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1.
Sci Total Environ ; 649: 1293-1298, 2019 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-30308899

RESUMEN

Despite a growing demand to integrate ecosystem services into sustainability decision-making, our understanding of the global distribution of the economic value of ES is scarce. We extracted information from provisioning and cultural ecosystem services (PCES) from The Economics of Ecosystems and Biodiversity (TEEB) database using a meta-analytical approach. We then employed geostatistical methods to analyze the relationship between economic values and environmental and socio-economic predictors. Here we show that anthropogenic related factors such as accessibility, spatially explicit gross domestic product and ecosystem services scarcity explain global trends of PCES economic values. We observe higher PCES values in agricultural areas of strong human presence such as the British Isles, Southwest of Brazil and India and lower values in less disturbed natural areas. These findings highlight the decisive role that human systems play in the economic realization of PCES and caution that single-criterion sustainability and conservation policies aimed at maximizing the economic returns of PCES may not overlap with wild nature.


Asunto(s)
Biodiversidad , Conservación de los Recursos Naturales/economía , Ecosistema , Agricultura , Toma de Decisiones
2.
Ann Oncol ; 27(6): 1041-1047, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26940688

RESUMEN

BACKGROUND: The optimal regimen for adjuvant breast cancer chemotherapy is undefined. We compared sequential to concurrent combination of doxorubicin and cyclophosphamide with docetaxel chemotherapy in women with node-positive non-metastatic breast cancer. We report the final, 10-year analysis of disease-free survival (DFS), overall survival (OS), and long-term safety. PATIENTS AND METHODS: A total of 3298 women with HER2 nonamplified breast cancer were randomized to doxorubicin and cyclophosphamide every 3 weeks for four cycles followed by docetaxel (AC → T) every 3 weeks for four cycles or docetaxel, doxorubicin, and cyclophosphamide (TAC) every 3 weeks for six cycles. The patients received standard radiotherapy and endocrine therapy and were followed up for 10 years with annual clinical evaluation and mammography. RESULTS: The 10-year DFS rates were 66.5% in the AC → T arm and 66.3% in the TAC arm (P = 0.749). OS was 79.9% in the AC → T arm and 78.9% in the TAC arm (P = 0.506). TAC was associated with higher rates of febrile neutropenia, although G-CSF primary prophylaxis greatly reduced this risk. AC → T was associated with a higher rate of myalgia, hand-foot syndrome, fluid retention, and sensory neuropathy. CONCLUSION: This 10-year analysis of the BCIRG-005 trial confirmed that the efficacy of TAC was not superior to AC → T in women with node-positive early breast cancer. The toxicity profiles differ between arms and were consistent with previous reports. The TAC regimen with G-CSF support provides shorter adjuvant treatment duration with less toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00312208.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/fisiopatología , Taxoides/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/efectos adversos , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Docetaxel , Doxorrubicina/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Femenino , Factor Estimulante de Colonias de Granulocitos/genética , Humanos , Metástasis Linfática , Persona de Mediana Edad , Receptor ErbB-2/genética , Taxoides/efectos adversos
3.
Ann Oncol ; 26(12): 2429-36, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26387142

RESUMEN

BACKGROUND: To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or both (THP), or monoclonal antibodies alone (HP). PATIENTS AND METHODS: Immune gene mRNA expression (n = 350, 83.8%), lymphocyte infiltration (TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry (n = 305, 73.1%) were correlated with pCRB. We studied five selected genes (IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells (IGG), T cells (CD8A), antigen-presenting cells (MHC2), and to MHC1 genes (MHC1), STAT1 co-expressed genes (STAT1), and interferon-inducible genes (IF-I). Gene expression data from the NOAH trial were used for validation. RESULTS: TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only. CONCLUSIONS: The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors.


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Terapia Neoadyuvante/métodos , Receptor ErbB-2/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Femenino , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/inmunología , Persona de Mediana Edad , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/administración & dosificación , Resultado del Tratamiento , Adulto Joven
4.
Br J Cancer ; 111(11): 2051-7, 2014 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-25268370

