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Background/Aim: In 2020, the percentages were removed from the World Health Organization’s criteria for mixed carcinoma. The aim was to examine the clinical significance of an area of serous carcinoma (SC)

ObjectiveTo examine clinico-pathological factors associated with surgical complications and postoperative therapy for clinical stage IB-IIB cervical cancer.MethodsThis nationwide multicenter retrospective study examined women with clinical stage IB-IIB cervical cancer who underwent radical hysterectomy plus pelvic and/or para-aortic lymphadenectomy between 2008-2009 at 87 institutions of the Japanese Gynecologic Oncology Group (n = 693). Multivariate models were used to identify independent predictors of perioperative grade 3-4 complications and bladder dysfunction.ResultsThe overall intraoperative and postoperative complication rates were 3.3% and 9.8%, respectively. Clinical stage was not associated with perioperative complications (P = 0.15). Radiotherapy-based adjuvant therapy was significantly associated with an increased risk of postoperative complications (radiotherapy alone: adjusted-odds ratio [OR] 3.19, 95% confidence interval [CI] 1.46-6.99, P = 0.004; radiotherapy plus chemotherapy: adjusted-OR 3.26, 95%CI 1.66-6.41, P = 0.001), whereas chemotherapy was not (P = 0.45). Nerve-sparing surgery significantly reduced the risk of postoperative bladder dysfunction (adjusted-OR 0.57, 95%CI 0.37-0.90, P = 0.02) whereas adjuvant chemotherapy increased the risk of bladder dysfunction (adjusted-OR 2.06, 95%CI 1.16-3.67, P = 0.01). Among women receiving adjuvant chemotherapy, nerve-sparing radical hysterectomy significantly reduced the risk of bladder dysfunction (15.0% versus 32.9%, OR 0.31, 95%CI 0.14-0.68, P = 0.004). After propensity score matching, survival outcomes were similar with both types of adjuvant therapy (radiotherapy-based versus chemotherapy, P>0.05).ConclusionOur study highlighted two distinct complication profiles of adjuvant therapy after radical hysterectomy for clinical stage IB-IIB cervical cancer, with radiotherapy increasing grade 3-4 adverse events and chemotherapy increasing bladder dysfunction. In this setting, nerve-sparing surgery may be useful if chemotherapy is being considered for adjuvant therapy.

Aim This study aimed to assess adequate conditions for omitting parametrectomy for stage IB1–IIA2 cervical cancer with the aim of reducing postoperative complications during Type III radical hysterectomy (RH). Methods We investigated factors associated with parametrial invasion (PMI) in patients who underwent Type III RH for stage IB1, IB2, IIA1, IIA2 and IIB cervical cancer at two tertiary institutions from November 2006 to February 2018. Both clinicopathological and preoperatively estimated factors were assessed. Results One hundred fifty‐six patients were preoperatively diagnosed with stage IB1 to IIB disease. Thirty‐four patients (21.8%) showed PMI on histological analyses. In the multivariate analysis, an age older than 50 years, tumor size larger than 40 mm, common iliac lymph node metastasis and lymphovascular space invasion were identified as significant risk factors for PMI (P‐values = 0.008, 0.003, 0.004 and 0.004, respectively). The preoperatively estimated risk factors for PMI were an older age, larger tumor size, and common iliac lymph node metastasis (P‐values = 0.007, 0.002 and 0.001, respectively). A combination of these three factors was sufficient to estimate PMI with a high specificity (100%) and positive predictive value (100%) in patients with stage IB1 to IIA2 disease. Conclusion During RH, resecting the posterior layer of the vesicouterine ligament and the paracolpium without removing the cardinal ligament (avoiding parametrectomy) might be feasible for stage IB1–IIA2 cervical cancer in patients younger than 50 years presenting with smaller tumors (

Objective: To evaluate the usefulness of intraoperative ultrasonography (IU) for para-aortic nodes to identify women who do not require pelvic and paraaortic lymphadenectomy in ovarian carcinoma. Methods: Computed tomography (CT) was used for assessing both pelvic and para-aortic lymph nodes, and IU only for para-aortic nodes in 87 women with ovarian carcinoma. All women underwent surgery with routine systematic pelvic and para-aortic lymphadenectomy. We assumed that no lymphadenectomy had been performed when no enlarged node was detected by either CT or IU or when the woman was in T1 stage. Under these assumptions, the numbers of women who would have had missed metastases and who could have avoided lymphadenectomy were counted. These figures were recounted on the combination of T stage and IU. Results: A total of 22 women had pathological node metastases. The numbers of women with missed metastases on the basis of CT, IU, and T stage were 12, 2, 5, and these who could have avoided lymphadenectomy were 72, 39, and 49, respectively. There were more women avoiding lymphadenectomy by CT than IU and T stage; however, more women with missed node metastases. Both numbers were not significantly different between IU and T stage. On the combination of T stage and IU, 29 of 49 women in T1 stage could have avoided lymphadenectomy without missed metastases. Conclusions: IU for the para-aortic node is a useful method for identifying women who do not require lymphadenectomy for T1 stage ovarian carcinoma.

