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Kyosuke Yamada,
Hiroshi Tanabe,
Manami Imai,
Toshiko Jobo,
Kazuya Kudo,
Hiroyuki Fujiwara,
Chie Nagata,
Kenichi Furuya,
Mitsuaki Suzuki,
Kazunori Ochiai,
Tadao Tanaka, Makoto Yasuda
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ABSTRACT: Aim: The optimal chemotherapy regimen for patients with endometrial cancer has not been established. We assessed the feasibility of paclitaxel plus carboplatin (TC) for postoperative chemotherapy in patients with endometrial cancer. Material and Methods: Patients with newly diagnosed endometrial cancer received TC (paclitaxel 180 mg/m(2) , carboplatin AUC6 mg/mL/min) every three weeks. Treatment was continued until disease progression or completion of six cycles. Toxicities were evaluated every cycle according to NCI-CTCAE version 3.0. Results: Sixty patients were registered from December 2005 through November 2006. Forty-four of 60 (73.3%) cases completed all of the planned six cycles. Grades 3 and 4 hematologic toxicities were observed as follows: leukopenia (61.7%), neutropenia (95.0%), anemia (21.7%), and thrombocytopenia (5.0%). There were six patients who dropped out from the protocol by neutropenia. Grade 3 non-hematologic toxicities were observed as follows: nausea (3.3%), vomiting (1.7%), neuropathy (5.0%), myalgia (6.7%) and constipation (1.7%). No grade 4 non-hematologic toxicity was observed. Conclusion: This TC regimen is feasible for endometrial cancer patients.
Journal of Obstetrics and Gynaecology Research 05/2012; · 0.94 Impact Factor
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ABSTRACT: To evaluate the incidence of anemia in patients with epithelial ovarian cancer receiving paclitaxel-carboplatin combination therapy (TC) using data from the Japanese Gynecologic Oncology Group (JGOG) 3016 trial, and to examine the effect of severe anemia on survival during dose-dense TC.
Retrospective analysis was conducted in patients enrolled in the JGOG 3016 trial who underwent at least one cycle of the protocol therapy (n = 622). Hemoglobin values at enrollment and during each cycle of TC were collected. One-to-one matching was performed between patients with and patients without grade 3/4 anemia during TC (anemia and nonanemia groups) to adjust the baseline characteristics of the patients. The cumulative survival curve and median progression-free survival were estimated using the Kaplan-Meier method.
Grades 2 to 4 anemia was observed in 19.8% of patients before first-line TC. The incidence of grade 3/4 anemia rapidly increased to 56.1% after the fourth cycle of dose-dense TC. After matching, the median progression-free survival in the anemia (hemoglobin <8.0 g/dL) and nonanemia (hemoglobin >8.0 g/dL) groups was 777 and 1100 days, respectively (P = 0.3493) for patients receiving dose-dense TC. The median progression-free survival in patients receiving conventional TC was similar between the 2 groups.
The difference in progression-free survival between patients with epithelial ovarian cancer with and those without severe anemia during TC was not statistically significant, but for patients receiving dose-dense TC, severe anemia seems to have prognostic relevance. Prospective trials are needed to investigate whether the optimal management of chemotherapy-induced anemia, including appropriate use of erythropoiesis-stimulating agents, would further improve the survival of patients with ovarian cancer receiving dose-dense TC.
