Combination chemotherapy of ovarian granulosa cell tumor with cis-platinum and doxorubicin

Two patients with metastatic granulosa cell tumors were treated with cis-platinum and doxorubicin, 50 mg/m² of each drug being given by intravenous bolus every 21 days. Both patients attained complete clinical remission. One, who refused second-look surgery, is alive and free of disease 18 months after cessation of treatment. The other patient had minimal gross residual disease at second-look laparotomy. This regimen shows promise in the treatment of disseminated stromal cord tumors.     

Characterization of newly established human ovarian carcinoma cell line—Special reference of the effects of cis-platinum on cellular proliferation and release of CA125

The cell line HTOA was established from a well-differentiated human ovarian serous cystadenocarcinoma. This line grew well and without interruption for 51 months and was subcultivated over 130 times. The cells were epithelial in shape, and neoplastic and pleomorphic features, a jigsaw puzzle-like arrangement, desmosomal junctional complexes, and multilayering without contact inhibition. The chromosome number was stable at a hypertetraploid range. The culture cells transplanted into BALB/c nude mice and or hamster cheek pouch produced serous cystadenocarcinomas. The cells were found to produce an antigen (CA125) of ovarian cancer, both in vitro and in vivo. The CA125 levels correlated with cellular proliferation in vitro and also with tumor growth, in the nude mouse. These results indicate that the amount of CA125 in the serum is a good marker for detecting early stages of ovarian cancer and in particular for the evaluation of anticancer drugs.     

Feasibility of ovarian preservation in patients with early stage endometrial carcinoma

OBJECTIVES: Our objective was to determine the frequency of a coexisting ovarian malignancy and to evaluate the feasibility of ovarian preservation in patients with early stage endometrial carcinoma. METHODS: Endometrial cancer patients who received primary surgical treatment between 1992 and 2004 were identified using the institution's tumor registry. Information regarding patient age, preoperative and intraoperative evaluations, pathologic reports, and follow-up results was abstracted from medical records. RESULTS: Coexisting ovarian malignancy was detected in 19 (7.31%) of 260 patients who underwent surgical treatment (12 metastatic and 7 synchronous primaries). The independent risk factors of a coexisting ovarian malignancy, as determined using a logistic regression model, were intraoperative extrauterine disease, non-endometrioid histology, lymph node metastasis, and patient age, and the presence of intraoperative extrauterine disease was found to most significantly predict ovarian involvement (OR=542.1; 95% CI, 57.18 to 5139.23). Seventeen of the 19 cases showed abnormal intraoperative gross findings around adnexa or other sites. Among the 206 patients without any evidence of intraoperative extrauterine disease, the coexisting ovarian malignancy rate was 0.97% (2/206), and zero for those under age of 45. In 35 patients, grossly normal ovaries were selectively saved, and no recurrence or cancer-related death occurred (median duration of follow-up: 76 months, range 3-121). CONCLUSIONS: The risk of coexisting malignancy in patients without predictable risk factors is minimal. Therefore, it is possible to preserve ovaries in young women with early stage endometrial carcinoma with a thorough preoperative evaluation and extensive intraoperative exploration.     

Lymph node sampling is of prognostic value in early stage epithelial ovarian carcinoma

PURPOSE: The importance of lymph node involvement as a prognostic factor is still under debate. In the present study, the impact of surgical staging for prognosis in early stages of epithelial ovarian cancer was evaluated in a series of 113 patients. MATERIAL AND METHODS: A retrospective study was carried out at the Department of Gynecological Oncology, Orebro University Hospital, during the period 1994-1998. In a subgroup of 20 out of 113 patients, pelvic lymph node sampling or pelvic lymphadenectomy was included in the standard surgical procedure. In cases of positive lymph nodes, the tumors were upstaged to FIGO Stage III. Pearson's chi-square, the t-test, the log-rank test and Cox multivariate analysis were used in the statistical analyses. RESULTS: The 20 patients with lymph node sampling or lymphadenectomy were compared with the remaining 93 patients without a comprehensive surgical staging procedure. A survival analysis demonstrated a significant (p = 0.005) difference in disease-free survival rates between the two subgroups, where there was a survival benefit in the subgroup of patients who had undergone comprehensive surgical staging. In a Cox proportional hazard regression analysis with disease-free survival as the endpoint, high tumor grade (HR = 3.14) and comprehensive surgical staging with at least a node sampling (HR = 0.09) were significant and independent prognostic factors. CONCLUSION: The benefit in survival after the procedure of lymph node sampling in early stages of epithelial ovarian carcinoma could probably be explained by the fact that the surgical procedure detects otherwise unrecognized Stage III disease.     