The efficacy and adverse events of neoadjuvant chemotherapy with irinotecan hydrochloride and nedaplatin were evaluated in patients with bulky stage Ib2 to IIb cervical squamous cell carcinoma. Eligibility included patients who received irinotecan (60 mg/m2) on days 1 and 8 and nedaplatin (80 mg/m2) on day 1 of a 21-day cycle. After 1-3 courses of chemotherapy, radical hysterectomy was performed. Sixty-eight patients were enrolled. Sixty-six were included in the full analysis set. Their median age was 47 years (range 22-71), the FIGO stage was Ib2 in 18 patients, IIa in 10, and IIb in 38. Radical hysterectomy was performed after NAC in 63 patients (95.5%). The number of administered courses of NAC was 1 in 13 patients, 2 in 43, and 3 in 10. The response rate, the primary endpoint of this study, was 75.8% (CR in 2 patients, PR in 48, SD in 12, PD in 0, and NE in 4). The mean number of treatment courses required for a response was 1.42 (1 course in 30 patients, 2 courses in 19, and 3 courses in 1). The incidences of grade 3 or 4 hematological toxicities were: neutropenia 72.2%, leukopenia 16.7%, anemia 13.6%, thrombocytopenia 7.6%, febrile neutropenia 1.5%, and elevations of alanine aminotransferase and aspartate aminotransferase 1.5%. Grade 3 or 4 non-hematologic toxicities were as follows: diarrhea 6.1%, nausea 3%, anorexia 1.5%, vomiting 1.5%, fever 1.5%, allergic reactions 1.5%, ileus 1.5% and vesicovaginal fistula 1.5%. Neoadjuvant chemotherapy with irinotecan and nedaplatin was an effective and well-tolerated treatment for patients with bulky stage Ib2 to IIb squamous cell carcinoma of the uterine cervix.

Objectives:The purpose of this study was to evaluate the association of ABCF2 (adenosine triphosphate-binding cassette superfamily F2) protein expression with response to chemotherapy and prognosis in patients with clear cell adenocarcinoma (CCC) of the ovary.Methods:One hundred sixty-five patients with CCC were studied, and cytoplasmic ABCF2 expression was detected by immunohistochemical staining. All patients underwent platinum-based primary chemotherapy followed by primary surgery.Results:Adenosine triphosphate-binding cassette superfamily F2 expression was detected in 118 (71.5%) of 165 patients and was not related to age or clinical stage. The response rate to chemotherapy in 38 patients with measurable disease was 47.3% (18/38). The response rate tended to be higher in patients without ABCF2 expression than in those with ABCF2 expression; however, this difference was not significant (66.7% vs 34.8%, P = 0.096). There was no significant difference in overall survival between ABCF2-positive and ABCF2-negative cases (median survival time, 1175 vs 1257 days; P = 0.24).Conclusions:Adenosine triphosphate-binding cassette superfamily F2 protein was highly expressed in CCC of the ovary, but expression was not related to age, clinical stage, chemoresponse, or prognosis.

Clear cell carcinoma (CCC) of the ovary has been recognized to show resistance to anticancer agents in the first-line chemotherapy. Our aim was to evaluate the effect of second-line chemotherapy in a retrospective study. A total of 75 patients diagnosed with CCC and treated between 1992 and 2002 in collaborating hospitals were reviewed. Criteria for the patients' enrollment were 1) diagnosis of pure-type CCC at the initial operation, 2) treatment after one systemic postoperative chemotherapy, 3) measurable recurrent or refractory tumor, 4) at least two cycles of second-line chemotherapy and assessable for the response, and 5) adequate clinical information. Regimens of first-line chemotherapy were conventional platinum-based therapy in 33 cases, paclitaxel plus platinum in 24 cases, irinotecan plus platinum in 9 cases, and irinotecan plus mitomycin C in 7 cases. Treatment-free periods were more than 6 months in 24 cases (group A) and less than 6 months in 51 cases (group B). In group A, response was observed in two cases (8%): one with conventional platinum therapy and another with irinotecan plus platinum. In group B, three cases (6%) responded: two with platinum plus etoposide and one case with irinotecan plus platinum. Median overall survival was 16 months in group A and 7 months in group B (P= 0.04). These findings suggest recurrent or resistant CCC is extremely chemoresistant, and there is only small benefit of long treatment-free period in CCC patients. Another strategy including molecular-targeting therapy is warranted for the treatment of recurrent or refractory CCC.

The transporter protein genes and lipids in human ovarian carcinoma-derived KF28 cells with anticancer-drug-sensitive properties were compared with those in resistant cells, taxol-resistant KF28TX, cisplatin-resistant KFr13, and taxol- and cisplatin-resistant KFr13TX, to identify the molecules required for anticancer-drug resistance. In accordance with previous reports, taxol and cisplatin resistance was closely correlated with expression of the multidrug resistance 1 and bile acid export pump, and multidrug resistance-associated protein 2 genes, respectively. In addition, we found a distinct difference in glycosphingolipids between the sensitive and resistant cells. Although GlcCer was the major glycolipid (83.0%) in sensitive cells, GalCer, LacCer and, particularly, Gb3Cer were characteristically increased in all resistant cells, irrespective of whether the resistance was to taxol or cisplatin, and comprised 65–84% of total glycosphingolipids. GM3, which was present at 0.04 µg/mg dry weight in the sensitive cells, showed a twofold increase in the taxol-resistant cells, but was absent in the cisplatin-resistant cells. The altered glycolipid composition was proven to be due to enhanced or suppressed expression of the respective sugar transferase genes. In addition, the ceramide moiety of ceramide monohexoside in the sensitive cells constituted 83% of non-hydroxy fatty acids, but that in the resistant cells comprised 67–74% of α-hydroxy fatty acids. Thus, cells containing Gb3Cer with α-hydroxy fatty acids were found to survive selectively in the presence of taxol and cisplatin, and modification of the glycolipid structure was revealed to occur in association with anticancer-drug resistance. (Cancer Sci 2006; 97: 1321–1326)

Accurate preoperative diagnosis for gastrointestinal stromal tumor (GIST) was obtained using the endoscopic approach in about 50% of the cases. Preoperative assessment is quite important in reproductive women for the treatment of pelvic tumor. We report the first case of GIST of the rectum that was accurately diagnosed with preoperative needle biopsy from the vaginal wall. The case was a 38-year-old woman who presented with a history of genital bleeding. Internal examination revealed a round and elastic mass (7 x 7 cm) in the left pelvic cavity. The biopsy specimen from the left sidewall of the vagina using a manually manipulated biopsy needle showed strong reaction for CD34 and CD117 (c-KIT). The patient underwent low anterior resection of the rectum, tumor resection, and partial resection of the posterior vagina. Preoperative biopsy with vaginal approach might be helpful to make a diagnosis for pelvic tumor of unknown origin and unknown malignant potential.

