Daigo Yamamoto

Effects of genistein and synergistic action in combination with eicosapentaenoic acid on the growth of breast cancer cell lines.

Abstract Genistein, a prominent isoflavone in soy products, produced dose- and time-dependent in vitro growth inhibition at high concentrations (at least 185 μM) with an IC50 of 7.0–274.2 μM after 72 h incubation in four breast cancer cell lines (DD-762, Sm-MT, MCF-7 and MDA-MB-231) and one breast epithelial cell line (HBL-100) of human and animal origin; it stimulated estrogen-receptor-positive MCF-7 cells at low concentrations (3.7 nM–37 μM). Genistein-exposed cells underwent apoptosis, confirmed by G2/M arrest followed by the appearance of a sub-G1 fraction in cell-cycle progression, and by a characteristic cell ultrastructure. The apoptosis cascade was due to up-regulation of Bax protein, down-regulation of Bcl-XL protein, and activation of caspase-3. Genistein acted in synergism with eicosapentaenoic acid (EPA), a fish oil component, on human breast cancer MCF-7 cells (genistein > 93.2 μM and EPA > 210.9 μM) and on MDA-MB-231 cells (genistein > 176.1 μM and EPA > 609.3 μM). Dietary intake of genistein in combination with EPA may be beneficial for breast cancer control.

A utility of ductography and fiberoptic ductoscopy for patients with nipple discharge

AbstractBackground. Breast carcinoma and precancer are thought to start in the lining of the milk duct or lobule. While ductography has been advocated as the main procedure in patients with nipple discharge, fiberoptic ductoscopy (FDS) is an emerging technique allowing direct visual access to the ductal system of the breast through nipple orifice exploration. Methods. We applied ductography and FDS to 65 women who had nipple discharge, and compared their utility. Results. Intraductal lesions occurred in the segmental duct and the first, second, third, fourth, fifth, and sixth branches in decreasing frequency with ductography and FDS screening. The detection rates of intraductal abnormal lesions by ductography and FDS and the their combination were 89.1 (37 patients), 97.4 (38 patients), and 97.5% (39 patients) respectively. Ductal washings performed during FDS were effective to obtain representative exfoliated ductal cells which could be evaluated (sensitivity 50%, specificity 94.3%, and diagnostic accuracy 89.7%). As a result, we diagnosed 35 cases of benign lesions and four cases of malignant lesions by cytological or/and histological examination. Conclusion. Ductography and fiberoptic ductoscopy are useful procedure in guiding subsequent breast surgery in the treatment of nipple discharge.

Cycloprodigiosin hydrochloride, a H+/Cl− symporter, induces apoptosis in human breast cancer cell lines

Abstract The effect of cycloprodigiosin hydrochloride (cPrG · HCl), a H+/Cl− symporter, on five human breast cancer cell lines (KPL-1, T-47D, MCF-7, MKL-F, and MDA-MB-231), a human breast epithelial cell line (HBL-100), and a human fibroblast cell line (WI-38–40) was examined. cPrG · HCl inhibited the growth of all five breast cancer cell lines (IC50: 0.46–0.62 μM) and slightly inhibited HBL-100 and WI-38–40 cell growth (IC50: 1.75 μM and 2.26 μM respectively). cPrG · HCl treatment in KPL-1 cells increased the pH of acidic organelles, decreased intracellular pH, and caused apoptosis, which was confirmed by the appearance of a sub-G1 population by flow cytometry and DNA fragmentation. In addition, cPrG · HCl-induced apoptosis was strongly suppressed by imidazole, a cell-permeable base, suggesting that intracellular acidification was essential for the apoptosis. Further, cPrG · HCl treatment up-regulated Bax and Bak expression, down-regulated Bcl-2 expression, and activated caspase-3. Therefore, the intracellular acidification by cPrG · HCl treatment suppressed the growth of human breast cancer cell lines by inducing apoptosis.