Weekly cis-diamminedichloroplatinum II as induction chemotherapy in recurrent carcinoma of the cervix

Twenty-four evaluable patients with recurrent carcinoma of the cervix after previous pelvic irradiation were treated with cis-diamminedichloroplatinum II (cis-DDP). Of the 14 patients who received low-dose (1 mg/kg) weekly induction cis-DDP, 10 (71%) responded, 6 (43%) of which were complete responses. Four (40%) of the ten patients who received high-dose (100 mg/m2) monthly cis-DDP responded, two of which were complete responses. Maintenance of these responses by combination chemotherapy which includes cis-DDP remains a significant problem.     

Demographic and genetic characteristics of patients with borderline ovarian tumors as compared to early stage invasive ovarian cancer

OBJECTIVE: Evaluation whether Jewish founder mutations in BRCA predispose to borderline tumors as they do to early invasive ovarian cancers. METHODS: All Jewish women with borderline or invasive ovarian tumors, diagnosed over a 5-year period (1994-1999), were identified in the frame of a nationwide epidemiological study on ovarian cancer in Israel. Out of a total of 1489 patients, 1269 were interviewed; of them 256 (20.2%) patients were identified with stage I and II invasive epithelial ovarian tumors, and 233 (18.3%) patients were identified with borderline tumors. All patients underwent interviews, and blood or tissue samples from 117 borderline tumors and 161 early stage invasive tumors were analyzed for the presence of the 185delAG and 5382insC BRCA1, and the 6174delT BRCA2 Jewish founder mutations. RESULTS: Patients with borderline tumors were younger at diagnosis, and more frequently of the serous type (P < 0.001) as compared to patients with early stage ovarian cancer. Prevalence of Jewish founder mutations in BRCA1 and BRCA2 was only 4.3% of patients with borderline tumors as compared to 24.2% of patients with early stage ovarian cancer (P = 0.001). CONCLUSIONS: This nationwide study comparing patients with early stage borderline and invasive epithelial tumors of the ovary confirms our previous pilot study that showed a lower incidence of BRCA mutations in patients with borderline tumors. Our results suggest that the genetic predisposition and the molecular mechanisms underlying tumor initiation differ between invasive and borderline tumors of the ovary.     

Squamous cell carcinoma antigen serum levels as prognostic parameter in patients with early stage vulvar cancer

OBJECTIVE: To determine whether SCC-Ag serum levels can be used as a prognostic parameter in surgically treated early stage vulvar cancer. METHODS: SCC-Ag serum levels were measured preoperatively in 61 surgically staged patients with squamous cell vulvar cancer (UICC pT1 and pT2). Results were correlated to clinical data. RESULTS: Mean (standard deviation) SCC-Ag serum levels in patients with vulvar cancer were 1.5 (1.99) ng/mL. SCC-Ag serum levels were significantly higher in patients with pT2 vulvar cancer (2.2 [2.6] ng/mL) compared with patients with pT1 vulvar cancer (1.0 [1.2] ng/mL, P = 0.034). SCC-Ag serum levels were not associated with lymph node involvement (P = 0.1), tumor grade (P = 0.6), and patients' age (P = 0.5). Multivariate Cox regression models considering tumor stage, lymph node involvement, patients' age, and SCC-Ag serum levels as covariates showed that lymph node involvement (P = 0.04 and P = 0.01) and tumor stage (P = 0.006 and P = 0.009), but not SCC-Ag serum levels (P = 0.8 and P = 0.6), and patients' age (P = 0.08 and P = 0.22) are prognostic factors for disease-free and overall survival, respectively. CONCLUSION: SCC-Ag serum levels cannot be used as an additional prognostic parameter in patients with surgically treated early stage vulvar cancer.     

