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PURPOSE: To compare taxane maintenance chemotherapy, paclitaxel (P) and paclitaxel poliglumex (PP), with surveillance (S) in women with ovarian, peritoneal, or fallopian tube (O/PC/FT) cancer who attained clinical complete response after first-line platinum-taxane therapy. METHODS: Women diagnosed with O/PC/FT cancer who attained clinical complete response after first-line platinum-taxane-based chemotherapy were randomly allocated 1:1:1 to S or maintenance, P 135 mg/m2 once every 28 days for 12 cycles, or PP at the same dose and schedule. Overall survival (OS) was the primary efficacy end point. RESULTS: Between March 2005 and January 2014, 1,157 individuals were enrolled. Grade 2 or worse GI adverse events were more frequent among those treated with taxane (PP: 20%, P: 27% v S: 11%). Grade 2 or worse neurologic adverse events occurred more often with taxane treatment (PP: 46%, P: 36% v S: 14%). At the fourth scheduled interim analysis, both taxane regimens passed the OS futility boundary and the Data Monitoring Committee approved an early release of results. With a median follow-up of 8.1 years, 653 deaths were reported; none were attributed to the study treatment. Median survival durations were 58.3, 56.8, and 60.0 months for S, P, and PP, respectively. Relative to S, the hazard of death for P was 1.091 (95% CI, 0.911 to 1.31; P = .343) and for PP, it was 1.033 (95% CI, 0.862 to 1.24; P = .725). The median times to first progression or death (PFS) were 13.4, 18.9, and 16.3 months for S, P, and PP, respectively. Hazard ratio = 0.801; 95% CI, 0.684 to 0.938; P = .006 for P and hazard ratio = 0.854; 95% CI, 0.729 to 1.00; P = .055 for PP. CONCLUSION: Maintenance therapy with P and PP did not improve OS among patients with newly diagnosed O/tubal/peritoneal cancer, but may modestly increase PFS. GI and neurologic toxicities were more frequent in the taxane treatment arms.
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Neoplasias , Platino (Metal) , Femenino , Humanos , Inutilidad MédicaRESUMEN
PURPOSE: We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS: A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m2) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS: Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non-BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION: No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma Epitelial de Ovario/mortalidad , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. METHODS: In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. FINDINGS: Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. INTERPRETATION: The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. FUNDING: National Cancer Institute.
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Bevacizumab/efectos adversos , Bevacizumab/uso terapéutico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/mortalidad , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Topotecan/administración & dosificación , Topotecan/efectos adversosRESUMEN
PURPOSE: The purpose of this study was to determine locoregional control (LRC), disease-free survival (DFS), and toxicity of high-dose-rate interstitial brachytherapy (HDR-ISBT) in the treatment of locally advanced cervical cancer. METHODS AND MATERIALS: Between March 1996 and May 2009, 116 patients with cervical cancer were treated. Of these, 106 (91%) patients had advanced disease (International Federation of Gynecology and Obstetrics stage IIB-IVA). Ten patients had stage IB, 48 had stage II, 51 had stage III, and 7 had stage IVA disease. All patients were treated with a combination of external beam radiation therapy (EBRT) to the pelvis (5040 cGy) and 2 applications of HDR-ISBT to a dose of 3600 cGy to the implanted volume. Sixty-one percent of patients also received interstitial hyperthermia, and 94 (81%) patients received chemotherapy. RESULTS: Clinical LRC was achieved in 99 (85.3%) patients. Three-year DFS rates were 59%, 67%, 71%, and 57% for patients with stage IB, II, III, and IVA disease, respectively. The 5-year DFS and overall survival rates for the entire group were 60% and 44%, respectively. Acute and late toxicities were within acceptable limits. CONCLUSIONS: Locally advanced cervical cancer patients for whom intracavitary BT is unsuitable can achieve excellent LRC and OS with a combination of EBRT and HDR-ISBT.