The aim of this study is to evaluate clinical usefulness of Korean red ginseng (RG) on various postmenopausal syndromes. Total plasminogen inhibitor-1 (tPAI-1) in peripheral blood from 9 postmenopausal women with climacteric syndromes (CS) was measured before and 3 months after treatment with daily oral administrat i on of 6g RG and that from 8 postmenopausal women without any CS was also measured as healthy controls. Blood samples were collected in the early morning on the bed-rest. Psychological conditions of postmenopausal women with CS were measured before and 3 months after treatment with RG using simplified menopausal index (SMI). In addition, OKETSU (blood stagnation) syndrome scores and KI deficiency (generalized energy stagnation) scores proposed by Terasawa et al., were recorded before and 3months after treatment with RG in postmenopausal women with CS and in healthy postmenopausal women. OKETSU syndrome scores and tPAI-1 levels in postmenopausal patients with CS were significantly (P P

In 5-day incubation of an estrogen receptor-negative human ovarian cancer cell line (KF) with N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl (DPPE), the concentration of DPPE required for 50% inhibition of KF cell proliferation (IC50) was 1.7 microM. The IC50 of DPPE for inhibition of protein kinase C (PKC) activity was 3.0 microM, a similar value to those of other antiestrogens such as tamoxifen and clomiphene. DPPE also inhibited phosphorylation of mitogen-activated protein kinase in KF cells. When treatment with DPPE was started 7 days after inoculation of KF cells into nude mice, 50 mg/kg DPPE alone resulted in a significant growth retardation in the early stage of tumor growth. Although 25 mg/kg DPPE showed a similar effect to 2 mg/kg cisplatin (CDDP), the combination had the most marked tumor growth-inhibitory effect. Nude mice treated with combinations of CDDP and DPPE survived significantly longer than not only untreated, but also CDDP-alone-treated mice, while 50 mg/kg but not 25 mg/kg DPPE alone had an effect comparable to that of 2 mg/kg CDDP alone. If treatment with DPPE was begun from the day after tumor inoculation, the inhibitory effect of DPPE was further enhanced, especially when combined with CDDP. If treatment with DPPE was started in nude mice with a lower tumor burden, 25 mg/kg as well as 50 mg/kg DPPE had a similar effect to 2 mg/kg CDDP, in terms of survival. When DPPE was combined with CDDP, the effect was significantly enhanced, compared to that of either alone. These treatments could be done without any adverse side effect. Thus, we conclude that DPPE has an antiestrogen action and its tumor growth-inhibiting activity is enhanced on administration in combination with CDDP.

This study was designed to elucidate the mechanisms of cisplatin (CDDP) resistance using two human ovarian cancer cell lines, KF and TYK, and two CDDP-resistant lines, KFr and TYK/R, derived from the former lines. KFr and TYK/R showed about 3-fold higher resistance to the cytotoxic effects of CDDP than their parental lines. They also showed a significant increase in sensitivity to not only etoposide, but also (+)-(4S)-4, 11-diethyl-4-hydroxy-9-[(4-piperidino -piperidino)carbonyloxy]-1H -pyrano[3',4':6,7]inodolizino[1,2-b]quinoline-3,14(4H, 12H)-dione hydrochloride trihydrate (CPT-11). Cellular CDDP accumulation levels in KFr and TYK/R were decreased from those of the parental cells. By contrast, the cellular glutathione (GSH) content in KFr cells was 1.7-fold higher than that in KF, whereas TYK/R cells had a 40% lower content than TYK cells. Cellular mRNA levels of drug-resistance-related genes, such as DNA topoisomerase (topo) I and topo II, glutathione S-transferase-pi (GST-pi), gamma-glutamylcysteine synthetase (gamma-GCS), and metallothionein (hMT) genes, were compared between drug-sensitive KF or TYK and KFr or TYK/R. KFr cells had 8.5- and 24.7-fold higher mRNA levels of gamma-GCS and topo II genes than KF cells while KFr had only a slight increase in GST-pi mRNA level as compared with KF. By contrast, TYK/R cells had 2.9- and 1.7-fold higher hMT and topo I mRNA levels than TYK cells. Acquisition of CDDP resistance in human ovarian cancer cells thus appeared to be related mainly to expression of gamma-GCS, topo II and hMT genes, and partly to that of topo I and GST-pi genes, in addition to a decrease in CDDP accumulation.

Objective Combination therapy using gemcitabine with oxaliplatin (GEMOX) showed moderate activity in recurrent ovarian cancers. However, severe toxicities have been observed in patients who received full-dose therapy of GEMOX. On the other hand, bevacizumab enhances chemotherapeutic efficacy in various cancers. Here, we evaluated the effect of weekly low-dose administration of GEMOX in combination with bevacizumab (B-GEMOX) for patients with recurrent and refractory ovarian cancers (ROCs). Methods A total of 19 patients with ROC were treated with B-GEMOX: 2 mg/kg of bevacizumab, 300 mg/m2 of gemcitabine, and 30 mg/m2 of oxaliplatin, 3 weeks on and 1 week off, q4weeks. The treatment was continued until development of severe toxicities or progressive disease. Tumor responses were assessed using the Response Evaluation Criteria in Solid Tumors and Gynecologic Cancer Intergroup criteria. Results Median number of the B-GEMOX therapy was 5 cycles. Response was observed in 4 (34%) cases by Response Evaluation Criteria in Solid Tumors, and in 2 (29%) cases by Gynecologic Cancer Intergroup criteria, resulting in overall response rate of 32%. Clinical benefit excluding progressive disease was obtained in 79% of the patients. Median progression-free survival was 4.5 months (range, 2–16+ months). Toxicities were mild and mainly consisted of hematologic, gastrointestinal, and neuropathy; however, there were no nonhematologic toxicities more than grade 1. Conclusions Weekly administration of B-GEMOX was active for patients with ROC and showed mild toxicities. These results warrant further prospective studies for patients with ROC.