International Journal of Gynecological Cancer 12/2011; 21(9):1585-91. · 1.65 Impact Factor
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ABSTRACT: We previously reported that cyclin E (CCNE1) amplification is strongly associated with resistance to treatment in serous ovarian cancer by high-resolution oligonucleotide copy number analysis. Dysregulation of cell cycle control has been implicated as the key event in human oncogenesis, and aberrant expression of G1-S phase-related genes in particular has been reported in epithelial ovarian cancer (EOC). Nevertheless, there are conflicting results concerning the prognostic values of these abnormalities in EOC. This study focused on advanced serous EOC cases and investigated the association between the expression of G1-S phase-regulatory proteins and clinicopathological parameters. The utility of these proteins as prognostic factors was assessed, and whether these targets reflect chemoresistance of advanced serous EOC was investigated. A total of 66 patients treated by primary surgery were evaluated in this study. Immunohistochemical analysis for cyclin D1, pRb, p16, p53, p27(Kip1), p21(Waf1/Cip1) and cyclin E was performed on formalin-fixed tissue sections collected from primary surgical specimens. The correlations between the expression of these proteins and the clinicopathological parameters, including progression-free survival (PFS), overall survival (OS) and chemosensitivity, were examined. Upon univariate analysis, overexpression of cyclin D1 was positively correlated with reduced PFS (p=0.00062) and OS (p=0.00037). Reduced expression of p27(Kip1) was associated with shorter OS (p=0.064). Upon multivariate analysis, overexpression of cyclin D1 (p=0.0019), reduced expression of p27(Kip1) (p=0.042) and residual tumor volume (p=0.0092) were identified as independent predictors of OS. Overexpression of cyclin D1 (p=0.011) as well as residual tumor volume (p=0.006) were significantly associated with first-line chemosensitivity. In advanced serous EOC, overexpression of cyclin D1 contributed largely to poor prognosis, and this may have been in part mediated by chemoresistance. Cyclin D1 is a possible target for overcoming the refractory nature of advanced serous EOC.
Experimental and therapeutic medicine 01/2011; 2(2):213-219.
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Noriyuki Katsumata, Makoto Yasuda,
Fumiaki Takahashi,
Seiji Isonishi,
Toshiko Jobo,
Daisuke Aoki,
Hiroshi Tsuda,
Toru Sugiyama,
Shoji Kodama,
Eizo Kimura,
Kazunori Ochiai,
Kiichiro Noda
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ABSTRACT: Paclitaxel and carboplatin given every 3 weeks is standard treatment for advanced ovarian carcinoma. Attempts to improve patient survival by including other drugs have yielded disappointing results. We compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer.
Patients with stage II to IV epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were eligible for enrolment in this phase 3, open-label, randomised controlled trial at 85 centres in Japan. Patients were randomly assigned by computer-generated randomisation sequence to receive six cycles of either paclitaxel (180 mg/m(2); 3-h intravenous infusion) plus carboplatin (area under the curve [AUC] 6 mg/mL per min), given on day 1 of a 21-day cycle (conventional regimen; n=320), or dose-dense paclitaxel (80 mg/m(2); 1-h intravenous infusion) given on days 1, 8, and 15 plus carboplatin given on day 1 of a 21-day cycle (dose-dense regimen; n=317). The primary endpoint was progression-free survival. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00226915.
631 of the 637 enrolled patients were eligible for treatment and were included in the ITT population (dose-dense regimen, n=312; conventional regimen, n=319). Median progression-free survival was longer in the dose-dense treatment group (28.0 months, 95% CI 22.3-35.4) than in the conventional treatment group (17.2 months, 15.7-21.1; hazard ratio [HR] 0.71; 95% CI 0.58-0.88; p=0.0015). Overall survival at 3 years was higher in the dose-dense regimen group (72.1%) than in the conventional treatment group (65.1%; HR 0.75, 0.57-0.98; p=0.03). 165 patients assigned to the dose-dense regimen and 117 assigned to the conventional regimen discontinued treatment early. Reasons for participant dropout were balanced between the groups, apart from withdrawal because of toxicity, which was higher in the dose-dense regimen group than in the conventional regimen group (n=113 vs n=69). The most common adverse event was neutropenia (dose-dense regimen, 286 [92%] of 312; conventional regimen, 276 [88%] of 314). The frequency of grade 3 and 4 anaemia was higher in the dose-dense treatment group (214 [69%]) than in the conventional treatment group (137 [44%]; p<0.0001). The frequencies of other toxic effects were similar between groups.
Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer.
