Junzo Kigawa

Clinical characteristics of clear cell carcinoma of the ovary

A retrospective review of treatment results comparing women with clear cell carcinoma of the ovary (CCC) with a group with serous adenocarcinoma of the ovary (SAC) was conducted.

Detection of peritoneal dissemination in gynecological malignancy: evaluation by diffusion-weighted MR imaging

The aim of this study is to evaluate the usefulness of diffusion-weighted (DW) magnetic resonance (MR) imaging in detecting peritoneal dissemination in cases of gynecological malignancy. We retrospectively analyzed MR images obtained from 26 consecutive patients with gynecological malignancy. Peritoneal dissemination was histologically diagnosed in 15 of the 26 patients after surgery. We obtained DW images and half-Fourier single-shot turbo-spin-echo images in the abdomen and pelvis, and then generated fusion images. Coronal maximum-intensity-projection images were reconstructed from the axial source images. Reader interpretations were compared with the laparotomy findings in the surgical records. Receiver-operating characteristic (ROC) curves were used to represent the presence of peritoneal dissemination. In addition, the sensitivity and specificity were calculated. DW imaging depicted the tumors in 14 of 15 patients with peritoneal dissemination as abnormal signal intensity. ROC analysis yielded Az values of 0.974 and 0.932 for the two reviewers. The mean sensitivity and specificity were 90 and 95.5%. DW imaging plays an important role in the diagnosis and therapeutic management of patients with gynecological malignancy.

Mechanisms of chemoresistance and poor prognosis in ovarian clear cell carcinoma.

Clear cell carcinoma (CCC) accounts for 4% to 12% of epithelial ovarian cancer in Western countries and, for some unknown reasons, it comprises more than 20% of such cancers in Japan. CCC shows unique clinical features such as a high incidence of stage I disease, a large pelvic mass, an increased incidence of vascular thromboembolic complications, and hypercalcemia. It is frequently associated with endometriosis. Compared to serous adenocarcinoma (SAC), CCC is relatively resistant to conventional platinum, or taxane‐based chemotherapy which is associated with its poor prognosis. However, the mechanisms underlying CCCs resistance to chemotherapy have not been understood. Although several mechanisms involved in drug resistance exist in CCC, including decreased drug accumulation, increased drug detoxification, and an increased DNA repair activity; however, no particular chemoresistance system has been identified. On the other hand, an in vitro study revealed that low cell proliferation may cause the insensitivity of CCC to cisplatin. The Ki‐67 labeling index in CCC tumors was significantly lower than SAC. The Ki‐67 labeling index for responders was significantly higher than that for non‐responders in both tumor types. A multivariable analysis revealed that Ki‐67 labeling index and residual tumor size were independent prognostic factors in CCC. Therefore, lower proliferation of the tumor cells may contribute to their resistance to chemotherapy. However, further investigation into the molecular biology and genetics of CCC is warranted. This review discusses the current state of knowledge of the chemoresistance mechanism in CCC and novel treatment strategies for CCC. (Cancer Sci 2008; 99: 653–658)

Low proliferation activity may be associated with chemoresistance in clear cell carcinoma of the ovary

