Kiyomi Takaishi

Detection of M2 macrophages and colony‐stimulating factor 1 expression in serous and mucinous ovarian epithelial tumors

Tumor‐associated macrophages (TAM) are known to possess the immunosuppressive M2 macrophage phenotype. They contribute to tumor growth, invasion, and metastasis by producing various mediators. Macrophages, especially M2 polarized macrophages, preferentially express CD163 and CD204, but few studies have investigated macrophage phenotypes in human ovarian tumors. The purpose of the present study was therefore to present results on macrophage differentiation in human ovarian serous and mucinous epithelial tumors. The method focused on immunostaining of paraffin‐embedded tumor samples. Almost all macrophages infiltrating tumor tissues expressed CD163 and CD204, indicating the phenotypic shift toward M2 macrophage. The numbers of CD68‐positive macrophages as well as of CD163‐ and CD204‐positive macrophages in borderline and malignant tumors were significantly higher than in benign tumors. They correlated well with histological gradient of malignancy. Macrophage colony‐stimulating factor (also known as colony‐stimulating factor; CSF‐1), which is one of the cytokines considered to induce TAM to polarize toward an M2 phenotype, was then evaluated. CSF‐1 expression in malignant tumor cells was significantly higher than that in benign tumor cells and correlated with histological malignancy. These results suggest that CSF‐1 derived from tumor tissues induces macrophages to shift toward the M2 phenotype, which is considered to promote tumor growth.

Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation

Ascites macrophages in advanced epithelial ovarian cancer (AdEOC) are involved in cancer metastasis and progression by modifying the tumor microenvironment. However, the precise mechanisms of cell‐to‐cell interaction between macrophages and tumor cells are still unclear. This study focused on the activation of signal transducer and activator of transcription 3 (Stat3) which is a critical signal transduction molecule at a point of convergence for numerous oncogenic signaling pathways as well as controlling the M2‐poralization of macrophages. AdEOC ascites, in which high concentration of interleukin (IL)‐6, IL‐10, growth‐related oncogene‐alpha and vascular endothelial growth factor were detected, stimulated the proliferation of SKOV3 cells, a human ovarian cancer cell line. The simultaneous blocking of IL‐6 and IL‐10 by neutralizing antibodies suppressed ascites‐induced tumor cell proliferation. Stat3 activation in SKOV3 cells was induced by co‐culture with macrophages especially with macrophage colony stimulating factor‐primed M2 macrophages but lesser extent with granulocyte‐macrophage colony stimulating factor‐primed immature macrophages. Cyclin‐D1 expression in SKOV3 cells was also significantly induced by co‐culture with macrophages. Blocking of Stat3 in macrophages by small interfering RNA inhibited the production of IL‐6 and IL‐10 by macrophages, and suppressed Stat3 activation and cyclin‐D1 induction in co‐cultured SKOV3 cells. Stat3 activation in SKOV3 cells was abrogated by simultaneous neutralization of IL‐6 and IL‐10. These results indicate that Stat3 activation by IL‐6 and IL‐10 plays an important role in cell‐to‐cell interaction between tumor cells and macrophages in the ascites of AdEOC. (Cancer Sci 2010)

Hypertriglyceridemic acute pancreatitis during pregnancy: Prevention with diet therapy and ω-3 fatty acids in the following pregnancy

Acute pancreatitis complicating pregnancy is rare and has previously been associated with high mortality rates. We report a case of repeated hypertriglyceridemia during pregnancy. During the patients first pregnancy, acute pancreatitis was elicited in the third trimester by pregnancy-induced hypertriglyceridemia. The patient was treated successfully with a conservative treatment course. The hypertriglyceridemia recurred during her second pregnancy. She carried the pregnancy to term without incident while maintaining a diet low in fat diet and high in omega-3 fatty acids. Early diagnosis and intensive treatment can help to preserve the lives of the patient and the fetus. Prophylactic diet therapy and omega-3 fatty acids may prevent recurrent hypertriglyceridemia during pregnancy.