Background: Although uterine leiomyosarcoma (ULMS) has been treated with adriamycin, dacarbazine, ifosfamide, gemcitabine, docetaxel, et al, the effect is not satisfactory. We have reported the effect of temozolomide (T) combined with bevacizumab (B) in heavily pretreated relapsed ULMS. In this study, we evaluated the effects of addition of cabozantinib (C) to T and B. Methods: From 2009 to 2015, total 18 patients (pts) with heavily pretreated relapsed ULMS were enrolled. They were treated with T (80mg/body/day) and B (2mg/kg; days 1, 8 and 15, q4 weeks). Since 2013, we expected better efficacy, nine pts out of 18 pts were treated by adding C (140mg/body/week) which is a c-MET inhibitor (TB, n = 9, CTB, n = 9). Treatment was continued until disease progression and/or unmanageable toxicities. The response and adverse events were evaluated using the response evaluation criteria in solid tumors (RECIST), and common terminology criteria for adverse events (CTCAE) version 3.0. Results: As shown in Table, three (18%) of 17 pts had complete response (CR), two (12%) had partial response (PR) and eight (47%) had stable disease (SD) for at least three months. The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD>3mo) were 29% and 76%, respectively. The median progression-free survival was 9.6 (3 - 58) months. When compared CTB with TB, CBR was better in CTB (87.5% vs 67%), but the median administration cycles and progression free interval were not improved. Two peritoneal perforation were observed in CTB. Conclusions: Not only TB but also CTB showed remarkable effect in heavily pretreated relapsed ULMS. These results warrant further prospective and randomized studies. nCRPRSDPDRR(%)CBR(%)TB/CTB1732842976TB921333367CTB811512587.5 Citation Format: Sayaka Ikeda, Kazuya Kudoh, Naoki Sasaki, Masashi Takano, Tomoko Goto, Ryoko Kikuchi, Tsunekazu Kita, Masaru Sakamoto, Nobuyuki Susumu, Daisuke Aoki, Hiroko Kouta, Yoshihiro Kikuchi. The effect of cabozantinib to temozolomide and bevacizumab in patients with heavily pretreated relapsed uterine leiomyosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-226.

Objective: To evaluate the usefulness of intraoperative ultrasonography (IU) in reducing the number of unnecessary para-aortic lymphadenectomy in women with endometrial carcinoma. Methods: Computed tomography (CT) and IU were used to assess whether para-aortic lymph nodes were enlarged in 91 women with endometrial carcinoma. All women underwent hysterectomy and systematic pelvic and para-aortic lymphadenectomy. On the basis of the intrauterine pathological findings (IPF) of the removed uterus, the women were classified into low- and high-risk groups. It was assumed that para-aortic lymphadenectomy would be performed only when enlarged nodes were detected by CT or IU or only when women were classified into the high-risk group. The numbers of women who would have had missed metastases and who could have avoided para-aortic lymphadenectomy were calculated. Results: Eighteen women had pathological para-aortic node metastases. Theoretically, the number of women who would have had missed metastases on the basis of CT, IU, and IPF were 11, 2, and 2, respectively; more metastases were missed with CT than with the other 2 methods. The number of women who could have avoided para-aortic lymphadenectomy on the basis of CT, IU, and IPF were 84, 59, and 29, respectively; compared to IPF, IU helped avoid para-aortic lymphadenectomy in more women. Conclusions: Intraoperative ultrasonography is the most efficient method for avoiding both unnecessary para-aortic lymphadenectomy and missed para-aortic node metastases in women with endometrial carcinoma.

Camptothecin (CPT) and its structural analogues including topotecan and irinotecan, are inhibitors of topoisomerase I. These drugs are clinically active against a broad spectrum of cancers. To understand the genesis of chemotherapeutic resistance to the CPT family of anticancer drugs, we examined by gene expression profiling the pharmacological response to topotecan in the human hepatoma HepG2 cells and found a striking induction of the phospholipid transfer protein (PLTP) gene expression by topotecan. We showed that activation of PLTP gene expression is specific to CPT and its analogues including specific enantiomers that inhibit topoisomerase I. PLTP-mediated lipid transfer to high-density lipoprotein (HDL) is thought to be important for shuttling and redistribution of lipids between lipoproteins, which are normally returned to the liver for metabolism via the reverse cholesterol transport pathway. Hence, we asked whether elevated PLTP levels might increase the transfer of drugs into HDL. We observed that CPT was not accumulated in HDL and other lipoproteins. In addition, topotecan treatment in mice caused a marked reduction in serum HDL that was accompanied by an increase in triglyceride and cholesterol levels. These results showed that PLTP does not mediate the transfer of topoisomerase I inhibitors to serum lipoproteins. However, elevated serum PLTP levels following treatment with topoisomerase I inhibitors in cancer patients may serve as a biomarker for monitoring the development of hypertriglyceridemia and acute pancreatitis.

