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NCI CANCERLIT^® Search: Therapy of Ovarian Cancer - October 2002

National Cancer Institute^®
Last Modified: October 1, 2002

Lactacystin enhances cisplatin sensitivity in resistant human ovarian cancer cell lines via inhibition of DNA repair and ERCC-1 expression.
Clinical trial and pharmacokinetic study of combination paclitaxel and carboplatin in patients with epithelial ovarian cancer.
Ovarian cancer chemotherapy: carboplatin as standard.
Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin
Immunohistochemically detected p53 mutations in epithelial tumors and results of treatment with chemotherapy and radiotherapy. A
Progestin therapy for advanced ovarian cancer: a phase II Eastern Cooperative Oncology Group trial.
[Prognosis and fertility after conservative treatment for ovarian tumors of limited malignity: review of 68 cases]
Gynaecological cancer services: time for change.
Resources and use of the intensive care unit in patients who undergo surgery for ovarian carcinoma.
p53 mutations in leukemia and myelodysplastic syndrome after ovarian cancer.
Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian
Population pharmacokinetic and limited sampling models for carboplatin administered in high-dose combination regimens with peripheral blood
Evaluation of beta1,4-galactosyltransferase as a potential biomarker for the detection of subclinical disease after the completion of primary
Pegylated liposomal doxorubicin (Caelyx) in recurrent ovarian cancer.
[Management of dermoid ovarian cysts. Report of 58 cases]
Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: comparative
[Expression of c-erbB-2 and topoisomerase II alpha in relation to chemoresistance in ovarian cancer]
[Ovarian tumors in pregnancy]
[Ovarian cancer in a pregnant woman and limited treatment strategy--a case report]
[Coexistence of ovarian carcinoma with pregnancy--case report]
[Ovarian tumors in the reproductive age group]
[Ovarian tumors in pregnancy]
[Ovarian tumors in pregnancy in the material of the Department of Gynecology and Oncology Collegium Medicum of Jagiellonian University in
[The number and histopathologic type of ovarian tumors operated during cesarean section at the Polish Mother's Health Institute between
Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel.
Efficacy of low-dose topotecan in second-line treatment for patients with epithelial ovarian carcinoma.
The trajectory of fatigue in adult patients with breast and ovarian cancer receiving chemotherapy.
[A specific marker of thrombolysis: DDE complex]

1
UI - 11936875
AU - Li QQ; Yunmbam MK; Zhong X; Yu JJ; Mimnaugh EG; Neckers L; Reed E
TI - Lactacystin enhances cisplatin sensitivity in resistant human ovarian cancer cell lines via inhibition of DNA repair and ERCC-1 expression.
SO - Cell Mol Biol (Noisy-le-grand) 2001;47 Online Pub():OL61-72
AD - Medical Ovarian Cancer Section, Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, MD 20892, USA. qli@hsc.wvu.edu
Cisplatin is among the most effective chemotherapeutic agents in the treatment of human ovarian cancer. The cytotoxicity of cisplatin results primarily from its ability to bind covalently to DNA and prevent DNA replication and transcription. The ubiquitin-proteasome pathway plays important roles in a broad array of basic cellular processes. Lactacystin is a selective inhibitor of the proteasome that can inhibit the ubiquitin pathway. However, the effect of lactacystin on DNA repair and the antitumor activity of cisplatin in ovarian cancer have not been evaluated. We report in this work that lactacystin, at concentrations that do not appear harmful, increased cisplatin toxicity in three resistant human ovarian carcinoma cell lines. In addition, lactacystin significantly enhanced DNA platination and decreased DNA repair of cisplatin-DNA adducts in these cell lines, as measured by atomic absorption spectrometry. Furthermore, Northem blot analysis and in vitro nuclear transcript elongation assay demonstrated that lactacystin dramatically reduced the steady-state mRNA expression and the rate of transcription of the DNA repair gene ERCC-1 in these cells. These observations indicate that proteasome inhibition has impact on nucleotide excision repair in several ways: i/ the normal ERCC-1 message upregulation is suppressed; ii/ cisplatin-DNA adduct repair is inhibited, and iii/ DNA platination, as well as cisplatin cytotoxicity, is enhanced.

2
UI - 12172979
AU - Yamamoto R; Kaneuchi M; Nishiya M; Todo Y; Takeda M; Okamoto K; Negishi
TI - H; Sakuragi N; Fujimoto S; Hirano T Clinical trial and pharmacokinetic study of combination paclitaxel and carboplatin in patients with epithelial ovarian cancer.
SO - Cancer Chemother Pharmacol 2002 Aug;50(2):137-42
AD - Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-8638, Japan. rityam@med.hokudai.ac.jp
PURPOSE: To determine the recommended dose of paclitaxel in chemotherapy used in combination with carboplatin, and to examine the pharmacokinetic parameters of paclitaxel and carboplatin in Japanese patients with epithelial ovarian cancer. METHODS:The study group comprised 18 patients (median age 53 years, range 30-67 years) who received a total of 28 courses of first-line chemotherapy. The paclitaxel levels were set at 150 mg/m(2) ( n=5), 175 mg/m(2) ( n=6) and 200 mg/m(2) ( n=7), with the fixed dose of carboplatin at AUC 5. The plasma concentrations of paclitaxel in 28 courses and platinum in 23 courses were measured to determine the in vivo pharmacokinetics parameters. RESULTS: The nadir of neutrophils in the paclitaxel 200 mg/m(2) group was significantly lower ( P<0.05) than in the 150 and 175 mg/m(2) groups. Of seven patients in the paclitaxel 200 mg/m(2) group, one had grade 3 myalgia, another grade 3 neuropathy, and two grade 4 neutropenia. Paclitaxel AUC and the peak level tended to be dose-dependent, clearly indicating a two-phase disappearance. Further, the paclitaxel dosage and paclitaxel AUC were also dose-dependent. Using a limited sampling protocol for carboplatin, the carboplatin AUC was found to change little in relation to the paclitaxel dosage. CONCLUSIONS: Based on the results of this clinical trial and pharmacokinetic study, 175 mg/m(2) of paclitaxel as a 3-h infusion in combination with carboplatin AUC 5 can be considered as the recommended dose for Japanese ovarian cancer patients.