RESUMEN

BACKGROUND: The randomised phase III TURANDOT trial compared first-line bevacizumab-paclitaxel (BEV-PAC) vs bevacizumab-capecitabine (BEV-CAP) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). The interim analysis revealed no difference in overall survival (OS; primary end point) between treatment arms; however, progression-free survival (PFS) and objective response rate were significantly superior with BEV-PAC. We sought to identify patient populations that may be most appropriately treated with one or other regimen. METHODS: Patients with HER2-negative LR/mBC who had received no prior chemotherapy for advanced disease were randomised to either BEV-PAC (bevacizumab 10 mg kg(-1) days 1 and 15 plus paclitaxel 90 mg m(-2) days 1, 8 and 15 q4w) or BEV-CAP (bevacizumab 15 mg kg(-1) day 1 plus capecitabine 1000 mg m(-2) bid days 1-14 q3w). The study population was categorised into three cohorts: triple-negative breast cancer (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High- and low-risk HR+ were defined, respectively, as having ⩾2 vs ⩽1 of the following four risk factors: disease-free interval ⩽24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; and metastases in ⩾3 organs. RESULTS: The treatment effect on OS differed between cohorts. Non-significant OS trends favoured BEV-PAC in the TNBC cohort and BEV-CAP in the low-risk HR+ cohort. In all three cohorts, there was a non-significant PFS trend favouring BEV-PAC. Grade ⩾3 adverse events were consistently less common with BEV-CAP. CONCLUSIONS: A simple risk factor index may help in selecting bevacizumab-containing regimens, balancing outcome, safety profile and patient preference. Final OS results are expected in 2015 (ClinicalTrials.gov NCT00600340).


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Bevacizumab , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Receptor ErbB-2/análisis , Factores de Riesgo
5.
Pol J Pathol ; 65(4): 283-90, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25693082

RESUMEN

The main purpose of the study was to compare topoisomerase 2α (TOP2A) status in invasive breast carcinomas to the outcome of a therapy containing neoadjuvant treatment with anthracyclines (a combination chemotherapy treatment for breast cancer, namely AC [cyclophosphamide, doxorubicin]). To achieve these goals we created a method of evaluation with criteria based on two methods used in the present study (immunohistochemical [IHC] and fluorescence in situ hybridization [FISH]). The threshold for positive immunohistochemically evaluated status was set for all cases with: nuclear stain intensity score 3+ in 10% or more nuclei and nuclear stain intensity score 2+ in 50% or more nuclei. Our results suggest that TOP2A status may be used as a predictive factor for patient selection for protocols which include anthracyclines as one of the chemotherapeutics. Both methods, IHC and FISH, are suitable for implementation for diagnostic purposes, but IHC positive status measured according to the criteria presented above is the best predictor of longer disease-free survival (DFS) according to our study. Immunohistochemical also gave satisfactory results in all analyzed cases in comparison to only 60% of cases analyzed by FISH.


Asunto(s)
Antraciclinas/uso terapéutico , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/enzimología , Carcinoma Ductal de Mama/enzimología , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Proteínas de Unión a Poli-ADP-Ribosa
6.
Ann Oncol ; 22(3): 595-602, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20819780

RESUMEN

BACKGROUND: First-line bevacizumab combined with chemotherapy significantly improves efficacy versus chemotherapy alone in human epidermal growth factor receptor 2 (HER2)-negative locally recurrent or metastatic breast cancer (LR/mBC). This large, open-label study further assesses first-line bevacizumab with taxane-based chemotherapy in routine oncology practice. PATIENTS AND METHODS: Patients with HER2-negative LR/mBC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two and no prior chemotherapy for LR/mBC received bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks plus taxane-based chemotherapy (or other non-anthracycline chemotherapy) until disease progression, unacceptable toxicity or patient withdrawal. The primary end point was safety; time to progression (TtP) was a secondary end point. RESULTS: Median follow-up in 2251 treated patients was 12.7 months. Median age was 53 years and 94% of patients had ECOG PS of zero or one. Bevacizumab was most commonly administered with single-agent paclitaxel (35%), single-agent docetaxel (33%) or taxane-based combination therapy (10%). The most frequent grade ≥3 adverse event (AE) was neutropenia (5.4%). Grade ≥3 AEs previously associated with bevacizumab included hypertension (4.4%), arterial/venous thromboembolism (3.2%), proteinuria (1.7%) and bleeding (1.4%). No new bevacizumab safety signals were observed. Median TtP was 9.5 months (95% confidence interval 9.1-9.9). CONCLUSIONS: The study population in ATHENA was more representative of general oncology practice than populations enrolled into randomised trials, although there may have been some bias towards younger, fitter patients. The safety and efficacy of bevacizumab-taxane therapy in this large study were consistent with results from randomised first-line trials.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/secundario , Masculino , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Taxoides/administración & dosificación , Resultado del Tratamiento , Adulto Joven
7.
Ann Oncol ; 21(5): 917-24, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-19717536

