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1.
ESMO Open ; 9(9): 103694, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39232440

RESUMEN

BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPis) improved advanced ovarian cancer treatment. Most patients progress during or following PARPi exposure, however, with concerns about sensitivity of subsequent chemotherapy. PATIENTS AND METHODS: In this international cohort study, we evaluated the efficacy of a subsequent chemotherapy following PARPi exposure in high-grade ovarian carcinoma patients. Endpoints included progression-free survival (PFS), overall survival and a multivariable Cox model was built to identify factors influencing PFS. RESULTS: We included 291 patients from four international centers treated between January 2002 and December 2021. The median number of previous chemotherapy was 1 (1.0-7.0), the median duration of PARPi exposure was 6.5 months (0.2-54.3 months). PARPi was used in first line in 14.1% patients. Most progressions occurred under PARPi exposure (89.1%). A BRCA pathogenic variant was identified in 130 patients (44.7%), absent in 157 patients (54.0%), and undocumented in 4 patients (1.4%). Platinum-based CT (PBC) and non-PBC were administered as subsequent treatments in, respectively, 182 patients (62.5%) and 109 patients (37.5%). Multivariable analyses showed that platinum-free interval (PFI) >6 months [adjusted hazards ratio (HR), 0.52; 95% confidence interval (CI) 0.39-0.70] and type of initial surgery (adjusted HR, 1.41; 95% CI 1.07-1.87; interval or closing surgery versus primary surgery) were associated with PFS, independent of BRCA status or line of therapy (≥2 versus 1). In patients with a PFI >6 months, PBC was numerically associated with the best PFS (adjusted HR, 0.68; 95% CI 0.46-1.01). CONCLUSION: This is the largest real-world study assessing the efficacy of subsequent chemotherapy in patients progressing during PARPi exposure. The patients have poor outcomes. PBC is the best option in patients progressing on PARPi and eligible for PBC rechallenge (PFI >6 months).


Asunto(s)
Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/genética , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Anciano , Progresión de la Enfermedad , Adulto , Supervivencia sin Progresión , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Estudios de Cohortes , Anciano de 80 o más Años
2.
Gynecol Oncol ; 187: 139-144, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38776631

RESUMEN

BACKGROUND: Chemotherapy (CT) remains a backbone treatment of epithelial ovarian cancer (EOC) inducing persistent peripheral neuropathy (CIPN). Using a dedicated patient-reported outcome tool, this study investigated persistent CIPN and its pharmacogenetic predictors in a cohort of long-term EOC survivors. METHODS: Vivrovaire was a French multicenter cohort of patients with EOC free of disease 3 years after CT completion. Persistent CIPN was assessed using the FACT/GOG-Ntx4 self-questionnaire. The association of homozygous (hom) or heterozygous (het) single nucleotide polymorphisms (SNPs) in selected genes was evaluated. RESULTS: 130 patients were included with a median time from CT completion of 63 [35-180] months. The median CIPN score was 37 [18-44], with 35 (26.9%) patients reporting severe CIPN (<33). SNPs were identified as follows: CYP2C8 [hom, n = 32 (24.6%)/het, n = 99, (76.2%)]; CYP3A4 [hom, n = 0 (0%)/het, n = 8 (6.2%)], ERCC1 [hom, n = 21 (16.2%)/het, n = 57 (43.8%)], and XPC [hom, n = 45 (34.6%)/het, n = 66 (50.8%)]. In univariate analysis, the identification of ≥1 hom SNP was associated with a lower CIPN score (continuous variable; p = 0.045). Patients harboring hom or het CYP2C8_rs1934951 SNP reported more likely severe CIPN (threshold <33) score (OR 2.482; 95% CI [1.126-5.47], p = 0.024). In the multivariate analyses, age, interval from CT completion, type and number of CT courses were not significantly associated with CIPN score (OR 5.165, 95% CI [0.478-55.83], p = 0.176). CONCLUSIONS: Persistent CIPN is common among ovarian cancer long-term survivors. CYP2C8_rs1934951 SNP may be associated with severe residual CIPN in EOC survivors. More studies are warranted to identify predictive factors of CIPN.