3
UI - 12241648
AU - Tattersall MN
TI - Ovarian cancer chemotherapy: carboplatin as standard.
SO - Lancet 2002 Aug 17;360(9332):500-1
AD - Department of Cancer Medicine, University of Sydney, Sydney, NSW 2006, Australia. mtatt@med.usyd.edu.au

5
UI - 12240546
AU - Thames HD; Petersen C; Petersen S; Nieder C; Baumann M
TI - Immunohistochemically detected p53 mutations in epithelial tumors and results of treatment with chemotherapy and radiotherapy. A treatment-specific overview of the clinical data.
SO - Strahlenther Onkol 2002 Aug;178(8):411-21
AD - Department of Biomathematics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
BACKGROUND: The aim was to ascertain whether many hundreds of clinical reports over the last decade are consistent with the prediction of a poorer outcome in cancer patients with p53 abnormalities treated with cytotoxic drugs and radiation. MATERIAL AND METHOD: There are 301 studies on the influence of p53 overexpression published through summer 2000, in which chemotherapy or radiotherapy was used alone or in combination with surgery. From 45 reports meeting stringent selection rules, comparison groups are identified in whom the same measure of outcome was reported for the same treatment applied to the same tumor, with results corrected for important prognostic factors. Metaanalysis techniques are then applied to the comparison groups. Attention was limited to reports using immunohistochemical techniques, to form comparison groups of sufficient size. RESULTS: Four comparison groups were identified by treatment and endpoint: 1) Stage I-III breast cancer (surgery and chemotherapy, disease-free survival, seven studies); 2) stage I-III breast cancer (surgery and chemotherapy, overall survival, six studies); 3) stage II-IV head and neck cancer (radiotherapy and chemotherapy, overall survival, five studies); 4) FIGO I-IV ovarian cancer (surgery and chemotherapy, overall survival, six studies). In the breast (disease-free survival) and ovarian (overall survival) comparison groups, the hazard ratio for a deleterious effect of p53 overexpression was significant or marginally significant, depending on assumed ranges for unreported hazard ratios in non-significant studies. CONCLUSIONS: Despite the many caveats related to metaanalysis applied to retrospective data, high variability of immunohistochemical technique, etc., a nearly significant negative effect of p53 overexpression on outcome of treatment with cytotoxic drugs and radiation emerges in the few studies where heterogeneity can be sufficiently reduced or accounted for.

6
UI - 7273026
AU - Slayton RE; Pagano M; Creech RH
TI - Progestin therapy for advanced ovarian cancer: a phase II Eastern Cooperative Oncology Group trial.
SO - Cancer Treat Rep 1981 Sep-Oct;65(9-10):895-6

7
UI - 12199041
AU - Camatte S; Rouzier R; Boccara-Dekeyser J; Pautier P; Pomel C; Lhomme C;
TI - Duvillard P; Castaigne D; Morice P [Prognosis and fertility after conservative treatment for ovarian tumors of limited malignity: review of 68 cases]
SO - Gynecol Obstet Fertil 2002 Jul-Aug;30(7-8):583-91
AD - Service de chirurgie oncologique-gynecologique, Institut Gustave-Roussy, 39, rue Camille-Desmoulins, 94805 Villejuif, France.
The aim of this retrospective study was to evaluate the rate of recurrence and the reproductive outcome after surgical conservative treatment of low malignant ovarian tumors (LMOT). MATERIAL AND METHODS: Sixty-eight patients with 50 Stage I LMOT and 18 LMOT with peritoneal implants treated conservatively at institut Gustave-Roussy, between adnexectomy (associated twelve times with a contralateral cystectomy), Seven had a bilateral cystectomy and two an unilateral cystectomy. Five patients received adjuvant therapy. RESULTS: With a median follow-up of 71.5 months, 16 patients recurred and one had evolutive peritoneal disease. The histologic pattern of ovarian recurrences was always of borderline type. The histologic patterns of peritoneal recurrence was similar to those initially diagnosed except in one case. Peritoneal implants, exophytic tumor and serous type tumor were significatively associated with a higher 5-year recurrence rate. Recurrence was more frequent after cystectomy than unilateral adnexectomy (p = 0.13). None of patients treated conservatively recurred under the form of ovarian carcinoma. None patient died of tumor. Nineteen patients experienced 26 pregnancies: 24 were spontaneous in a median delay of 19 months. Seven infertile patients underwent ovarian stimulation. None recurred after infertility treatments. The 2-year and 5-year cumulative pregnancy rate were respectively 41.9% and 59.8%. Four patients experienced a pregnancy after a conservative treatment of their recurrence. CONCLUSION: Despite a high recurrence rate, especially in stage II and III serous LMOT, conservative treatment of LMOT does not affect survival and should be considered in young patients. Such treatment is not advised in case of invasive peritoneal implants. Spontaneous pregnancy rate is good but the frequent infertility associated with these tumors can afterwards require ovarian stimulation. Limited number of stimulation cycles is acceptable in such patients.