RESUMEN

BACKGROUND: Patients with metastatic central nervous system (mCNS) disease progression from breast cancer have a poor prognosis and often develop associated neurological complications. Human epidermal growth factor receptor 2 (HER2)-positivity status increases the risk of developing mCNS disease. Trastuzumab is an mAb that targets HER2 and is known to extend survival across all stages of HER2-positive breast cancer. DESIGN: This review considers evidence from preclinical and clinical studies examining the value of continuing trastuzumab treatment in patients who develop mCNS disease. A wealth of data from clinical studies showed that trastuzumab prolonged survival in patients with mCNS disease, compared with no trastuzumab treatment, by effectively controlling their non-CNS disease. Trastuzumab has also been shown to penetrate an impaired blood-brain barrier to a limited degree, such as during radiotherapy, and intrathecal delivery of trastuzumab to the central nervous system (CNS) has shown promise. Research efforts are focussing on improving the delivery of trastuzumab to the CNS. CONCLUSION: Evidence indicates that patients with mCNS disease from HER2-positive breast cancer should continue to receive trastuzumab to control HER2-positive metastases outside the CNS and receive established therapies to control the mCNS disease.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/secundario , Femenino , Humanos , Pronóstico , Receptor ErbB-2/metabolismo , Trastuzumab
8.
Eur J Cancer ; 46(1): 56-71, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19811907

RESUMEN

ONCOPOOL is a retrospectively compiled database of primary operable invasive breast cancers treated in the 1990s in 10 European breast cancer Units. Sixteen thousand and nine hundred and forty four cases were entered, with tumours less than 5 cm diameter in women aged 70 or less (mean age 55). DATA: Data were date of birth, mode of diagnosis, pathology (size, lymph node status, grade, type, lympho-vascular invasion and hormone receptor) and therapies and outcome measures: first local, regional or distant recurrences, contralateral primary, date and cause of death. TUMOUR CHARACTERISTICS: Mean diameter 1.8 cm, 66% lymph node negative, 24% 1-3 lymph nodes involved and 10% had 4 or more involved. Grade 1, 29%; Grade 2, 41%; and Grade 3, 30%. Polynomial relationships were established between grade, stage and size. Seventy-five percent were oestrogen receptor (ER) positive. ER closely related to grade. OUTCOMES: Overall Survival was 89% at 5 years from diagnosis, 80% 10 years and 73% 15 years; Breast Cancer-Specific survivals were 91%, 84% and 79%. Survival strongly related to the Nottingham Prognostic Index (NPI). Cases detected at screening had 84% 10-year survival, those presenting symptomatically 76%. ER positive cases treated with adjuvant hormone therapy had a reduction in risk of death of 13% over those not receiving adjuvant therapy (p=0.000). ER negative cases treated with chemotherapy showed a risk reduction of 23% over those not receiving chemotherapy (p=0.000).


Asunto(s)
Neoplasias de la Mama/epidemiología , Bases de Datos Factuales , Adulto , Distribución por Edad , Factores de Edad , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante , Europa (Continente)/epidemiología , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Estadificación de Neoplasias , Pronóstico , Garantía de la Calidad de Atención de Salud , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Análisis de Supervivencia
9.
Ann Oncol ; 20(9): 1489-1498, 2009 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19474112

RESUMEN

BACKGROUND: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial. METHODS: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. RESULTS: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy. CONCLUSIONS: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/complicaciones , Fracturas Óseas/epidemiología , Nitrilos/uso terapéutico , Tamoxifeno/uso terapéutico , Triazoles/uso terapéutico , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Método Doble Ciego , Femenino , Fracturas Óseas/etiología , Humanos , Incidencia , Letrozol , Persona de Mediana Edad , Posmenopausia , Factores de Riesgo
10.
Cancer Chemother Pharmacol ; 59(6): 703-9, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17021821