Effects of antineoplastic prostaglandins (PG) on human ovarian cancer cell growth were examined by using HR cells derived from ascites of a patient with serous cystadenocarcinoma of the ovary. With regard to inhibition of cancer cell proliferation in vitro, the effects of delta 7-PGA1 was most marked, followed by that of delta 12-PGJ2, PGJ2 and PGD2. When antineoplastic prostaglandins were administered to nude mice bearing HR cells, tumor growth in groups treated with PGJ2 and delta 12-PGJ2 alone was significantly inhibited 63 days after tumor inoculation, compared to that in an untreated group. Consequently, a significant prolongation of median survival was obtained with delta 12-PGJ2, compared to that in untreated groups and in groups with cisplatin alone. In addition, when prostaglandins were administered together with cisplatin, adjuvant inhibitory effects on the tumor growth were obtained 35, 56 and 63 days after tumor inoculation. Subsequently a significant prolongation of median survival was observed when cisplatin was combined with PGD2 or delta 7-PGA1, compared to the results in groups treated with PGD2 alone, delta 7-PGA1 alone or cisplatin alone. Combination of PGJ2 or delta 12-PGJ2 and cisplatin resulted in a significant decrease of hematocrit and body weight 63 days after tumor inoculation, suggesting a deterioration of the median survival. These results suggest that combination of PGD2 or delta 7-PGA1 with cisplatin may be of clinical use for ovarian cancer resistant to cisplatin.

Screening method of endometrial cancer (EC) has not been established yet. Our study was to explore serum biomarkers of EC patients using surface-enhanced laser desorption and ionization-time-of-flight mass spectrometry (SELDI-TOF MS). Serum samples from 65 EC patients and 40 controls were analyzed by SELDI-TOF MS (training set). Single- and multi-variant analyses were performed to compare protein profiles in serum of EC patients and healthy controls. Subsequently, blind test set including 40 EC patients and 40 controls were analyzed for validation. A panel of four biomarker candidates were selected in training set analysis. These markers could also distinguish stage I patients from controls. Among them, two biomarkers were purified and identified as apolipoprotein A1 and a modified form of apolipoprotein C1. Screening for blind test set using dual-biomarker analysis yielded a sensitivity of 82% and a specificity of 86%. Involvement of apolipoproteins with EC is first suggested in this study. In addition to possibility of screening method for EC, findings of these new biomarkers might be related with carcinogenesis or predisposition to EC.

Pure-type clear cell carcinoma (CCC) has been recognized as a distinct subtype of ovarian cancer, showing a resistance to chemotherapy and resulting in poor prognosis. Our aim was to evaluate the effects of complete surgical procedures followed by adjuvant chemotherapy for CCC patients whose tumors were confined to the ovary (pT1M0). During the period of 1987-2005, 56 patients with stage I CCC were identified and two cases were excluded due to retroperitoneal lymph node metastasis. A total of 54 patients were enrolled in the study and divided into two groups: Group A (n=38, 1993-2005) underwent complete surgical staging including pelvic and para-aortic lymphadenectomy. Group B (n=16, 1987-1992) underwent a hysterectomy, bilateral salpingo-oopherectomy, omentectomy without comprehensive lymphadenectomy. Every patient received six courses of adjuvant chemotherapy using a platinum agent. Survival analysis was estimated by the Kaplan-Meier method and prognostic factors were evaluated using a Cox regression model. The clinical characteristics of the two groups were similar, except for the rate of conventional platinum-based chemotherapy (p=0.02). Multiple regression survival analysis revealed that the completion of a comprehensive staging operation was the only independent factor for progression-free survival of stage I CCC patients (p=0.03) and that the chemotherapeutic regimen was not a prognostic factor (p=0.43). The present study indicates that we should accomplish complete surgical staging procedures for CCC confined to the ovary.

The mechanism of cis-diamminedichloroplatinum (II) (CDDP) resistance was examined by using a CDDP-resistant (KFr) cell line established by continuous exposure of KF cells (derived from serous cystadenocarcinoma of the ovary) to escalating doses of CDDP. When KFr cells were incubated with 66.7 microM CDDP, the uptake of CDDP was significantly inhibited and the cellular content in the KFr cells was about a half of that in KF cells after incubation for 4 h. When the KF or KFr cells were incubated for 4 h with 100 microM CDDP, the release pattern of CDDP from KFr cells was similar to that from KF cells. In addition, the DNA histogram of both KF and KFr cells revealed that KF cells seemed to contain two clones of cell population and the KFr cells may have been selected by exposure to CDDP. At 3 h after intraperitoneal administration of 0.5 mg of CDDP per mouse to nude mice with KF or KFr tumor, the CDDP content in the KFr tumor was significantly lower than that in the KF tumor. In contrast, at 6 or 9 h after CDDP administration the CDDP content in the KFr tumor was significantly higher than that in the KF tumor. Furthermore, the KFr cells had cross-resistance to various CDDP analogues including carboplatin. It was shown that cellular uptakes of two CDDP analogues into KFr cells were significantly lower than those into KF cells.

Comparison was made between lymphocyte subsets in peripheral blood from patients with benign ovarian tumor and those with advanced ovarian carcinoma. In addition, changes of lymphocyte subsets of patients with ovarian carcinoma before and after operation were also examined. The percentage and absolute number of CD3-/HLA-DR+ (B cells) in peripheral blood from patients with advanced ovarian carcinoma were significantly lower than values from patients with benign ovarian tumor, whereas both percentage and absolute number of CD3-/HLA-DR- (null cells) cells in patients with advanced ovarian carcinoma were significantly higher. Although there was no significant difference in natural killer (NK) cell subsets (CD57+ CD16- and CD57+ CD16+ cells) between patients with benign ovarian tumor and ovarian carcinoma, the percentage and absolute number of CD57-/CD16+ (highly differentiated NK cells) cells in patients with ovarian carcinoma were significantly higher than those in patients with benign ovarian tumor. Both the absolute number and percentage of CD3+/HLA-DR+ (activated T cells) cells in ovarian cancer patients with minimal residual tumors after operation were significantly increased, compared to the levels before operation, while the values in the patients with large residual tumors were significantly decreased. In addition, the percentage and absolute number of CD3-/HLA-DR- (null cells) cells in the patients with minimal residual tumors were significantly decreased after operation, while values in the patients with large residual tumors remained unchanged before and after operation. The patients with minimal residual tumors after operation were characterized by a significant increase in the percentage of CD57- CD16+ (highly differentiated NK cells) cells. On the other hand, in the patients with large residual tumors no change of the NK cell subsets was observed before and after operation.