Bristol-Myers Squibb.
The Lancet 09/2009; 374(9698):1331-8. · 38.28 Impact Factor
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ABSTRACT: A cell line designated as NEYS was established from ovarian carcinosarcoma (stage IIIc) of a 56-year-old Japanese woman. The extirpated original tumor was carried in growth medium at 0 degrees C to the culture room. The primary culture was done on 20 August 2003. The cell line was composed of angular adhesive cells and showed neoplastic and pleomorphic features, such as bizarre aggregation of chromatin granules, an irregular thickening nuclear membrane and multiple large nucleoli. They grew as multi-layered cultures without contact inhibition. The cells proliferated moderately, and population doubling time was about 56 h. The chromosome number showed an underdiploidy of aneuploidy. The modal chromosome numbers were 37 (36%) and 38 (26%). The cultures produced carcinoembryonic antigen (27.4 ng/mL), carbohydrate antigen 19-9 (210 U/mL), and carbohydrate antigen 125 (526 U/mL). The NEYS cells did not give rise to transplant tumors in nude mice, and showed no susceptibility against cisplatin (CDDP), CPT-11, carboplatin, Paclitaxel, Taxotere and 5-FU. This cell line is useful for studies on the histogenesis of carcinosarcoma and susceptibility of cancer drugs in human ovarian carcinosarcoma. The immunohistochemical and ultrastructual analysis demonstrated that NEYS cells showed epithelial and mesenchymal differentiation, and supported the metaplasis theory as the cause of carcinosarcoma.
Human Cell 09/2009; 22(3):72-80. · 1.27 Impact Factor
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ABSTRACT: We developed mitochondrial (MT) scoring system based on MT ultrastructural findings in association with response to chemotherapy in ovarian cancer (OC). Ultrathin sections of MT prepared from 28 OC patients before chemotherapy were examined by electron microscopy. Platinum-sensitive ovarian carcinoma cell line 2008 and its resistant variant C13 were used as control cells. Seven independent MT features including, diameter, pattern of cresta structure, electron density, distribution-density and -pattern, ratio of minimal/maximal diameter and MT architecture were examined and were assigned a score between 0 and 2. Twenty-eight cases were primary advanced OC, including 4 recurrent cases. Nine cases were chemosensitive while 19 were resistant. Univariate and multivariate analysis in each factor showed good correlation to chemosensitivity for 2 factors of electron density, distribution pattern. Total score of these 2 factors in 9 sensitive cells was 1.44+/-0.41 (M +/- SE) and was 3.58+/-0.18 in 19 resistant cells (P<0.001). Receptor operative characteristics (ROC) analysis revealed that total 'cut-off' score was 3 point (P<0.05; AUC=0.84). In conclusion, this MT scoring system was excellently correlated to response regardless of histopathologic findings and this strongly suggests that the system is deemed to be of great value as biomarker for the chemosensitivity in OC.
Oncology Reports 01/2009; 21(1):199-204. · 1.84 Impact Factor
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ABSTRACT: Standard chemotherapy for endometrial cancer, including therapy with adriamycin and cisplatin (AP therapy), has not been established. However, recently, many studies have reported the efficacy of taxanes. We retrospectively investigated 46 patients with endometrial cancer who were diagnosed and treated in our hospital. As a rule, 6 courses of TC therapy (paclitaxel (PTX): 180 mg/m2, carboplatin (CBDCA): AUC 5), as initial chemotherapy, were performed at 3-week intervals in 18 patients with advanced or recurrent cancer from whom informed consent was obtained. In endometrioid adenocarcinoma patients, the response rate was 66.6%. A complete response for celomic fluid was achieved in 1 patient (1/1). Overall, the response rate was 50.0%. Adverse reactions such as digestive symptoms, alopecia, and peripheral neuropathy were observed in all patients. Concerning Grade 3 or higher blood toxicity, thrombopenia was noted in 1 patient. There was no hypersensitivity. Two patients with a partial response (PR) (1 with endometrioid adenocarcinoma, 1 with serous adenocarcinoma) achieved a disease-free survival of more than 30 months. Relapse was detected in 1 patient with a stage I c G3 lesion (response period: 20 months). Thus, TC therapy may be effective for endometrial cancer. However, in the future, the long-term outcome should be further investigated.