Asunto(s)
Supervivientes de Cáncer , Carcinoma Epitelial de Ovario , Citocromo P-450 CYP3A , Neoplasias Ováricas , Enfermedades del Sistema Nervioso Periférico , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/genética , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Anciano , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Supervivientes de Cáncer/estadística & datos numéricos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP2C8/genética , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Adulto , Estudios de Cohortes , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
3.
ESMO Open ; 6(3): 100150, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33984675

RESUMEN

BACKGROUND: Leptomeningeal metastasis (LM) is a rare complication of metastatic breast cancer (MBC), with high morbidity/mortality rates. Our study aimed to describe the largest-to-date real-life population of MBC patients treated with intrathecal (IT) therapy and to evaluate prognostic models. METHODS: The Epidemiological Strategy and Medical Economics (ESME) MBC database (NCT03275311) includes all consecutive patients who have initiated treatment for MBC since 2008. Overall survival (OS) of patients treated with IT therapy was estimated using the Kaplan-Meier method. Prognostic models were constructed using Cox proportional hazards models. Performance was evaluated using C-index and calibration plots. RESULTS: Of the 22 266 patients included in the database between 2008 and 2016, 312 received IT therapy and were selected for our analysis. Compared with non-IT-treated patients, IT-treated patients were younger at MBC relapse (median age: 52 years versus 61 years) and more often had lobular histology (23.4% versus 12.7%) or triple-negative subtype (24.7% versus 13.3%) (all P < 0.001). Median OS was 4.5 months [95% confidence interval (CI) 3.8-5.6] and 1-year survival rate was 25.6%. Significant prognostic factors associated with poorer outcome on multivariable analysis were triple-negative subtype (hazard ratio 1.81, 95% CI 1.32-2.47), treatment line ≥3 (hazard ratio 1.88, 95% CI 1.30-2.73), ≥3 other metastatic sites (hazard ratio 1.33, 95% CI 1.01-1.74) and IT cytarabine or thiotepa versus methotrexate (hazard ratio 1.68, 95% CI 1.28-2.22), while concomitant systemic therapy was associated with better OS (hazard ratio 0.47, 95% CI 0.35-0.62) (all P < 0.001). We validated two previously published prognostic scores, the Curie score and the Breast-graded prognostic assessment, both with C-index of 0.57. CONCLUSIONS: MBC patients with LM treated with IT therapy have a poor prognosis. We could identify a subgroup of patients with better prognosis, when concomitant systemic therapy and IT methotrexate were used.


Asunto(s)
Neoplasias de la Mama , Carcinomatosis Meníngea , Mama , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico
4.
Gynecol Oncol ; 158(3): 666-672, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32624235

RESUMEN

BACKGROUND: Malignant ovarian germ cell tumors are rare tumors, affecting young women with a generally favorable prognosis. The French reference network for Rare Malignant Gynecological Tumors (TMRG) aims to improve their management. The purpose of this study is to report clinicopathological features and long-term outcomes, to explore prognostic parameters and to help in considering adjuvant strategy for stage I patients. PATIENTS AND METHODS: Data from patients with MOGCT registered among 13 of the largest centers of the TMRG network were analyzed. We report clinicopathological features, estimated 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) of MOGCT patients. RESULTS: We collected data from 147 patients including 101 (68.7%) FIGO stage I patients. Histology identifies 40 dysgerminomas, 52 immature teratomas, 32 yolk sac tumors, 2 choriocarcinomas and 21 mixed tumors. Surgery was performed in 140 (95.2%) patients and 106 (72.1%) received first line chemotherapy. Twenty-two stage I patients did not receive chemotherapy. Relapse occurred in 24 patients: 13 were exclusively treated with upfront surgery and 11 received surgery and chemotherapy. 5y-EFS was 82% and 5y-OS was 92.4%. Stage I patients who underwent surgery alone had an estimated 5y-EFS of 54.6% and patients receiving adjuvant chemotherapy 94.4% (P < .001). However, no impact on estimated 5y-OS was observed: 96.3% versus 97.8% respectively (P = .62). FIGO stage, complete primary surgery and post-operative alpha fetoprotein level significantly correlated with survival. CONCLUSION: Adjuvant chemotherapy does not seem to improve survival in stage I patients. Active surveillance can be proposed for selected patients with a complete surgical staging.