Recent studies have shown that platelet-derived growth factors and their receptors are frequently co-expressed in ovarian cancers. Herein, we investigated the role of the platelet-derived growth factor pathway in the development of ovarian clear-cell adenocarcinoma, a highly chemoresistant form of ovarian cancer. Immunohistochemical expression of platelet-derived growth factor receptor-alpha and receptor-beta, platelet-derived growth factor A-chain and B-chain was examined in 31 cases of clear-cell adenocarcinoma and 56 coexisting putative precursor lesions: 17 non-atypical and 19 atypical endometrioses, and 10 non-atypical and 10 atypical clear-cell adenofibroma components. Twenty-one solitary endometrioses were also examined. Vascular endothelial cells were always positive for all the markers examined, and were used as positive controls. The frequencies of positivity for platelet-derived growth factor receptor-alpha and receptor-beta, and platelet-derived growth factor A-chain increased in accordance with higher cytologic atypia in the putative precursors: 71, 47, and 59% in the 17 non-atypical endometrioses, 84, 73, and 84% in the 19 atypical endometrioses, 0% each in the 10 non-atypical clear-cell adenofibromas, 100, 90, and 90% in the 10 atypical clear-cell adenofibromas, and 97, 97, and 100% in the 31 clear-cell adenocarcinomas, respectively. Positivity for platelet-derived growth factor B-chain increased in accordance with increased atypia in clear-cell adenofibroma: 0% in non-atypical clear-cell adenofibromas, 30% in atypical clear-cell adenofibromas, and 60% in coexisting carcinomas. However, in contrast, positivity for platelet-derived growth factor B-chain decreased in accordance with increased atypia in endometriosis coexisting with clear-cell adenocarcinomas: 35% in non-atypical endometrioses, 11% in atypical endometrioses, and 5% in coexisting carcinomas. Platelet-derived growth factor receptor-alpha and receptor-beta, and their ligands A-chain and B-chain were positive in 14, 29, 19, and 62% of the solitary endometrioses, respectively. These results indicate activation of the platelet-derived growth factor pathway in ovarian clear-cell adenocarcinomas and suggest biological differences between carcinomas that arise in association with clear-cell adenofibroma vs endometriosis.

Actinin-4 is an isoform of non-muscular alpha-actinin and actin-bundling protein. By enhancing cell motility, actinin-4 shows different biological properties from another isoform of non-muscular actinin 'actinin-1' and variable clinicopathological implications of actinin-4 have been demonstrated in some human malignancies such as breast cancers, lung cancers, and colorectal cancers. We herein described the clinicopathological and prognostic significance of actinin-4 expression in ovarian cancers. Actinin-4 expression was analyzed immunohistochemically in 265 primary ovarian carcinomas: 116 serous, 71 clear cell, 43 endometrioid, and 35 mucinous adenocarcinomas. With reference to endothelial immunoreactivity, cytoplasmic expression of actinin-4 was classified as either low (including negative) or high. Then, various parameters such as patients' characteristics, histopathological findings including E-cadherin and beta-catenin immunoreactivity, and clinical outcome, were compared between groups showing differences in the intensity or intracellular distribution of actinin-4 immunoreactivity. High expression of actinin-4 was demonstrated in 137 (57%) cases and was associated with serous histology (P=0.0075), high histological grade (P0.0001), an advanced disease stage (P=0.036), a high degree of residual disease after initial surgery (P=0.0047), poor patient outcome (5-year survival: 52.4% in the high-expression group vs 71.9% in the low expression group, P=0.0043 by log-rank test), and also with reduced E-cadherin and preserved beta-catenin expressions (P=0.0097 and 0.017, respectively). Nuclear immunoreactivity for actinin-4 was detected in 20 (7.5%) cases and was associated with low histological grade (P=0.0079) but not with other variables. Multivariate analysis showed that high actinin-4 expression was an independent prognostic factor for overall survival, as well as a high degree of residual disease and clear-cell histology. Accumulation of actinin-4 in the cytoplasm may be related to a higher propensity for tumor invasiveness and metastasis, probably by enhancing cell motility, and could be a novel prognostic indicator for patients with ovarian carcinomas.

In the current study, we identified paclitaxel-resistant related genes by comparing gene expression profiles of paclitaxel-resistant and parent ovarian cancer cell lines. Gene expression profiles of the human ovarian cancer cell line (KF28), cisplatin-resistant cell line (KFr13) induced from KF28, and paclitaxel-resistant cell lines (KF28TX and KFr13TX) induced by exposing KF28 and KFr13 to dose-escalating paclitaxel were compared and analyzed using cDNA microarray. Of 557 human cancer-related cDNA transcripts compared, 5 genes were found to be underexpressed and 5 genes overexpressed in the paclitaxel-resistant KF28TX, while another paclitaxel-resistant KFr13TX had 5 underexpressed and 8 overexpressed genes. Among these genes, overexpression of the ATP-binding cassette subfamily (MDR-1), Rho guanine dinucleotide phosphate dissociation inhibitor beta (RhoGDI) and insulin-like growth factor binding protein 3 (IGFBP-3) was observed in both paclitaxel-resistant cell lines. Using real-time quantitative PCR, we confirmed the array results. We therefore conclude that IGFBP-3, RhoGDI and MDR-1 were correlated with paclitaxel resistance. Moreover, immunohistochemical staining was analyzed in 22 serous ovarian cancer tissues from patients who received paclitaxel-based chemotherapy, and RhoGDI overexpression was observed more frequently in non-responsers than in responders (p=0.004). RhoGDI expression proved to be a predictive marker of paclitaxel resistance not only in paclitaxel-resistant cell lines, but also in clinical samples.

