is not successfully integrated irrespective of the highly malignant potential.

Human saliva chromogranin A (CgA) is clinically promising as a psychological stress marker. However, expression of CgA is poorly understood in humans, although salivary gland localization of CgA in other mammals, such as rodents and horses, has been demonstrated. In the present study, we investigated the expression and localization of CgA in the human submandibular gland (HSG) using various methods. CgA was consistently localized in serous and ductal cells in HSG, as detected by immunohistochemistry and in situhybridization. Reactivity was stronger in serous cells than in ductal cells. In addition, strong immunoreactivity for CgA was observed in the saliva matrix of ductal cavities. Western blotting gave one significant immunoreactive band of 68 kDa in the adrenal gland, HSG and saliva. Finally, CgA was detected in secretory granules of serous and ductal cells by immunoelectron microscopy. In conclusion, CgA in humans is produced by HSG and secreted into saliva.

Thyrotropin (TSH)-secreting adenomas are rare and, as most adenomas are large, invasive and difficult to cure by surgery only, many require additional medical treatment. Many TSH-secreting adenomas cosecrete growth hormone (GH) and/or prolactin (PRL). We evaluated the relationship between pathology and the effect of dopamine agonist bromocriptine and somatostatin analogue octreotide in 20 operated patients with TSH-secreting adenomas. The four men and 16 women ranged in age from 23 to 62 years; three had clinically overt acromegaly; two manifested galactorrhea-amenorrhea. Endocrinologically, elevated serum GH, and/or IGF-1 were observed in six patients and elevated serum PRL was observed in eight. Immunohistochemically, 16 of the 20 adenomas were positive for GH and/or PRL (GH-positive, n=13; PRL-positive, n=9). Pituitary-specific transcription factor Pit-1 was demonstrated in the nuclei of all adenoma cells. Octreotide tests showed suppression of serum TSH (<50%) in ten of 14 patients. Preoperative octreotide treatment effectively reduced serum TSH and tumor size in two patients. Electron micrographs of octreotide-treated TSH-secreting adenomas showed shrinkage of the cytoplasm and diffuse distribution of secretory granules. Our study suggests that cosecretion of GH and/or PRL from TSH-secreting adenoma has no correlation with response of tumor cells to medical treatment.

We describe a rare case of macroprolactinoma with subclinically synchronous growth hormone (GH) production. A 59-year-old man with a giant adenoma in his pituitary had elevated serum prolactin (PRL) and insulin-like growth factor (IGF)-I levels, despite normal levels of basal GH. Serum GH levels were paradoxically increased in response to an intravenous administration of thyrotropin-releasing hormone (TRH). Prolonged exposure to glucose as a result of oral glucose tolerance testing (oGTT) failed to decrease GH levels. Two-week treatment with cabergoline, a dopamine D2 receptor agonist, decreased serum PRL and GH levels, and size of the tumor. Immunohistochemistry and in situ hybridization revealed PRL-producing cells capable of synchronous GH production. Acidophilic stem cell adenoma may be responsible for these phenomena. The nature of high proliferation and invasive tumor growth should be kept in mind when managing patients with this cell type of adenoma. IGF-I levels should be followed in PRLoma, even when basal GH levels are within the normal range, because mixed PRL- and GH-producing tumors would lie underneath. Further endocrinological examinations such as TRH test and oGTT are recommended when elevated IGF-I levels are detected.

Background: It is widely accepted that histological diagnosis of parathyroid tumors is established with great difficulty. Carcinomas cannot be reliably separated from adenomas by histology alone. In this study, immunohistochemical staining for proliferating cell nuclear antigen (PCNA) and Ki-67 was determined in 10 cases of parathyroid carcinomas, labeling indices (LIs) were calculated, and the results were correlated with the clinical outcomes., Methods: Ten cases of formalin-fixed, paraffin-embedded tissue with surgically resected parathyroid carcinoma were used. Immunohistochemical staining for PCNA and Ki-67 was performed and the LIs were calculated. We also examined whether LI could become a useful marker for parathyroid carcinomas., Results: Although nine patients with minimally invasive growth without recurrence of the tumor showed a low LI for both markers, one patient with a widely invasive neoplasm, and who died, had a high LI., Conclusions: These results suggested that the LI of PCNA and Ki-67, in addition to the histological appearance, may be markers of the biological behavior of parathyroid carcinomas. However, this study was on a small scale, so it may be valuable to repeat these studies in a larger group of patients with better defined histological criteria.