Asunto(s)
Neoplasias de Células Germinales y Embrionarias/terapia , Neoplasias Ováricas/terapia , Espera Vigilante , Adolescente , Adulto , Anciano , Coriocarcinoma/tratamiento farmacológico , Coriocarcinoma/patología , Coriocarcinoma/cirugía , Coriocarcinoma/terapia , Disgerminoma/tratamiento farmacológico , Disgerminoma/patología , Disgerminoma/cirugía , Disgerminoma/terapia , Tumor del Seno Endodérmico/tratamiento farmacológico , Tumor del Seno Endodérmico/patología , Tumor del Seno Endodérmico/cirugía , Tumor del Seno Endodérmico/terapia , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/cirugía , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Pronóstico , Estudios Retrospectivos , Teratoma/tratamiento farmacológico , Teratoma/patología , Teratoma/cirugía , Teratoma/terapia , Adulto Joven
5.
Ann Pharm Fr ; 77(5): 426-434, 2019 Sep.
Artículo en Francés | MEDLINE | ID: mdl-31288930

RESUMEN

OBJECTIVES: The oral route is becoming increasingly important in the panel of anti-cancer therapeutics, but it generates difficulties (adherence, management of adverse effects...). In order to secure medication management, the pharmaceutic team chose to set up pharmaceutical consultations. Its objectives are multiple: understanding of treatment for better adherence, pharmaceutical analysis, enhancement of the city-hospital link. This work presents the setting up of the pharmaceutical consultations and makes an assessment after one year. METHODS: The initial step was a meeting with institutional health professionals who work with patients to define the place, the objectives, and the patients targeted by the pharmaceutical consultation. The targeted patients are all patients receiving temozolomide and some patients initiating oral chemotherapy, considered at risk, on medical solicitation. Documents were created to standardize practices in the team from the collection of information and pharmaceutical analysis until the conduct of the consultation and the consultation report (integrated into the computerized patient's medical file). Activity indicators were defined and collected. RESULTS: Over one year, 65 pharmaceutical consultations were conducted, of which 23 % resulted in pharmaceutical interventions. The average duration of consultation was 34minutes. The whole team (four pharmacists and two residents) was involved in this activity. CONCLUSIONS: Pharmaceutical consultations help secure medical care of patients, providing tools, dedicated and personalized time, pharmaceutical analysis, etc. Ultimately, the goal is to accompany the patient throughout his treatment by having follow-up pharmaceutical consultations, in collaboration with community pharmacists thanks to the city-hospital link that we have established.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Derivación y Consulta , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/uso terapéutico , Prestación Integrada de Atención de Salud , Femenino , Humanos , Masculino , Oncología Médica , Persona de Mediana Edad , Grupo de Atención al Paciente , Farmacéuticos , Temozolomida/administración & dosificación , Temozolomida/uso terapéutico
6.
Rev Med Interne ; 39(11): 855-862, 2018 Nov.
Artículo en Francés | MEDLINE | ID: mdl-29661593

RESUMEN

The most potential causes of "non hemolytic" anemias are iron, folate or vitamin B12 deficiencies, severe renal impairment, endocrine diseases, inflammation and medullary disorders. In a non-exceptionnal way no cause is found, sometimes because of a wrong interpretation of analysis results and sometimes because of a little known etiology. The goal of this review is to point out analytical difficulties and to remember some rarer etiologies.


Asunto(s)
Anemia/diagnóstico , Anemia/etiología , Técnicas y Procedimientos Diagnósticos , Medicina Interna/métodos , Factores de Edad , Algoritmos , Anemia/genética , Anemia Sideroblástica/diagnóstico , Árboles de Decisión , Humanos , Enfermedades Raras
7.
Rev Med Interne ; 38(11): 774-777, 2017 Nov.
Artículo en Francés | MEDLINE | ID: mdl-28668372

RESUMEN

INTRODUCTION: Myeloid sarcomas are uncommon proliferations of immature myeloid cells occurring in any extramedullary organ. We report here two cases of myeloid sarcomas in patients with, respectively, a polycythemia vera and a myelodysplastic syndrome. CASE REPORTS: The first is an 81-year-old woman who presented with osteolytic lesions. Diagnosis has been highlighted using anatomopathological study after bone marrow biopsy, but it was delayed because of a very localized basin lesion and few positive myeloid markers. The second patient is an 86-year-old man who presented with pancytopenia and several lymph nodes. Lymph node cytology failed because of the rarity of blast cells. Diagnosis was done after anatomopathological study on lymph node biopsy which revealed a localized form of myeloid sarcoma. CONCLUSION: The diagnosis of myeloid sarcoma must be considered when unusual tumors occur in patients with a chronic myeloid disease. In that case, therapeutic options are those of an acute myeloid leukemia.


