RESUMEN
PURPOSE: KRAS mutation has been associated with enhanced dependency on the folate metabolism in preclinical studies. However, whether KRAS mutation correlates to increased sensitivity to pemetrexed in patients with advanced NSCLC is unknown. METHODS: Patients with advanced non-squamous NSCLC who had a documented EGFR and ALK WT genotype with simultaneous KRAS mutation assessment were evaluated for clinical outcome to pemetrexed- and non-pemetrexed-based first-line platinum doublet according to KRAS mutation status. RESULTS: Of 356 patients identified, 138 harbored a KRAS mutation. Among KRAS-mutant NSCLCs, those treated with platinum/pemetrexed (81/138) had significantly lower ORR (30.9% versus 47.4%, P = 0.05), DCR (51.8% versus 71.9%, P = 0.02) and shorter median progression-free survival [mPFS 4.1 versus 7.1 months, HR 1.48 (95% CI 1.03-2.12), P = 0.03] and median overall survival [mOS 9.7 versus 26.9 months, HR 1.93 (95% CI 1.27-2.94), P = 0.002] compared to those who received a non-pemetrexed-based platinum doublet (57/138). No difference in ORR, DCR, mPFS and mOS was observed between KRAS WT patients who received a pemetrexed-based (124/218) versus non-pemetrexed base platinum doublets (94/218). After adjusting for performance status, age and the presence of brain metastasis at baseline, treatment with pemetrexed-based platinum doublet was associated with an increased risk of death [HR 2.27 (95% CI 1.12-4.63), P = 0.02] among KRAS-mutant patients in multivariate analysis. CONCLUSION: Patients with KRAS-mutant lung adenocarcinoma have a poorer outcome on pemetrexed-based first-line chemotherapy. Whether KRAS-mutant NSCLCs should be excluded from pemetrexed-containing regimens should be assessed prospectively.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Pemetrexed/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Platino (Metal)/uso terapéutico , Supervivencia sin Progresión , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Contextual fear conditioning (CFC) paradigm is routinely used to study fear-based learning in animals and it provides a useful model for understanding fear and anxiety in human. In the present study, such model was used following the previously established CFC protocol, and immunohistochemistry, enzymatic activity and western blotting analysis approaches were used to identify the expression of acid sphingomyelinase (aSMase) and vitamin D receptor (VDR) in prefrontal region brain of rat. Results revealed an increase of aSMase activity in conditioned rats, suggesting an apoptotic condition in such animals. In addition, an increase of density and organization of axonal neurofilaments and of VDR expression has been observed in brain of conditioned rats, supporting an induction of growth and organization of new neurons in prefrontal regions, whose contribution to various aspects of contextual fear learning is still largely unknown.
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Regulación de la Expresión Génica , Aprendizaje , Corteza Prefrontal , Receptores de Calcitriol , Esfingomielina Fosfodiesterasa , Animales , Condicionamiento Clásico/fisiología , Miedo , Modelos Animales , Corteza Prefrontal/enzimología , Ratas , Receptores de Calcitriol/genética , Esfingomielina Fosfodiesterasa/metabolismoRESUMEN
The 3ß-hydroxysterol Δ14-reductase, encoded by the Tm7sf2 gene, is an enzyme involved in cholesterol biosynthesis. Cholesterol and its derivatives control epidermal barrier integrity and are protective against environmental insults. To determine the role of the gene in skin cholesterol homeostasis, we applied 12-o-tetradecanoylphorbol-13-acetate (TPA) to the skin of Tm7sf2(+/+) and Tm7sf2(-/-) mice. TPA increased skin cholesterol levels by inducing de novo synthesis and up-take only in Tm7sf2(+/+) mouse, confirming that the gene maintains cholesterol homeostasis under stress conditions. Cholesterol sulfate, one of the major players in skin permeability, was doubled by TPA treatment in the skin of wild-type animals but this response was lost in Tm7sf2(-/-) mice. The expression of markers of epidermal differentiation concomitant with farnesoid-X-receptor and p38 MAPK activation were also disrupted in Tm7sf2(-/-) mice. We then subjected Tm7sf2(+/+) and Tm7sf2(-/-) mice to a classical two-stage skin carcinogenesis protocol. We found that the loss of Tm7sf2 increased incidence and multiplicity of skin papillomas. Interestingly, the null genotype showed reduced expression of nur77, a gene associated with resistance to neoplastic transformation. In conclusion, the loss of Tm7sf2 alters the expression of proteins involved in epidermal differentiation by reducing the levels of cholesterol sulfate.