RESUMEN

PURPOSE: Intravenous (i.v.) vinorelbine (VRL) generally given on days 1 and 8 of an every three-week cycle in combination with paclitaxel (PTX) is an effective option for the treatment of metastatic breast cancer (MBC). In an effort to improve both patient and chemotherapy unit convenience, oral VRL was used at equivalent doses of i.v. VRL. PATIENTS AND METHODS: The maximal tolerated dose (MTD) was determined during the first cycle of oral VRL given on days 1 and 8 or 15 and PTX infused over 3 h on day 1 every 3 weeks, maximum of 6 cycles. The dose of oral VRL was escalated from 60 to 80 mg/m2 in 10 mg/m2 increments. Paclitaxel was administered at 110 and then 135 mg/m2. The combination regimen was given as first-line chemotherapy of MBC. Three to six patients per cohort were treated. RESULTS: Twenty-two patients were treated in the first four cohorts (oral VRL/PTX): 60/110, 70/110, 80/110 and 80/135. In cohort 4, seven patients were treated, one patient being non-evaluable for MTD, three of them presented a dose-limiting toxicity (DLT) consisting of febrile neutropenia and neutropenic infection. Therefore 80/135 was the MTD. Because 36% of oral VRL administrations on day 8 were delayed to day 15 at 80/110, two additional cohorts were tested: in cohort 5, oral VRL 60 mg/m2 on days 1 and 15 and PTX 135 mg/m2 on day 1 and in cohort 6, oral VRL 80 mg/m2 on days 1 and 15 and PTX 110 mg/m2 on day 1, every 3 weeks. In cohort 5, six out of eight patients had DLTs: omission of oral VRL on day 15 for five patients, grade 4 neutropenia>7 days for another one. Therefore the recommended dose (RD) for further clinical testing was oral VRL 80 mg/m2 on days 1 and 15 and PTX 110 mg/m2 on day 1 of an every 3-week cycle. Two of the three evaluable patients treated at the RD had a partial response. The pharmacokinetics of VRL and PTX is being analysed and will be further presented in a separate publication. CONCLUSIONS: This phase I study has determined the doses of oral VRL and PTX to be used in combination for the benefit of the patient and of the chemotherapy unit in term of nurse's workload. The recommended regimen of oral VRL 80 mg/m2 on days 1 and 15 and PTX 110 mg/m2 on day 1 given every 3 weeks will be further tested in phase II.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Paclitaxel/administración & dosificación , Vinblastina/análogos & derivados , Administración Oral , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Esquema de Medicación , Femenino , Humanos , Dosis Máxima Tolerada , Metástasis de la Neoplasia , Neutropenia/inducido químicamente , Paclitaxel/efectos adversos , Terapia Recuperativa , Vinblastina/administración & dosificación , Vinblastina/efectos adversos , Vinorelbina
11.
Breast Cancer Res Treat ; 92(2): 169-74, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15986127

RESUMEN

There is a need for new endocrine agents that lack cross-resistance with currently available treatments to extend the endocrine treatment window and delay the need for cytotoxic chemotherapy. This retrospective analysis evaluated the response of postmenopausal patients with previously untreated metastatic/locally advanced breast cancer to further endocrine treatment following progression on first-line fulvestrant or tamoxifen. Patients received fulvestrant 250 mg (intramuscular injection every 28 days) plus matching tamoxifen placebo (once daily), or tamoxifen 20 mg (orally once daily) plus matching fulvestrant placebo (every 28 days) in a double-blind, randomized, phase III trial. Treatment continued until disease progression or withdrawal, when further endocrine therapy was initiated (at the treating physician's discretion). Information regarding subsequent therapies and responses was obtained by follow-up questionnaire. Two-hundred-and-forty-five questionnaires were returned (from 587 patients), 149 of which yielded follow-up data on patients receiving second-line endocrine therapy following fulvestrant (n=83) and tamoxifen (n=66). Second-line therapy produced objective responses (OR) in 6/44 (13.6%) and clinical benefit (CB) in 25/44 (56.8%) patients who had CB with fulvestrant and produced OR in 5/41 (12.2%) patients and CB in 27/41 (65.8%) patients who had CB with first-line tamoxifen. For patients deriving no CB from trial therapy, second-line therapy produced OR in 3/39 (7.7%) and CB in 15/39 (38.5%) patients in the fulvestrant group and OR in 4/25 (16.0%) and CB in 12/25 (48.0%) patients in the tamoxifen group. Results from this questionnaire-based study suggest that postmenopausal women with advanced breast cancer who respond to first-line fulvestrant or tamoxifen retain sensitivity to subsequent endocrine therapy.


Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Estradiol/análogos & derivados , Terapia Recuperativa , Tamoxifeno/farmacología , Adulto , Anciano , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/patología , Estradiol/farmacología , Estradiol/uso terapéutico , Femenino , Fulvestrant , Humanos , Acetato de Medroxiprogesterona/farmacología , Acetato de Medroxiprogesterona/uso terapéutico , Acetato de Megestrol/farmacología , Acetato de Megestrol/uso terapéutico , Persona de Mediana Edad , Metástasis de la Neoplasia , Posmenopausia , Estudios Retrospectivos , Tamoxifeno/uso terapéutico , Resultado del Tratamiento
12.
Eur J Gynaecol Oncol ; 25(4): 470-4, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-15285306