Mutation and expression of the TP53 gene in early stage epithelial ovarian carcinoma

OBJECTIVE: The early natural history of epithelial ovarian carcinoma remains poorly understood. Mutation of the TP53 gene is common in advanced-stage (III-IV) ovarian cancers, but less well described in early stage (I-II) tumors. The purpose of this study was to perform a comprehensive analysis of TP53 mutation and p53 expression status in early stage ovarian carcinomas. METHODS: Seventy-three cases of various histologic types, including 46 stage I and 27 stage II tumors, were subjected to direct sequence analysis of the entire TP53 coding region and exon-intron junctions as well as immunohistochemical assessment of p53 expression. RESULTS: Overall, mutations were identified in 24 of 73 (34%) cases. However, a significant difference in the distribution of mutations among histologic types was observed; TP53 mutations were present in 14 of 21 (67%) serous cancers and 11 of 52 (21%) non-serous cancers (P = 0.0002). Mutations were equally common between stage I and stage II tumors of serous histology. With respect to the correlation between TP53 mutation and p53 immunopositivity, the sensitivity (58%), specificity (71%), positive predictive value (64%), and negative predictive value (83%) were not sufficiently robust to justify use of p53 expression as a surrogate or screen for mutation. CONCLUSIONS: These data indicate that TP53 mutation is common in early stage ovarian carcinomas of serous histology, with a mutation frequency comparable to that reported for advanced-stage tumors, and is therefore likely to occur early in the progression of the most common histologic variant of ovarian carcinoma.     

Oat cell carcinoma of the uterine cervix in a pregnant woman treated with cis-diamminedichloroplatinum

We report a case of oat cell carcinoma of the cervix whose diagnosis was established by light and electron microscopic studies. The patient was pregnant with a male fetus, and was given a course of cis-diamminedichloroplatinum before definitive surgical therapy. The effects of this treatment upon the tumor and the fetus are discussed.     

The feasibility of early administration of combination chemotherapy following cytoreductive surgery and second-look operation in patients with stage III ovarian carcinoma: a pilot study

The purpose of this study is to evaluate the feasibility of early use of modified PAC-1 chemotherapy following debulking surgery and its efficacy by assessing disease status during a second-look operation. Twenty-six consecutive previously untreated patients with stage III ovarian carcinoma were evaluated in a prospective study over the 5-year period March 1981 to August 1986. Initial exploratory laparotomy was performed for staging and maximum cytoreduction. Within 24 hr postoperative modified PAC-1 (M-PAC-1) combination chemotherapy was administered and then repeated every 4 weeks for 11 months which was then followed by second-look operation. Patients were analyzed according to the following pretreatment characteristics: age, FIGO stage, histologic tumor type, extent of initial surgery, size of residual tumor, and findings during second-look. Nineteen patients were evaluable. No evidence of either microscopic or macroscopic disease was noted in 15 patients (79%), whereas the remaining 4 (21%) exhibited persistent disease. Of the remaining 7 patients not undergoing SLO, 4 completed 12 courses of chemotherapy but did not undergo surgery for medical reason (n = 2) or patient refusal (n = 2). Two more patients refused chemotherapy after 9 courses and the seventh patient expired with persistent disease after 8 courses. The early use of combination chemotherapy was well tolerated. Neurological, hematological, and renal toxicity was never severe enough to cause discontinuation of therapy.     

The role of cytoreductive surgery in the management of stage IV epithelial ovarian carcinoma.

Patients with Stage IV epithelial ovarian carcinoma are generally treated in the same manner as are patients with disease confined to the abdomen--cytoreductive surgery followed by combination chemotherapy. Between 1980 and 1990, 35 women with histologically or cytologically documented Stage IV ovarian carcinoma were treated in this fashion. Sixteen women (45%) underwent optimal initial cytoreductive surgery, defined as less than 2 cm maximum residual disease. Eleven of the 19 women undergoing suboptimal initial procedures underwent interval cytoreduction after two to four cycles of chemotherapy, with 7 achieving an optimal status after the interval procedure. Overall, 23 of 35 patients (66%) were successfully cytoreduced to less than 2 cm either initially or at an interval procedure. Thirty-one of the 35 patients received combination regimens containing platinum as part of their initial therapy. Kaplan-Meier survival curves demonstrated no significant difference in survival between those groups of women cytoreduced intervally or initially, or between those groups of women optimally cytoreduced at some point during their initial therapy and those who were not. The 5-year survival for the entire group was less than 5%, with no significantly prolonged survival seen in those patients undergoing successful cytoreduction.     