Possible involvement of signal transducer and activator of transcription-3 in cell-cell interactions of peritoneal macrophages and endometrial stromal cells in human endometriosis

OBJECTIVE To investigate interactions between peritoneal macrophages and endometrial stromal cells (ESCs) involved in the development of endometriosis. DESIGN Clinicopathologic and in vitro studies. SETTING Department of Obstetrics and Gynecology and Department of Pathology, Kumamoto University Hospital. PATIENT(S) Women undergoing laparoscopy or laparotomy to treat endometriosis or other benign gynecologic conditions. INTERVENTION(S) We collected samples of peritoneal fluid (ascites), endometrium, and endometriotic tissues. We cocultured ESCs in vitro with or without human macrophages. MAIN OUTCOME MEASURE(S) Macrophage phenotypes in peritoneal fluid were determined via immunostaining. Proliferation of ESCs and activation of signal transducer and activator of transcription-3 (Stat3) in cocultures were evaluated. RESULT(S) The endometriosis group had a significantly higher total number of macrophages in ascites compared with the control group, but the ratios of CD163+ alternatively activated macrophages (M2) in the two groups did not differ significantly. Coculture with M2 macrophages significantly up-regulated ESC proliferation and Stat3 activation in ESCs in vitro. Proliferation of ESCs was suppressed after Stat3 was down-regulated by small interfering RNA. Stat3 was activated in epithelial cells and ESCs in human endometriotic lesions. CONCLUSION(S) Interactions between M2 macrophages and ESCs via Stat3 activation may play an important role in the development of endometriosis.

Corosolic acid enhances the antitumor effects of chemotherapy on epithelial ovarian cancer by inhibiting signal transducer and activator of transcription 3 signaling

Resistance to chemotherapy poses a serious problem for the treatment of advanced epithelial ovarian cancer patients. The mechanisms of chemoresistance are complex and studies have implicated signal transducer and activator of transcription 3 (STAT3) signaling in the chemoresistance of cancer cells. The present study investigated whether corosolic acid (CA), which has been previously reported to be a STAT3 inhibitor, was able to increase the sensitivity to chemotherapeutic drugs in epithelial ovarian cancer cells. CA also markedly enhanced the anticancer effect of paclitaxel, cisplatin and doxorubicin. In addition, CA abrogated the cell-cell interactions between macrophages and epithelial ovarian cancer cells and inhibited the macrophage-induced activation of epithelial ovarian cancer cells. These data indicated that CA was able to reverse the chemoresistance of epithelial ovarian cancer cells and suppress the cell-cell interaction with tumorigenic macrophages. Thus, CA may be useful as an adjuvant treatment to patients with advanced ovarian and other types of cancer due to the multiple anticancer effects.

Onionin A inhibits ovarian cancer progression by suppressing cancer cell proliferation and the protumour function of macrophages

It is well known that tumour-associated macrophages (TAMs) play an important role in tumour development by modulating the tumour microenvironment, and targeting of protumour activation or the M2 polarization of TAMs is expected to be an effective therapy for cancer patients. We previously demonstrated that onionin A (ONA), a natural low molecular weight compound isolated from onions, has an inhibitory effect on M2 macrophage polarization. In the present study, we investigated whether ONA had a therapeutic anti-ovarian cancer effect using in vitro and in vivo studies. We found that ONA reduced the extent of ovarian cancer cell proliferation induced by co-culture with human macrophages. In addition, we also found that ONA directly suppressed cancer cell proliferation. A combinatorial effect with ONA and anti-cancer drugs was also observed. The activation of signal transducer and activator of transcription 3 (STAT3), which is involved in cell proliferation and chemo-resistance, was significantly abrogated by ONA in ovarian cancer cells. Furthermore, the administration of ONA suppressed cancer progression and prolonged the survival time in a murine ovarian cancer model under single and combined treatment conditions. Thus, ONA is considered useful for the additional treatment of patients with ovarian cancer owing to its suppression of the protumour activation of TAMs and direct cytotoxicity against cancer cells.

Pancreatic metastasis from mixed adenoneuroendocrine carcinoma of the uterine cervix: a case report.

