| 1. |
- Blom, René, et al.
(författare)
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Endometrial stromal sarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53, and mdm-2 analysis of 17 cases
- 1999
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Ingår i: International Journal of Gynecological Cancer. - : BMJ. - 1048-891X .- 1525-1438. ; 9:2, s. 98-104
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Tidskriftsartikel (refereegranskat)abstract
- Seventeen patients with endometrial stromal sarcoma (ESS) diagnosed between 1970 and 1996 were evaluated according to DNA ploidy, S-phase fraction (SPF), p53, and mdm-2 expression, as well as traditional clinical and pathologic prognostic factors, such as tumor stage, grade, and mitotic index. DNA flow cytometric analysis and immunohistochemical staining for p53 and mdm-2 were performed on paraffin-embedded archival tissue from the uterine tumors. Flow cytometric DNA histograms were obtained from 16 patients. The patients ranged in age from 41 to 78 years (median, 57 years). Seven (41%) patients were premenopausal. Thirteen low-grade ESS were DNA diploid and had a low SPF. Of these, two overexpressed p53, while only one was mdm-2 positive. Among the four high-grade ESS we found one (25%) DNA diploid tumor and three (75%) DNA aneuploid tumors. Two (50%) had an SPF greater than 10%, three (75%) were p53-positive, and two (50%) overexpressed mdm-2. During the observation period, nine (53%) patients (five with low-grade and four with high-grade tumors) died of disease. The 5-year survival rate for patients with low-grade ESS was 74%, while all four patients with high-grade ESS died of disease within 14 months of diagnosis. Using the log-rank test, we found a significant correlation between survival and tumor grade (P = 0.007), DNA ploidy (P = 0.026), SPF (P = 0.048), and FIGO surgical stage (P = 0.026). In conclusion, we found that tumor grade was a strong predictor of clinical outcome in ESS. In addition, a worse prognosis was found for those ESS patients with advanced disease, DNA aneuploidy, and a high SPF. There was no difference between the recurrent and nonrecurrent group of early stage (surgical stage I), low-grade ESS with regard to clinicopathological features, DNA ploidy, SPF, p53, and mdm-2 expression. All patients with high-grade ESS died of disease within 14 months of diagnosis. In contrast, only three of the 11 patients with early stage, low-grade ESS died of disease.
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| 2. |
- Blom, René
(författare)
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Sarcoma of the female genital tract : Histopathology, DNA cytometry, p53 and mdm-2 analysis related to prognosis
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Sarcomas of the female genital tract are rare tumors and account for less than 5% of gynecologic malignancies. Traditionally, gynecologic sarcomas have been divided into different tumor types according to their histopathological features. The most common are leiomyosarcoma (LMS), malignant mixed Müllerian tumors (MMMT), endometrial stromal sarcoma (ESS) and (Müllerian) adenosarcoma. The different tumor types are highly aggressive with early lymphatic and/or hematogenous spread. Treatment is difficult and it is believed that sarcomas have a low radio-and chemosensitivity, and the mainstay in treatment is surgical removal of the tumor. The most important prognostic feature has been tumor stage. Nevertheless, there are some early-stage tumors that run a biological course different from that expected and additional prognostic factors indicating high-risk tumors are desirable.The study cohort consists of 49 uterine LMS, 44 uterine MMMTs, 17 uterine ESS, 11 uterine adenosarcomas and 26 ovarian MMMTs. The tumors were analyzed in a retrospective manner for DNA ploidy, S-phase fraction (SPF), p53 and mdm-2 expression, as well as traditional clinical and pathological prognostic factors, such as tumor stage. grade, atypia and mitotic index.Of the 49 LMS, 36 (86%) were non-diploid and 13 (27%) were p53-positive. Among the 44 uterine MMMTs, 30 (68%) were non-diploid and 27 (61%) had an SPF>10%. Twenty-seven (61%) overexpressed p53 and 11 (25%) were mdm-2 positive. Furthermore, 40 (91%) of the uterine MMMTs had a high mitotic count and 42 (95%) had high grade cytologic atypia. All low-grade ESS were DNA diploid and had a low SPF. Among the four high-grade ESS, three (75%) were DNA aneuploid and three (75%) were p53-positive. Among 1 1 adenosarcomas, eight (73%) were non-diploid. All ovarian MMMTs were non-diploid and all but two had an SPF>10%. 