Uterine carcinosarcoma histologically comprises the components of epithelial and mesenchymal malignancies, and is known to be clinically highly aggressive. To reveal the significance of the expression of tyrosine-kinase-receptor-type oncoproteins in this tumor type, the incidence and distribution of the KIT, EGFR, and HER-2 (c-erbB-2) oncoproteins were immunohistochemically examined in 16 surgically resected cases. For 6 cases, the EGFR and HER-2 amplifications were also examined by fluorescence in situ hybridization (FISH). In the epithelial component, overexpressions of KIT, EGFR, and HER-2 were detected in 4 (25%), 5 (31%), and 9 (56%) cases, respectively, whereas these overexpressions in the mesenchymal component were detected in 6 (38%), 8 (50%), and 1 (6%) cases, respectively. KIT and EGFR were co-overexpressed in the mesenchymal component of 4 cases and in the epithelial component of 2 cases. However, HER-2 overexpression was mostly detected in the epithelial component only, and tended to occur independently of KIT and/or EGFR overexpression. By FISH, one of the 4 cases with HER-2 overexpression showed low-level gene amplification. In two cases with EGFR overexpression, the gain of EGFR alleles and/or polyploidization of chromosome 7 had occurred. The expression patterns of KIT, EGFR, and HER-2 differed between the epithelial and mesenchymal components, and the regulation of their expression appeared important in the acquisition of mesenchymal metaplasia in uterine carcinosarcoma. Structural and/or numerical alterations of chromosomes might be in part involved in EGFR and/or HER-2 overexpression in this tumor type.

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.

Background: We have previously reported that paclitaxel (taxol) results in cisplatin sensitization to human ovarian cancer cells with cisplatin resistance in vitro. This study was designed to determine effects of taxol and its combination with cisplatin on growth of cisplatin-sensitive cell line (KF28) and the cisplatin-resistant counterpart (KFr13) in nude mice. Methods: From 14 days after tumor inoculation treatment was initiated. Taxol (3 mg/kg) and cisplatin (2 mg/kg) were administered i.p. once a week for 5 weeks. Results: In nude mice bearing cisplatin-sensitive cells (KF28), taxol followed by cisplatin and cisplatin plus taxol inhibited significantly (P < 0.05) the tumor growth rate compared with that in nude mice treated with cisplatin alone or taxol alone and cisplatin followed by taxol. On the other hand, in nude mice bearing cisplatin-resistant KFr13 cells, treatment with taxol alone inhibited completely the tumor growth rate, whereas no schedule-dependent interaction of taxol with cisplatin was observed. Conclusion: These results suggest that treatment with taxol alone may be superior to combination of taxol with cisplatin in patients with cisplatin-resistant ovarian carcinoma.

Ginsenoside Rh2 (Rh2), isolated from an ethanol extract of the processed root of Panax ginseng CA Meyer, inhibits the growth of B16 melanoma cells. This study was designed to evaluate the ability of Rh2 to inhibit growth of human ovarian cancer cells (HRA) in vitro and in nude mouse. Rh2 inhibited proliferations of various established human ovarian cancer cell lines in a dose-dependent manner between 10 and 60 microM in vitro and induced apoptosis at around the IC50 dose. When HRA cells were inoculated s.c. into the right flank of nude mice, all mice formed a palpable tumor within 14 days. Although i.p. administration of Rh2 alone hardly inhibited the tumor growth, when Rh2 was combined with cis-diamminedichloroplatinum(II) (CDDP) the tumor growth was significantly inhibited, compared to treatment with CDDP alone. When mice were treated p.o. with Rh2 daily (but not weekly), the tumor growth was significantly (P

The aim of this study was to elucidate the effect of intraperitoneal (i.p.) instillations of granulocyte-colony-stimulating factor (G-CSF) and/or interleukin-2 (IL-2) on ascites formation and the survival time of nude mice with malignant ascites, produced by i.p. inoculation of human ovarian cancer cells. When the nude mice were treated with medium alone, ascites was observed in all mice 28 days after tumor inoculation. When the mice were treated with cis-diamminedichloroplatinum(II) (cisplatin) alone, G-CSF alone or IL-2 alone, it took 35 days for the ascites to form in all mice. When cisplatin was combined with G-CSF or IL-2, one of ten mice did not form ascites during the observation period. Surprisingly, when G-CSF and IL-2 were simultaneously administered, ascites formation was not observed in any mice. Although i.p. treatment with cisplatin alone significantly prolonged the survival time, compared to medium alone, the lytic activity of spleen cells against HRA cells was significantly suppressed. When G-CSF or IL-2 was combined with cisplatin, the suppression by cisplatin was eliminated and subsequently resulted in a prolongation of the survival time. When G-CSF was combined with IL-2, both the peritoneal and splenic macrophages/ monocytes were stimulated and the splenic lytic activity was about double that following treatment with G-CSF alone on IL-2 alone, suggesting that complete inhibition of ascites formation results not only from a significant increase of the peritoneal macrophages but also from enhancement of the lytic activity. Two mice, died from dissemination of tumor in the abdominal cavity, but eight mice survived without tumor for more than 90 days. As confirmed by monitoring body weight and hematocrit, G-CSF and IL-2 seemed to have no adverse effect. From these results, we conclude that a combination therapy with G-CSF and IL-2 might be of clinical use for inhibiting large amounts of ascites, which may inhibit therapeutic effects for ovarian cancer patients.