RESUMEN

UNLABELLED: In 48 women with familial breast cancer as well as in 22 women with familial ovarian cancer, the presence of pathogenic mutations in BRCA1 gene were found in 35.4% and 54.6% of patients, respectively. From the patients with mutations we created two groups: the CaM--probands with breast cancer and CaOv--probands with ovarian cancer. The probands with breast cancer were younger by a mean of five years than the probands with ovarian cancer (p = 0.048). METHODS: The PCR-SSCP procedure was used to find mutations in the BRCA1 gene. Fragments suspected of mutation were subjected to nucleotide sequencing. RESULTS: In the CaM group, which consisted of 17 women with breast cancer, the following mutations in the BRCA1 gene were detected: 5382insC, T300G, 3819del5 and IVS20+60ins12. The probands of the CaM group and their relatives developed a total of 49 breast and ovarian cancers. Among all these tumours the breast cancers of the probands made up 34.7%, the breast cancers of proband relatives made up 57.1% and the ovarian cancers of probands and their relatives made up only 8.2%. The CaOv group consisted of 12 probands with ovarian cancers in whom we detected only two kinds of mutations: 5382insC and 185delAG. The probands of the CaOv group and their relatives developed a total of 38 ovarian and breast cancers. Among all these tumours the ovarian cancers of the probands made up 31.6%, the ovarian cancers of their relatives made up 34.2% and the breast cancers of the relatives 34.2% of tumours. In the probands with breast or ovarian cancer the predominant mutation was 5382insC--in the BRCA1 gene detected in 76.5%, and 91.7%, respectively. Despite the predominant presence of the same mutation in probands from both groups the ratio of the number of breast cancers to the number of ovarian cancers in their relatives differed significantly (p = 0.0003). CONCLUSION: This data shows that the presence of the 5382insC mutation in the BRCA1 gene is not always associated with the development of ovarian cancer. It is very likely that the development of ovarian cancer requires some additional factor, which was common among the familial ovarian cancer patients, and was almost inexistent among the familial breast cancer patients. On the other hand, the development of ovarian cancer at a later age than breast cancer in probands suggests that some factors exist which slow down the development of ovarian cancer or which accelerate the development of breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Genes BRCA1 , Predisposición Genética a la Enfermedad , Mutación , Neoplasias Ováricas/genética , Adulto , Factores de Edad , Neoplasias de la Mama/epidemiología , Estudios de Cohortes , Femenino , Pruebas Genéticas , Humanos , Incidencia , Persona de Mediana Edad , Neoplasias Ováricas/epidemiología , Linaje , Polonia/epidemiología , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo , Sensibilidad y Especificidad
13.
Cytokines Cell Mol Ther ; 7(1): 15-24, 2002 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12171247

RESUMEN

Dendritic cell (DC) counts and function were assayed in peripheral blood of lymphoma and solid tumor patients before and after chemotherapy. The DC counts declined significantly within the first week from the start of chemotherapy, recovered in the second week, and exceeded the baseline values in the third week. DC recovery was usually similar after the first and after the last cycle of chemotherapy. DC1 and DC2 subsets followed the pattern of reconstitution found for the DC population as a whole. Monocytes and granulocytes recovered 1-2 weeks later than DC. The primary proliferative response to keyhole lympet hemocyanin (KLH), totally DC-dependent, declined within the first week from the start of chemotherapy, and in the majority of patients (including those initially unresponsive) recovered along with DC counts. The recovered responsiveness to KLH, but not to anti-CD3 antibody, disappeared at the end of chemotherapy in lymphoma and some solid tumor patients. Prolonged depletion of CD4+ T cells could contribute to the loss of responsiveness in lymphoma patients receiving multiple cycles of chemotherapy. However, in some solid tumor patients, the reactivity to KLH was absent, despite the reconstitution of both DC and CD4+ T-cell counts. Our data show that numerical reconstitution of DC is not necessarily accompanied by functional recovery. The early recovery of DC should be considered while designing protocols for DC collection for immunotherapy.


Asunto(s)
Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales/metabolismo , Complejo CD3/biosíntesis , Linfocitos T CD4-Positivos/metabolismo , División Celular , Células Dendríticas/citología , Femenino , Hemocianinas/metabolismo , Humanos , Inmunofenotipificación , Inmunoterapia/métodos , Interleucina-2/metabolismo , Linfoma/sangre , Linfoma/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Factores de Tiempo
14.
Br J Cancer ; 86(9): 1367-72, 2002 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-11986765

RESUMEN

Capecitabine, an oral fluoropyrimidine carbamate, was designed to generate 5-fluorouracil preferentially at the tumour site. This randomised, phase II trial evaluated the efficacy and safety of capecitabine or paclitaxel in patients with anthracycline-pretreated metastatic breast cancer. Outpatients with locally advanced and/or metastatic breast cancer whose disease was unresponsive or resistant to anthracycline therapy were randomised to 3-week cycles of intermittent oral capecitabine (1255 mg m(-2) twice daily, days 1-14, (22 patients)) or a reference arm of i.v. paclitaxel (175 mg m(-2), (20 patients)). Two additional patients were initially randomised to continuous capecitabine 666 mg m(-2) twice daily, but this arm was closed following selection of the intermittent schedule for further development. Overall response rate was 36% (95% CI 17-59%) with capecitabine (including three complete responses) and 26% (95% CI 9-51%) with paclitaxel (no complete responses). Median time to disease progression was similar in the two treatment groups (3.0 months with capecitabine, 3.1 months with paclitaxel), as was overall survival (7.6 and 9.4 months, respectively). Paclitaxel was associated with more alopecia, peripheral neuropathy, myalgia and neutropenia, whereas typical capecitabine-related adverse events were diarrhoea, vomiting and hand-foot syndrome. Twenty-three per cent of capecitabine-treated patients and 16% of paclitaxel-treated patients achieved a > or =10% improvement in Karnofsky Performance Status. Oral capecitabine is active in anthracycline-pretreated advanced/metastatic breast cancer and has a favourable safety profile. Furthermore, capecitabine provides a convenient, patient-orientated therapy.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Paclitaxel/farmacología , Administración Oral , Adulto , Anciano , Antibióticos Antineoplásicos/uso terapéutico , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Neoplasias de la Mama/patología , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Femenino , Fluorouracilo/análogos & derivados , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Resultado del Tratamiento
15.
Pol J Pathol ; 52(1-2): 21-6, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11505677