Asunto(s)
Colesterol/biosíntesis , Oxidorreductasas/metabolismo , Neoplasias Cutáneas/genética , Piel/metabolismo , Animales , Carcinógenos , Diferenciación Celular/genética , Transformación Celular Neoplásica/genética , Colesterol/genética , Humanos , Ratones , Ratones Transgénicos , Oxidorreductasas/genética , Papiloma/patología , Papiloma/virología , Piel/patología , Piel/virología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Insulin-like growth factor 1 receptor (IGF1R) represents a novel molecular target in non-small-cell-lung cancer (NSCLC). IGF1R and epidermal growth factor receptor (EGFR) activation are essential to mediate tumor cell survival, proliferation, and invasion. This study investigates the prognostic role of IGF1R and EGFR in surgically resected NSCLC. MATERIALS AND METHODS: IGF1R and EGFR copy number gain (CNG) were tested by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC) in 125 stage I-II-IIIA NSCLC patients. RESULTS: Fourty-six tumors (40.3%) were IGF1R FISH-positive (FISH+), and 76 (67.2%) were EGFR FISH+. Tumors with concomitant IGF1R/EGFR FISH+ were observed in 34 cases (30.1%). IGF1R and EGFR FISH+ were associated with SCC histology (p = 0.01 and p = 0.04, respectively). IGF1R and EGFR protein over-expression (IHC+) were detected in 45 (36.0%) and 69 (55.2%) cases, respectively. Tumors with concomitant IGF1R/EGFR IHC+ were detected in 31 (24.8%) patients. IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were significantly associated (χ(2) = 4.02, p = 0.04). Patients with IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were associated with shorter disease-free survival (DFS) (p = 0.05 and p = 0.05, respectively). Patients with concomitant IGF1R/EGFR FISH+/IHC+ had a worse DFS and overall survival (p = 0.005 and p = 0.01, respectively). The multivariate model confirmed that IGF1R/EGFR FISH+/IHC+ (hazard ratio (HR), 4.08; p = 0.01) and tumor stage (II-III vs I) (HR, 4.77; p = 0.003) were significantly associated with worse DFS. CONCLUSIONS: IGF1R/EGFR FISH+ correlates with IGF1R/EGFR IHC+. IGF1R/EGFR FISH+/IHC+ is an independent negative prognostic factor for DFS in early NSCLC. These features may have important implications for future anti-IGF1R therapeutic approaches.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Receptores ErbB/biosíntesis , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Receptor IGF Tipo 1/biosíntesis , Receptor IGF Tipo 1/genética , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Dosificación de Gen , Expresión Génica/fisiología , Humanos , Inmunohistoquímica , Hibridación in Situ , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Factores Sexuales , Fumar/efectos adversosRESUMEN
BACKGROUND: We present a comprehensive analysis of KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations in advanced non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs), with the aim of clarifying the relative contribution of these molecular alterations to resistance. PATIENTS AND METHODS: One hundred and sixty-six patients with advanced NSCLC treated with EGFR-TKIs with available archival tissue specimens were included. EGFR (exons 18-21), KRAS (exons 2, 3), PIK3CA (exons 9, 20), and MET (exons 14, 15) mutations were analyzed using PCR-based sequencing. Among all the mutations evaluated, only KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations, defined as "TKI non-sensitizing mutations" were used for response, time to progression (TTP), and overall survival (OS) analysis. RESULTS: TKI non-sensitizing mutations were associated with disease progression (p = 0.001), shorter TTP (p < 0.0001), and worse OS (p = 0.03). Cox's multivariate analysis including histology and performance status showed that TKI non-sensitizing mutations were independent factors for shorter TTP (p < 0.0001) and worse OS (p = 0.01). CONCLUSIONS: When KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations are concomitant, up to 96.0% of NSCLC patients unlikely to respond to TKIs can be identified, and they represented independent negative prognostic factors. Comprehensive molecular dissection of EGFR signaling pathways should be considered to select advanced NSCLC patients for TKIs therapies.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/tratamiento farmacológico , Selección de Paciente , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Fosfatidilinositol 3-Quinasa Clase I , Receptores ErbB/genética , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mutación , Fosfatidilinositol 3-Quinasas/genética , Pronóstico , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas p21(ras) , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Proteínas ras/genéticaRESUMEN