Gan to kagaku ryoho. Cancer & chemotherapy 12/2008; 35(11):1901-5.
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Kyosuke YAMADA,
Toshiaki TACHIBANA,
Yasushi IIDA,
Kazu UEDA,
Akihiko MISAWA,
Nagazumi SUZUKI,
Hiroyuki TAKAHASHI,
Hiroyuki KATO,
Eizo KIMURA, Makoto YASUDA,
Tadao TANAKA,
Hiroshi ISHIKAWA
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ABSTRACT: Abstract The cell line designed JHUCS-1 was established from a carcinosarcoma (malignant mixed mesodermal tumor) of the uterus that was surgically removed from a 57-year-old Japanese woman. We carefully examined the histopathology of the original tumor after the cell line was established and noted differentiation into a neuroendocrine carcinoma within the tumor's epithelial components. Immunohistochemical staining of the tumorous tissue that had been heterotransplanted was positive for Leu7. Additionally, secretary granules were observed in the grafted cells as determined by electron microscopy. These results support the existence of neuroendocrine cells within the JHUCS-1 cell line.
Human Cell 10/2008; 17(3):139 - 144. · 1.27 Impact Factor
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ABSTRACT: Ovarian small cell carcinoma of hypercalcemic type is a rare neoplasm that typically occurs in young females. We describe three cases of ovarian small cell carcinoma of hypercalcemic type occurring in patients aged 24, 37, and 25 years. The first patient had stage IIc disease and had primary surgery with a left salpingo-oophorectomy and omentectomy, followed by chemotherapy with cisplatin and etoposide. Upon a second relapse, pelvic lymphadenectomy was performed, followed by chemotherapy with docetaxel. She is alive for 4 years without any recurrence after the initial treatment. In vitro drug-sensitivity assay revealed the tumor cells were sensitive to taxane and resistant to irinotecan. The second patient had stage III disease and had primary debulking surgery with bilateral salpingo-oophorectomy, simple hysterectomy, omentectomy, low-anterior resection, and lymphadenectomy, followed by chemotherapy with paclitaxel and carboplatin. Four months after the initial treatment she relapsed and died. The tumor cells were sensitive to platinum, taxane, and doxorubicin, but resistant to irinotecan. The third patient had stage III disease and had right salpingo-oophorectomy, omentectomy, and lymphadenectomy, followed by chemotherapy with cisplatin, cyclophosphamide, and doxorubicin. She relapsed 4 months after completing the chemotherapy and died 5 months after secondary debulking surgery. The tumor cells were sensitive to platinum, taxane, and doxorubicin, but resistant to irinotecan. The drug-sensitivity assays suggested that a non-irinotecan, taxane-containing combination might have been suitable as first-line chemotherapy for these patients. However, an effect of such a regimen was seen in only one patient with early-stage disease, and this questions the validity of chemosensitivity testing.
International Journal of Clinical Oncology 05/2008; 13(2):161-5. · 1.41 Impact Factor
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ABSTRACT: A very rare case of mesonephric adenocarcinoma with lobular mesonephric hyperplasia in the uterine cervix of a 46-year-old female is presented. The lesion was a 4 cm, exophytic, almost circumferential, whitish yellow, friable mass in the uterine cervix. Microscopically, the tumor was composed predominantly of atypical round to polygonal cells arranged in a ductal, tubular, or papillary pattern. The tumor involved the entire cervix with varying depths of penetration. Lobular mesonephric hyperplasia was also observed in the lateral cervical wall and adjacent to the tumor. Immunohistochemically, the tumor was positive for CAM5.2, CK7, epithelial membrane antigen, calretinin, and chromogranin A, and was negative for vimentin, carcinoembryonic antigen, estrogen and progesterone receptors, and CD10. An ultrastructural analysis showed telolysomes, which were characteristic features of mesonephric epithelium. The patient was alive without disease at 4 months after surgery.