OBJECTIVE To estimate whether and how the biologic behavior of clear cell carcinoma contributes to the chemoresistance mechanism. METHODS Forty‐one patients with clear cell carcinoma and 90 patients with serous adenocarcinoma, who had measurable disease after initial surgery, were examined. All patients underwent cytoreductive surgery followed by platinum‐based chemotherapy. P‐glycoprotein, multidrug resistance‐associated protein, and Ki‐67 expression were determined by immunohistochemical staining. RESULTS The 5‐year survival rate for patients with clear cell carcinoma was significantly poorer, compared with serous adenocarcinoma (20.0% versus 31.9%). Response rate to chemotherapy was 14.6% for clear cell carcinoma and 72.2% for serous adenocarcinoma. The expression of P‐glycoprotein and multidrug resistance‐associated protein did not differ between responders and nonresponders in both tumor types. The Ki‐67 labeling index (LI) in clear cell carcinoma was significantly lower than serous adenocarcinoma (18.4% versus 38.8%). The LI for responders was significantly higher than that for nonresponders in both tumor types. In clear cell carcinoma, the mean value of LI was 15.3% for nonresponders, but that for responders was 30.2%, which was similar to that for serous adenocarcinoma. When the cutoff value of LI was set at 18.4% (mean value), the 5‐year survival rate for high LI (over 18.4%) patients was significantly greater than that for low LI patients (46.3% versus 9.2%). Multivariable analysis revealed that LI and residual tumor size were the independent prognostic factors. CONCLUSION Lower proliferation of tumor may be a behavior of clear cell carcinoma of the ovary that contributes to its resistance to chemotherapy.

Diagnostic accuracy of diffusion-weighted imaging in differentiating benign from malignant ovarian lesions.

To clarify the diagnostic accuracy of diffusion‐weighted imaging (DWI) in differentiating benign from malignant ovarian lesions.

Clinicopathological characteristics of mucinous adenocarcinoma of the ovary

OBJECTIVE We conducted the present study to clarify the clinicopathological characteristics of mucinous adenocarcinoma. METHODS Two hundred twenty-five patients were diagnosed with mucinous adenocarcinoma at individual institutes and underwent primary treatment between 1998 and 2003. Of these patients, 189 patients who could undergo central pathological review were enrolled in this study. Of 189 patients undergoing central pathological review, 64 patients (33.9%) were diagnosed with mucinous invasive adenocarcinoma, 45 mucinous intraepithelial carcinoma, and 42 mucinous tumor of borderline malignancy. Twenty-five patients were diagnosed with other histological subtypes, including 8 endometrioid adenocarcinoma, 5 clear cell carcinoma, 3 serous adenocarcinoma, and 4 mixed type. There were 13 cases of metastatic mucinous adenocarcinoma, including 7 pseudomyxoma peritonei. Four hundred thirty-three patients with serous adenocarcinoma were used as controls. RESULTS Forty-five patients with mucinous invasive carcinoma were in FIGO I-II stages and 19 in III-IV stages. There was no difference in the outcome between mucinous invasive adenocarcinoma and serous adenocarcinoma in I-II stage patients and III-IV stage patients with optimal operation. In contrast, patients with mucinous invasive adenocarcinoma receiving suboptimal operation showed a significantly worse prognosis (survival rate: 27.8% vs. 61.5%). The response rate to chemotherapy for mucinous invasive adenocarcinoma was significantly lower than for serous adenocarcinoma (12.5% vs. 67.7%). CONCLUSIONS The diagnosis of mucinous invasive adenocarcinoma was difficult. Since patients with mucinous invasive adenocarcinoma had a lower response to chemotherapy, aggressive cytoreductive surgery was an effective treatment to improve the prognosis for advanced stage patients. A new chemotherapeutic regimen should be established for mucinous adenocarcinoma of the ovary.

Regulation of Autophagy and Its Associated Cell Death by “Sphingolipid Rheostat” RECIPROCAL ROLE OF CERAMIDE AND SPHINGOSINE 1-PHOSPHATE IN THE MAMMALIAN TARGET OF RAPAMYCIN PATHWAY

