RESUMO
Triple negative breast cancer (TNBC) [negative for expression of estrogen and progesterone receptors (ER, PR) and HER2÷neu protein] represent a subtype of breast cancer associated with poor prognosis and highly aggressive behavior. The characterization of stem cell in this type of carcinoma could determine the appearance of new ideas concerning origin and evolution. There is an impressive amount of data in the literature related to TNBC and a growing interest for stem cell research during the past years, but there are no data concerning the genetic characterization of stem cells in the context of cell biology of TNBC as compared with associated DCIS. We performed immunohistochemical studies for the expression and distribution of several stem cell-related antigens, focusing on the association of TNBC with DCIS and comparing the presence of stem cells in the invasive and in the in situ component. Optimization of detection, identification and characterization of tumorigenic breast cancer stem cells might permit further identification of targeted treatment.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma in Situ/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Família Aldeído Desidrogenase 1 , Carcinoma in Situ/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Citoplasma/patologia , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Isoenzimas/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Retinal Desidrogenase/metabolismo , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
Flow cytometry (FC) immunophenotyping of fine-needle aspiration (FNA) has been reported to be useful in the diagnosis of non-Hodgkin lymphomas (NHL). The authors reviewed their 5-year experience to assess the ability that FC has in improving the diagnostic capacity of cytomorphology in the diagnosis and subclassification of NHL according to the World Health Organization's classification. FC was performed on 252 FNA specimens. These included 123 cases of NHL (89 primary and 34 recurrent lymphomas). The FC immunophenotyping included CD3, CD4, CD8, CD10, CD19, CD20, CD45, and kappa/lambda antibodies combinations in the screening panel and additional panels for B or T lineage in the presence of positivity for lymphoma after the screening. An immunologic diagnosis was obtained by FC in 90% (111/123) of cases identified as NHL. FC was able to improve the total number of NHL detected in 8 cases where cytomorphology had failed to do so. In 7% (9/123) of cases, FC failed to formulate a diagnostic hypothesis owing to the sample inadequacy; 2 cases (2%) were not identified as lymphomas by FC (1 of them considered only "suggestive" also by cytomorphology); 1 case was not identified neither by FC, nor by cytomorphology. In cases having a histologic follow-up, levels of diagnostic sensitivity and specificity of the combination cytomorphology/FC were 97% and 94%, respectively. FC applied to FNA enhanced the diagnostic potential of cytologic diagnosis and subclassification of NHL, thus avoiding the need for invasive surgical biopsies in many cases.
Assuntos
Biópsia por Agulha Fina , Citometria de Fluxo , Imunofenotipagem , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/citologia , Linfócitos B/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Linfoma não Hodgkin/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade , Linfócitos T/citologia , Linfócitos T/imunologia , Adulto JovemRESUMO
The clinical significance of micropapillary growth pattern in ductal carcinoma in situ is controversial and the impact of nuclear grading in terms of recurrence of this lesion is yet to be clarified. Our aim was to evaluate, on a series of micropapillary in situ carcinomas, the histological features correlated with recurrence and whether the micropapillary subtype had a different behavior from other non-micropapillary ductal carcinoma in situ. We collected 55 cases of micropapillary in situ carcinomas from four institutions. All cases were reviewed for nuclear grade, extent, necrosis, microinvasion and tested for estrogen and progesterone receptors, Ki67, HER2, EGFR and p53 expression. Clinical data, type of surgery and follow up were obtained for all patients. Our results showed that the nuclear grade is crucial in determining the biology of micropapillary carcinoma in situ, so that the high nuclear grade micropapillary ductal carcinoma in situ more frequently overexpressed HER2, showed higher proliferation index, displayed necrosis and microinvasion and was more extensive than low/intermediate nuclear grade. Logistic regression analysis confirmed the high nuclear grade (Odds ratio: 6.86; CI: 1.40-33.57) as the only parameter associated with elevated risk of local recurrence after breast-conserving surgery. However, the recurrence rate of 19 micropapillary carcinoma in situ, which were part of a cohort of 338 consecutive ductal carcinoma in situ, was significantly higher (log-rank test, P-value=0.019) than that of non-micropapillary, independently of the nuclear grade. In conclusion, although nuclear grade may significantly influence the biological behavior of micropapillary ductal carcinoma in situ, micropapillary growth pattern per se represents a risk factor for local recurrence after breast-conserving surgery.