Recently two new compounds, ginsenosides Rh1 and Rh2, have been isolated from an ethanol extract of the processed root of Panax ginseng CA Meyer, and Rh2 (but not Rh1) has been found to cause growth inhibition of cultured B16 melanoma cells. We have also demonstrated that Rh2 caused inhibition of cultured human ovarian cancer cell (HRA) proliferation. The effect of oral administration of Rh2 on tumor growth and survival of nude mice bearing HRA cells was examined. Nude mice were inoculated subcutaneously in the right flank with 10(6) HRA cells. After 7 days of tumor inoculation 2 mg/kg cis-diamminedichloroplatinum(II) (cisplatin) was administered intraperitoneally once a week for 5 weeks. In Rh2-treated groups. Rh2 was dissolved in absolute ethanol, adjusted with distilled water to 1, 15, and 120 microM, and 0.4 ml of each concentration was administered orally by canula every day for 90 days, from the next day of tumor inoculation. The tumor volume, hematocrit and body weight were measured every week. On days 56 and 63 after tumor inoculation, the tumor volumes in all groups treated with Rh2 were significantly less than those in an ethanol-treated control group and also in cisplatin treated group. After 70 days, the tumor growth in nude mice treated with 15 microM and 120 microM Rh2 was significantly inhibited compared to that in a cisplatin treated group as well as a control group. Consequently, the survival of nude mice treated with 15 microM and 120 microM Rh2 was also significantly prolonged, compared to that of cisplatin treated mice. No toxic effects were observed in any of the mice.

The present study was designed to explore the effects of opioid peptides on the lytic activity of spleen cells from intact nude mice or nude mice bearing human ovarian cancer cells (KF). When the spleen cells from intact nude mice were incubated with various concentrations of opioid peptides, the ability of the spleen cells to lyse the KF cells was significantly stimulated between 0.05 nM and 50 nM concentrations of all opioid peptides used in this study. The degree of stimulation was most marked at 5 nM opioid peptides and the most marked stimulatory effect was obtained by alpha-endorphin. On the other hand, the lytic activity of spleen cells from nude mice challenged with the KF cells was about two-fold higher than that of intact nude mice, suggesting that spleen cells from nude mice challenged with KF cells have KF-cell-specific cytotoxicity. Even if the spleen cells were incubated with any concentration of alpha-endorphin or [Met]enkephalin indicated, the lytic activity remained unchanged. In contrast, only beta-endorphin resulted in a significant increase of the lytic activity between 0.5 nM and 50 nM. These results suggest that opioid peptides play a crucial role in immune surveillance mechanisms.

The effect of intraperitoneal instillations of interleukin-2 (IL-2) and/or lymphokine-activated killer (LAK) cells on the ascites formation and the survival time was examined using nude mice as a model, with malignant ascites produced by intraperitoneal inoculation of human ovarian cancer cells derived from ascites of a patient with serous cystadenocarcinoma of the ovary. Twenty-eight days after tumor inoculation, all nude mice in the untreated group and in the group treated with spleen cells alone formed ascites. Two of ten nude mice treated with IL-2 alone after tumor inoculation survived without forming ascites during the experimental period. On the other hand, all nude mice treated with LAK cells alone had formed ascites 14 days after tumor inoculation. When LAK cells and IL-2 were combined, five of ten mice survived without forming ascites during the experimental period. The survival time of the group treated with IL-2 alone was significantly prolonged compared to the groups that received medium alone, spleen cells alone and LAK cells alone. When administration of LAK cells was followed by IL-2, the survival time was further prolonged.

In order to establish that the tumor burden in nude mice bearing a xenografted human ovarian tumor can be assessed by measuring plasma levels of alpha-hydroxybutyrate dehydrogenase (HBD) (E.C. 1.1.1.30), the plasma HBD and the tumor volume were measured every week after inoculation of a human ovarian carcinoma cell line designated HR. About 3 weeks after tumor inoculation, all nude mice had a palpable tumor while elevated levels of HBD were observed in a half of the mice at that time. Thereafter the HBD levels rose with increasing tumor volume. There was a quantitative linear relationship between the tumor weight and HBD activity per mouse. When 40 micrograms of cisplatin (about 2 mg/kg) was administered i.p. every week for 5 weeks 2 weeks after inoculation, plasma levels of HBD were significantly decreased on day 27 compared to those in untreated nude mice. Decreases in the HBD levels during treatment with cisplatin occurred 7 days prior to changes in tumor volumes. Further, removal of local tumor mass resulted in a marked decrease in HBD levels on day 1 after surgery and the HBD levels in nude mice which had no recurrent tumor fell into the normal range 8 days after surgery.

The present study was designed to elucidate the mechanism of resistance to cisplatin. A cisplatin-resistant cell line (KFr) was established from KF cells derived from human serous cystadenocarcinoma of the ovary. The DNA histogram revealed an increase of S-phase cells and a decrease of G1-phase cells in cultured KFr cells, compared to that in cultured KF cells. Although the cisplatin content in the KF cells incubated with cisplatin at 10 micrograms/ml increased in a time-dependent manner, that in the KFr cells remained unchanged during the experimental period. When 0.5 mg of cisplatin was administered ip to nude mice with KF or KFr tumor, the cisplatin content in the KFr tumor was significantly lower than that in the KF tumor. The KFr cells showed a cross-resistance to L-phenylalanine mustard, while no cross-resistance to vincristine or 5-fluorouracil was observed. These findings suggest that the mechanism of cisplatin resistance in the KFr cells involves a decrease of cisplatin accumulation in the tumor cells.