Pathology - Research and Practice 04/2008; 204(9):671-6. · 1.21 Impact Factor
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ABSTRACT: A cell line designated "HEPFT" was established from a human fallopian tubal hepatoid carcinoma. This line grew well without interruption for 13 months and was subcultivated over 35 times. The cells were spherical and polygonal in shape and showed neoplastic and pleomorphic features such as a bizarre aggregation of chromatin granules, an irregular thickening membrane and multiple large nucleoli. The cells formed epithelial colonies with a jigsaw puzzle-like arrangement and multilayering without contact inhibition. The cells contained moderate to abundant amounts of eosinophilic cytoplasm and were immunohistochemically positive for alpha-fetoprotein. The cells proliferated rapidly, and the population doubling time was about 45 h. The chromosome number showed a wide distribution of aneuploidy. The modal chromosome number was stable in the hyper triploid range and many marker chromosomes were observed. The culture cells produced bile and a large amount of lentil lectin-reactive alpha-fetoprotein. The recently developed bacterial artificial chromosome array comparative genomic hybridization facilitated detailed analysis with high resolution and sensitivity. Different profiles of genomic copy-number abnormalities were demonstrated in various chromosomal regions in HEPFT cells.
Human Cell 12/2007; 20(4):119-30. · 1.27 Impact Factor
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ABSTRACT: Paclitaxel (PX) binds to and stabilizes tubulin, preventing depolymerization, and resulting in cell death. Based on a previous report showing the activity of phosphatidylinositol kinase (PIK) on tubulin, we investigated the effect of the PI4K inhibitor orobol and the PI3K activator platelet derived growth factor (PDGF) on PX sensitivity. Drug sensitivity was examined by classical colony forming assay. Tubulin isotype expression was determined by semi-quantitative RT-PCR. Microtubule texture was observed by laser confocal microscope using anti-beta-tubulin antibody. Apoptotic activity was estimated by frequency of condensed nuclear chromatin with Hoechst 33342 stain. Orobol enhanced PX sensitivity of human ovarian carcinoma 2008 cells by 18.9+/-1.2-fold (N=3; P<0.01). In contrast, pretreatment with PDGF rendered cells resistant to PX by 2.3+/-0.4-fold (N=3; P<0.01). Neither orobol nor PDGF showed any effect on cell growth. Orobol produced a 2.5-fold sensitization in cisplatin-resistant 2008/C13*5.25 (C13) cells, and PDGF rendered the cells 2.3-fold resistant to PX. Orobol suppressed the beta 4a-tubulin isotype expression by 85% and other isotypes by 20%. In contrast, PDGF induced beta 4a-tubulin isotype expression by 1.3-fold, while it supressed all the other isotypes by 20-40%. Orobol produced thick microtubules and PDGF generated ring condensed microtubules. Orobol promoted PX-induced apoptosis, while PDGF caused 50% reduction of apoptosis. These results indicate that orobol and PDGF regulate PX sensitivity by reciprocally altering the proportion of tubulin isotype expression and PX-induced apoptotic signaling.