Asunto(s)
Sarcoma Mieloide/diagnóstico , Anciano de 80 o más Años , Biopsia , Médula Ósea/patología , Diagnóstico Diferencial , Femenino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/diagnóstico , Sarcoma Mieloide/etiología
8.
Eur J Cancer ; 50(12): 2082-9, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24910417

RESUMEN

BACKGROUND: Patients with high-risk gestational trophoblastic neoplasia (GTN) need multi-agent chemotherapy to be cured. The most common regimen is etoposide (E), methotrexate (M) and actinomycin D (A), alternating weekly with cyclophosphamide (C) plus vincristine (O) (EMA/CO). Cisplatin (P) is a very active drug, but it is usually restricted to second-line therapies. Herein, we report the results of a cisplatin-based therapy: APE (actinomycin D, cisplatin, and etoposide). PATIENTS AND METHODS: The efficacy and safety of APE for high-risk GTN (defined by Institut Gustave-Roussy (IGR) criteria and/or an International Federation of Gynaecology and Obstetrics (FIGO) score >6) are reported. Patients with brain metastasis or placental-site trophoblastic tumour were excluded. RESULTS: Between 1985 and 2013, 95 patients were treated with APE for high-risk GTN: 59 patients as first-line, 36 as ⩾ 2nd-line therapy. There was 94.7% complete remission, though five patients relapsed. One patient died from GTN after multiple lines of chemotherapy. The five-year overall survival rate (median follow-up 5.7 years) was 97% (95% confidence interval (CI): 91-99%). No death from toxicity occurred. Long-term, six grade-1 neuro-toxicities, three grade-1 and two grade-2 oto-toxicities, and one grade-1 renal toxicity were recorded. One patient developed AML-M4 after APE and EMA/CO. Thirty-four of 35 women, who wished to become pregnant, succeeded and all had at least one live birth. CONCLUSION: With a 97% long-term overall survival rate, limited long-term toxicity, and an excellent reproductive outcome, APE could be regarded as an alternative option to EMA/CO as a standard therapy for high-risk GTN.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad Trofoblástica Gestacional/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Dactinomicina/administración & dosificación , Dactinomicina/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Inducción de Remisión , Análisis de Supervivencia , Adulto Joven
9.
Support Care Cancer ; 22(10): 2831-7, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24821366

RESUMEN

BACKGROUND: Induction chemotherapy with docetaxel-cisplatin and 5-fluorouracil (DCF) for locally advanced head and neck cancers (HNC) is associated with a high risk of severe neutropenia or febrile neutropenia (FN). We conducted a retrospective study to evaluate the efficacy and safety of administering granulocyte colony-stimulating factor (G-CSF) on day 3 (D3) during chemotherapy (early G-CSF stimulation) versus after the end of chemotherapy, as per current guidelines (i.e., after the end of 5-FU perfusion; D7), and its impact on patient outcomes. PATIENTS AND METHODS: Patients ≥19 years old, with advanced HNC who received DCF induction chemotherapy (D and P 75 mg per meter squared (mg/m(2)) on day 1 and 5-FU 750 mg/m(2)/day from D1 to D5), were included in the analysis. RESULTS: Data of 70 patients were analyzed from 01 January 2003 to 01 December 2010. Mean age was 56 years (range 45 to 77 years). Thirty-six patients (51.4 %) received pegfilgrastim on D7, and 28 (40 %) started G-CSF prophylaxis during chemotherapy; 12 (17.1 %) had daily filgrastim and 16 (22.9 %) pegfilgrastim on D3. Overall response rate (ORR) was 89.6 % (three early deaths due to infectious complications; 4.3 %). The 3-year overall survival (OS) rate was 72.8 %. FN rate was 14.3 % and chemotherapy delay was 12.9 %. In the D7 G-CSF arm, incidence of grade 3-4 neutropenia (p = 0.023), FN (p = 0.029), and cycle delays (p = 0.006) was statistically higher than the "early" G-CSF arm. A decrease of OS was observed at 2 years (from 85.1 to 63.5 %) of chemotherapy discontinuation or FN (p = 0.0348). DISCUSSION: Early administration of G-CSF is safe and seems to be more effective than D7. Future prospective trials are required to confirm our results.