Recent literature highlights the importance of pro-inflammatory cytokines in the biology of breast cancer stem cells (CSCs), unraveling differences with respect to their normal counterparts. Expansion of mammospheres (MS) is a valuable tool for the in vitro study of normal and cancer mammary gland stem cells. Here, we expanded MSs from human breast cancer and normal mammary gland tissues, as well from tumorigenic (MCF7) and non-tumorigenic (MCF10) breast cell lines. We observed that agonists for the retinoid X receptor (6-OH-11-O-hydroxyphenanthrene), retinoic acid receptor (all-trans retinoic acid (RA)) and peroxisome proliferator-activated receptor (PPAR)-γ (pioglitazone (PGZ)), reduce the survival of MS generated from breast cancer tissues and MCF7 cells, but not from normal mammary gland or MCF10 cells. This phenomenon is paralleled by the hampering of pro-inflammatory Nuclear Factor-κB (NF-κB)/Interleukin-6 (IL6) axis that is hyperactive in breast cancer-derived MS. The hindrance of such pathway associates with the downregulation of MS regulatory genes (SLUG, Notch3, Jagged1) and with the upregulation of the differentiation markers estrogen receptor-α and keratin18. At variance, the PPARα agonist Wy14643 promotes MS formation, upregulating NF-κB/IL6 axis and MS regulatory genes. These data reveal that nuclear receptors agonists (6-OH-11-O-hydroxyphenanthrene, RA, PGZ) reduce the inflammation dependent survival of breast CSCs and that PPARα agonist Wy14643 exerts opposite effects on this phenotype.
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Supervivencia Celular/efectos de los fármacos , Células Madre Neoplásicas/citología , Fenantrenos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazolidinedionas/farmacología , Tretinoina/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , FN-kappa B/metabolismo , PPAR gamma/agonistas , PPAR gamma/metabolismo , Fenantrenos/química , Pioglitazona , Pirimidinas/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide/agonistas , Receptores X Retinoide/metabolismo , Tiazolidinedionas/química , Tretinoina/químicaRESUMEN
Juvenile papillomatosis of the breast ("Swiss cheese disease'') is a benign localized proliferative condition of the breast which occurs almost exclusively in young adult women. Patients with this lesion often have a family history of breast carcinoma, but rarely carcinoma may coexist with the lesion at the time of diagnosis. We present a case of a young male with juvenile papillomatosis of the breast. The pathology and clinical management of this rare lesion is discussed.
Asunto(s)
Neoplasias de la Mama Masculina/diagnóstico , Papiloma/diagnóstico , Adolescente , Neoplasias de la Mama Masculina/complicaciones , Neoplasias de la Mama Masculina/patología , Hemorragia/etiología , Humanos , Hiperplasia , Macrófagos/patología , Masculino , Glándulas Mamarias Humanas/patología , Pezones , Papiloma/complicaciones , Papiloma/patologíaRESUMEN
Mammary carcinoma arising in ectopic breast tissue is an uncommon occurrence. Most reported cases have involved ductal carcinoma, but other types, such as medullary, papillary, and lobular carcinomas, have been described. For pathologists, the diagnosis of mammary carcinoma arising in ectopic breast tissue can be difficult, especially in the axilla, where carcinoma of adnexal origin must be excluded. We describe a 51-year-old woman who developed invasive secretory ductal carcinoma in ectopic left axillary breast tissue and micrometastatic carcinoma in an ipsilateral axillary lymph node. The carcinoma arose in a left axillary mass that had been present for several years, from which she had secreted fluid during prior menstrual periods.