Oncology Reports 08/2007; 18(1):195-201. · 1.84 Impact Factor
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Miho Takao,
Aikou Okamoto,
Takashi Nikaido,
Mitsuyoshi Urashima,
Satoshi Takakura,
Misato Saito,
Motoaki Saito,
Sanshiro Okamoto,
Osamu Takikawa,
Hiroshi Sasaki, Makoto Yasuda,
Kazunori Ochiai,
Tadao Tanaka
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ABSTRACT: We previously reported that indoleamine-2,3-dioxygenase (IDO) is associated with paclitaxel resistance and that IDO serves as a marker of poor prognosis in ovarian serous adenocarcinomas (SA). In this study, to explore the role of IDO in the development of various histological types of ovarian cancer, we further examined IDO expression not only in SA but also in other types of ovarian cancers. Expression of IDO protein was analyzed by immunohistochemistry for a total of 122 ovarian cancers including 40 SA, 67 clear cell adenocarcinomas (CCA), and 15 endometrioid adenocarcinomas (EA) with informed consent. Among these cases, there were 11 CCA accompanied with endometriosis and 60 cases with lymph node metastasis. We classified the samples into four categories by IDO staining pattern. IDO staining was positive in 57.5% of SA, 49.2% of CCA, and 73.3% of EA, respectively. The Kaplan-Meier survival curve showed a clear relationship between staining score and overall survival for patients with advanced (stages III and IV) SA (n=33) who underwent optimal surgery and paclitaxel-carboplatin (TC) chemotherapy as a first-line regimen. There was no association between IDO staining score and overall survival in the CCA cases. Eight of 11 cases (72.7%) of CCA accompanied by endometriosis presented identical staining patterns of IDO between CCA and endometriosis. In 43 of 60 cases (71.6%) with lymph node metastasis, the staining patterns of IDO showed a correspondence between the primary lesion and metastatic site. These results suggested that the increased synthesis of IDO protein was positively associated with impaired survival only in the serous type of ovarian cancer.
Oncology Reports 07/2007; 17(6):1333-9. · 1.84 Impact Factor
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Kazu Ueda,
Kyosuke Yamada,
Mitsuyoshi Urashima,
Yoshio Ishibashi,
Misako Shirai,
Takashi Nikaido,
Hiroyuki Takahashi,
Aikou Okamoto,
Misato Saito, Makoto Yasuda,
Kiyoshi Ohkawa,
Tadao Tanaka
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ABSTRACT: Extracellular matrix metalloproteinase inducer (EMMPRIN) is a member of the immunoglobulin superfamily of adhesion molecules and has a role in the activation of several matrix metalloproteinases (MMPs). We evaluated whether EMMPRIN expression is related to tumor progression and patient outcome in human endometrial carcinoma. Paraffin-embedded surgical tissue samples from 112 patients with endometrial carcinoma were stained with anti-EMMPRIN antibody (monoclonal antibody 12C3:MoAb 12C3) for immunohistochemical analysis. EMMPRIN protein was expressed in cancerous lesions with the incidence of 97.3% (109 of 112 cases), but not in normal lesions. The scores determined by the combination of intensity and pattern of EMMPRIN staining in cancer cells correlated significantly with various histopathological risk factors: advanced stage, P=0.001; poorly differentiated carcinoma, P<0.001; lymph node metastasis, P=0.002; and lymphatic vessel infiltration, P=0.027. More importantly, recurrence-free survival was shortened in patients with higher EMMPRIN scores (HR, 3.08; 95% CI, 1.32-7.19; P=0.01). These results suggest that measurement of EMMPRIN expression with simple immunohistochemical staining may enhance the understanding of the pathophysiology of endometrial carcinoma.