8
UI - 9442179
AU - Wolfe CD; Raju KS
TI - Gynaecological cancer services: time for change.
SO - Br J Obstet Gynaecol 1998 Jan;105(1):127

9
UI - 12237914
AU - Brooks SE; Ahn J; Mullins CD; Baquet CR
TI - Resources and use of the intensive care unit in patients who undergo surgery for ovarian carcinoma.
SO - Cancer 2002 Oct 1;95(7):1457-62
AD - Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. sbrooks@umm.edu
BACKGROUND: The objective of the current study was to determine the association of age, comorbid illness, and length of stay (LOS) in the intensive care unit (ICU) in women who underwent oophorectomy for ovarian carcinoma. METHODS: The authors conducted a population-based analysis of all women with a primary or secondary diagnosis of ovarian carcinoma who underwent oophorectomy between 1994-1999. Chi-square tests and Student t tests were used to determined differences in means or proportions. Multivariate regression methods were used to build predictive models. RESULTS: Of 8109 women who were admitted, 1412 women underwent oophorectomy, 1045 of 1412 women (74%) underwent hysterectomy, 325 of 1412 women (23%) underwent intestinal surgery, and 296 of 1412 women (21%) were admitted to the ICU. Overall (+/- standard deviation) LOS was 8.3 days +/- 6.90 days, and the total charges were $16,675 +/- $15,590 (1999 dollars). Patients who underwent intestinal surgery were older (62.5 years vs. 57.1 years; P = 0.01), had a longer LOS (11.62 days vs. 7.33 days; P = 0.01), had a longer ICU stay (1.15 days vs. 0.58 days; P = 0.01), and had a higher mean Charlson Comorbidity Index (CCI) (16.01 vs. 8.73; P = 0.01) compared with patients who did not undergo intestinal surgery. Multivariate regression analysis revealed that age, intestinal surgery, CCI, ICU stay, and African-American race were associated with LOS and contributed indirectly to total charges, whereas age and ICU say were the two most important direct determinants of total charges. CONCLUSIONS: Advancing age, ICU stay, intestinal surgery, African-American race, and comorbid illness were the most prominent predictors of LOS, whereas age and ICU stay were the most important factors predicting total charges in women who underwent oophorectomy for ovarian carcinoma. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10872

10
UI - 12006509
AU - Leonard DG; Travis LB; Addya K; Dores GM; Holowaty EJ; Bergfeldt K;
TI - Malkin D; Kohler BA; Lynch CF; Wiklund T; Stovall M; Hall P; Pukkala E; Slater DJ; Felix CA p53 mutations in leukemia and myelodysplastic syndrome after ovarian cancer.
SO - Clin Cancer Res 2002 May;8(5):973-85
AD - Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
PURPOSE: Although p53 mutations occur in alkylating agent-related leukemias, their frequency and spectrum in leukemias after ovarian cancer have not been addressed. The purpose of this study was to examine p53 mutations in leukemias after ovarian cancer, for which treatment with platinum analogues was widely used. EXPERIMENTAL DESIGN: Adequate leukemic or dysplastic cells were available in 17 of 82 cases of leukemia or myelodysplastic syndrome that occurred in a multicenter, population-based cohort of 23,170 women with ovarian cancer. Eleven of the 17 received platinum compounds and other alkylating agents with or without DNA topoisomerase II inhibitors and/or radiation. Six received other alkylating agents, in one case, with radiation. Genomic DNA was extracted and p53 exons 5, 6, 7, and 8 were amplified by PCR. Mutations and loss of heterozygosity were analyzed on the WAVE instrument (Transgenomic) followed by selected analysis by sequencing. RESULTS: Eleven p53 mutations involving all four exons studied and one polymorphism were identified. Genomic DNA analyses were consistent with loss of heterozygosity for four of the mutations. The 11 mutations occurred in 9 cases, such that 6 of 11 leukemias after platinum-based regimens (55%) and 3 of 6 leukemias after other treatments (50%) contained p53 mutations. Two leukemias that occurred after treatment with platinum analogues contained two mutations. Among eight mutations in leukemias after treatment with platinum analogues, there were four G-to-A transitions and one G-to-C transversion. CONCLUSIONS: p53 mutations are common in leukemia and myelodysplastic syndrome after multiagent therapy for ovarian cancer. The propensity for G-to-A transitions may reflect specific DNA damage in leukemias after treatment with platinum analogues.