Asunto(s)
Antineoplásicos/farmacología , Cisplatino/farmacología , Fluorouracilo/farmacología , Factor Estimulante de Colonias de Granulocitos/farmacología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Taxoides/farmacología , Anciano , Antineoplásicos/efectos adversos , Protocolos Antineoplásicos , Cisplatino/efectos adversos , Docetaxel , Quimioterapia Combinada , Femenino , Fluorouracilo/efectos adversos , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Taxoides/efectos adversos
10.
J Neurooncol ; 117(2): 253-9, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24481998

RESUMEN

Brain metastases (BM) can affect up to 45 % of a high-risk breast cancer (BC) population. Liposomal doxorubicin (LD)-based chemotherapy has demonstrated efficacy in the treatment of BC and LD crosses the blood-brain barrier. The aim of this retrospective study is to evaluate the efficacy of the LD-cyclophosphamide (CTX) combination in BM related to BC. Patients diagnosed with BM related to BC and treated with the LD-CTX combination were eligible. BM objective response rate (BM-ORR), BM disease control rate (BM-DCR), BM progression-free survival, overall survival (OS) and safety were analyzed. 29 patients were eligible. The median time from metastatic diagnosis to brain involvement was 12 months. BM was more frequently observed in HER2+ patients. On average, three courses of chemotherapy were administered without grade 3-4 limiting adverse events. After three cycles, BM-ORR and BM-DCR were 41.4 and 58.6 % respectively versus 50 and 62.5 % when no prior radiotherapy was administered. From BM diagnosis, OS was 23 months. A high BM-ORR is observed with the LD-CTX combination in patients with BM related to BC. This is an attractive therapeutic option for these patients, especially when no prior whole brain radiotherapy has been administered.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Carcinoma/tratamiento farmacológico , Carcinoma/secundario , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Encefálicas/mortalidad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Carcinoma/mortalidad , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapéutico , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Modelos de Riesgos Proporcionales , Estudios Retrospectivos
11.
Cancer Radiother ; 18(2): 142-6, 2014 Mar.
Artículo en Francés | MEDLINE | ID: mdl-24433952

RESUMEN

Magnetic resonance imaging (MRI) is a method of choice for follow-up of irradiated brain metastasis. It is difficult to differentiate local tumour recurrences from radiation induced-changes in case of suspicious contrast enhancement. New advanced MRI techniques (perfusion and spectrometry) and amino acid positron-emission tomography (PET) allow to be more accurate and could avoid a stereotactic biopsy for histological assessment, the only reliable but invasive method. We report the case of a patient who underwent surgery for a single, left frontal brain metastasis of a breast carcinoma, followed by adjuvant stereotactic radiotherapy in the operative bed. Seven months after, she presented a local change in the irradiated area on the perfusion-weighted MRI, for which the differentiation between a local tumour recurrence and radionecrosis was not possible. PET with 2-deoxy-((18)F)-fluoro-D-glucose (FDG) revealed a hypermetabolic lesion. After surgical resection, the histological assessment has mainly recovered radionecrosis with few carcinoma cells. The multimodal MRI has greatly contributed to refine the differential diagnosis between tumour recurrence and radionecrosis, which remains difficult. The FDG PET is helpful, in favour of the diagnosis of local tumour recurrence when a hypermetabolic lesion is found. Others tracers (such as carbon 11 or a fluoride isotope) deserve interest but are not available in all centres. Stereotactic biopsy should be discussed if any doubt remains.


Asunto(s)
Neoplasias Encefálicas/cirugía , Traumatismos por Radiación/diagnóstico , Radiocirugia/efectos adversos , Adulto , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Carcinoma/patología , Carcinoma/secundario , Diagnóstico Diferencial , Femenino , Fluorodesoxiglucosa F18 , Humanos , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Traumatismos por Radiación/etiología , Radiofármacos
14.
Oncogene ; 18(2): 533-41, 1999 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-9927210