Oncology Reports 04/2007; 17(4):731-5. · 1.84 Impact Factor
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ABSTRACT: One of the mechanisms of cisplatin cell cytotoxicity is the mitochondria-associated induction of apoptosis. The morphological or functional change of mitochondria in cisplatin-resistant cells has already been reported. Herein we present additional data describing the mitochondrial genomic and functional changes in cisplatin- resistant cells. Cisplatin increased the level of apoptotic cells in cisplatin-sensitive human ovarian carcinoma OV 2008 and C13 cells by 3.90+/-1.01 (SD; N=3) (p<0.01)-fold and 2.03+/-0.20 (SD; N=3) (p<0.01)-fold compared to the basal apoptotic level. This indicates a lower level induction of apoptosis by 50% in cisplatin-resistant OV 2008/C13 *5.25 variant (C13) cells. In both cell types, cisplatin cytotoxicity is mostly inhibited by the caspase-9 inhibitor as well as the caspase-3 inhibitor, Ac-DEVD-CHO, suggesting that the mitochondrial downstream event was functioning well in both the C13 cells and in OV 2008 cells. Mitochondrial transmembrane potential (DeltaPsim) determined by flow cytometry using DiOC6-stained cells revealed a significant depolarization of C13 cells as compared to OV 2008 cells. Treatment of these cells with cisplatin or hydrogen peroxide induces complete mitochondrial DNA damage in OV 2008 cells, while only partial DNA-destruction is observed in C13 cells, strongly suggesting that mitochondria are resistant to cisplatin and oxidative stress response. Continuous oxygen consumption of these cells monitored by a multi-channel dissolved oxygen meter is 1.70-fold higher in OV 2008 cells than C13 cells and the oxygen consumption was decreased by 30% in C13 cells, suggesting mitochondrial respiratory malfunction in these cells. The hypothesis generated here is that mitochondrial DNA resistance to cisplatin and oxidative stress response might be one of the main characteristics concerning the lower level of apoptosis induced by cisplatin. However, the mechanism by which the mitochondrial DNA encoded molecule is involved in cisplatin resistance remains to be determined.
Oncology Reports 11/2006; 16(5):997-1002. · 1.84 Impact Factor
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ABSTRACT: The current initial standard chemotherapy for advanced ovarian cancer is a regimen with a combination of platinum and taxane. However, the 5-year survival rate remains at 40% or lower, and the recurrence rate is as high as 70-80%. Second-line chemotherapy for recurrent cases has not yet been established. We conducted a phase I study of combined chemotherapy with paclitaxel (TXL) and carboplatin (CBDCA) administered weekly for recurrent and refractory ovarian cancer. The subjects were patients with a histopathologically confirmed diagnosis of malignant epithelial ovarian cancer, with recurrent or refractory disease after the initial chemotherapy. TXL was administered at escalating concentrations up to 60-100 mg/m(2), while the dose of CBDCA was fixed at an AUC of 2. In regard to the dosing schedule, premedication was performed as defined before TXL administration, and TXL and CBDCA were administered, in that order, by intravenous infusion for over at least 1 hour. The 4-week period, including the administration of both drugs on Day 1, 8, and 15, was regarded as one course of treatment. No cases developed grade 4 hematoxicity, but leukopenia and neutropenia occurred. All cases of leukopenia of step 4 and step 5 developed grade 3 leukopenia. Grade 2 thrombocytopenia was one example at a low rate. Non-hematological toxicity included neuropathy, arthralgia and muscle pain, but none of the patients developed grade 3 or 4. The response rate was 41.7% (5/12). The response rate of cases administered over TXL 80 mg was 66.7% (4/6). Based on these results,the following dose schedule was recommended for planning and designing a phase II study in the future: CBDCA AUC 2+TXL 80 mg/m(2) (Days 1, 8, and 15 q 4 weeks).
Gan to kagaku ryoho. Cancer & chemotherapy 11/2006; 33(10):1445-52.
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ABSTRACT: The current treatment of patients with recurrent ovarian cancer who have received initial platinum- or taxane-based chemotherapy depends on the results of the initial chemotherapy. The purpose of this study was to evaluate how to make the selection of second-line agents for patients with recurrent ovarian carcinoma initially diagnosed as stage II to IV.
We conducted a retrospective crossover study in patients who received second-line chemotherapy at Jikei University School of Medicine. We evaluated the responses, progression-free survivals, survivals of second-line chemotherapy, and overall survivals after primary surgery for 51 patients. The treatment cohorts were defined as follows: TC1, patients who were given paclitaxel and carboplatin as first-line chemotherapy and who, upon recurrence, were treated with a platinum-based combination as second-line; and TC2, patients who were given a non-taxane-based platinum combination as first-line chemotherapy, followed, at the time of recurrence, with paclitaxel and carboplatin.