11
UI - 12006545
AU - Saga Y; Mizukami H; Suzuki M; Kohno T; Urabe M; Ozawa K; Sato I
TI - Overexpression of PTEN increases sensitivity to SN-38, an active metabolite of the topoisomerase I inhibitor irinotecan, in ovarian cancer cells.
SO - Clin Cancer Res 2002 May;8(5):1248-52
AD - Department of Obstetrics and Gynecology, Jichi Medical School, Yakushiji, Minamikawachi, Tochigi 329-0498, Japan. saga@jichi.ac.jp
PURPOSE: PTEN is a tumor suppressor gene that was identified on chromosome 10q23. In addition to its original function as a tumor suppressor, this gene product was recently reported to enhance the sensitivity of cancer cells to anticancer agents. It is for the purpose of this study to investigate its function and the mechanisms by which PTEN enhances the sensitivity of ovarian cancer to antitumor agents. EXPERIMENTAL DESIGN: PTEN cDNA was introduced into the ovarian cancer cell line SHIN-3 and a high-expression cell line (SHIN-3/PTEN) was established. This cell line and a control were further analyzed. RESULTS: SHIN-3 cells did not carry any mutations in its genome after sequencing. In vitro examination of sensitivity to anticancer agents showed that the 50% growth-inhibitory concentration value for irinotecan metabolite (SN-38) in SHIN-3/PTEN was 800 nM, a 6.6-fold higher sensitivity compared with that of the control (5300 nM). There were no differences in sensitivity to cisplatin, paclitaxel, or gemcitabine between SHIN-3/PTEN and the controls. The percentage of apoptotic cells in SHIN-3/PTEN was 16.6 +/- 0.7% 24 h after addition of SN-38, a significant increase over controls (8.6 +/- 0.9%; P < 0.01). Lower topoisomerase I activity was observed in SHIN-3/PTEN, compared with controls. CONCLUSIONS: These results indicate that high PTEN expression enhances the sensitivity of ovarian cancer cells to irinotecan and the induction of apoptosis and the suppression of topoisomerase I activity in cancer cells are suggested as possible mechanisms attributable to high PTEN expression.

12
UI - 12203107
AU - Shen M; Schilder RJ; Obasaju C; Gallo JM
TI - Population pharmacokinetic and limited sampling models for carboplatin administered in high-dose combination regimens with peripheral blood stem cell support.
SO - Cancer Chemother Pharmacol 2002 Sep;50(3):243-50
AD - Department of Pharacology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
OBJECTIVE: By means of a nonlinear mixed effect modeling technique, a population pharmacokinetic (PK) model was developed to evaluate the effects of a variety of covariates on clearance and other pharmacokinetic parameters of ultrafilterable carboplatin administered in high-dose combination regimens with peripheral blood stem cell support. In addition, single-sample and two-sample limited sampling models (LSMs) were derived to estimate carboplatin's AUC that could be used in the design of drug dosing regimens. METHODS: A total of 44 female patients with advanced ovarian cancer participated in two phase I studies. All 44 patients received a high-dose carboplatin chemotherapy with other anticancer drugs. A population PK model was applied to the plasma concentration-time data of ultrafilterable carboplatin using the NONMEM and Xpose computer programs. The Xpose program utilized a general additive modeling technique to identify significant patient covariates and PK parameter relationships. The resultant PK model was validated using a bootstrap method. Stepwise linear regression analyses were used to develop LSMs based on the correlation between carboplatin's AUC and plasma concentrations. RESULTS: The best structural covariate-free model for high-dose carboplatin was a linear two-compartment model with an exponential error model to account for intersubject variability and a CCV error model to account for intrasubject variability. Subsequently, a final covariate model for clearance (l/min) was obtained as follows: TVCL=0.101+0011*(WT-62.35)-0.0658*(SCR-0.65) where WT is body weight (kg) and SCR is serum creatinine (mg/dl). Both WT and SCR were found to significantly influence carboplatin's total clearance. It was determined that the best single-sample LSM was AUC(LSM)=0.553*C(240min) ( r=0.998). CONCLUSION: Both a population PK model and a LSM for high-dose carboplatin were developed following its administration in combination chemotherapeutic regimens with peripheral blood stem cell support. In both cases, the models performed well when analyzed in the context of the retrospective and bootstrap analyses. Prospective studies in ovarian cancer patients should be conducted to further tailor the current models.

14
UI - 12297120
AU - Stebbing J; Gaya A
TI - Pegylated liposomal doxorubicin (Caelyx) in recurrent ovarian cancer.
SO - Cancer Treat Rev 2002 Apr;28(2):121-5
AD - Pan Thames Rotation, Hammersmith Hospitals NHS Trust, Fulham Palace Road, London W6 8RF, UK.
Epithelial ovarian cancer (EOC) is the most common gynaecological malignancy in the Western world and a leading cause of death. Patients with relapsed EOC are incurable and therefore the toxicity of palliative chemotherapy and effects on health-related Quality of Life are important factors. Several newer cytotoxic agents have been used in these patients. Pegylated liposomal doxorubicin (Caelyx) has a different spectrum of activity from standard doxorubicin with response rates up to 25% in these patients and a low toxicity profile. In addition it is non cross resistant with platinum compounds. In a randomised phase III trial (n=474) of Caelyx versus Topotecan there were no significant differences in response rates, time to progression, overall survival or quality of life. Patients receiving Topotecan had more side effects requiring admission to hospital. Caelyx is a valuable therapy in platinum resistant patients with an efficacy equivalent to Topotecan but at a lower cost when side-effects and admission costs are included.

15
UI - 12355638
AU - Chechia A; Koubaa A; Makhlouf T; Messaoudi Y; Terras K; Riahi J
TI - [Management of dermoid ovarian cysts. Report of 58 cases]
SO - Tunis Med 2002 Mar;80(3):131-5
AD - Service de gynecologie obstetrique A EPS Charles Nicolle, Tunis.
OBJECTIVE: To assess diagnosis and therapeutic problems of der mo id cysts.' METHODS: A retrospective study of 58 patients having undergone surgery for dermoid cyst between 1991 and 1999. Clinical, ultrasonographic and therapeutic data were analysed. RESULTS: Dermoid cyst accounts for 21.8% of all ovarian tumours. The mean age of patients was 34.75 years (17-73 years). 48 patients (82.7%) presented symptoms. In 10 cases (17.3%), the cysts were discovered during gynaecological and or ultrasonographic examination. The pre-operative diagnosis was precised with the help of ultrasonography in 52 cases, with standard abdominal X-ray in 19 cases and with computed tornography scan in 4 cases. Laparotornic and laparoscopic treatment were performed in respectively 51 and 7 cases. One case of granulornatous peritonitis after laparoscopic surgery was observed. Histological findings were 64 dermoid cysts and 2 serous cysts. Dermoid cysts were bilateral in 6 cases (10.34%) and associated with contro-laterally serous cyst in 2 cases. CONCLUSION: Dermoid cysts are tumors encountered mainly in young patients. After a careful pre-operative assessment, the laparoscopic approach is very interesting. However, a laparotomy should be considered in case of suspected malignancy.