Asunto(s)
Axila , Neoplasias de la Mama/diagnóstico , Mama , Carcinoma Ductal de Mama/diagnóstico , Coristoma/diagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/terapia , Quimioterapia Adyuvante , Coristoma/cirugía , Diagnóstico Diferencial , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Neoplasias Primarias Múltiples/terapia , Radioterapia Adyuvante , Resultado del TratamientoRESUMEN
Melanocytic matricoma is a rare recently described lesion. It usually presents as a pigmented, dark-papular, crusted lesion on sun-damaged skin of adult patients. Histopathologically, these lesions are characterized by well-circumscribed nodules composed of matrical and supramatrical cells with clustered shadow cells, and admixed pigmented dendritic melanocytes. It differs from matricomas and pilomatricomas by its lack of calcification, cyst formation, granulomas, and connections to the epidermis and other adnexal structures. The clinical differential diagnosis includes hemangioma, pigmented basal cell carcinoma, and melanoma. Melanocytic matricoma presumably is the representation of an epithelial-melanocytic interaction in the anagen phase of the hair cycle. An extensive search of the medical literature revealed 11 reports of benign melanocytic matricomas and 5 malignant counterparts. We report an additional case of melanocytic matricoma with discussion of clinicopathologic features and differential diagnosis.
Asunto(s)
Enfermedades del Cabello/patología , Melanocitos/patología , Pilomatrixoma/patología , Neoplasias Cutáneas/patología , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma Basocelular/diagnóstico , Diagnóstico Diferencial , Enfermedades del Cabello/metabolismo , Enfermedades del Cabello/cirugía , Hemangioma/diagnóstico , Humanos , Inmunohistoquímica , Masculino , Melanocitos/metabolismo , Melanoma/diagnóstico , Pilomatrixoma/metabolismo , Pilomatrixoma/cirugía , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: In an attempt to identify markers of resistance to trastuzumab, we evaluated both the profiling of human epidermal growth factor receptor 2 (HER2)-positive tumor cells measuring the relative levels of EGFR, pMAPK, pAkt and PTEN and their correlations with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. PATIENTS AND METHODS: Tumor tissues for this retrospective analysis were available from 45 out of 76 patients with metastatic breast cancer treated from April 1999 to March 2006 with trastuzumab-based therapy at our Institution. Evaluations of EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry (IHC) were carried out on all 45 tissue samples and their correlations with response to trastuzumab, incidence of central nervous system (CNS) metastases, time to progression (TTP), overall survival from diagnosis of breast cancer (OS1), from diagnosis of metastatic disease (OS2) and from the start of trastuzumab (OS3) were analyzed. RESULTS: We observed that TTP (P = 0.001) and median OS2 and OS3 were significantly longer in patients responsive to trastuzumab-based regimen compared with nonresponsive patients. EGFR, pMAPK, pAkt and PTEN status by IHC were not significantly associated with response to trastuzumab, TTP, overall survival (OS1, OS2, OS3) and CNS metastases incidence. A trend for shorter OS3 was observed for pMAPK-positive patients compared with pMAPK-negative patients (22.8 versus 31.2 months; P = 0.076). Median OS1 resulted shorter in 22 pAkt-positive patients (69.8 months) compared with 23 pAkt-negative patients (108.2 months); P = 0.091. It is likely that high expression of pMAPK (pMAPK-positive status) or pAkt (pAkt-positive status) could identify a subgroup of HER2-positive tumors with high activity of proliferation and survival pathways and with resistance to trastuzumab. CONCLUSIONS: In HER2-positive metastatic breast cancers, EGFR, pMAPK, pAkt and PTEN status evaluated by IHC was not significantly associated with response to trastuzumab, TTP, OS and CNS metastases incidence. However, HER2 status determined by IHC and/or FISH assays may not be sufficient to predict response to trastuzumab-based therapy.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Receptores ErbB/metabolismo , Genes erbB-2 , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Metástasis de la Neoplasia , Fosfohidrolasa PTEN/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Trastuzumab , Resultado del TratamientoRESUMEN
BACKGROUND: Insulin-like growth factor receptor-1 (IGFR-1) represents a novel molecular target in non-small-cell lung cancer (NSCLC). IGFR-1 and epidermal growth factor receptor (EGFR) activation is essential to mediate tumor cell survival, proliferation and invasion. We explored the correlation between IGFR-1 and EGFR, their relationship with clinicopathological parameters and their impact on outcome in resected stage I-III NSCLC patients. PATIENTS AND METHODS: Tumors from 125 surgical NSCLC patients were evaluated for IGFR-1 and EGFR expression by immunohistochemistry. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis. RESULTS: IGFR-1 protein overexpression was detected in 36.0% of NSCLC patients and was associated with larger tumor size (P = 0.04) but not with other clinical or biological characteristics. EGFR protein overexpression was observed in 55.2% of NSCLC, more frequently in squamous cell carcinoma (SCC) than non-SCC (63.7% versus 36.3%, chi(2) = 9.8, P = 0.001). IGFR-1 protein expression was associated with EGFR protein expression (P = 0.03). At the multivariate analysis, high coexpression of both IGFR-1 and EGFR was a significant prognostic factor of worse disease-free survival (DFS) (hazard ratio 2.51, P = 0.01). CONCLUSION: A statistically significant association was observed between high coexpression of both IGFR-1 and EGFR and worse DFS in early NSCLC patients.
Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Receptores ErbB/análisis , Neoplasias Pulmonares/cirugía , Neumonectomía , Receptor IGF Tipo 1/análisis , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/química , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Pulmonares/química , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Escisión del Ganglio Linfático , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia ArribaRESUMEN
OBJECTIVE: Liquid-based cytology using the thin layer technique has recently been introduced in thyroid fine needle aspiration cytology together with or in substitution of direct smears, but its usefulness is still controversial and relatively few studies have been published in this field. The aim of the present study was to compare the results obtained from conventional smears with those from thin layer smears. DESIGN: In 3875 thyroid nodules, a double cytologic sampling was taken in randomized order, to prepare conventional or thin layer smears. MAIN OUTCOME: The diagnoses agreed in 2934 (75.7%) cases and disagreed in 941 (24.3%). The analysis of discordant data showed there were fewer non-diagnostic cases in the thin layer smears (377 vs 541, p<0.001) whereas in conventional smears there were more cases positive for carcinoma (27 vs 4, p<0.001). The cytohistologic correlation was available for 194 cases and showed that conventional smears had a greater capacity for revealing carcinomas (44 vs 31). Finally, diagnoses based on conventional smears were more sensitive than thin layer smears (93.6% vs 65.9%) whereas specificity was constant. CONCLUSIONS: From our experience, the conventional smear offers a greater possibility of diagnosis when suspecting malignancy or diagnosing malignancy cases, whereas thin layer smears significantly reduce the number of non-diagnostic cases. For this reason, we suggest combining the two techniques in routine cytologic diagnosis.
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Biopsia con Aguja Fina/métodos , Biopsia con Aguja Fina/normas , Nódulo Tiroideo/patología , Biopsia con Aguja/normas , Histocitoquímica/instrumentación , Histocitoquímica/métodos , Humanos , Nódulo Tiroideo/química , Nódulo Tiroideo/diagnósticoRESUMEN
BACKGROUND: We explored the correlation between serum human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD) and tissue HER2 status, their relationship with clinicopathological parameters and their impact on disease-free survival (DFS) and overall survival in early breast cancer patients. PATIENTS AND METHODS: This prospective trial included patients with stage I-III breast cancer. Serum HER2 ECD levels were measured by two enzyme-linked immunosorbent assays before surgical treatment. Tissue HER2 status was analyzed by immunohistochemistry (IHC) in all tumors; FISH assay was utilized in HER2 2+ tumors by IHC. RESULTS: From May 2000 to July 2005, 256 consecutive stage I-III breast cancer patients were included in this study. High serum HER2 ECD levels (>or=15 ng/ml) were reported in 23 patients (9.0%) and HER2-positive status in tumor tissue was observed in 42 patients (16.4%) with a concordance of 87.1%. High HER2 ECD levels were significantly associated with high histological grade (P = 0.003), stage III (P = 0.008), lymph node involvement (P = 0.035) and negativity of both estrogen (P = 0.016) and progesterone (P = 0.007) receptors. At multivariate analysis, high serum HER2 ECD levels were a significant independent prognostic factor of worse DFS (P = 0.009). CONCLUSIONS: A statistically significant association was observed between high serum HER2 ECD levels and worse DFS in early breast cancer patients.