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Braquiterapia/métodos , Carcinoma de Células Escamosas/radioterapia , Neoplasias del Cuello Uterino/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Braquiterapia/efectos adversos , Carcinoma de Células Escamosas/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Hidronefrosis/diagnóstico por imagen , Hipertermia Inducida/métodos , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Radiografía , Radioterapia/métodos , Dosificación Radioterapéutica , Resultado del Tratamiento , Carga Tumoral , Neoplasias del Cuello Uterino/patología , Adulto JovenRESUMEN
At the 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG) held in Vancouver, Canada, in June 2010, representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. The process focused on 13 predetermined questions. Group A, 1 of the 3 discussion groups, addressed the first 5 questions, examining first-line therapies in newly diagnosed ovarian cancer patients. A1: What are the appropriate end points for different trials (maintenance, upfront chemotherapy trials including molecular drugs)? A2: Are there any subgroups defined by tumor biology who need specific treatment options/trials? A3: Is the 2004 GCIG-recommended standard comparator arm still valid? A4: What is the role of modifying dose, schedule, and delivery of chemotherapy? A5: What role does surgery play today?
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Carcinoma/terapia , Ensayos Clínicos como Asunto/métodos , Terapia Neoadyuvante/métodos , Neoplasias Ováricas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/diagnóstico , Consenso , Determinación de Punto Final/métodos , Femenino , Procedimientos Quirúrgicos Ginecológicos/métodos , Procedimientos Quirúrgicos Ginecológicos/normas , Humanos , Terapia Molecular Dirigida/métodos , Neoplasias Ováricas/diagnóstico , PronósticoRESUMEN
A proportion of reproductive age women are affected by gynecologic malignancies. This patient population is faced with difficult decisions, related to their cancer care and treatment, as well as future childbearing potential. Therefore, it is important for gynecologists to be familiar with fertility sparing management options in patients with cervical, ovarian, and endometrial cancer. In addition to understanding the surgical approaches available, providers should be able to counsel patients regarding their eligibility for and the indications and limitations of fertility sparing therapy for gynecologic cancer, allowing for appropriate referrals. A comprehensive PUBMED literature search was conducted using the key words "fertility preservation," "cervical cancer," "endometrial cancer," "ovarian cancer," "borderline tumor of the ovary," "germ cell tumor," "obstetrical outcomes," "chemotherapy," and "radiation." The following review summarizes fertility sparing options for patients with cervical, ovarian and endometrial cancer, with an emphasis on appropriate patient selection, oncologic, and obstetric outcomes.
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Fertilidad , Neoplasias de los Genitales Femeninos/patología , Neoplasias de los Genitales Femeninos/terapia , Infertilidad Femenina/prevención & control , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Procedimientos Quirúrgicos Ginecológicos/métodos , Humanos , Histerectomía/métodos , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Ovariectomía/métodos , Pronóstico , Radioterapia Adyuvante , Medición de Riesgo , Resultado del Tratamiento , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/terapia , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapiaRESUMEN
Endometrial stromal sarcoma (ESS) formerly classified as low-grade endometrial stromal sarcoma is a rare uterine malignancy with a good prognosis despite a tendency to recur. Primary surgical management for ESS includes total abdominal hysterectomy and bilateral salpingo-oophorectomy. Patients with ESS have long disease-free survival rates when treated with primary surgical therapy, but nearly fifty percent of these patients will recur. We present the case of a patient with recurrent ESS who had an excellent response to combined therapy with megestrol and leuprolide.
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The rates of cervical cancer in the United States are low in comparison with developing nations. Whereas the Papanicolaou smear has performed well in terms of detecting both precursors of squamous cell carcinoma and squamous cell carcinoma of the cervix, this test has been less successful at identifying those women with the highest-risk premalignant disease. The use of human papillomavirus testing has also contributed to the improved sensitivity of screening for cervical cancer. In light of this, the colposcopy clinic retains high referral rates yet has poor diagnostic accuracy. Unfortunately, patients are triaged to follow-up for abnormal Papanicolaou smears based on algorithms that rely on the less evidence-based techniques of colposcopy. Therefore, the need to improve the specificity of colposcopic-guided biopsy remains. The colposcopic procedure is highlighted in this review and evaluated in terms of current literature on technique, the colposcopic impression, cervical biopsy, and methods proposed to enhance appreciation of the highest-risk lesions. By outlining certain flaws in technique and discussing the proposal of new tests to supplement the current standard of care, this review aimed to highlight the need for future research to maintain sensitivity but improve the specificity of colposcopy.