19 (73%) ovarian MMMTs were p53positive.The 5-year survival rate was 33% for LMS, 38% for uterine MMMT, 57% for ESS, 69% for adenosarcoma and 30% for ovarian MMMT.Thirty-five (71%) patients with LMS died of disease and two of intercurrent disease. Stage was found to be the most important factor for survival (p=0.007); in addition DNA ploidy (p=0.045) and SPF (p=0.041) had prognostic significance.Twenty-seven (61%) patients with uterine MMMT died of disease and six (14%) died of intercurrent disease. Stage was the only prognostic factor for survival.Nine (53%) patients with ESS died of disease. There was a significant correlation of survival to tumor grade (p=0.007), DNA ploidy (p=0.026), SPF (p=0.048) and stage (p=0.026).Of the 11 patients with adenosarcoma, four (36%) patients died of disease and three (27%) patients died of intercurrent disease. There were no variables that correlated with survival.Eighteen (69%) patients with ovarian MMMT died of disease and two (8%) patients died of intercurrent disease. In a multivariate analysis, only stage reached independent prognostic significance for survival (p=0.023).In summary, stage represents the most important prognostic factor for survival for uterine and ovarian sarcomas. DNA flow cytometry is useful in gaining additional prognostic information for LMS and ESS. P53-and mdm-2 overexpression had no prognostic value for survival rate. Most of the MMMT overexpressed p53 and were non-diploid. Treatment of sarcomatous neoplasms is difficult and the mainstay remains surgical removal of the tumor. For patients with early stage sarcoma there was a high recurrence rate, which suggests that a large proportion of patients may have systemic micrometastasic disease at the time of diagnosis. Recurrent and metastatic uterine sarcoma remains an incurable disease, and treatment must be considered palliative.
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| 3. |
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| 4. |
- Malmström, Henric
(författare)
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Intraperitoneal Chemotherapy of Ovarian Cancer
- 1993
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian cancer is still the most common cause of death among gynecologic malignancies in spite of the fact that newer and more effective drugs and/or administration techniques have been developed in the last decade. However, substantial improvements in response rate andprogression-free survival have been reported in many studies.In this study the efficacy, toxicity and feasibility of different drugs administered IP were evaluated in patients with ovarian cancer. The maximum tolerated dose of carboplatin administered IP was determined to be 500 mg!m2 This dose was given adjuvantly in a phase IT study to 47 women with early-stage disease. There were 10 patients in this study who developed recurrent disease. The toxicity was acceptable, the major dose-limiting toxic effect being hematologic, especially thrombocytopenia. One patient developed grade 3 nephrotoxicity after the second course. There was no incidence of treatment-related death.Thirty-five patients with advanced ovarian cancer were treated with an aggressive combination regimen (cisplatin/etoposide) intraperitoneally with IV sodium thiosulphate as antidote. The dose-limiting toxic effect was hematologic. Two patients developed severe nephrotoxicity. The median progression-free interval was 13 months and the survival at closing point 31% with a median follow-up of 16 months.The patient acceptance and feasibility of using subcutaneously implantable peritoneal access devices were analyzed in 125 patients. Port-A-Cath was used in 98% of the patients, 465 IP courses were administered and 27 (21.6%) severe or moderate complications related to Port-A-Cath were registered.The incidence of nephrotoxicity in patients treated IP with platinum-containing regimens was analysed. Six of 135 patients (4%) developed severe nephrotoxicity; impairment of renal function, as judged by serum creatinine, was seen in most patients. This was cumulative during treatment and not completely reversible. Young age was a predictive factor for severe nephrotoxicity.