Cycloprodigiosin hydrochloride, H+/CL– symporter, induces apoptosis and differentiation in HL-60 cells

Cycloprodigiosin hydrochloride (cPrG • HCl), a novel H+/Cl– symporter, induces acidification of the cytosol and leads to apoptosis in rat and human liver cancer cells. In the present study, the effect of cPrG • HCl on a promyelocytic leukemia cell line (HL‐60) was examined. cPrG • HCl lowered intracellular pH and induced apoptosis through up‐regulation of Fas ligand, activation of stress‐activated protein kinase (SAPK/JNK) and caspase. Apoptosis induced by cPrG • HCl was strongly suppressed when a cell‐permeable weak base, imidazole, was present, indicating that cytosol acidification introduced by cPrG • HCl triggered caspase activation, leading to apoptosis. Concomitantly, cell differentiation into monocyte was also induced by cPrG • HCl both morphologically and functionally. However, the cPrG • HCl‐induced differentiation was not suppressed by addition of imidazole, indicating that the differentiation process is unrelated to cytosol acidification. Further, the differentiation induced by cPrG • HCl was blocked by tyrosine kinase inhibitors (lavendustin A and HMA) but unaffected by the inhibitors of A‐kinase (H‐89) or C‐kinase (H‐7). Taken together, these findings suggest that cPrG • HCl, through apoptosis and differentiation induction, may be useful in leukemia treatment. Int. J. Cancer 88:121–128, 2000.

Synergistic action of apoptosis induced by eicosapentaenoic acid and TNP‐470 on human breast cancer cells

The effects of eicosapentaenoic acid (EPA) and an angiogenesis inhibitor (TNP‐470) on the suppression of breast cancer cell growth were examined in five human breast cancer cell lines (MDA‐MB‐231, T‐47D, MCF‐7, KPL‐1, and MKL‐F). In all five cell lines, EPA and TNP‐470 alone both showed tumor growth inhibition in a time‐ and dose‐dependent manner, and in combination, a synergistic effect was seen at high concentrations. EPA plus TNP‐470 treatment evoked apoptosis as confirmed by the appearance of sub G1 populations, by DNA fragmentation, and by cell morphology. With the combination, the expression of Bax and Bc1‐xS, the apoptosis‐enhancing proteins, was more up‐regulated and that of Bcl‐2 and Bcl‐xL, the apoptosis‐suppressing proteins, was more down‐regulated compared to the use of EPA or TNP‐470 alone, suggesting that their synergistic effect was due to an acceleration of apoptosis.

An autopsy case of malignant mesothelioma with osseous and cartilaginous differentiation bone morphogenetic protein-2 in mesothelial cells and its tumor

An autopsy case of biphasic malignant mesothelioma with osseous and cartilaginous differentiation diffusely involving the peritoneal cavity was confirmed by light microscopic histochemistry, immunohistochemistry, and electron microscopy. A reverse transcription-polymerase chain reaction using specific primers for bone morphogenetic protein-2 (BMP-2) revealed weak positive transcript in normal mesothelial cells and up-regulated expression around bone-forming malignant mesothelioma tissue. However, BMP-2 protein expression was detected only in the marginal zone of bone trabeculae and spindle-shaped mesothelioma cells distributed around bone trabeculae in tumor tissue. The distribution of type IV collagen in tumor tissue was in accordance with the BMP-2 expression. Normal mesothelial cells and tumor cells expressed BMP-2 mRNA, but the BMP-2 protein expression was restricted to the bone-forming area in the malignant mesothelioma.

