Hidemi Kawajiri

Changes caused by microbial transglutaminase on physical properties of thermally induced soy protein gels

Abstract Two types of soy protein product, soy protein isolate (SPI) and soy protein concentrate (SPC), were incubated with a Ca 2+ -independent microbial transglutaminase to prepare thermally induced gels. Polymerization of soy protein molecules in the gels were shown on SDS-polyacrylamide gel electrophoresis. In the appropriate range of enzyme concentration several physical properties of the thermally induced gels were substantially enhanced. The impairment of physical properties due to the addition of NaCl as well as the reduction of solid content were well compensated by the enzyme treatment. Thus, the transglutaminase treatment was very useful for the improvement of heat induced gel of soy proteins.

A Novel Transforming Growth Factor β Receptor Kinase Inhibitor, A-77, Prevents the Peritoneal Dissemination of Scirrhous Gastric Carcinoma

Purpose: Transforming growth factor β receptor (TGFβ-R) is reported to correlate with the malignant potential of scirrhous gastric carcinoma. The aim of the current study is to clarify the possibility of molecular target therapy with a TGFβ-R inhibitor, A-77, for the treatment of peritoneal dissemination of scirrhous gastric cancer. Experimental Design: Three scirrhous gastric cancer cell lines and two fibroblasts were used. For in vivo experiments, the A-77 was administered i.p. to mouse models of peritoneal dissemination. The influences of A-77 on the adhesion ability, invasion ability, and the expression of adhesion molecules were examined in vitro. Results: The A-77 administration resulted in a significantly (P < 0.01) better prognosis for the mice with peritoneal dissemination (median survival time, 51 days), compared with the control (median survival time, 25 days). A-77 therefore significantly (P < 0.01) decreased the weight and number of metastatic nodes. The adhesive ability and invasion ability of cancer cells were significantly decreased by A-77. A-77 decreased the expression of α2, α3, and α5 integrins in gastric cancer cells. The histologic findings showed the degree of fibrosis to be less in the tumors treated by A-77. A-77 decreased the growth of fibroblast and invasion-stimulating activity of fibroblasts on cancer cells. Conclusion: The TGFβ-R inhibitor, A-77, decreased the expression of integrins in cancer cells and the proliferation of fibroblasts, which resulted in the decreased adhesive and invasive abilities of scirrhous gastric cancer cells to peritoneum. A-77 is thus considered to be useful for the inhibition of peritoneal dissemination of scirrhous gastric carcinoma.

Carcinoid Tumor of the Kidney Presenting as a Large Abdominal Mass: Report of a Case

Carcinoid tumors are known to occur frequently in the gastrointestinal tract and they can develop in nearly every organ system. However, a carcinoid tumor of the kidney is an extremely rare entity and only 38 cases have been reported in the English literature. We herein describe the 39th case of primary renal carcinoid tumor, found in a young Japanese woman 2 months after delivery. The pathologic similarities of our case with those of previously reported cases are briefly reviewed together with some aspects of clinical features and prognostic factors of this rare disease.

Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer

Overexpression of HER2 – found in approximately 15–20% of all breast cancers – is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2-positive metastatic breast cancer.

Carbonic anhydrase 9 is associated with chemosensitivity and prognosis in breast cancer patients treated with taxane and anthracycline

BackgroundNeoadjuvant chemotherapy (NAC) is one of the standard care regimens for patients with resectable early-stage breast cancer. It would be advantageous to determine the chemosensitivity of tumors before initiating NAC. One of the parameters potentially compromising such chemosensitivity would be a hypoxic microenvironment of cancer cells. The aim of this study was thus to clarify the correlation between expression of the hypoxic marker carbonic anhydrase-9 (CA9) and chemosensitivity to NAC as well as prognosis of breast cancer patients.MethodsA total of 102 patients with resectable early-stage breast cancer was treated with NAC consisting of FEC (5-fluorouracil, epirubicin, and cyclophosphamide) followed by weekly paclitaxel before surgery. Core needle biopsy (CNB) specimens and resected tumors were obtained from all patients before and after NAC, respectively. Chemosensitivity to NAC and the prognostic potential of CA9 expression were evaluated by immunohistochemistry.ResultsCA9 positivity was detected in the CNB specimens from 47 (46%) of 102 patients. The CA9 expression in CNB specimens was significantly correlated with pathological response, lymph node metastasis, and lymph-vascular invasion. Multivariate analysis revealed that the CA9 expression in CNB specimens was an independent predictive factor for pathological response. The Kaplan-Meier survival curve revealed a significant negative correlation (p = 0.013) between the disease-free survival (DFS) and the CA 9 expression in resected tissues after NAC. Multivariate regression analyses indicated that the CA9 expression in resected tissues was an independent prognostic factor for DFS.ConclusionsCA9 expression in CNB specimens is a useful marker for predicting chemosensitivity, and CA9 expression in resected tissue is prognostic of DFS in patients with resectable early-stage breast cancer treated by sequential FEC and weekly paclitaxel prior to resection.