Assuntos
Neoplasias da Mama/patologia , Carcinoma in Situ/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Papilar/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Carcinoma in Situ/metabolismo , Carcinoma in Situ/cirurgia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/cirurgia , Carcinoma Papilar/metabolismo , Carcinoma Papilar/cirurgia , Receptores ErbB/biossíntese , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Antígeno Ki-67/biossíntese , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Receptor ErbB-2/biossíntese , Fatores de Risco , Proteína Supressora de Tumor p53/biossínteseRESUMO
PURPOSE: To evaluate response rate, toxicity and epidermal growth factor (EGFR) mutations and gene copy number as outcome predictive factors in Italian patients with non-small cell lung cancer (NSCLC) treated with gefitinib (Iressa) in an expanded access program (EAP). PATIENTS AND METHODS: A total of 137 patients with advanced NSCLC received gefitinib as first line treatment or after failure of chemotherapy. In 43 cases, tissue specimens were available for EGFR status evaluation: immunohistochemical (IHC) for EGFR, fluorescence in situ hybridisation (FISH) or Chromogenic in situ hybridisation (CISH)-(ISH) analysis for EGFR and HER2 gene copy number, and PCR-DNA sequencing for mutational analysis of EGFR were performed. RESULTS: In the study population, response rate (PR) was 13%; disease stabilization (DS) 26%; overall disease control rate 39%; median survival 6.3 months and time to progression 2.7 months. Toxicity was mild (G3 skin toxicity in 3% and G3 liver toxicity in 4% of patients). An EGFR-mutation was detected in 9/43 patients: Eight deletions in exon 19 and 1 missense mutation in exon 21. Increased gene copy number for EGFR and/or HER2 was detected in 17/43 patients. Response rate was significantly higher in women, non-smokers, in mutation carriers than in wild type carriers, in EGFR-trisomy/polysomy carriers and HER2-trisomy/polysomy carriers. CONCLUSIONS: In this study, response rate and toxicity to gefitinib treatment were consistent with previously reported data for whites. Female gender, absence of smoking history, EGFR-mutations, EGFR and HER2-polysomy were significantly associated with response to gefitinib therapy in NSCLC patients.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Feminino , Gefitinibe , Dosagem de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Prognóstico , Resultado do TratamentoRESUMO
In human myometrial cells, the promiscuous coupling of the oxytocin receptors (OTRs) to G(q) and G(i) leads to contraction. However, the activation of OTRs coupled to different G protein pathways can also trigger opposite cellular responses, e.g. OTR coupling to G(i) inhibits, whereas its coupling to G(q) stimulates, cell proliferation. Drug analogues capable of promoting a selective receptor-G protein coupling may be of great pharmacological and clinical importance because they may target only one specific signal transduction pathway. Here, we report that atosiban, an oxytocin derivative that acts as a competitive antagonist on OTR/G(q) coupling, displays agonistic properties on OTR/G(i) coupling, as shown by specific (35)S-labeled guanosine 5'-3-O-(thio) trisphosphate ([(35)S]GTPgammaS) binding. Moreover, atosiban, by acting on a G(i)-mediated pathway(,) inhibits cell growth of HEK293 and Madin-Darby canine kidney cells stably transfected with OTRs and of DU145 prostate cancer cells expressing endogenous OTRs. Notably, atosiban leads to persistent ERK1/2 activation and p21(WAF1/CIP1) induction, the same signaling events leading to oxytocin-mediated cell growth inhibition via a G(i) pathway. Finally, atosiban exposure did not cause OTR internalization and led to only a modest decrease (20%) in the number of high affinity cell membrane OTRs, two observations consistent with the finding that atosiban did not lead to any desensitization of the oxytocin-induced activation of the G(q)-phospholipase C pathway. Taken together, these observations indicate that atosiban acts as a "biased agonist" of the human OTRs and thus belongs to the class of compounds capable of selectively discriminating only one among the multiple possible active conformations of a single G protein-coupled receptor, thereby leading to the selective activation of a unique intracellular signal cascade.