Background: The sphingolipids ceramide and sphingosine 1-phosphate (S1P) control various cellular functions, including proliferation, cell death, and autophagy. Results: Binding of S1P to its receptor S1P3 counteracts ceramide-mediated autophagy by activating the mammalian target of rapamycin (mTOR) pathway. Conclusion: Sphingolipid rheostat between ceramide and S1P plays an important role in regulating mTOR-controlled autophagy. Significance: We provide new insights into novel regulatory mechanisms in autophagy induction. The role of “sphingolipid rheostat” by ceramide and sphingosine 1-phosphate (S1P) in the regulation of autophagy remains unclear. In human leukemia HL-60 cells, amino acid deprivation (AA(−)) caused autophagy with an increase in acid sphingomyleinase (SMase) activity and ceramide, which serves as an autophagy inducing lipid. Knockdown of acid SMase significantly suppressed the autophagy induction. S1P treatment counteracted autophagy induction by AA(−) or C2-ceramide. AA(−) treatment promoted mammalian target of rapamycin (mTOR) dephosphorylation/inactivation, inducing autophagy. S1P treatment suppressed mTOR inactivation and autophagy induction by AA(−). S1P exerts biological actions via cell surface receptors, and S1P3 among five S1P receptors was predominantly expressed in HL-60 cells. We evaluated the involvement of S1P3 in suppressing autophagy induction. S1P treatment of CHO cells had no effects on mTOR inactivation and autophagy induction by AA(−) or C2-ceramide. Whereas S1P treatment of S1P3 overexpressing CHO cells resulted in activation of the mTOR pathway, preventing cells from undergoing autophagy induced by AA(−) or C2-ceramide. These results indicate that S1P-S1P3 plays a role in counteracting ceramide signals that mediate mTOR-controlled autophagy. In addition, we evaluated the involvement of ceramide-activated protein phosphatases (CAPPs) in ceramide-dependent inactivation of the mTOR pathway. Inhibition of CAPP by okadaic acid in AA(−)- or C2-ceramide-treated cells suppressed dephosphorylation/inactivation of mTOR, autophagy induction, and autophagy-associated cell death, indicating a novel role of ceramide-CAPPs in autophagy induction. Moreover, S1P3 engagement by S1P counteracted cell death. Taken together, these results indicated that sphingolipid rheostat in ceramide-CAPPs and S1P-S1P3 signaling modulates autophagy and its associated cell death through regulation of the mTOR pathway.

The Behavior of Endometrial Hyperplasia: A Prospective Study

Objective: To clarify the behavior of endometrial hyperplasia in a prospective study.

Glutathione S-transferase-π expression and glutathione concentration in ovarian carcinoma before and after chemotherapy

To clarify the role of glutathione (GSH) in the chemotherapy resistance of ovarian carcinoma, the authors examined the expression of glutathione S‐transferase‐π (GST‐π) and the concentration of glutathione in tumors before and after chemotherapy in the same patients.

PTEN expression is associated with prognosis for patients with advanced endometrial carcinoma undergoing postoperative chemotherapy

The prognostic significance of PTEN expression in endometrial carcinoma has not been clear. We conducted the present study to clarify the relationship between PTEN expression and prognosis in advanced endometrial carcinoma. Of 784 patients with endometrial carcinoma who underwent primary treatment between 1985 and 2000 at 5 institutions, 98 pure endometrioid carcinomas with retroperitoneal lymph node metastasis were provided for our study. PTEN expression was determined by immunohistochemic staining. Negative or mixed PTEN staining was observed in 64 (65.3%) patients. The survival rate for PTEN‐positive patients was significantly higher than that for PTEN‐negative or ‐mixed patients. PTEN‐staining status was not associated with patient age, International Federation of Gynecology and Obstetrics (FIGO) stage, myometrial invasion or histologic grade. Of the 98 patients, 87 received radiation therapy (n = 25) or chemotherapy (n = 62) after surgery. PTEN expression did not relate to survival for patients receiving radiation therapy. In contrast, the survival rate for PTEN‐positive cases was significantly higher than that for PTEN‐negative or ‐mixed cases when patients underwent chemotherapy (62.4% vs. 11.8%). Subsequent multivariate analysis revealed that PTEN staining was an independent prognostic factor for patients undergoing chemotherapy. PTEN‐positive staining was a significant prognostic indicator of favorable survival for patients with advanced endometrial carcinoma who underwent postoperative chemotherapy.