RESUMEN

The study was performed for answering the question whether metastatic breast cancer has the same overexpression of HER2/neu as primary breast tumor. We assumed that study on this subject could give a valuable information for proper interpretation of HER2/neu overexpression in breast cancer patients designated for therapy with Herceptin. Our study was performed on 71 breast cancer patients qualified for clinical trial with Herceptin therapy. All patients selected for this trial have had surgery and two episodes of unsuccessful adjuvant therapy. Tissue samples were routinely fixed in 4% formalin and embedded in paraffin. Immunohistochemical assays were performed on 5 microns slides using DAKO HercepTest and semi-quantitative methods to determine HER2 protein overexpression were used. All study cases were subdivided into two groups. First group--49 cases in which expression of HER2 was examined in tissue from primary breast tumors, and second group--22 cases in which expression of HER2 was examined in tissue from metastatic lesions. In the whole study group (71 cases) overexpression was confirmed in 29 (40.8%) cases. In the group of primary breast tumors overexpression of HER2 was present in 20 (40.8%) of cases. In the group of metastatic breast tumors overexpression of HER2 was present in 9 (40.9%) of cases. The result suggests that overexpression which appears in primary breast carcinoma is also preserved in metastases. Direct prove of such a conclusion, would be a study on HER2/neu expression estimated in primary and metastases in the same patients. It requires a proper quantity and quality of material. Our results indicate that there is no difference between the estimation of HER2/neu overexpression in primary and metastatic breast cancer in patients with disseminated disease after double failure of chemotherapy. Evaluation of overexpression of HER2/neu in cases of planned Herceptin therapy can be done both in material from primary and from metastatic tumor.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Adulto , Anciano , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad
16.
J Clin Oncol ; 19(6): 1707-15, 2001 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-11251000

RESUMEN

PURPOSE: This phase III trial compared the efficacy and safety of doxorubicin and paclitaxel (AT) to 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line therapy for women with metastatic breast cancer. PATIENTS AND METHODS: A total of 267 women with metastatic breast cancer were randomized to receive either AT (doxorubicin 50 mg/m(2) followed 24 hours later by paclitaxel 220 mg/m(2)) or FAC (5-fluorouracil 500 mg/m(2), doxorubicin 50 mg/m(2), cyclophosphamide 500 mg/m(2)), each administered every 3 weeks for up to eight cycles. Patients had to have measurable disease and an Eastern Cooperative Oncology Group performance status of 0 to 2. Only one prior non-anthracycline, nontaxane-containing adjuvant chemotherapy regimen was allowed. RESULTS: Overall response rates for patients randomized to AT and FAC were 68% and 55%, respectively (P =.032). Median time to progression and overall survival were significantly longer for AT compared with FAC (time to progression 8.3 months v 6.2 months [P =.034]; overall survival 23.3 months v 18.3 months [P =.013]). Therapy was generally well-tolerated (median of eight cycles delivered in each arm). Grade 3 or 4 neutropenia was more common with AT than with FAC (89% v 65%; P <.001); however, the incidence of fever and infection was low. Grade 3 or 4 arthralgia and myalgia, peripheral neuropathy, and diarrhea were more common with AT, whereas nausea and vomiting were more common with FAC. The incidence of cardiotoxicity was low in both arms. CONCLUSION: AT conferred a significant advantage in response rate, time to progression, and overall survival compared with FAC. Treatment was well-tolerated with no unexpected toxicities.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/patología , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Análisis de Supervivencia , Resultado del Tratamiento
17.
Int J Clin Pharmacol Res ; 21(3-4): 111-7, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-12067140