We studied the expression of prolactin (PRL) mRNA in the mammary gland of resting, pregnant, lactating, and weanling rats using in situ and solution reverse transcriptase-polymerase chain reaction (RT-PCR). In mid- to late pregnancy and throughout lactation, PRL mRNA was detected in both in situ and solution RT-PCR. These PRL mRNA signals were clearly identified in the cytoplasm of alveolar and ductal mammary epithelial cells by the in situ RT-PCR method. In mid- to late pregnancy, such as at the initiating point of PRL mRNA expression, we confirmed in some cases a lack of PRL mRNA by solution RT-PCR. In addition, in the early weaning phase, no signals were detected by solution RT-PCR. However, slight focal signals were detected in some poorly vacuolated cytoplasm of regressing acinar cells by in situ RT-PCR. These findings suggest that PRL mRNA in rat mammary gland begins in mid- to late pregnancy in parallel with the development of the mammary gland, continues throughout lactation, and declines in the early phase of weaning, with regression of mammary epithelial cells.

BACKGROUND: Prognostic factors for predicting the recurrence of node-negativebreast cancers have been controversial. The present study was performed to elucidate practically useful prognostic factors using formalin-fixed paraffin sections. METHODS: This was a case-controlled multi-institutional study that composed 40 patients with recurrent node-negative breast cancer and 80 patients with node-negative breast cancer but without recurrence after radical surgery. Tumors weresmaller than 3 cm in diameter and were treated surgically between January 1, 1985 and December 31, 1990. The recurrent and non-recurrent cases were matched with regard to their age, adjuvant chemotherapy and the year in which surgery was performed. Fourteen immunohistochemical factors and 8 histological factors of theprimary tumor were studied on formalin-fixed, paraffin-embedded sections by immunohistochemical and histochemical analyses. RESULTS: According to univariate analysis, factors such as progesterone receptor (PgR), MIB-1, CD44v6, CD44v9 and platelet-derived endothelial cell growth factor (PDECGF) were significantly different between the recurrent and non-recurrent groups (p &ly; 0.1; Wilcoxon-Mann-Whitney analysis). Chi-squared test showed significant differences in MIB-1, cdc2 and stromal plasminogen activator receptor (suPAR). Histologically, mitotic count was also significantly different between the two groups (p < 0.005). Multivariate analysis revealed that positivity for cdc2 (p=0.01), high mitotic count (p=0.04) and negativity for CD44v9 (p=0.02)were independent prognostic factors among variables selected by univariate analysis, and that positivity for MIB-1 (p=0.03) and cdc2 (p =0.01), and negativity for CD44v9 (p =0.03) were independent prognostic factors among the immunohistochemical markers examined. CONCLUSION: Our results indicated that positivity for MIB-1 and cdc2, high mitotic count and negativity for CD44v9 could serve as independent factors for predicting the recurrence of node-negative breast cancer.

The proliferative potential of 45 pituitary adenomas was compared with their biological behaviour as determined by immunohistochemical studies, radiological findings, and clinical manifestations. The PCI (proliferating cell index) as measured using antibody MIB-1 in this study ranged from 0.05 to 4.80%, with an average PCI of 1.49 +/- 0.19% (mean +/- standard error of the mean). There was no significant correlation between proliferation and hormonal state, maximum size, intra-adenomatous haemorrhage, or invasiveness. However, a PCI > or = 1.5% appeared to correlate with the likelihood of tumour regrowth (regrowth rate: 50%); for PCIs < 1.5%, the rate was 16%. Regrowth adenomas had a higher mean MIB-1 PCI than non-regrowth adenomas [2.34 +/- 0.58% (SE) versus 1.14 +/- 0.16%, p < or = 0.05]. MIB-1 PCIs may provide information that is useful for planning follow-up studies and treatment after surgical resection.