16
UI - 12216079
AU - Nakayama K; Kanzaki A; Ogawa K; Miyazaki K; Neamati N; Takebayashi Y
TI - Copper-transporting P-type adenosine triphosphatase (ATP7B) as a cisplatin based chemoresistance marker in ovarian carcinoma: comparative analysis with expression of MDR1, MRP1, MRP2, LRP and BCRP.
SO - Int J Cancer 2002 Oct 10;101(5):488-95
AD - Department of Pathology Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
Intrinsic or acquired resistance to chemotherapy is the major obstacle to overcome in the treatment of patients with solid carcinoma. Cisplatin is one of the most effective chemotherapeutic agents for treating ovarian carcinoma. Recently, copper-transporting P-type adenosine triphosphatase (ATP7B) has been demonstrated as one of the genes responsible for cisplatin resistance in vitro. We hypothesized that the expression of ATP7B gene increases resistance to cisplatin in ovarian carcinoma and a priori knowledge of its expression is important for the choice of therapy. The aim of our study was to assess the role of ATP7B gene in ovarian carcinoma and compare its expression with those of multidrug resistance-related transporters such as MDR1, MRP1, MRP2, LRP and BCRP genes. The transporters' gene expression profiles from 82 patients treated with cisplatin-based chemotherapy after surgery were assessed by RT-PCR. We did not observe any significant correlation between ATP7B gene expression and those of MDR1, MRP1, MRP2, LRP or BCRP. The expression level of ATP7B gene was significantly increased (p < 0.05) in patients with moderately-/poorly-differentiated ovarian carcinomas treated with cisplatin-based chemotherapy, thus ATP7B may serve as an independent prognostic factor in these patients. In contrast, the expression level of MDR1, MRP1, MRP2, LRP and BCRP genes were not prognostic indicators of disease. These findings suggest that ATP7B gene may be considered as a novel chemoresistance marker and that inhibitor(s) of ATP7B might be useful, in patients with ovarian carcinoma treated with cisplatin-based chemotherapy. Copyright 2002 Wiley-Liss, Inc.

17
UI - 12070798
AU - Tanner B; Pilch H; Schaffer U; Franzen A; Seufert R; Hengstler JG
TI - [Expression of c-erbB-2 and topoisomerase II alpha in relation to chemoresistance in ovarian cancer]
SO - Zentralbl Gynakol 2002 Mar;124(3):176-83
AD - Universitatsfrauenklinik Mainz, Langenbeckstasse 1, Germany.
In the present study, we examined die role of c-erbB-2 for chemoresistance in ovarian cancer. Overexpression of c-erbB-2 mRNA in tumor tissue was associated with a shorter survival of patients with primary ovarian cancer (P = 0.0001, N = 77) and was an independent prognostic factor in the proportional-hazard model (P = 0.035). A significant association between expression of c-erbB-2 mRNA und survival was obtained for the subgroup of patients who received a standard chemotherapy with carboplatin or cisplatin and cyclophosphamide (P = 0.0003). In addition, the application of a standard chemotherapy improved the survival of patients with relatively low c-erbB-2 expression (P = 0.013), but not of patients with overexpression of c-erbB-2 (P = 0.359). Expression of c-erbB-2 mRNA correlated with expression of topoisomerase IIalpha mRNA determined by a reverse semiquantitative PCR technique (P = 0.009), whereas expression of c-erbB-2 und topoisomerase IIbeta mRNA dit not correlate (P = 0.221). The data suggest that topoisomerase IIalpha, which correlates with c-erbB-2 expression, contributes to the resistance of c-erbB-2-overexpressing carcinomas.

18
UI - 12152281
AU - Dudkiewicz J; Kowalski T; Grzonka D; Czarnecki M
TI - [Ovarian tumors in pregnancy]
SO - Ginekol Pol 2002 Apr;73(4):342-5
AD - Katedry i Kliniki Ginekologii S. A. M w Zabrzu.
OBJECTIVE: The clinical characteristics of pregnancy complicated by ovarian tumors were investigated. MATERIAL AND METHODS: A review was performed of patients who were seen with ovarian tumors in pregnancy complex tumors > 5 cm that were seen on ultrasonographic evaluation. RESULTS: 23 patients of 21,506 deliveries were identified with ovarian tumors that met the criteria. 21 had operative intervention, whereas 2 were managed conservatively. Gestational ages at the time of surgery ranged from 16 to 24 weeks. No intraoperative et postoperative maternal or fetal complications occurred. In 2 cases adnexal masses seen on ultrasonography resolved spontaneously by 16 weeks. 19 ovarian tumors were benign. One patient had a stage III ovarian carcinoma and went to total hysterectomy, and other patient had a stage IA ovarian carcinoma and went to simple adnexectomy. CONCLUSIONS: Ovarian surgery in pregnancy for persistent masses is important to obtain a final histologic diagnosis. Optimal gestational age for the surgery is among 16 and 24 weeks.