Asunto(s)
Neoplasias de la Mama/sangre , Carcinoma/sangre , Proteínas de Neoplasias/sangre , Receptor ErbB-2/sangre , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma/química , Carcinoma/mortalidad , Carcinoma/patología , Carcinoma/terapia , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Genes erbB-2 , Humanos , Mastectomía , Persona de Mediana Edad , Neoplasias Hormono-Dependientes/sangre , Neoplasias Hormono-Dependientes/química , Neoplasias Hormono-Dependientes/mortalidad , Neoplasias Hormono-Dependientes/patología , Neoplasias Hormono-Dependientes/terapia , Pronóstico , Estudios Prospectivos , Estructura Terciaria de Proteína , Radioterapia Adyuvante , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Análisis de SupervivenciaRESUMEN
Small integrin-binding ligand N-linked glycoproteins (SIBLINGs) constitute a family of extracellular matrix proteins involved in bone homeostasis. Their pattern of expression has been primarily reported in bone and tooth and, more recently, in several cancer types. Dentin matrix protein 1 (DMP1), a SIBLING family member, expression was investigated by immunohistochemistry in a retrospective series of 148 primary human breast cancers. Correlations between DMP1 expression levels in the tumors and clinicopathologic features, bone metastases development and relapse of the disease were examined. DMP1 was expressed by 63.5% of the breast tumors analyzed. Significant inverse associations were found between DMP1 expression levels and the size and grade of the tumors (both, P < 0.0001). High DMP1 expression levels in the primary breast lesions were associated with a lower risk of subsequent development of skeletal metastases (P = 0.009). Patients with tumors expressing high levels of DMP1 had a significantly higher disease-free survival rate than those with low DMP1-expressing tumors (P = 0.0062). When DMP1 expression was examined in breast cancer cell lines, we found that non invasive MCF-7 and T47-D cells expressed higher levels than highly invasive MDA-MB-231 and Hs578T cells. Moreover, the specific inhibition of DMP1 expression in MCF-7 cells using siRNAs promoted significantly their migratory capability. Our data implicate for the first time DMP1 expression in breast cancer progression and bone metastases development.
Asunto(s)
Neoplasias de la Mama/patología , Proteínas de la Matriz Extracelular/biosíntesis , Regulación Neoplásica de la Expresión Génica , Fosfoproteínas/biosíntesis , Adulto , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Movimiento Celular , Supervivencia sin Enfermedad , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , ARN Interferente Pequeño/metabolismo , Factores de Tiempo , Cicatrización de HeridasRESUMEN
Angiomyolipoma is a lesion usually observed in the kidney of patients with tuberous sclerosis. Extrarenal sites are very unusual with sporadic cases in internal organ, soft tissue and skin (fifteen cases have been described in this site). Herein we describe an adding case located on the ear in 58-year-old man reviewing the pertinent literature. The main diagnostic differential criteria are also discussed.
Asunto(s)
Angiomiolipoma/patología , Neoplasias del Oído/patología , Oído Externo/patología , Neoplasias Cutáneas/patología , Actinas/análisis , Angiomiolipoma/diagnóstico , Angiomiolipoma/cirugía , Biomarcadores de Tumor/análisis , Diagnóstico Diferencial , Neoplasias del Oído/diagnóstico , Neoplasias del Oído/cirugía , Oído Externo/cirugía , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/cirugíaRESUMEN
The search for single independent prognostic factors in breast cancer has often produced conflicting results. Therefore, prognostic indexes have been compiled by combining several parameters. In this study we compare the Nottingham Prognostic Index (NPI), which is based on traditional prognostic factors (diameter of the neoplasm, lymph node status and histological grade) with the Adelaide Prognostic Index (API), which is based on the tumour diameter and two biological parameters: oestrogen receptors and cell kinetics. We considered 82 cases of breast cancer observed over the period 1987-1990 with a minimum follow-up of 60 months. The NPI gives a better definition of the prognostic profile for each patient. Our results indicate three prognostic groups (good, moderate, unfavourable), which differ with respect to disease-free survival (DFS; P=0.0024) and overall survival (OS; P=0.0033). In contrast, the API scores showed no significant correlation with OS or DFS. The use of prognostic indexes, especially when compiled using traditional parameters, is a useful aid to the clinician, since they can provide a reliable indication of how individual tumours will evolve.