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Carcinoma de Células Escamosas/patología , Colposcopía/métodos , Lesiones Precancerosas/patología , Neoplasias del Cuello Uterino/patología , Biopsia/métodos , Femenino , Humanos , Embarazo , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: To determine if low node count from superficial groin dissection correlated with first recurrence in the groin for patients with early vulvar cancer. METHODS: The Gynecologic Oncology Group (GOG) conducted a trial for patients with early stage squamous vulvar cancer, lesions <2 cm in size and <5 mm in depth. All fatty tissue below the inguinal ligament, medial to the sartorious and lateral to the adductor longus was removed. Incision of the fascia and skeletonizing the femoral vessels were not required. For this secondary analysis, we reviewed the records of all patients to assess node counts. RESULTS: Of the 113 patients eligible for the study, 104 patients (with 117 dissected groins) did not have a first recurrence in the groin. The median number of negative nodes was 9 (range: 1-26). Nine patients (with 9 dissected groins) suffered a first recurrence in the groin. The median number of negative nodes removed per groin was 7 (range: 4-22). There were no significant differences between patients with first recurrence in the groin and those without (p value=0.7475). There was a broad overlap of the confidence intervals. CONCLUSIONS: We were unable to show that groin failure after superficial lymphadenectomy was a result of low lymph node count. The small number of recurrences made firm conclusions impossible. Variations in anatomy and other factors may make node counting an unreliable measure of surgical quality.
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Ganglios Linfáticos/patología , Recurrencia Local de Neoplasia/patología , Neoplasias de la Vulva/patología , Femenino , Humanos , Conducto Inguinal/patología , Conducto Inguinal/cirugía , Escisión del Ganglio Linfático , Ganglios Linfáticos/cirugía , Metástasis Linfática , Persona de Mediana Edad , Factores de Riesgo , Neoplasias de la Vulva/cirugíaRESUMEN
OBJECTIVES: To determine the importance of margin status and other prognostic factors associated with the recurrence and survival of patients with squamous cell vulvar carcinoma. METHODS: Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression. All slides were re-reviewed by two gynecologic pathologists. RESULTS: Ninety patients (median age: 69) were treated for vulvar carcinoma from 1984 to 2002, including 28 FIGO stage I, 20 stage II, 26 stage III and 16 with stage IV disease. Sixty-three (70%) patients underwent complete radical vulvectomies and 27 (30%) had modified radical vulvectomies. Nineteen (20%) patients received adjuvant radiotherapy. Five-year disease-specific survival rates were 100%, 100%, 86% and 29% for stages I-IV, respectively. None of the 30 patients with a pathologic margin distance >8 mm had local recurrence. Of the 53 women with tumor-free pathologic margin of <8 mm, 12 (23%) had a local recurrence. Moreover, women with >2 positive groin nodes had significantly higher recurrence risk compared to those with <2 metastatic groin nodes (p<0.001). On multivariate analysis, positive groin nodes and margin distance were important prognostic factors for recurrence. Moreover, stage, tumor size, margin distance, and depth of invasion were significant independent predictors for disease-specific survival. The median follow-up was 58 months (range: 2-188). CONCLUSIONS: Pathologic margin distance is an important predictor of local vulvar recurrence. Our data suggest that a > or =8-mm pathologic margin clearance leads to a high rate of loco-regional control.
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Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Neoplasias de la Vulva/patología , Neoplasias de la Vulva/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/radioterapia , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante , Neoplasias de la Vulva/radioterapiaRESUMEN
OBJECTIVE: Primary lymphoma of the uterine cervix is rare, with less than 60 cases reported. We present a series of 6 patients with cervical lymphoma and review the literature. STUDY DESIGN: Between 1988 and 2003, we identified 6 women with primary lymphoma of the uterine cervix treated at our institutions. Data for analysis were obtained from hospital charts, office records, and tumor registry files. We also reviewed 20 published reports on cervical lymphoma, providing information on 58 additional patients. RESULTS: The median age at diagnosis was 52 years (range 40-76). Three patients had an abnormal Papanicolaou test within 6 months of the diagnosis. Mean tumor size was 8.3 cm (range 3-14 cm). On the basis of the Ann Arbor system of staging where "E" denotes extranodal tumor origin, 2 patients had stage IE, 1 had stage IIIE, and 3 had stage IVE disease. The median follow-up for these 6 women was 33 months (range 12-120). Adding the 6 patients in our series to the 58 patients obtained from published reports, 43 had stage IE, 14 had stage IIE, 2 had stage IIIE, and 5 had stage IVE disease. There was no consistent pattern of treatment identified from our literature review. CONCLUSION: Primary lymphoma of the uterine cervix is a rare malignancy. Most patients present with stage IE disease. Women with localized disease typically respond to various combinations of surgery, chemotherapy, and radiotherapy. Combination chemotherapy with tailored radiotherapy appears to be the preferred treatment option in women with advanced disease.