19
UI - 12152282
AU - Elias M; Goluda M; Jedryka M
TI - [Ovarian cancer in a pregnant woman and limited treatment strategy--a case report]
SO - Ginekol Pol 2002 Apr;73(4):346-9
AD - II Katedry i Kliniki Ginekologii AM we Wroclawiu.
We present the case of 31-year-old woman in 13th week of pregnancy with the diagnosis of the ovarian cancer (cystadenocarcinoma papillare serosum G1) in the FIGO stage Ia. Taking into consideration this data and the patient's wish of preserving the pregnancy and the childhood bearing possibility in the future we performed only left salpingooophorectomy. Postoperative and further pregnancy course was uncomplicated. The pregnancy was terminated in the 40th week by cesarean section--a well doing male newborn in term was delivered. The cesarean section was at the same time the second look procedure. All organs of peritoneal cavity were inspected--no macroscopic changes were observed, oncologic smears and specific biopsies were taken showing no neoplasmatic lesions present in the histology. Nowadays it is the 5th year of systematic patient's control, who is in complete remission. This case report is the example of the limited treatment strategy success based on prognosing factors (tumor histology, grading, staging) as well as patient's wishes of preserving the fertility.

20
UI - 12152283
AU - Makarewicz H; Olszewski J; Krolikowska B; Brzoska B; Emerich J
TI - [Coexistence of ovarian carcinoma with pregnancy--case report]
SO - Ginekol Pol 2002 Apr;73(4):350-3
AD - II Kliniki Poloznictwa i Ginekologii Akademii Medycznej w Gdansku.
OBJECTIVE: Ovarian tumors during pregnancy are a rare event. More ovarian tumors are detected accidently during ultrasonography examination or caesarean section at term. STUDY DESIGN: Ovarian tumor was recognized at the 36 years old patient during 21 weeks of pregnancy and was observed and treated during caesarean section. RESULTS: During caesarean section the mesonephroid ovarian carcinoma at IA stage has been diagnosed and unilateral cystectomy after meticulous surgical exploration was done.

21
UI - 12152284
AU - Nowak M; Szpakowski M; Malinowski A; Romanowicz H; Wieczorek A;
TI - Szpakowski A; Wilczynski JR; Maciolek-Blewniewska G; Kolasa D [Ovarian tumors in the reproductive age group]
SO - Ginekol Pol 2002 Apr;73(4):354-8
AD - Kliniki Chirurgii Ginekologicznej Instytutu Centrum Zdrowia Matki Polki w Lodzi.
OBJECTIVES: Analysis of the type and localization of the ovarian tumors in the reproductive age group of women. MATERIALS AND METHODS: The study group consisted of all women operated on Gynecologic Surgery Department of Polish Mothers's Memorial Hospital-Research Institute due to ovarian tumors in 1996-99. As the reproductive age we defined 18-39 year, when the majority of deliveries occurs. RESULTS: We analyzed 326 patients operated on the ovarian tumors. In 60 cases (18.4%) we noticed ovarian malignant tumors, in 7 (2.1%) borderline tumors and in 259 (79.5%) benign cysts. In the reproductive age (130 women) the incidence of ovarian malignancies was significantly lower (4.6%), higher for benign tumors (93.1%) and constant for borderline malignancy (2.3%), p < 0.005. The most common malignancy among all patients was epithelial cancer--83.4% (germ cell and metastatic--8.3%, both), but in the reproductive age group (6 cases) germ cell tumors were the majority--66.8% (epithelial and metastatic--16.6%, both), p < 0.005. In women aged 18-39 yr. with ovarian malignancies 4 of them had I stage of the disease and 2 were in the stage III. 121 women in the reproductive age were operated on the benign ovarian tumors; 107 (88.4%) had unilateral cysts and 14 (11.6%) had tumors in both ovaries. On histology we revealed 31.1% of endometrioid cysts, 28.9%--teratomas, 19.3%--serous, 3.7%--mucinous and others (hemorrhagic, functional, sex cord, inflammatory) in the remaining 17%. CONCLUSION: In the reproductive age ovarian tumors are mainly unilateral benign cysts. Only a few of ovarian tumors were malignant but the majority of them were in the early stage of the disease.

22
UI - 12152285
AU - Olejek A; Kaminski K; Kniazewski B; Grochal S; Chimiczewski P
TI - [Ovarian tumors in pregnancy]
SO - Ginekol Pol 2002 Apr;73(4):359-63
AD - Katedry i Oddzialu Klinicznego Poloznictwa i Ginekologii Sl.A.M. w Bytomiu.
OBJECTIVES: The presence of adnexal tumours in pregnancy is a significant problem for obstetricians requiring quick diagnosis and operation. MATERIALS AND METHODS: The paper presents 22 cases of ovarian tumours diagnosed and treated during pregnancy. In 12 cases laparoscopical cystectomies were performed, in 10 cases laparotomies were done. RESULTS: Fifteen patients delivered at term, 7 of them by the natural way. In 8 cases cesarean sections were performed: in 4 cases because of obstacle to labour in the next 4 because of other obstetricians reasons. Benign ovarian tumors were found in 20 cases (cystis dermoidalis 18%, cystis follicularis 13.8%, cystoma serosum 13.8%, cystis simplex 18%, cystis corporis lutei 9.2%, cystis picea 18%). In 1 case borderline malignancy cystadenoma papillare mucinosum were diagnosed and in 1 case during laparoscopy in 21 weeks of pregnancy ovarian malignant metastatic tumors were found. Two patients miscarriage in 11 and 13 weeks of pregnancy. Last two pregnancies are still observed. CONCLUSION: Ovarian tumors diagnosed during pregnancy have to be removed because of the thread of malignancy and pregnancy or labour complications.

