Masayuki Futagami

Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma.

Objectives ARID1A is a recently identified tumor suppressor participating in chromatin remodeling. Somatic inactivating mutations of ARID1A and loss of its expression occur frequently in ovarian clear cell and endometrioid carcinomas and in uterine endometrioid carcinomas. Because endometriotic epithelium is thought to be the cell of origin of most ovarian clear cell and endometrioid carcinomas, we undertook an analysis of ARID1A expression of these tumors arising within an endometriotic cyst (endometrioma). Materials and Methods Our immunohistochemical study set consisted of 47 endometriotic cysts containing clear cell carcinoma in 24 cases, well-differentiated ovarian endometrioid carcinoma in 20 cases, and mixed clear cell and endometrioid carcinoma in 3 cases. Results ARID1A loss was observed in 31 (66%) of 47 carcinomas; and therefore, these cases were informative for determining the temporal sequence of loss of ARID1A expression in tumor progression. In 16 of the 47 cases, ARID1A immunoreactivity was retained in both the endometriotic cyst and the carcinoma; and thus, these cases were not informative. All of the 31 informative cases showed loss of ARID1A immunoreactivity in the carcinoma and in the endometriotic cyst epithelium in direct continuity with the carcinoma but not in the cyst epithelium that was not adjacent to the tumor. Conclusions Loss of ARID1A function as shown by loss of expression, presumably due to mutations, is an early molecular event in the development of most ovarian clear cell and endometrioid carcinomas arising in endometriomas.

Clofibric acid, a peroxisome proliferator–activated receptor α ligand, inhibits growth of human ovarian cancer

Recent reports have shown that peroxisome proliferator–activated receptor (PPAR)α ligands reduce growth of some types of malignant tumors and prevent carcinogenesis. In this study, we investigated the inhibitory effect of clofibric acid (CA), a ligand for PPARα on growth of ovarian malignancy, in in vivo and in vitro experiments using OVCAR-3 and DISS cells derived from human ovarian cancer and aimed to elucidate the molecular mechanism of its antitumor effect. CA treatment significantly suppressed the growth of OVCAR-3 tumors xenotransplanted s.c. and significantly prolonged the survival of mice with malignant ascites derived from DISS cells as compared with control. CA also dose-dependently inhibited cell proliferation of cultured cell lines. CA treatment increased the expression of carbonyl reductase (CR), which promotes the conversion of prostaglandin E2 (PGE2) to PGF2α, in implanted OVCAR-3 tumors as well as cultured cells. CA treatment decreased PGE2 level as well as vascular endothelial growth factor (VEGF) amount in both of OVCAR-3–tumor and DISS-derived ascites. Reduced microvessel density and induced apoptosis were found in solid OVCAR-3 tumors treated by CA. Transfection of CR expression vector into mouse ovarian cancer cells showed significant reduction of PGE2 level as well as VEGF expression. These results indicate that CA produces potent antitumor effects against ovarian cancer in conjunction with a reduction of angiogenesis and induction of apoptosis. We conclude that CA could be an effective agent in ovarian cancer and should be tested alone and in combination with other anticancer drugs. [Mol Cancer Ther 2007;6(4):1379–86]

Inhibitory effect of meloxicam, a selective cyclooxygenase-2 inhibitor, and ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, on the growth of human ovarian cancers.

It was recently reported that high expression of peroxisome proliferator‐activated receptor γ (PPARγ) and low expression of cyclooxygenase‐2 (COX‐2) might be involved in the inhibition of ovarian tumor progression and confirmed that PPARγ activation could suppress COX‐2 expression via the nuclear factor‐κB pathway in ovarian cancer cells.

Significance of Multi‐Drug‐Resistant Proteins in Predicting Chemotherapy Response and Prognosis in Epithelial Ovarian Cancer*

Objectives: To clarify the expression of multi‐drug‐resistant (MDR) markers, GST‐π, c‐Jun, P‐glycoprotein (Pgp), and MDR‐associated protein (MRP) in epithelial ovarian cancer, and to determine whether their expression is predicitve of chemotherapy response and patient prognosis.

Decreased ARID1A expression is correlated with chemoresistance in epithelial ovarian cancer

Objective Loss of ARID1A is related to oncogenic transformation of ovarian clear cell adenocarcinoma. The present study was conducted in epithelial ovarian cancer of all tissue types to investigate whether an increased or decreased expression level of ARID1A can be a prognostic factor for ovarian cancer or can influence the sensitivity to anticancer drugs. Methods The expression level of ARID1A was investigated in 111 patients with epithelial ovarian cancer who received initial treatment at the Hirosaki University Hospital between 2006 and 2011. The expression level of ARID1A was immunohistochemically graded using staining scores, which were calculated by multiplying the staining intensity of the nuclei by the stain-positive area. Results The level of ARID1A was significantly lower in clear cell adenocarcinoma than in other histologic types. Among the patients with stage III, IV cancer (n=46), the level of ARID1A was significantly lower (p=0.026) in patients who did not achieve complete response (CR; n=12) than in patients who achieved CR (n=34). The level of ARID1A was relatively lower (p=0.07) in patients who relapsed after achieving CR (n=21) than in patients who did not relapse (n=13). When the staining score of 0 was defined as ARID1A-negative and other staining scores were defined as ARID1A-positive, there was significant difference in progression-free survival between ARID1A-negative (n=11) and ARID1A-positive (n=35) patients in stage III, IV disease. Conclusion The result suggests that decreased ARID1A expression is correlated with chemoresistance and may be a predictive factor for the risk of relapse of advanced cancer after achieving CR.