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Linfoma/patología , Neoplasias del Cuello Uterino/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Humanos , Linfoma/diagnóstico , Linfoma/tratamiento farmacológico , Linfoma/cirugía , Persona de Mediana Edad , Estadificación de Neoplasias , Ovariectomía , Prueba de Papanicolaou , Prednisona/uso terapéutico , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/cirugía , Hemorragia Uterina/etiología , Frotis Vaginal , Vincristina/uso terapéuticoRESUMEN
OBJECTIVE: To determine clinical or biological associations between mast cell density, blood clotting, angiogenesis, and survival of patients with advanced ovarian cancer. METHODS: Tumor tissue sections were assessed for mast cell density by staining for mast cell tryptase, blood clotting by staining of thrombosed blood vessels, and angiogenesis by CD34 expression. Chi-square, Kaplan-Meier, and Cox proportional hazard statistical analyses were used. RESULTS: 44 women with stage III-IV ovarian cancers had tumor blocks available for immunohistochemical analysis. Higher mean vessel density (MVD) (>11 vessels/400x field) predicted for better survival than lower MVD (< or =11 vessels/400x field) (P = 0.004). Women whose tumors had low levels of peri-tumoral mast cell infiltration had a mean survival of 40.6 months compared to 50.6 months in those whose tumors had high levels (P = 0.47). Tumors with higher MVD and high peri-tumoral mast cell infiltration had a mean survival of 80.3 months compared to 37.8 months in those with low mast cell density or low MVD (P = 0.015). Patients with tumors showing a low degree of blood clotting had a mean survival of 45.5 compared to 45.1 months in those with tumors showing a high degree of blood clotting (P = 0.91). There was no significant association between angiogenesis and mast cell density (P = 0.123). In multivariate analysis, higher MVD remained as a significant prognostic factor for improved survival after adjusting for clotting and mast cell density. CONCLUSIONS: Our data suggest that peri-tumoral mast cell infiltration in tumors with high MVD predicts for improved survival in women with advanced epithelial ovarian cancer.
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Coagulación Sanguínea , Mastocitos/patología , Neoplasias Ováricas/irrigación sanguínea , Neoplasias Ováricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Recuento de Células , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Estadificación de Neoplasias , Neovascularización Patológica/sangre , Neovascularización Patológica/patología , Neoplasias Ováricas/sangre , PronósticoRESUMEN
PURPOSE: To compare the in vitro drug resistance profiles of advanced stage primary and recurrent epithelial ovarian cancer specimens using the tritiated thymidine uptake assay. METHODS: Extreme drug resistance (EDR) to cisplatin, paclitaxel, 4-hydroxycyclophosphamide, and topotecan was determined for an unselected population of primary and metastatic malignant ovarian tissues, synchronous tumors (primary and metastatic tissues obtained from the same patient at diagnosis), and metachronous lesions (specimens from the same patient before and after chemotherapy). RESULTS: For the large unselected population of malignant tissues (total, N = 6990; primary ovarian, N = 2031; metastatic ovarian, N = 4959), no statistically significant differences were discovered between primary tissues and metastatic lesions when a comparison was made between the percentage of tumors from each group that exhibited extreme drug resistance to the agents assayed. From the library of 6990 specimens, 119 synchronous pairings were identified. These synchronous lesions did not differ significantly in the %EDR between primary and metastatic sites in the same patient; approximately 10% shifted between low drug resistance and EDR. A total of 334 metachronous pairings were identified and the percentage of tissues that exhibited EDR also failed to show a significant difference when primary tumors were compared with matched recurrences in the same patient. CONCLUSIONS: For the agents studied, acquired resistance was not a function of disease site. In vitro drug resistance observed at recurrence was not influenced significantly by intervening therapy. It is possible that assay results at diagnosis could be used to guide subsequent therapy at relapse, especially when recurrent tissue is not available for analysis.