Metastatic cancers of the pancreas are rare, accounting for approximately 2-4% of all pancreatic malignancies. Renal cell carcinoma is the most common solid tumor that metastasizes to the pancreas. Here, we present a case of uterine cervical carcinoma metastasizing to the pancreas and review the literature regarding this rare event. A 44-year-old woman with a uterine cervical tumor had undergone radical hysterectomy and had been diagnosed pathologically with stage Ib mixed adenoneuroendocrine carcinoma in 2004. She underwent concurrent radiotherapy and chemotherapy postoperatively. Pulmonary metastases subsequently appeared in 2008 and 2011, and she underwent complete resection of the lung tumors by video-assisted thoracic surgery. Although she was followed up without any treatment and with no other recurrences, positron emission tomography revealed an area of abnormal uptake within the pancreatic body in 2012. Enhanced computed tomography demonstrated a 20-mm lesion in the pancreatic body and upstream pancreatic duct dilatation. Endoscopic ultrasonography-guided fine needle aspiration was performed and pathological examination suggested neuroendocrine carcinoma (NEC). On the basis of these results and the patients oncological background, lesions in the pancreatic body were diagnosed as secondary metastasis from the cervical carcinoma that had been treated 8 years earlier. No other distant metastases were visualized, and the patient subsequently underwent middle pancreatectomy. Pathological examination showed NEC consistent with pancreatic metastasis from the uterine cervical carcinoma. The patient has survived 7 months since the middle pancreatectomy without any signs of local recurrence or other metastatic lesions.

High-dose oral tegafur-uracil maintenance therapy in patients with uterine cervical cancer

Objective The aim of this study was to determine the efficacy and toxicity of oral administration of tegafur-uracil (UFT) at a high dose, 600 mg/day, based on the tegafur dose, against uterine cervical cancer. Methods This study consisted of a retrospective analysis. From April 1986 to March 1997, 309 patients with uterine cervical cancer were registered. Oral UFT was administered to 162 patients for maintenance therapy after an initial treatment (the UFT group). The other 147 patients were not treated with UFT (the control group). The survival rate was calculated for both groups and statistically analyzed using the log-rank test. Adverse events were compared between the UFT and control groups. Results In the UFT group, 103 patients (63.6%) received UFT for ≥90 days. The drug dose was 600 mg/day for 137 patients (84.6%) and 300 to 400 mg/day for the remainder. The overall survival rate was significantly higher in the UFT group than in the control group (p<0.05). The prognosis was particularly favorable in stage III cases, in cases of squamous cell carcinoma, and in cases that were treated by radiotherapy. The most frequent side effects were nausea/vomiting (12.2%), appetite loss (10.1%), and leukopenia/neutropenia (5.8%). Conclusion High-dose oral UFT maintenance treatment prolonged the disease-free survival and overall survival of patients with uterine cervical cancer, particularly of those with advanced disease.

Choriocarcinoma coexisting with epithelioid trophoblastic tumor of the uterine horn

Highlights • We report a choriocarcinoma coexisting with an epithelioid trophoblastic tumor.• Chemotherapy with methotrexate, etoposide, and actinomycin-D was efficacious.• Choriocarcinoma with epithelioid trophoblastic tumor may benefit from chemotherapy.

A Giant Ovarian Tumor Causing Anasarca and Dyspnea Successfully Managed after Preoperative Drainage

Serious complications are likely to accompany the treatment of giant ovarian tumors, and resection with or without preoperative drainage has been previously reported. Here, we report the case of a 27-year-old Japanese woman with a significant weight gain of 50 kg, who was referred to the Kumamoto University Hospital because of gait impairment and dyspnea. Imaging tests revealed an ovarian tumor, 37 cm in diameter, with two solid components. The patients condition improved after the removal of 31.5 l tumor fluid by using a suprapubic urinary catheter for 3 days. The tumor was subsequently resected without complications, and was diagnosed as a left mucinous ovarian tumor with malignant components, weighing 37 kg (81.5 lb). The patient was discharged after her anasarca improved, and her body weight decreased from 100 to 50 kg with accompanying considerable urination within two weeks. She was in good condition with no evidence of recurrence at 15 months after surgery. Tumor resection after preoperative drainage was effective in the management of a patient with dyspnea induced by a giant ovarian tumor. We suggest the use of a suprapubic urinary catheter for preoperative drainage because of its ease of use in preventing fluid leakage from the possibly malignant tumor.