The response rates of the second-line chemotherapy for the TC1 and TC2 groups were 44% and 25% (P=0.09). The median progression-free survivals of TC1 and TC2 were 12.9 and 6.4 months (P=0.018; hazard ratio [HR], 2.42; 95% confidence interval [CI], 1.16-5.04). The median survivals after second-line chemotherapy for the two groups were 16.8 and 10.4 months (P=0.007; HR, 2.78; 95% CI, 1.33-5.84) and overall survivals after primary surgery were 36.6 and 27.9 months (P=0.007; HR, 2.36; 95% CI, 1.07-5.21).
The TC1 group demonstrated a significantly better response and extension of progression-free survival, as well as significantly better survival after crossover and overall survival after primary surgery. As this was a retrospective analysis, this effect should be considered as hypothesis-generating and assessed prospectively in other trials comparing these two chemotherapy schedules.
International Journal of Clinical Oncology 07/2006; 11(3):236-42. · 1.41 Impact Factor
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Nippon rinsho. Japanese journal of clinical medicine 11/2004; 62 Suppl 10:546-9.
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ABSTRACT: To evaluate the significance of the expression of HER-2/neu as a prognostic factor, we retrospectively examined its overexpression rates chiefly in ovarian clear cell adenocarcinoma (CCA) and their relationships with FIGO stage, lymph node metastasis, and prognosis.
In addition to 90 specimens of CCA (stage I, 52; stage II, 7; stage III, 28; stage IV, 3) obtained between 1987 and 2002, 19 specimens of serous adenocarcinoma (S), 19 specimens of mucinous adenocarcinoma (M), and 19 specimens of endometrioid adenocarcinoma (E) collected at initial surgery were studied. The expression of HER-2/neu was immunohistologically scored on a scale of 0 to 3+ according to the HercepTest scoring system, and 2+ and 3+ were regarded as overexpression. The relationship between HER-2/neu overexpression and outcome was evaluated by the Kaplan-Meier method and the log-rank test. The relationship with advanced-stage cancer was analyzed by Fisher's exact test. The relationships with lymph node metastasis and histologic types were compared by the t test.
The rate of HER-2/neu overexpression in CCA was 45.6% (0, 1+, 2+, and 3+ in 14, 35, 36, and 5 cases, respectively), and no differences in the overexpression rate were noted among histologic types: 52.7% in S, 42.1% in M, and 26.4% in E. In CCA, no association was observed between HER-2/neu overexpression and cumulative survival rate (P = 0.5708), FIGO stage (P = 0.5147), or lymph node metastasis (P = 0.3624).
The absence in CCA of an association between HER-2/neu overexpression and outcome, stage, or lymph node metastasis indicates that HER-2/neu overexpression is not a prognostic risk factor.
Gynecologic Oncology 10/2004; 94(3):735-9. · 3.89 Impact Factor
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Kyosuke Yamada,
Toshiaki Tachibana,
Yasushi Iida,
Kazu Ueda,
Akihiko Misawa,
Nagazumi Suzuki,
Hiroyuki Takahashi,
Hiroyuki Kato,
Eizo Kimura, Makoto Yasuda,
Tadao Tanaka,
Hiroshi Ishikawa
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[hide abstract]
ABSTRACT: The cell line designed JHUCS-1 was established from a carcinosarcoma (malignant mixed mesodermal tumor) of the uterus that was surgically removed from a 57-year-old Japanese woman. We carefully examined the histopathology of the original tumor after the cell line was established and noted differentiation into a neuroendocrine carcinoma within the tumor's epithelial components. Immunohistochemical staining of the tumorous tissue that had been heterotransplanted was positive for Leu7. Additionally, secretary granules were observed in the grafted cells as determined by electron microscopy. These results support the existence of neuroendocrine cells within the JHUCS-1 cell line.
Human Cell 10/2004; 17(3):139-44. · 1.27 Impact Factor