In vitro and in vivo evidence that a combination of lapatinib plus S-1 is a promising treatment for pancreatic cancer

Lapatinib is a small molecule inhibitor of both HER2 and the epidermal growth factor receptor (EGFR). We investigated the effect of treatment with lapatinib alone or in combination with a fluoropyrimidine derivative S‐1 against pancreatic cancer. The HER2/EGFR expression in each of the four pancreatic cancer cell lines MiaPaca‐2, PANC‐1, Capan‐1 and Capan‐2 was measured by flow cytometry. The anti‐tumor effects of lapatinib (30 mg/kg) and/or S‐1 (10 mg/kg) were evaluated using female BALB/c nude mice xenografts generated using these four cell lines. Synergy between lapatinib and S‐1 was examined by median effect analysis in vitro. Resected pancreatic cancer tissues from 137 patients were immunohistochemically stained with anti‐human HER2 and EGFR antibodies. The administration of lapatinib as a single agent substantially suppressed tumor growth in vivo of all pancreatic cancer cell lines examined. A strong correlation was observed between HER2 expression and the anti‐tumor effect of lapatinib in vivo. Lapatinib synergized with S‐1 to inhibit the tumor growth of MiaPaca‐2 and PANC‐1 xenografts. When used as a single agent in vitro, lapatinib barely inhibit the cell growth of any cell line. However, lapatinib synergized with the anti‐tumor activity of the S‐1 components 5‐fluorouracil and 5‐chloro‐2,4‐dihydrogenase against all cell lines. Immunohistochemical staining demonstrated that 70% of the pancreatic cancers overexpressed HER2 and/or EGFR. Both lapatinib monotherapy and combined treatment with S‐1 may be promising treatments for patients with pancreatic cancers; the majority these cancers express lapatinib target molecules. (Cancer Sci 2009; 00: 000–000)

Combination effect of a TGF-β receptor kinase inhibitor with 5-FU analog S1 on lymph node metastasis of scirrhous gastric cancer in mice

Transforming growth factor‐β (TGF‐β) signals are closely associated with the distant metastases of gastric cancer. The aim of this study was to clarify the effect of a TGF‐β receptor I (TβR‐I) phosphorylation inhibitor, Ki26894, in combination with anticancer drugs, on the lymph node (LN) metastasis of scirrhous gastric cancer. A novel TβR‐I kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at the ATP binding site of TβR‐I. S1 is a 5‐fluorouracil analog. The human scirrhous gastric cancer cell line OCUM‐2MLN and the human gastric fibroblasts NF‐33 were used. OCUM‐2MLM cells in the upper well and NF‐33 cells in the lower well were co‐incubated with or without Ki26894. The proliferation of OCUM‐2MLN cells was significantly stimulated by co‐culture with NF‐33 cells. Ki26894 significantly suppressed the growth interactions between OCUM‐2MLN cells and NF‐33 cells. Gastric cancer models established by orthotopic inoculation of OCUM‐2MLN cells showed diffusely infiltrating gastric adenocarcinoma accompanied by LN metastases. We divided these mice into four groups, (control vehicle, Ki26894, S1, Ki26894 plus S1), and examined the effect of Ki26894 and/or S1 on phosphorylation of Smad2, tumor size, LN metastases, and lymphatic involvements. Ki26894 inhibited the Smad2 phosphorylation of cancer cells and decreased the extent of lymphatic involvement, compared with the control or S1 only group. The Ki26894 plus S1 administration group significantly suppressed tumor growth and decreased LN metastasis more effectively than either alone. These findings suggested that the TβR‐I kinase inhibitor with S1 is useful for the treatment of scirrhous gastric carcinoma with LN metastasis. (Cancer Sci 2010)