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| 5. |
- Sorbe, Bengt, et al.
(författare)
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A phase II study of docetaxel weekly in combination with carboplatin every three weeks as first line chemotherapy in stage IIB-IV epithelial ovarian cancer: Neurological toxicity and quality-of-life evaluation
- 2012
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Ingår i: International Journal of Oncology. - Athens : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 40:3, s. 773-781
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to assess the response rate, toxicity, progression-free survival (PFS) and overall survival (OS) in a series of advanced stage ovarian carcinoma patients treated with a first-line weekly docetaxel and three weekly carboplatin regimens. All eligible patients were treated with intravenous docetaxel (30 mg/m(2)) on Days 1, 8 and 15, and carboplatin (area under the curve, 5) on Day 1; Q21 days for at least 6 cycles. Neurological tests, questionnaires, and the EORTC QLQ-C30 and OV28 were used for quality-of-life assessments. One hundred and six patients received at least one cycle of primary chemotherapy (median 6.0; range, 1-9) and they were evaluable for toxicity assessment. Eighty-five patients had evaluable disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% CI 70.1-87.5%) and the biochemical response was 92.8% (95% CI 87.2-98.4%). The median PFS was 12.0 months and the median OS was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3-4 sensory neuropathy. Epiphora, nail changes and fatigue were frequently recorded non-hematological side effects. The tolerable hematological toxicity (no need for colony-stimulating factors) and the low rate of severe neurotoxicity (only grade 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgery make this regimen an interesting alternative in selected patients.
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| 6. |
- Sorbe, Bengt, et al.
(författare)
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Phase II Study of Docetaxel Weekly in Combination With Carboplatin Every 3 Weeks as First-Line Chemotherapy in Stage IIB to Stage IV Epithelial Ovarian Cancer
- 2012
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Ingår i: International Journal of Gynecological Cancer. - : Lippincott, Williams and Wilkins / Wiley-Blackwell. - 1048-891X .- 1525-1438. ; 22:1, s. 47-53
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The purpose of this study was to assess the response rate, toxicity, progression-free survival, and overall survival in a series of patients with advanced-stage ovarian carcinoma treated with a first-line weekly docetaxel and 3 weekly carboplatin regimen. less thanbrgreater than less thanbrgreater thanMethods: All eligible patients were treated with intravenous docetaxel (30 mg/m(2)) on days 1, 8, and 15, and carboplatin (area under the curve, 5) on day 1; every 21 days for at least 6 cycles. less thanbrgreater than less thanbrgreater thanResults: One hundred six patients received at least one cycle of primary chemotherapy (median, 6.0; range, 1-9), and they were evaluable for toxicity assessment. Eighty-five patients had evaluable (measurable) disease and received at least 3 courses of chemotherapy and were evaluable for clinical response rate. The overall response rate was 78.8% (95% confidence interval, 70.1%-87.5%), and the biochemical response 92.8% (95% confidence interval, 87.2%-98.4%). The median progression-free survival was 12.0 months and the median overall survival was 35.3 months. Thirty-six patients (34.0%) experienced grades 3 and 4 neutropenia, which resulted in the removal of 3 patients. Six patients (5.7%) experienced grades 3 or 4 thrombocytopenia. No patients experienced grade 3 to grade 4 sensory neuropathy. Epiphora, nail changes, and fatigue were frequently recorded nonhematologic adverse effects. less thanbrgreater than less thanbrgreater thanConclusions: The tolerable hematologic toxicity (no need for colony-stimulating factors) and the low rate of neurotoxicity (only grades 1-2) and response rates in line with the standard 3-week paclitaxel-carboplatin regimen for advanced primary ovarian carcinoma after suboptimal cytoreductive surgerymake this regimen an interesting alternative in selected patients.
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| 7. |
- Sörensen, Peter, et al.