RESUMEN

We have compared the DNase I hypersensitivity of the regulatory region of two estrogen-regulated genes, pS2 and cathepsin D in hormone-dependent and -independent breast carcinoma cell lines. This strategy allowed the identification of two important control regions, one in pS2 and the other in cathepsin D genes. In the hormone-dependent MCF7 cell line, within the pS2 gene 5'-flanking region, we detected two major DNase I hypersensitive sites, induced by estrogens and/or IGFI: pS2-HS1, located in the proximal promoter and pS2-HS4, located -10.5 Kb from the CAP site, within a region that has not been cloned. The presence of these two DNase I hypersensitive sites correlates with pS2 expression. Interestingly in MCF7 cells, estrogens and IGFI induced indistinguishable chromatin structural changes over the pS2 regulatory region, suggesting that the two transduction-pathways converge to a unique chromatin target. In two cell lines that do not express pS2, MDA MB 231, a hormone-independent cell line that lacks the estrogen receptor alpha, and HE5, a cell line derived from MDA MB 231 by transfection that expresses estrogen receptor alpha, there was only one hormone-independent DNase I hypersensitive site. This site, pS2-HS2, was located immediately upstream of pS2-HS1. In MCF7 cells, two major DNase I hypersensitive sites were present in the 5'-flanking sequences of the cathepsin D gene, which is regulated by estrogens in these cells. These sites, catD-HS2 and catD-HS3, located at positions -2.3 Kb and -3.45 Kb, respectively, were both hormone-independent. A much weaker site, catD-HS1, covered the proximal promoter. In MDA MB 231 cells, that express cathepsin D constitutively, we detected an additional strong hormone-independent DNase I hypersensitive site, catD-HS4, located at position -4.3 Kb. This region might control the constitutive over-expression of cathepsin D in hormone-independent breast cancer cells. All together, these data demonstrate that a local reorganization of the chromatin structure over pS2 and cathepsin D promoters accompanies the establishment of the hormone-independent phenotype of the cells.


Asunto(s)
Neoplasias de la Mama/genética , Catepsina D/genética , Cromatina/genética , Neoplasias Hormono-Dependientes/genética , Proteínas/genética , Secuencia de Bases , Neoplasias de la Mama/patología , Cromatina/química , Cartilla de ADN , Antagonistas de Estrógenos/farmacología , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Datos de Secuencia Molecular , Neoplasias Hormono-Dependientes/patología , Regiones Promotoras Genéticas , Conformación Proteica , ARN Mensajero/genética , Secuencias Reguladoras de Ácidos Nucleicos , Factor Trefoil-1 , Células Tumorales Cultivadas , Proteínas Supresoras de Tumor
15.
J Steroid Biochem Mol Biol ; 57(5-6): 283-91, 1996 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-8639464

RESUMEN

Retinoic acid (RA) regulation of human cathepsin D (cath D) gene expression was investigated in this study. RA enhanced cath D mRNA levels in a concentration-dependent manner in MCF-7 human breast carcinoma cells. RA regulation of cath D mRNA levels was predominantly transcriptional because RA also increased cath D gene core promoter activity. Upon further characterization of the core promoter we localized RA responsive region to proximal 112-bp. The proximal 112-bp region of cath D gene promoter harbours several retinoid response element (RARE)-like sequences. In gel shift experiments the sequence between -100 and -74 nucleotides in the CD112 region carrying imperfect direct repeat and a palindrome competed with RARE for binding to RAR/RXRs. These sequences, however, exhibited binding to protein complexes which could not be competed with unlabeled RARE or up-shifted with RAR/RXR-specific antibodies. We conclude that RA predominantly regulates cath D gene expression from the proximal 112-bp of the promoter region, but this regulation appears indirect.


Asunto(s)
Catepsina D/genética , Tretinoina/farmacología , Secuencia de Bases , Neoplasias de la Mama/genética , Cartilla de ADN/química , Proteínas de Unión al ADN/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Datos de Secuencia Molecular , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas , ARN Mensajero/genética , Receptores de Ácido Retinoico/metabolismo , Mapeo Restrictivo , Receptores X Retinoide , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas
16.
Biochem Biophys Res Commun ; 203(1): 711-8, 1994 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-8074726

RESUMEN

In MCF7 cells, transcription of the lysosomal protease cathepsin D is stimulated by estrogens via a non-consensus estrogen responsive element (ERE). By contrast, in estrogen responsive Ishikawa endometrial cancer cells, the cathepsin D gene is unresponsive to estrogens. We now show that the transfected cathepsin D promoter, which can be induced by estrogens in several cell types, is insensitive in Ishikawa cells. The block is not due to a mutation in the cathepsin D promoter or estrogen receptor, but involves the cathepsin D ERE, and implies a C at position 3 of the ERE sequence. Our results suggest that in Ishikawa cells, cathepsin D insensitivity to estrogen most likely occurs through a specific interaction with the ER, or with an endometrial factor which may compete with the ER for binding to the cathepsin D ERE.