23
UI - 12152288
AU - Pitynski K; Basta A; Szczudrawa A; Oplawski M
TI - [Ovarian tumors in pregnancy in the material of the Department of Gynecology and Oncology Collegium Medicum of Jagiellonian University in Cracow]
SO - Ginekol Pol 2002 Apr;73(4):371-5
AD - Katedry i Kliniki Ginekologii i Onkologii Collegium Medicum Uniwersytetu Jagiellonskiego.
OBJECTIVES: Although ovarian tumors are rare in pregnancy, they constitute a real diagnostic and therapeutic challenge. DESIGN: The aim of the study was to describe pathomorphological and clinical characteristic of ovarian tumor in pregnancy and to review the effects of diagnostics and treatment. MATERIALS AND METHODS: The study included 76 pregnant women treated due to ovarian tumors at Department of Gynaecology and Oncology, Collegium Medicum of Jagiellonian University. The age of patients range from 18 to 41 years (mean age 26 years). Diameter of each tumor was more then 5 cm. RESULTS: The symptoms of the tumors occurred in 25% of patients. Most of them were unilateral (96.05% cases). In 88.16% of cases the tumor diameter did not exceeded 10 cm. 71.05% of tumors were detected in first trimester of pregnancy. More then 50% of cystic tumors, that had not been surgically treated directly after detection disappeared during observation. Most common histological type of operated tumors were teratoma adultum (50%) and corpus luteum cyst. The malignant tumor of ovary was detected in 3.12% of cases. Spontaneous abortion after surgical treatment occurred in one patient after, emergency operation due to tumor torsion. CONCLUSIONS: Most of the ovarian tumors in pregnancy were benign. Incidence of ovarian malignancies in pregnancy did not exceed 4%. More then 50% of tumors that had not been removed directly after detection disappeared in the course of observation. Spontaneous abortion after operation rarely complicated surgical treatment.

24
UI - 12152290
AU - Szpakowski M; Wilczynski JR; Wieczorek A; Raczkowska Z; Malinowski A;
TI - Nowak M; Kaminski T; Szpakowski A; Wladzinski J; Jaczewski B; Sobantka S; Podciechowski L; Krawczyk T [The number and histopathologic type of ovarian tumors operated during cesarean section at the Polish Mother's Health Institute between 1990-2000]
SO - Ginekol Pol 2002 Apr;73(4):379-85
OBJECTIVES: The differences exist in concerning the estimation of number and histopathological type of ovarian tumors in pregnancy. MATERIAL AND METHODS: From all 41,661 labours which took place in our Institute between 1990-2000 retrospective analysis of medical documentation of 11,050 caesarean sections (CS) as well as histopathological protocols were performed. RESULTS: The prevalence of ovarian tumors removed during CS performed between 28-41 weeks of gestation was 0.19%. The prevalence of malignancy was low (0.005% of all labours). Unilateral cystectomy was found to be the most frequent kind of surgery and adult teratoma, serous cyst and paraovarian cyst as most common histopathological tumor types. CONCLUSION: We conclude that ovarian tumors, especially of malignant type are rarely the complication of pregnancy. The most are benign, small, unilocular and smooth-wall cystic tumors.

25
UI - 12087097
AU - Mabuchi S; Ohmichi M; Kimura A; Hisamoto K; Hayakawa J; Nishio Y; Adachi
TI - K; Takahashi K; Arimoto-Ishida E; Nakatsuji Y; Tasaka K; Murata Y Inhibition of phosphorylation of BAD and Raf-1 by Akt sensitizes human ovarian cancer cells to paclitaxel.
SO - J Biol Chem 2002 Sep 6;277(36):33490-500
AD - Department of Obstetrics and Gynecology, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
We studied the roles of the phosphatidylinositol 3-kinase (PI-3K)-Akt-BAD cascade, ERK-BAD cascade, and Akt-Raf-1 cascade in the paclitaxel-resistant SW626 human ovarian cancer cell line, which lacks functional p53. Treatment of SW626 cells with paclitaxel activates Akt and ERK with different time frames. Interference with the Akt cascade either by treatment with PI-3K inhibitor (wortmannin or LY294002) or by exogenous expression of a dominant negative Akt in SW626 cells caused decreased cell viability following treatment with paclitaxel. Interference with the ERK cascade by treatment with an MEK inhibitor, PD98059, in SW626 cells also caused decreased cell viability following treatment with paclitaxel. Treatment of cells with paclitaxel also stimulated the phosphorylation of BAD at both the Ser-112 and Ser-136 sites. The phosphorylation of BAD at Ser-136 was blocked by treatment with wortmannin or cotransfection with the dominant negative Akt. On the other hand, the phosphorylation of BAD at Ser-112 was blocked by PD98059. We further examined the role of BAD in the viability following paclitaxel treatment using BAD mutants. Exogenous expression of doubly substituted BAD2SA in SW626 cells caused decreased viability following treatment with paclitaxel. Moreover, because paclitaxel-induced apoptosis is mediated by activated Raf-1 and the region surrounding Ser-259 in Raf-1 conforms to a consensus sequence for phosphorylation by Akt, the regulation of Raf-1 by Akt was examined. We demonstrated an association between Akt and Raf-1 and showed that the phosphorylation of Raf-1 on Ser-259 induced by paclitaxel was blocked by treatment with wortmannin or LY294002. Furthermore, interference with the Akt cascade induced by paclitaxel up-regulated Raf-1 activity, and expression of constitutively active Akt inhibited Raf-1 activity, suggesting that Akt negatively regulates Raf-1. Our findings suggest that paclitaxel induces the phosphorylation of BAD Ser-112 via the ERK cascade, and the phosphorylation of both BAD Ser-136 and Raf-1 Ser-259 via the PI-3K-Akt cascade, and that inhibition of either of these cascades sensitizes ovarian cancer cells to paclitaxel.