RESUMEN

Vinorelbine has proven to be effective in pretreated metastatic breast cancer patients. In particular, no cross-resistance with anthracyclines has been demonstrated. Protracted 5-fluorouracil infusion presents a better pharmacological profile than its bolus administration. The aim of this study was to investigate the efficacy and toxicity of the combination of these two antitumor drugs in patients with metastatic breast cancer who had been previously treated with anthracycline-containing regimens. From February 1998 to January 2000, 65 patients were enrolled into the study The most important inclusion criteria were as follows: Karnofsky 70-100, measurable or evaluable disease and normal renal, hepatic, bone marrow and cardiac function. Mean age was 48 years (range: 31-70). Fourteen of the 65 women had already received more than one chemotherapy line. Twenty-three patients had previously been treated with taxanes. Sites of involvement were the lungs in 50% of the patients, the liver in 37%, soft tissue in 72%, bone in 58% and other sites in 32%. Treatment consisted of vinorelbine 25 mg/m2 administered on days 1 and 6 every 21 days and 5-fluorouracil 700 mg/m2/day for 5 consecutive days. The total number of cycles was 340 (mean: five cycles). The treatment was well tolerated. Febrile neutropenia was observed in 4.6% of patients. Fourteen percent of patients experienced grade 3 or 4 neutropenia, and 3% experienced grade 3 thrombocytopenia. Grade 3 stomatitis was observed in 9.2% of patients, grade 3 neurologic toxicity was observed in 1.5%, and grade 3 cardiotoxicity in 4.6%. Grade 3 site reaction occurred in 3% of patients. Sixty patients were evaluated for response. One patient (1.7%) attained complete clinical response and 28 (46.7%) attained partial response. In 22 patients (36.6%) stable disease was documented and nine patients (15%) progressed while on treatment. Median time to progression was 24 weeks, median duration of response was 35 weeks and median overall survival was 41 weeks. Vinorelbine with 5-day infusion of 5-fluorouracil presented high therapeutic activity in breast cancer patients previously treated with anthracyclines, with acceptable toxicity.


Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Fluorouracilo/administración & dosificación , Vinblastina/análogos & derivados , Vinblastina/administración & dosificación , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Evaluación de Medicamentos/métodos , Evaluación de Medicamentos/estadística & datos numéricos , Femenino , Fluorouracilo/efectos adversos , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Neutropenia/inducido químicamente , Pacientes/estadística & datos numéricos , Tasa de Supervivencia , Vinblastina/efectos adversos , Vinorelbina
18.
Br J Cancer ; 76(2): 270-7, 1997.
Artículo en Inglés | MEDLINE | ID: mdl-9231932

RESUMEN

The study was planned to compare, in a prospective double-blind randomized trial, the efficacy and safety of toremifene (TOR) and tamoxifen (TAM) in post-menopausal patients with advanced breast cancer who have not had prior systemic therapy for advanced disease. Four hundred and fifteen post-menopausal patients with oestrogen receptor (ER)-positive or ER-unknown advanced breast cancer were randomly assigned to receive daily either 60 mg TOR or 40 mg TAM. The patients were stratified to measurable and non-measurable but evaluable groups. They were assessed for response to therapy, time to progression (TTP), time to treatment failure (TTF), response duration, overall survival and drug toxicity. Two hundred and fourteen patients were randomized into TOR and 201 into TAM treatment. The response rate (complete + partial) was 31.3% for TOR and 37.3% for TAM (P = 0.215). The 95% confidence interval (CI) for the 6% difference was -15.1% to 3.1%. The median TTP was 7.3 months for TOR and 10.2 months for TAM (P = 0.047). The 95% CI for the hazard ratio of 0.80 was 0.64-1.00. A percentage of the TOR patients (9.8%) and the TAM patients (18.9%) discontinued the treatment prematurely (P = 0.011) for various reasons. Consequently, the median TTF of 6.3 vs 8.5 months did not differ significantly (P = 0.271). The hazard ratio was 0.89 and the subsequent 95% CI 0.73-1.09. The median overall survival was 33.0 months for TOR and 38.7 months for TAM (P = 0.645). The hazard ratio was 0.94 with 95% CI of 0.73-1.22. The transient difference in TTP may be related to an imbalance in ER content of the tumours. When only patients with ER-positive tumours were considered (n = 238), no difference between two treatments was seen (P = 0.578). TAM was associated with an overall slightly higher frequency of adverse drug reactions than TOR (44.3 vs 39.3%) and a higher discontinuation rate due to these events (3.5% vs 0.9%). Treatment-emerged moderate dizziness (P = 0.026) and cataracts (P = 0.026) were more frequent among TAM than among TOR patients. In conclusion, TOR (60 mg day(-1)) and TAM (40 mg day(-1)) are equally effective and safe in the treatment of advanced post-menopausal ER-positive or ER-unknown breast cancer.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Antagonistas de Estrógenos/uso terapéutico , Posmenopausia , Tamoxifeno/uso terapéutico , Toremifeno/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Método Doble Ciego , Antagonistas de Estrógenos/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Países Escandinavos y Nórdicos , Tasa de Supervivencia , Tamoxifeno/efectos adversos , Toremifeno/efectos adversos , Resultado del Tratamiento
19.
Neuroscience ; 63(1): 191-206, 1994 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-7534880