SDF-1/CXCR4对卵巢上皮性癌细胞增殖和侵袭的影响

目的:研究SDF-1/CXCR4在卵巢癌细胞生物学活性中的作用。方法:用RT-PCR方法检测卵巢癌细胞株SW626及Anglne中的SDF-1和CXCR4的表达。细胞经外源性SDF-1或者抗CXCR4单克隆抗体干预后,用MTT法检测细胞增殖,PI测细胞凋亡,Annexin-V/PI法检测细胞早期凋亡,Transwell小室检测细胞的迁移侵袭活性。结果:两株卵巢癌细胞株中,SW626细胞既表达SDF-1又表达CXCR4,Anglne细胞则两者均不表达。在SW626细胞中,SDF-1作用于无血清状态下培养的细胞(吸光度A值为0.911±0.01),与对照组(吸光度A值为0.506±0.01)相比,差异有统计学意义(P<0.01),而加入抗CXCR4单克隆抗体作用后(10μg/ml A值为0.725±0.01,20μg/ml A值为0.650±0.02),与SDF-1组相比,差异均有统计学意义(分别为P<0.05和P<0.01);抗CXCR4单克隆抗体作用于无血清状态下培养的细胞(10μg/ml A值为0.655±0.11和20μg/ml A值为0.520±0.04),与对照组(A值为0.724±0.03)相比,差异均有统计学意义(P<0.05)。加入外源性SDF-1后,SW626细胞在无血清状态下的早期凋亡数为15.6%,相对于对照组,差异有统计学意义(P<0.01)。抗CXCR4单克隆抗体可增加SW626细胞中的PI阳性细胞数(P<0.01)。并且,与对照组相比,SDF-1促进SW626细胞的迁移和侵袭能力增强(P<0.01),而此活性可被抗CXCR4单克隆抗体阻断。结论:SDF-1/CXCR4可能通过促进细胞增殖、迁移、侵袭及抑制其凋亡,使卵巢癌细胞获得进展。     

Treatment of FIGO stage IV ovarian carcinoma: results of primary surgery or interval surgery after neoadjuvant chemotherapy: a retrospective study

The objective of the study is to determine whether surgery influences the outcome of stage IV ovarian cancer. The study design is as follows: From May 1995 to December 2000, 129 patients with FIGO stage IV ovarian cancer, recruited in 42 centers, were prospectively included in GINECO first-line randomized studies of platinum-based regimens with paclitaxel administered simultaneously or sequentially. In all, 109 were eligible for this study. Standard peritoneal cytoreductive surgery was defined as a procedure including at least total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and peritoneal debulking. Surgery was considered optimal if residual lesions were smaller than 1 cm. The Kaplan-Meier method was used to compare survival. Initial abdominopelvic cytoreductive surgery was considered standard in 55 (54%) patients. Abdominopelvic surgery was optimal in 29 patients and nonoptimal in 26. Twenty-two (22%) patients had a simple biopsy, and 25 (24%) patients underwent substandard surgery. Twenty-two of these 47 patients without initial standard surgery underwent a second surgical procedure, and 17 of the 22 patients completed standard surgery. The median overall survival time in the entire population was 24.3 months (95% confidence interval [CI], 19.5-29.1 months). Patients treated without a cytoreductive surgical procedure had significantly worse median survival (15.1 months; 95% CI, 5.4-24.9 months) than patients who had optimal primary surgery (22.9 months; 95% CI, 15.6-30.1 months), nonoptimal primary surgery (27.1 months; 95% CI, 21.2-32.9 months), or neoadjuvant chemotherapy followed by surgery (45.5 months; 95% CI, 23.5-67.5 months) (P= .001). In conclusion, this study shows a significant benefit of debulking surgery in stage IV ovarian cancer patients who responded to neoadjuvant chemotherapy. Neoadjuvant chemotherapy can help to select patients for surgery.     

An initial analysis of preoperative serum CA 125 levels in patients with early stage ovarian carcinoma

Preoperative serum CA 125 levels were determined for 36 patients with Stage I and II ovarian carcinoma. Levels ranged from 9 to 1962 U/ml with a mean of 216 U/ml. In Stage I patients, CA 125 levels averaged 133 U/ml and in Stage II patients 382 U/ml. Nine of 24 Stage I (38%) and 9 of 12 Stage II patients (75%) had CA 125 levels in excess of 65 U/ml in a population somewhat overrepresented in mucinous tumors. Patients with non-mucinous neoplasms had CA 125 elevations more often--in 75% of the cases--than those with mucinous tumors. A larger study will be required to more precisely estimate the fraction of early stage patients with elevated preoperative serum CA 125 levels; however, this investigation demonstrates an assay sensitivity minimally adequate to initiate a pilot evaluation of serum CA 125 levels in a population at risk for ovarian carcinoma.     