Asunto(s)
Catepsinas/biosíntesis , Catepsinas/genética , ADN/metabolismo , Endometrio/metabolismo , Estradiol/farmacología , Regiones Promotoras Genéticas , Células 3T3 , Animales , Secuencia de Bases , Sitios de Unión , Neoplasias de la Mama , Catepsina G , Línea Celular , Cloranfenicol O-Acetiltransferasa/biosíntesis , Chlorocebus aethiops , Femenino , Células HeLa , Humanos , Ratones , Datos de Secuencia Molecular , Mutagénesis Insercional , Oligodesoxirribonucleótidos , Regiones Promotoras Genéticas/efectos de los fármacos , Mapeo Restrictivo , Serina Endopeptidasas , Transfección , Células Tumorales Cultivadas
17.
Mol Endocrinol ; 8(6): 693-703, 1994 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-7935485

RESUMEN

Cathepsin D, a lysosomal proteinase, is induced by estrogens in mammary cancer cells where its concentration is correlated with a higher risk of metastasis. Its gene expression is stimulated by estrogens in MCF7 cells, and we have shown that a short proximal promoter fragment from -365 to -122 is required for this induction. We now characterize, at -261, a nonconsensus estrogen-responsive element (ERE) (E2) with two differences in the distal half of its palindrome, which confers estradiol responsiveness to the heterologous Herpes simplex virus thymidine kinase promoter in transient transfection experiments. This ERE is located in a 21-base pair sequence: 5'GGGCCGGGCTGACCCCGC GGG3', containing a GC-rich region in its 3'-part, which is almost perfectly repeated at -362 (the E1 site). The E2 site was necessary but not sufficient to mediate an estrogen response and required cooperation with the homologous E1 element and/or with general transcription sites located downstream. In vitro, the E2 site but not the E1 site was protected by estrogen receptor (ER) against DNAse I digestion, and gel shift experiments suggested an interaction with the ER as a dimer. Moreover, we showed in vivo that ER DNA binding domain was required to mediate estrogen induction from the cathepsin D ERE. We conclude that estradiol induction of cathepsin D is mediated by interaction of the ER with a nonconsensus ERE that requires synergy with other elements located upstream and/or downstream of this central ERE.


Asunto(s)
Catepsina D/genética , Estrógenos/farmacología , Regiones Promotoras Genéticas/genética , Secuencia de Bases , Neoplasias de la Mama/química , Neoplasias de la Mama/patología , Neoplasias de la Mama/ultraestructura , Catepsina D/análisis , ADN/análisis , ADN/genética , Elementos de Facilitación Genéticos/genética , Estrógenos/metabolismo , Regulación de la Expresión Génica , Humanos , Datos de Secuencia Molecular , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Timidina Quinasa/genética , Transcripción Genética , Transfección , Células Tumorales Cultivadas
18.
Cytogenet Cell Genet ; 62(1): 52-3, 1993.
Artículo en Inglés | MEDLINE | ID: mdl-8422757

RESUMEN

Specific tumor-associated rearrangements involving the regions 11p13 and 11p15 have been extensively documented. However, cytogenetic definition of the breakpoints occurring at the boundaries of these two regions was not precise enough to correlate with the molecular data. Using probes corresponding to the genes coding for MYOD1, CTSD, LDHA, and RBTN1 and to the anonymous sequence D11S776, we have reassessed the breakpoints of three hybrids (J1.10, BID7, and NYX3.1) and confirmed the localization or more precisely mapped these four genes and the anonymous DNA marker on different subregions of 11pter-->p13, including the smallest region of 11p15.5 duplicated in a patient with Beckwith-Wiedemann syndrome.


Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas , Cromosomas Humanos Par 11 , Neoplasias/genética , Animales , Línea Celular , Mapeo Cromosómico , Marcadores Genéticos , Humanos , Células Híbridas , Ratones , Células Tumorales Cultivadas
19.
Proc Natl Acad Sci U S A ; 90(1): 203-7, 1993 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-8419924

RESUMEN

The cathepsin D (cath-D) gene, coding for a ubiquitous lysosomal aspartyl protease, is overexpressed in aggressive human breast cancers, and its transcription is induced by estrogens in hormone-responsive breast cancer cells. We have determined the structure and function of the proximal 5' upstream region of the human cath-D gene from MCF7 cells. We show that the promoter has a compound structure with features of both housekeeping genes (high G+C content and potential transcription factor Sp1 sites) and regulated genes (TATAA sequence). By RNase protection assay, we show that transcription is initiated at five major transcription sites (TSSI to -V) spanning 52 base pairs. In hormone-responsive breast cancer cells, estradiol increased by 6- to 10-fold the level of RNAs initiated at TSSI, which is located about 28 base pairs downstream from the TATA box. The specific regulation by estradiol of transcription starting at site I exclusively was confirmed by primer extension. Moreover, the same estradiol effect was observed in the ZR75-1 cell line and in MDA-MB231 estrogen-resistant breast cancer cells stably transfected with the estrogen receptor. Site-directed mutagenesis indicated that the TATA box is essential for initiation of cath-D gene transcription at TSSI. In breast cancer biopsy samples, high levels of TATA-dependent transcription were correlated with overexpression of cath-D mRNA. We conclude that cath-D behaves, depending on the conditions, as a housekeeping gene with multiple start sites or as a hormone-regulated gene that can be controlled from its TATA box.


Asunto(s)
Neoplasias de la Mama/genética , Catepsina D/genética , Estradiol/farmacología , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Regiones Promotoras Genéticas , TATA Box , Transcripción Genética , Animales , Elementos sin Sentido (Genética) , Secuencia de Bases , ADN/genética , ADN/aislamiento & purificación , ADN de Neoplasias/genética , ADN de Neoplasias/aislamiento & purificación , Exones , Femenino , Humanos , Intrones , Ratones , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Sondas ARN , Ratas , Mapeo Restrictivo , Homología de Secuencia de Ácido Nucleico , Transcripción Genética/efectos de los fármacos , Transfección , Células Tumorales Cultivadas
20.
ASAIO J ; 38(1): 38-46, 1992.
Artículo en Inglés | MEDLINE | ID: mdl-1348192

RESUMEN

Over the past 6 years, research has led to development of a small, lightweight, power-efficient, uniquely simple ventricular assist device driven by a magnetic actuator. Magnetic actuation permits total elimination of all mechanical motion converter components used for pusher plate displacement, resulting in a significant reduction in complexity and resultant increase in reliability. Extensive in vitro mock loop development has resulted in a left ventricular assist device (LVAD), the primary design parameters of which for the clinical prototype actuator and pump are 1) an actuator weight of 312 g, 2) actuator size of 32.5 cm3, 3) power requirements of 7.8 to 11.4 watts (60-100 beats per minute [BPM]), and 4) system efficiency of 24% to 34% and average dynamic stroke volume of 65 ml. Initial in vivo tests assessed this LVAD's performance in four sheep under three acute conditions of ventricular dysfunction. The results demonstrate that, at a pump-rate of 100 BPM, mean aortic pressure increased by 45-50 mmHg during 1) beta blockade, 2) coronary ligation, and 3) ventricular fibrillation. Pump flow ranged from 2.71 L/min to a maximum of 4.6 L/min. Acute test periods were arbitrarily set for 6 hours duration. Of the four sheep, two survived, one lived 5 hours, and the fourth lived 4.5 hours. Global fibrillation was the primary cause of failure. This initial in vivo data demonstrates the pump's ability to maintain satisfactory hemodynamic parameters of flow and pressure under three acute conditions of extreme left ventricular dysfunction in an animal model. These initial LVAD performances were encouraging. Further tests will use calves with a greatly expanded performance evaluation protocol.


Asunto(s)
Corazón Auxiliar , Magnetismo , Antagonistas Adrenérgicos beta/farmacología , Animales , Materiales Biocompatibles , Enfermedad Coronaria/terapia , Suministros de Energía Eléctrica , Diseño de Equipo , Masculino , Propanolaminas/farmacología , Ovinos , Programas Informáticos , Fibrilación Ventricular/terapia , Función Ventricular Izquierda/fisiología
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