(författare)
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Phase II study of vinorelbine in the treatment of platinum-resistant ovarian carcinoma
- 2001
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 81:1, s. 58-62
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The purpose of this phase II study was to evaluate on an intent-to-treat basis the activity and toxicity of single-agent vinorelbine (VRL) as second-line chemotherapy of patients with platinum-resistant ovarian cancer. Platinum-resistant disease was defined as disease refractory to or relapsing within 12 months after finishing platinum-containing chemotherapy. Methods. VRL (30 mg/m2) was administered intravenously as a bolus injection days 1 and 8 every 21 days. Initially, four courses of VRL were given. Patients with responding or stable disease received four more courses of VRL to a maximum of eight courses. Results. Twenty-eight of 33 eligible patients were considered evaluable for response. The overall response rate was 21% (7/33) (95% CI: 7-35). Median time to progression was 3.1 months and median survival was 10.1 months. Toxicity was generally mild. Leukopenia was the dose-limiting toxicity. CALGB grade III/IV infection was observed in 15/0% of patients. The most important nonhematologic toxicities were nausea and constipation. Grade III/IV nausea was observed in 6/0% and grade III/IV constipation in 3/3% of patients. Peripheral neurotoxicity was only a minor problem with no grade III/IV toxicity. No patients stopped treatment because of toxicity and no toxic death was reported. Conclusion. VRL was generally well tolerated, but the activity in platinum-resistant ovarian cancer was only modest, although fully comparable to other second-line treatments. Further studies are required to define the role of VRL in combination chemotherapy for ovarian cancer.
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| 8. |
- Zackrisson, Anna-Lena, et al.
(författare)
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No evidence that amifostine influences the plasma pharmacokinetics of topotecan in ovarian cancer patients
- 2002
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 58:2, s. 103-108
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Tidskriftsartikel (refereegranskat)abstract
- Objective: This aim of this study was to compare the pharmacokinetics of topotecan in the presence and absence of preceding amifostine to reduce the risk of side effects in patients with advanced ovarian cancer. Methods: Ten patients with advanced ovarian cancer received topotecan, 1.5 mg/m2 for 5 days, as second-line therapy in an open phase-II study after previous platinum-containing first-line therapy. Patients were randomised to receive intravenous (IV) amifostine at a daily dose of 300 mg/m2 prior to topotecan in the first cycle and topotecan alone in the second cycle or vice versa. Thereafter all patients were given amifostine and topotecan for additional four cycles. Topotecan was given as a 30-min IV infusion. On day 1 of the first and second treatment cycles, venous blood samples were collected up to 24 h after the start of topotecan infusion. Plasma concentrations of total topotecan and its active lactone form were determined using high-performance liquid chromatography. Results: There was a rapid decline in total topotecan plasma concentrations after the end of the infusion followed by a slower decay. The initial decline was even faster for the lactone form. The inter-individual variability was pronounced and the area under the plasma concentration-time curve from time zero to infinity (AUC0-8) of the total topotecan plasma concentration ranged from 182 nmol/l h to 725 nmol/l h for topotecan alone and from 188 nmol/l h to 574 nmol/l h for topotecan and amifostine. The geometric mean of AUC0-8 values were 326 nmol/l h and 297 nmol/l h, respectively (P=0.41). In the cycles when the patients received topotecan alone, the plasma AUC of the lactone averaged 40% of the AUC of the total concentration compared with 39% in the cycles when topotecan was given after amifostine. The peak plasma concentration (Cmax) of the lactone averaged 72% of the Cmax of the total topotecan concentration in the topotecan-only group. The corresponding figure after topotecan and amifostine was 80% (P=0.11). A large intra-individual pharmacokinetic of topotecan between cycles 1 and 2 was also observed. Conclusion: Amifostine, 300 mg/m2, does not significantly affect the pharmacokinetics of topotecan and there are pronounced intra- and inter-individual variabilities in the topotecan pharmacokinetics.
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