Cervical carcinoma: a hazard model in early stage disease

The 235 patients with stage IB/IIA cervical carcinoma treated by Wertheim's hysterectomy, as a primary procedure, at St Mary's Hospital, Manchester between 1975 and 1989 inclusive, form the basis of this study. Using Cox's regression model, four variables were shown to have independent prognostic significance. These were: (1) lymphatic permeation (adjacent to the tumor); (2) tumor volume; (3) being pregnant at diagnosis and (4) lymph node metastases. A heuristic model was formulated which was based upon these four factors and by using this information it was possible to separate the patients into four distinct prognostic groups. It is suggested that this model may prove useful in identifying those patients at a higher risk of dying of disease and who would benefit from early adjuvant systemic therapy.     

Her-2/neu expression and amplification in early stage ovarian surface epithelial neoplasms

OBJECTIVE: The aim of this study is to examine Her-2/neu gene amplification and protein overexpression in a spectrum of ovarian neoplasms using both immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) techniques that are FDA approved. This study is focused on early stage tumors including both carcinomas and borderline tumors. METHODS: FDA-approved IHC and FISH for Her-2/neu were performed on formalin-fixed, paraffin-embedded tissue from 79 ovarian neoplasms representing a broad spectrum of tumor types as well as four normal ovaries. All tumors were either stage I or stage II. Tumor and normal tissue were studied collectively using a tissue microarray (TMA). HercepTest (DAKO) and PathVysion Her-2/neu probe kit (Vysis Inc.) were used for IHC and FISH analysis. RESULTS: FISH analysis of serous carcinomas demonstrated Her-2/neu gene amplification in 3 (18%) of 17 cases. Two of three cases showing Her-2/neu gene amplification were scored 1+ using IHC, while the remaining case was scored as 0. Analysis of endometrioid carcinomas demonstrated Her-2/neu amplification using FISH in 1 of 10 (10%) cases. IHC in this case was scored 2+ (positive). None of the remaining 44 tumors, including clear cell carcinoma (n = 12), transitional cell carcinoma (n = 1), mixed epithelial carcinoma (n = 7), carcinoma not otherwise specified (n = 1), and 31 borderline tumors (mucinous, n = 17; endometrioid, n = 7; serous, n = 7), showed Her-2/neu gene amplification or protein overexpression. Normal ovaries were negative as well. CONCLUSIONS: Amplification of Her-2/neu in early stage ovarian neoplasms is infrequent, 6.7% overall. Due to the limited number of informative cases, we were unable to determine the clinical significance of Her-2/neu amplification in this study. Her-2/neu amplification was restricted to carcinomas and was not encountered in ovarian borderline tumors.     

Intravenous chemotherapy, early debulking surgery, and consolidation intraperitoneal chemotherapy in advanced ovarian carcinoma

OBJECTIVE: The efficacy of a cisplatin-anthracycline combination, early debulking surgery, and intraperitoneal chemotherapy has been demonstrated through separate studies. We evaluated a multimodal treatment strategy integrating these therapeutic options. METHODS: Women with stage III or IV ovarian carcinoma received six cycles of cisplatin/epirubicin alternating with leucovorin and 5-fluorouracil. Patients with a residual disease (RD) measuring more than 2 cm after the initial laparotomy underwent an early debulking surgery after the first three cycles of chemotherapy. A second-look laparotomy (SLL) was performed after six cycles of intravenous chemotherapy. Intraperitoneal chemotherapy with cisplatin, VP16, and mitoxantrone was then administered in patients with no or RD < 2 cm after SLL. RESULTS: A total of 87 patients were included. After initial laparotomy, 11 patients (12%) had no macroscopic residual disease, 38 (44%) had a RD < or =2 cm, and 38 (44%) had a RD > 2 cm. After early debulking surgery, an additional 18 patients (21%) had a RD < 2 cm. Seventy-five patients were evaluable for response to intravenous chemotherapy: the overall response rate was 80%, and 30 patients achieved a pathological complete response (40%). Eight percent of the patients had stable disease and 12% had a progression. Sixty-eight patients received intraperitoneal chemotherapy after second-look laparotomy. With a 72-month median follow-up, median overall survival and progression-free survival were, respectively, 37 and 19 months. Five-year survival was 41%. CONCLUSION: The prognosis of patients with advanced ovarian carcinoma may be improved by a sequential treatment strategy including intravenous chemotherapy, early debulking surgery, and intraperitoneal chemotherapy.