Prognostic significance of pathological complete response following neoadjuvant chemotherapy for operable breast cancer

The aim of the present retrospective study was to ascertain the significance of pathological complete response (pCR) on overall survival (OS) and disease-free survival (DFS) in each disease subtype of operable breast cancer. Using a single-institution database, 90 patients were identified, who received neoadjuvant chemotherapy (NAC) for operable breast cancer and were eligible for the analysis. In total, 10 patients (11.1%) had succumbed to their diseases and 20 (22.2%) had succumbed to their diseases or exhibited recurrences. The OS of patients with triple-negative (TN) tumors was significantly lower than that of patients with other disease subtypes (P=0.016). The DFS of patients with luminal tumors was higher than that of patients with other subtypes. Survival was improved with pCR following NAC (P=0.044). Across all subtypes, patients who achieved pCR exhibited a higher DFS than patients who did not, but not significantly. pCR only improved OS and DFS in the TN disease subtype (P=0.022 and P=0.048, respectively). pCR following NAC may have prognostic value in TN breast cancer.

Clinical significance of the sub-classification of 71 cases mucinous breast carcinoma

ObjectiveMucinous breast carcinoma (MBC) is classified into mixed mucinous breast carcinoma (MMBC) and pure mucinous breast carcinoma (PMBC) based on whether the tumor is with or without a component of invasive ductal carcinoma, respectively. PMBC is subtyped into hypocellular PMBC (PMBC-A) and hypercellular PMBC (PMBC-B).MethodsOf 1,760 primary breast carcinomas, 71 were diagnosed as MBC, and were subtyped for comparison purposes.ResultsSeventy-one of all breast cancers (4.0%) were MBC, and consisted of 23 MMBC, 32 PMBC-A and 16 PMBC-B. The MBC tumors were more often hormone receptor-positive and HER2-negative than non-MBC tumors. Patients with MMBC, PMBC-B or PMBC-A, in this order, had significantly higher recurrence rates than non-MBC cases (p=0.006, log-rank).ConclusionsIn the NCCN guidelines, MBC is also regarded as “a histological type with a favorable prognosis” in a uniform manner, and “treatment for a histological type with a favorable prognosis” is recommended. However, the results of this study suggest that sub-classification-based, individualized therapeutic strategies should be considered.

Platelet–Lymphocyte Ratio as a Useful Predictor of the Therapeutic Effect of Neoadjuvant Chemotherapy in Breast Cancer

Background The peripheral blood platelet–lymphocyte ratio (PLR) has been proposed as an indicator for evaluating systemic inflammatory responses in cancer-bearing patients. While some reports suggest a correlation between PLR and prognosis, few studies have examined the relationship between PLR and sensitivity to chemotherapy. We conducted a study on whether PLR could serve as a predictor of the therapeutic effects of neoadjuvant chemotherapy (NAC). Methods PLR was evaluated in 177 breast cancer patients treated with the NAC 5-fluorouracil, epirubicin and cyclophosphamide, followed by weekly paclitaxel and subsequent curative surgery. The correlation between PLR and prognosis, and between PLR and the efficacy of NAC, were evaluated retrospectively. Results The low PLR group had significantly more patients > 56 years old (p = 0.001) and postmenopausal women (p = 0.001) than the high PLR group. The low PLR group also had a higher pathologic complete response (pCR) rate (p = 0.019). On examining the correlation with prognosis, the low-PLR group was found to have significantly longer disease-free survival (p = 0.004) and overall survival (p = 0.032) than the high PLR group. Multivariate analysis also revealed that lymph node metastasis (p = 0.043, hazard ratio = 4.40) and a high PLR (p = 0.005, hazard ratio = 2.84) were independent, unfavorable prognostic factors. Conclusions For patients with breast cancer treated with NAC, a low PLR indicated high chemotherapy sensitivity, suggesting that PLR could serve as a predictive marker of the therapeutic effect of NAC.