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Resistencia a Múltiples Medicamentos , Neoplasias Ováricas/tratamiento farmacológico , Cisplatino/farmacología , Ciclofosfamida/análogos & derivados , Ciclofosfamida/farmacología , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Metástasis de la Neoplasia , Neoplasias Primarias Múltiples/tratamiento farmacológico , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/patología , Neoplasias Ováricas/patología , Paclitaxel/farmacología , Topotecan/farmacologíaRESUMEN
The overexpression of the epidermal growth factor receptor (EGFR) is associated with a poor prognosis in ovarian cancer. The dominant-negative EGFR (EGFR-DNR) is a truncated receptor that lacks the tyrosine kinase domain and is devoid of signaling capability. This study tested the effects of a EGFR-DNR approach in ovarian cancer cells. NuTu-19, a rat ovarian cancer cell line was rendered resistant to cisplatin. Both NuTu-19 and resistant cells were infected with a retroviral vector containing the EGFR-DNR. NuTu-19 and NuTu-DNR (NuTu-19 cells expressing the EGFR-DNR) were injected into Fisher 344 immunocompetent rats. Western blot analyses were used to assess signal transduction pathways. All rats injected with NuTu-DNR cells remained healthy following tumor injection. In contrast, 100% of the rats injected with the NuTu-19 and NuTu-Sham (NuTu-19 cells expressing an empty vector) died of disease progression at the end of 15 weeks (P = 0.00009). On Western blot analysis, both NuTu-19 and NuTu-Sham cells showed a strong activation of mitogen-activated protein kinase (MAPK) after exposure to EGF. Cisplatin-resistant cell lines showed an enhanced EGF stimulatory effect via the MAPK pathway compared with parental cells. The EGFR-DNR significantly reduced the ability of EGF to induce cell signaling through the MAPK pathway. Lastly, the EGFR-DNR can partially reverse cisplatin resistance in drug-resistant cells. The EGFR-DNR approach suggests that EGFR confers a growth advantage to NuTu-19 cells in vivo. Thus, EGFR blockade may ultimately prove to be a useful therapeutic tool in the treatment of cisplatin-sensitive and cisplatin-resistant ovarian cancers.
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Antineoplásicos/farmacología , Cisplatino/farmacología , Receptores ErbB/genética , Neoplasias Ováricas/terapia , Animales , Línea Celular Tumoral , Resistencia a Antineoplásicos , Receptores ErbB/biosíntesis , Receptores ErbB/metabolismo , Femenino , Sistema de Señalización de MAP Quinasas , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , ARN/genética , Ratas , Ratas Endogámicas F344 , Retroviridae/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
OBJECTIVE: To evaluate prognostic factors that impacts the survival of women with sex cord stromal tumors of the ovary (SCST). METHODS: Cases were identified from tumor registry databases at three academic institutions between 1975 and 2003. Patient characteristics, surgical treatment, adjuvant therapy, pathologic and follow-up information were collected from hospital charts and clinic records. Kaplan-Meier and Cox proportional hazards analyses were used to identify predictors of outcome. RESULTS: Eighty-three women (median age: 49 years) with SCST of the ovary, including 73 with granulosa and 10 with Sertoli-Leydig cell tumors were identified. Fifty-one were stage I, 8 stage II, 10 stage III, 3 stage IV, and 11 patients were unstaged. The median and 5-year disease-specific survival of women with stage I-II vs. III-IV was 180 months and 85% compared to 58 months and 48%, respectively (P = 0.012). Furthermore, age <50 (P = 0.003), premenopausal status (P = 0.013), tumor size < 10 cm (P = 0.003), lack of lymph node invasion (P < 0.0005), and absence of residual disease (P = 0.002) were all significant predictors for improved survival. Of the patients who received adjuvant treatment, chemotherapy did not impact survival (P = 0.11). Twelve of 51 stage I patients underwent fertility-sparing surgery with three recurrences. In multivariate analysis, age <50, smaller tumor size, and absence of residual disease remained as independent prognostic factors. The median follow up was 58 months (range: 1-310). CONCLUSIONS: Age <50, smaller tumor size, and absence of residual disease are important predictors for improved survival in patients with SCST of the ovary.