Asunto(s)
Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Italia/epidemiología , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Índice de Severidad de la Enfermedad , Análisis de SupervivenciaRESUMEN
Synergism between anti-HER2 monoclonal antibody (trastuzumab) and paclitaxel has been shown in vitro and in vivo. In previous experiences, weekly administration of trastuzumab and paclitaxel has shown significant activity in metastatic breast cancer. In this phase II study, we evaluated the activity and the toxicity of this weekly regimen in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Between November 1999 and July 2001, 25 patients were treated with trastuzumab (4 mg kg(-1) i.v. loading dose followed by 2 mg kg(-1) i.v. week(-1)) and paclitaxel (60-90 mg m(-2) h(-1) i.v. infusion week(-1)). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, after 6 months of therapy, the decision to stop paclitaxel while continuing weekly trastuzumab was left to the physicians' judgement. At the median follow-up of 19.6 months (range 9.2-38.1), all patients are evaluable for response and toxicity. We obtained four (16%) complete responses (CR), 10 (40%) partial responses (PR), four (16%) stable diseases and seven (28%) disease progressions. The response rate (CR+PR) was 56% (95% CI, 36.5-75.5%). The median duration of response was 10.4 months (range 4.1-24.2+). Median time to progression was 8.6 months (range 2.5-24.2+). The toxicity was mild; five patients experienced fever and chills during the first infusion of trastuzumab (20%); leukopenia grade 2 was recorded in one patient (4%). Two patients (8%) came off study for grade 3 cardiotoxicity (after 9 and 17 weeks of treatment, respectively): both had already received anthracyclines and taxanes. Onycholysis grade 2 was observed in five patients (20%). These results confirm that weekly administration of trastuzumab and paclitaxel is active in anthracycline- and taxane-pretreated metastatic breast cancer patients HER2-overexpressing. Since cardiac disfunctions grade 3 were observed (8%), we recommend that cardiac function should be monitored in these patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Antineoplásicos Fitogénicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Regulación Neoplásica de la Expresión Génica , Genes erbB-2 , Corazón/efectos de los fármacos , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Receptor ErbB-2/biosíntesis , Taxoides/farmacología , Trastuzumab , Resultado del TratamientoRESUMEN
Literature data suggest that breast cancers occurring in young patients may be different from those arising in older women. In this study the clinicopathologic characteristics of 50 patients under 40 years of age were compared with those of patients aged over 60. Patients under 40 years old more frequently had a family history of breast cancer than did older patients (24% vs 17%) and had more often used oral contraceptives (29% vs 13%); on average they had experienced menarche 1 year earlier. For early onset breast carcinomas there was a higher frequency of grade 3 tumours (38% vs 17%) and oestrogen receptor negativity (46% vs 20%). In addition, in younger patients the carcinomas were mostly DNA aneuploid (78% vs 58%), with a higher proliferation rate (48% vs 26%) and more frequent c-erbB-2 overexpression (48% vs 26%) and p53 alteration (30% vs 8%). Our data demonstrate that breast cancers arising in young women have a significantly different biopathological profile from those in older patients, with a predominance of unfavourable prognostic parameters.
Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Adulto , Factores de Edad , Biopsia con Aguja , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Genes BRCA1 , Humanos , Italia/epidemiología , Persona de Mediana Edad , Estadificación de Neoplasias , Probabilidad , Pronóstico , Receptor ErbB-2/análisis , Estudios Retrospectivos , Medición de Riesgo , Tasa de SupervivenciaRESUMEN
In this study, we retrospectively evaluated the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in 228 and 213 specimens, respectively, from stages I and II breast cancer patients (pts) enrolled in a randomized phase III adjuvant chemotherapy trial comparing epirubicin to CMF, while tamoxifen was given to all postmenopausal pts. The expression of VEGF and MVD was assessed on tissue sections formalin-fixed and paraffin-embedded by immunohistochemical staining using anti-VEGF antibody of human origin and anti-CD34 monoclonal antibody. Univariate and multivariate analysis were performed using chi squared test, log-rank test and Cox's regression model. Sixty four of 228 pts were classified as VEGF positive (28%) with no significant difference in the two treatment arms. In 213 pts evaluated for CD34, 103 pts (48%) were classified as MVD high. No significant association between VEGF and MVD was found, and neither were they correlated with many known prognostic factors such as age, tumor size, nodal status, and histological grade. The only significant correlations observed were between VEGF and estrogen receptor (ER) status (p = 0.013) and between MVD and HER2 overexpression (p = 0.023). At a median follow up of 96 months VEGF and MVD were not correlated with relapse-free survival (RFS) and overall survival (OS) in all pts and in pts assigned to one of the two treatment arms. In conclusion, VEGF and MVD retrospectively evaluated, cannot be considered prognostic factors in node negative (N-) high risk and node positive (N+) breast cancer pts treated with two different regimens of adjuvant chemotherapy.