26
UI - 12365013
AU - Gronlund B; Hansen HH; Hogdall C; Engelholm SA
TI - Efficacy of low-dose topotecan in second-line treatment for patients with epithelial ovarian carcinoma.
SO - Cancer 2002 Oct 15;95(8):1656-62
AD - Department of Oncology, Finsen Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. bo.gronlund@dadlnet.dk
BACKGROUND: The high incidence of dose-limiting myelosuppresion using the U.S. Food and Drug Administration-approved topotecan dose of 1.5 mg/m(2) for 5 days every 3 weeks may have limited its utility in the treatment of patients with epithelial ovarian carcinoma. The objective of the study was to evaluate the treatment results and toxicity of a low-dose topotecan regimen as second-line treatment for patients with epithelial ovarian carcinoma. METHODS: A retrospective analysis was conducted of 203 consecutive patients with primary epithelial ovarian carcinoma who were referred to the Finsen Center during the period from June, 1996 to June, 2000. Eligibility criteria included histopathologically documented, International Federation of Gynecology and Obstetrics (FIGO) Stage IC-IV epithelial ovarian carcinoma; first-line treatment with paclitaxel and a platinum compound; and second-line treatment with topotecan (1.0 mg/m(2) intravenously for 5 days every 3 weeks). Efficacy and toxicity were compared with published results from pivotal trials using the approved dose of topotecan of 1.5 mg/m(2) for the same indication. RESULTS: A total of 56 patients received second-line treatment with the reduced-dose topotecan regimen because of refractory, persistent, or recurrent disease. In the subgroup of patients with platinum-resistant and paclitaxel-resistant disease (n = 43 patients), the response rate of 11.6% (95% confidence interval [95%CI], 3.9-25.1%) was similar to the response rate of 12.4% (95%CI, 6.9-19.9%) in a pivotal trial using standard-dose topotecan. In patients with platinum-resistant and paclitaxel-resistant disease, the median progression free survival and overall survival from the first day of second-line topotecan treatment were 2.7 months (range, 0.7-19.5 months) and 6.0 months (range, 1.0-32.8 months), respectively. In a multivariate Cox analysis, the initial performance status (0 vs. 1-2; P = 0.040; hazard ratio [HR], 2.05) and the performance status at the time of second-line treatment (0 vs. 1-2; P < 0.001; HR, 4.50) were identified as independent prognostic factors for overall survival from the start of second-line treatment. Grade 4 neutropenia was noted in only 5.1% of reduced-dose topotecan cycles (95%CI, 2.8-8.4%) compared with 33% and 57% of standard-dose cycles in pivotal studies. CONCLUSIONS: Topotecan at a dose of 1.0 mg/m(2) has similar efficacy based on response rate and lower toxicity compared with the approved schedule of 1.5 mg/m(2) for 5 days every 3 weeks in second-line treatment for patients with platinum-resistant and paclitaxel-resistant epithelial ovarian carcinoma. However, a comparison of different topotecan doses and schedules preferably should be made in a randomized setting in well-characterized populations with regard to established prognostic factors. Copyright 2002 American Cancer Society.

27
UI - 12370703
AU - Payne JK
TI - The trajectory of fatigue in adult patients with breast and ovarian cancer receiving chemotherapy.
SO - Oncol Nurs Forum 2002 Oct;29(9):1334-40
AD - College of Nursing, Wayne State University, Detroit, MI, USA. jkpayne@salud.unm.edu
PURPOSE/OBJECTIVES: To describe the trajectory of fatigue and determine the feasibility of exploring physiologic mechanisms of fatigue in adult patients receiving chemotherapy for breast and ovarian cancer. DESIGN: Descriptive, longitudinal, repeated measures. SETTING: Outpatient ambulatory cancer centers within two large, academic, teaching hospitals with overnight hospital stays in general clinical research centers. SAMPLE: Seventeen adult participants with either early-stage breast or ovarian cancer receiving chemotherapy for the first time. METHODS: Demographic questionnaire; Piper Fatigue Scale (PFS); hemoglobin, bilirubin, melatonin, and weight change were measured at baseline, three months, and approximately six months. PFS also was collected at three additional two-week nadir, post-treatment, measurement points. Descriptive statistics and repeated analysis of variance measures were used to analyze data. MAIN RESEARCH VARIABLES: Fatigue, hemoglobin, bilirubin, melatonin, and presence of other comorbid disease. FINDINGS: Subjective fatigue was experienced by the majority of patients receiving chemotherapy. It was irregular over time, intensified at three months, and continued after treatment ended. The physiologic trajectory of fatigue from baseline to three months indicated a significant change over time in hemoglobin in the breast cancer group (p = 0.02) and in nighttime melatonin levels for both breast and ovarian cancer groups (p = 0.03).

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