Asunto(s)
Neoplasias Ováricas/mortalidad , Tumores de los Cordones Sexuales y Estroma de las Gónadas/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Pronóstico , Modelos de Riesgos Proporcionales , Sistema de Registros , Tumores de los Cordones Sexuales y Estroma de las Gónadas/patología , Tasa de SupervivenciaRESUMEN
PURPOSE: The purpose of this study was to determine whether differences in molecular markers might explain the better prognosis of women < or =45 years of age versus women >45 years of age diagnosed with ovarian cancers. EXPERIMENTAL DESIGN: Tissue sections from women with stage III-IV ovarian cancers were examined for expression of CD34, p53, and HER2. The Kaplan-Meier method and Cox Proportional Hazard analyses were used to identify predictors for outcome. RESULTS: Fifty-two women < or =45 years of age were matched with 52 women who were >45 years old. Of the 46 available tissue sections, 24 were from the younger age group (mean age, 41 years), and 22 were from the older age group (mean age, 61 years). Based on CD34 expression, tumors from women >45 years of age had lower microvessel density (MVD) compared with tumors of younger women (10.3 versus 16.1 microvessels per x400 field; P = 0.03). Lower MVD (< or =11 microvessels per x400 field) predicted for a worse prognosis than higher MVD (>11 microvessels per x400 field) in the overall study group (P = 0.001) and within the older subgroup (P = 0.03). The expressions of p53 (P = 0.13) and HER2 (P = 0.49) did not vary between the two age groups. The median survivals of those with tumors that overexpressed p53 and HER2 were 28.6 and 23.9 months compared with 51.7 and 38.6 months in those with cancers that underexpressed these markers, respectively (P = 0.09 for p53, P = 0.15 for HER2). CONCLUSIONS: Ovarian cancers in women >45 years of age had lower MVD compared with those in women < or =45 years of age. Lower MVD was an independent prognostic factor for decreased survival. Lower frequency of neovascularization in these cancers may contribute to the decreased survival observed in women >45 years of age.
Asunto(s)
Antígenos CD34/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Ováricas/metabolismo , Receptor ErbB-2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Microcirculación , Persona de Mediana Edad , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias Ováricas/irrigación sanguínea , Neoplasias Ováricas/diagnóstico , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: A prospective study was undertaken within the Gynecologic Oncology Group to determine whether serum levels of soluble tumor necrosis factor receptors I (sTNFR-I) and II (sTNFR-II), alone or in combination with CA 125, were associated with clinicopathologic characteristics or outcome in patients with epithelial ovarian malignancies. METHODS: Quantitative immunoassays were performed on valid pretreatment serum specimens obtained from patients with epithelial ovarian malignancies to assess levels of sTNFR-I, sTNFR-II, and CA 125. The authors then analyzed the results of these immunoassays for potential correlations with clinicopathologic characteristics and outcome. RESULTS: The median age of the 139 women evaluated was 59 years. Seventy-eight percent had Stage III or IV disease, and 58% had serous carcinomas. sTNFR-II was associated with age (P = 0.013), and CA 125 was associated with histologic subtype (P = 0.0009). In addition, sTNFR-I (P = 0.037) and CA 125 (P < 0.0001) were associated with extent of disease. After adjusting for patient age, histologic subtype, and extent of disease, all three biomarkers were predictive of progression-free survival, but not overall survival, when the combination was included in the model. The authors observed a 51% reduction (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.24-0.99), a 2.9-fold increase (HR, 2.87; 95% CI, 1.15-7.20), and a 22% increase (HR, 1.22; 95% CI, 0.99-1.51) in the risk of progression for each unit increase in the log-transformed levels of sTNFR-I, sTNFR-II, and CA 125, respectively. CONCLUSIONS: The observations made in the current study-that among patients with low or high CA 125 levels, those with high sTNFR-I levels and low sTNFR-II levels had the lowest risk, that patients with low-low or high-high sTNFR-I and sTNFR-II levels, respectively, had an intermediate risk, and that patients with low sTNFR-I levels and high sTNFR-II levels had the highest risk of progression-suggested the potential value of simultaneous assessment of all three biomarkers in patients with epithelial ovarian malignancies.