RESUMEN

Mast cells and their location in the cat lateral geniculate complex of the thalamus were examined by means of histamine immunohistochemistry and the mast cell stain pinacyanol erythrosinate. Brain sections from seven normal adult pigmented cats were processed for light or electron microscopy. Histamine-containing and pinacyanol erythrosinate-stained mast cells were widespread throughout the dorsal and ventral lateral geniculate nuclei and the surrounding regions. Mast cells were especially numerous rostrally in the complex and in the geniculate C laminae. The cells were found consistently in association with blood vessels, ranging from capillary size to vessels c. 150 microns diameter, and twice as often with arterioles as with venules. Large clusters of many mast cells associated with single blood vessels were seen. Individual mast cells were typically 8 microns in diameter and somewhat oval, although multipolar and crescent-shaped cells were also seen, up to twice as long. The amount of histamine labeling varied across cells. When histamine-labeled material was secondarily stained with pinacyanol erythrosinate, many mast cells were double labeled. In addition, there was a small population of mast cells that stained only with pinacyanol erythrosinate, but was otherwise identical to the histamine-immunoreactive mast cells. Electron microscopic examination showed that the mast cells lie on the brain side of the blood-brain barrier. Mast cells were found in close proximity to the thalamic neuropil, primarily apposed to the processes of astrocytes, but also apposed to neural elements. The distinctive electron-dense cytoplasmic granules in the fully granulated, mature state were largely amorphous in appearance and as large as 700 nm in diameter. Histamine was dispersed throughout some granules and contained within restricted areas of other granules. In degranulated mast cells, large, irregularly shaped, electron-lucent granules were seen fused with the cell membrane on the neuropil side, as well as the lumen side of the mast cell. More mast cells were observed at the electron microscopic level than were expected from the light level observations, which suggests that, despite the numbers of mast cells labeled, these results may still underestimate the total mast cell population present in this region of the thalamus. Mast cells, by their numbers, their distribution and the potent chemical substances they contain, may significantly influence vascular and neural function, directly and indirectly, in the cat lateral geniculate complex.


Asunto(s)
Cuerpos Geniculados/citología , Histamina/metabolismo , Mastocitos/ultraestructura , Animales , Barrera Hematoencefálica/fisiología , Carbocianinas , Gatos , Eritrosina/análogos & derivados , Femenino , Cuerpos Geniculados/metabolismo , Cuerpos Geniculados/ultraestructura , Histocitoquímica , Masculino , Mastocitos/metabolismo , Microscopía Electrónica , Coloración y Etiquetado
20.
J Cell Sci ; 107 ( Pt 1): 135-43, 1994 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8175903

RESUMEN

We previously defined two classes of microtubule polymer in the axons of cultured sympathetic neurons that differ in their sensitivity to nocodazole by roughly 35-fold (Baas and Black (1990) J. Cell Biol. 111, 495-509). Here we demonstrate that virtually all of the microtubule polymer in these axons, including the drug-labile polymer, is stable to cold. What factors account for the unique stability properties of axonal microtubules? In the present study, we have focused on the role of tau, a microtubule-associated protein that is highly enriched in the axon, in determining the stability of microtubules to nocodazole and/or cold in living cells. We used a baculovirus vector to express very high levels of tau in insect ovarian Sf9 cells. The cells respond by extending processes that contain dense bundles of microtubules (Knops et al. (1991) J. Cell Biol. 114, 725-734). Cells induced to express tau were treated with either cold or 2 micrograms/ml nocodazole for times ranging from 5 minutes to 6 hours. The results with each treatment were very different from one another. Virtually all of the polymer was depolymerized within the first 30 minutes in cold, while little or no microtubule depolymerization was detected even after 6 hours in nocodazole. Based on these results, we conclude that tau is almost certainly a factor in conferring drug stability to axonal microtubules, but that factors other than or in addition to tau are required to confer cold stability.


Asunto(s)
Axones/ultraestructura , Frío , Microtúbulos/ultraestructura , Neuronas/ultraestructura , Proteínas tau/fisiología , Animales , Axones/fisiología , Baculoviridae , Línea Celular , Células Cultivadas , Femenino , Microscopía Electrónica , Microtúbulos/efectos de los fármacos , Microtúbulos/fisiología , Mariposas Nocturnas , Neuronas/efectos de los fármacos , Neuronas/fisiología , Nocodazol/farmacología , Ovario , Ratas , Transfección , Proteínas tau/biosíntesis
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