AN AUTOPSY CASE OF HEPATOID CARCINOMA OF THE OVARY WITH PIVKA-II PRODUCTION : IMMUNOHISTOCHEMICAL STUDY AND LITERATURE REVIEW

A case of hepatoid carcinoma of the ovary in a 61‐year‐old Japanese woman, who showed high serum levels of α‐fetoprotein and CA125, is reported. Grossly, the left ovarian tumor, which measured 12 × 9 cm, was solid and multinodular. Histologically, the tumor resembled hepatocellular carcinoma by its architectural and cytological features. Liver cell differentiation was indicated functionally by the immunohistochemical detection of α‐fetoprotein and protein induced by vitamin K absence or antagonist II (PIVKA‐II) and by positive bile production, and the hepatocellular differentiation was structurally in accord with keratin 7, 8 and 18 expression. CA125 expression, commonly present in ovarian surface epithelial carcinomas, suggested that this neoplasm originated from ovarian common epithelial cells. There are only nine such cases in the literature. A review of these cases reveals that hepatoid carcinoma of the ovary occurs exclusively in postmenopausal women (mean age, 62.7 years) and that the prognosis is poor.

Bevacizumab in the treatment of five patients with breast cancer and brain metastases: Japan Breast Cancer Research Network-07 trial

Background Brain metastases from breast cancer occur in 20%–40% of patients, and the frequency has increased over time. New radiosensitizers and cytotoxic or cytostatic agents, and innovative techniques of drug delivery are still under investigation. Methods Five patients with brain metastases who did not respond to whole-brain radiotherapy and then received bevacizumab combined with paclitaxel were identified using our database of records between 2011 and 2012. The clinicopathological data and outcomes for these patients were then reviewed. Results The median time to disease progression was 86 days. Of five patients, two (40%) achieved a partial response, two had stable disease, and one had progressive disease. In addition, one patient with brain metastases had ptosis and diplopia due to metastases of the right extraocular muscles. However, not only the brain metastases, but also the ptosis and diplopia began to disappear after 1 month of treatment. The most common treatment-related adverse events (all grades) were hypertension (60%), neuropathy (40%), and proteinuria (20%). No grade 3 toxicity was seen. No intracranial hemorrhage was observed. Conclusion We present five patients with breast cancer and brain metastases, with benefits from systemic chemotherapy when combined with bevacizumab.

Metastatic gastric tumor from renal cell carcinoma

Metastatic tumors of the stomach are rare, with an incidence of 0.2%–0.7%, and they have been reported to result mainly from primary breast cancers, lung cancers, and melanoma. Further, among such metastatic tumors, the metastasis of renal cell carcinoma (RCC) to the stomach is an extremely rare disease, and it is usually reported in autopsy series. We report a rare case of metastatic gastric tumor derived from right renal carcinoma. Gastric endoscopy confirmed a large, polypoid, friable mass (type 1 tumor, about 7 cm in diameter) in the middle part of the stomach body. The mass was surgically excised and pathological examination showed that the gastric tumor was derived from a metastasis from the right kidney, because it was composed of malignant cells that were identical to those from the removed RCC. In addition, the tumor cells were immunoreactive for CD10, CD15, Ecadherin, early membrane antigen (EMA), and vimentin, but no reactivity was observed for cytokeratins 7 and 20 or c-KIT. Although gastric metastatic tumor derived from renal carcinoma is rare, the precise pre- and postoperative diagnosis may be important; thus, investigation for such metastatic tumors should be performed routinely in the follow up of patients who have been treated for RCC.

Retracted Article: Prognostic Factors in Breast Cancer: The Value of the Nottingham Prognostic Index for Patients Treated in a Single Institution

PurposeThe Nottingham Prognostic Index (NPI) is used to predict survival in patients with breast cancer. This index is based on tumor size, lymph node stage, and histological grade and allows the stratification of patients into three different prognostic groups. Our aim was to verify the effect of some prognostic variables on survival and to establish the independent influence of each of these variables by a survival regression analysis. We applied the NPI to the same group of patients to assess its predictive power and reproducibility.MethodsWe evaluated 311 women with breast cancer treated between January 1993 and December 1998.ResultsIn a multivariate analysis (Cox proportional hazard model), only size, lymph node involvement, and histological grade were independent prognostic factors. The survival curves obtained after applying the NPI were similar to those for the factors with independent prognostic significance derived from our multivariate analysis.ConclusionThe NPI allows us to accurately predict prognosis, and we advocate its standardized use.