A Case of Uterine Leiomyoma with Intravenous Leiomyomatosis—Histological Investigation of the Pathological Condition—

Intravenous leiomyomatosis (IVL) is generally defined as a histologically benign leiomyoma derived from a uterine myoma or intrauterine venous wall that has grown and extended intravenously. We here report on a single case of IVL, and investigate its pathological genesis. Regarding the part of the myoma extending to the vessel lumen, observations found the myoma to be pushing into the vessel. Immunostaining with CD34 antibody gave an image of the area where the myoma pushed into the vessel, showing CD34-positive vessel endothelium cells folded back into a layer covering the myoma, and continuing to line of the surface of the myoma within the vessel. Early pathological genesis of IVL was clarified for the first time that the tumor did not invade the vessel by breaking the venous wall, but rather advanced by stretching the vascular wall and progressing into the vein like a polyp, covered in endothelium cells.

The prophylactic effects of a traditional Japanese medicine, goshajinkigan, on paclitaxel-induced peripheral neuropathy and its mechanism of action

BackgroundThis study aimed to evaluate the prophylactic effect of goshajinkigan (GJG) on paclitaxel (PTX)-induced neuropathy and to elucidate the mechanism of action.ResultsThere was a time-dependent irreversible decrease in pain threshold in PTX group. In PTX/GJG group, pain threshold showed changes in the same level as control. Electron microscope showed that although the ganglion cells of control and PTX/GJG groups were normal, degeneration of the nucleus and swelling of the mitochondria were observed in PTX group. Expression of transient receptor potential vanilloid 4 (TRPV4) gene in PTX group significantly increased compared with that in control and PTX/GJG groups. In TRPV4 knock-out mice, no PTX-induced hyperalgesia was observed, and there was no significant difference in pain threshold between the 3 groups.ConclusionsThese results showed that PTX induced hyperalgesia by enhancing TRPV4 expression, and suggested that GJG might alleviate hyperalgesia by preventing degeneration of the ganglion cells and suppressing TRPV4 expression.

Paclitaxel and carboplatin in patients with completely or optimally resected carcinosarcoma of the uterus: A phase II trial by the Japanese uterine sarcoma group and the tohoku gynecologic cancer unit

Objective This study aimed to evaluate the efficacy of paclitaxel and carboplatin in patients with completely or optimally resected uterine carcinosarcoma. Materials and Methods We conducted a single-arm multicenter prospective phase II trial at 20 Japanese medical facilities. Eligible patients had histologically confirmed uterine carcinosarcoma without prior chemotherapy or radiotherapy. Patients received 6 courses of 175 mg/m2 paclitaxel over 3 hours, followed by a 30-minute intravenous administration of carboplatin at an area under the serum concentration-time curve of 6. Results A total of 51 patients were enrolled in this study, 48 of whom underwent complete resection and 3 of whom underwent optimal resection. At 2 years, the progression-free survival and overall survival rates were 78.2% (95% confidence interval [CI], 64.1%–87.3%) and 87.9% (95% CI, 75.1%–94.4%), respectively. At 4 years, these rates were 67.9% (95% CI, 53.0%–79.0%) and 76.0% (95% CI, 60.5%–86.1%), respectively. Although 15 patients showed disease recurrence during the follow-up period (median, 47.8 months; range, 2.1–72.8 months), a total of 40 (78.4%) patients completed the 6 courses of treatment that had been planned. Conclusions The combination of paclitaxel and carboplatin was a feasible and effective postoperative adjuvant therapy for patients with completely or optimally resected uterine carcinosarcoma.

Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation

Carbonyl reductase 1 (CBR1) expression level is related to tumor progression. Decreased CBR1 expression is associated with poor prognosis in ovarian cancer. We investigated the relationship between CBR1 expression level and malignant potential of ovarian cancer. OVCAR‑3 cells overexpressing CBR1 or knocked down for CBR1 were obtained by transfecting CBR1 plasmid DNA (pDNA) or small interfering RNA (siRNA) by electroporation. In vitro cell proliferation and invasion were compared between the two cell types. Subcutaneous CBR1‑overexpressed OVCAR‑3 cells (n=10) and wild‑type ones (n=5) were injected into nude mice. The CBR1 siRNA was then injected twice a week into five of the 10 CBR1‑overexpressed OVCAR‑3 tumors. Tumor growth and metastatic behavior were observed 3 weeks after cell transplantation. Cell proliferation significantly decreased in CBR1‑overexpressed cells as compared to the control, whereas cell proliferation and invasion significantly increased in CBR1‑suppressed cells as compared to the control. The size of the CBR1 siRNA‑injected tumors (n=5) increased significantly as compared to the other two groups (n=5 for each group). The number of metastatic foci in the lungs was significantly higher in mice injected with CBR1 siRNA (7.0±2.0) compared to CBR1‑overexpressed and wild‑type tumors (0 and 2.0±2.0, respectively). Western blot analysis showed that, while vascular endothelial growth factor (VEGF)‑C expression was stable in the CBR1‑siRNA‑injected tumors, E‑cadherin expression was decreased, whereas matrix metalloproteinase (MMP)‑9 was increased in CBR1‑siRNA‑injected tumors compared to the other two groups. These results showed that CBR1 decreases promoted tumor proliferation and growth as well as invasion and metastasis, suggesting that CBR1 has potential to become a new candidate for molecular targeting therapy.

Carcinosarcoma of the fallopian tube: Report of four cases and review of literature

Aim:  Carcinosarcoma of the fallopian tube is extremely rare and the therapeutic prognosis of this disease is unknown.