RESUMO
In breast cancer (BC) patients, local recurrences often arise in proximity of the surgical scar, suggesting that response to surgery may have a causative role. Radiotherapy (RT) after lumpectomy significantly reduces the risk of recurrence. We investigated the direct effects of surgery and of RT delivered intraoperatively (IORT), by collecting irradiated and non-irradiated breast tissues from BC patients, after tumor removal. These breast tissue specimens have been profiled for their microRNA (miR) expression, in search of differentially expressed miR among patients treated or not with IORT. Our results demonstrate that IORT elicits effects that go beyond the direct killing of residual tumor cells. IORT altered the wound response, inducing the expression of miR-223 in the peri-tumoral breast tissue. miR-223 downregulated the local expression of epidermal growth factor (EGF), leading to decreased activation of EGF receptor (EGFR) on target cells and, eventually, dampening a positive EGF-EGFR autocrine/paracrine stimulation loop induced by the post-surgical wound-healing response. Accordingly, both RT-induced miR-223 and peri-operative inhibition of EGFR efficiently prevented BC cell growth and reduced recurrence formation in mouse models of BC. Our study uncovers unknown effects of RT delivered on a wounded tissue and prompts to the use of anti-EGFR treatments, in a peri-operative treatment schedule, aimed to timely treat BC patients and restrain recurrence formation.
Assuntos
Neoplasias da Mama/radioterapia , Fator de Crescimento Epidérmico/genética , Receptores ErbB/genética , MicroRNAs/genética , Recidiva Local de Neoplasia/radioterapia , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos da radiação , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Radioterapia , Recidiva , Transdução de Sinais/efeitos da radiação , CicatrizaçãoRESUMO
BACKGROUND: Locally advanced HER2-overexpressing breast cancer (BC) patients achieve a high rate of pathological complete responses (pCR) after neoadjuvant chemotherapy (NC). The apparently unaltered immune proficiency of these patients together with the immune-modulating activities of NC drugs suggest a potential contribution of host immunity in mediating clinical responses. We thus performed an extensive immunomonitoring in locally advanced BC patients undergoing NC to identify immunological correlates of pCR induction. METHODS: The immune profile of 40 HER2-positive and 38 HER2-negative BC patients was characterized at diagnosis and throughout NC (Paclitaxel and Trastuzumab, or Docetaxel and Epirubicin, respectively). The percentages of circulating immune cell subsets including T and B lymphocytes, Natural Killer (NK) cells, regulatory T cells, T helper 17 lymphocytes, were quantified by multiparametric flow cytometry. NK cells functional activity was evaluated through the analysis of NF-kB nuclear translocation by Multispectral flow cytometry, and with the in vitro monitoring of Trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC). CD8(+) T cell responses against six different tumor-associated antigens (TAA) were characterized by IFN-γ ELISPOT and IFN-γ/IL-2 DualSpot assays. RESULTS: After NC, HER2-positive patients showed a significant increase in the number of NK cells and regulatory T cells irrespective of the pathological response, whereas patients undergoing a pCR disclosed higher percentages of T helper 17 cells. Notably, a significant increase in the number of activated NK cells was observed only in HER2-positive patients achieving a pCR. Characterization of anti-tumor T cell responses highlighted sustained levels of CD8(+) T cells specific for survivin and mammaglobin-A throughout NC in patients undergoing a pCR in both arms. Moreover, HER2-positive patients achieving a pCR were characterized by a multi-epitopic and polyfunctional anti-tumor T cell response, markedly reduced in case of partial response. CONCLUSIONS: These results indicate that maintenance of functional T cell responses against selected antigens and improvement of NK cell proficiency during NC are probably critical requirements for pCR induction, especially in HER2-positive BC patients. Trail registration: TRIAL REGISTRATION NUMBER: NCT02307227, registered on ClinicalTrials.gov ( http://www.clinicaltrials.gov , November 26, 2014).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Matadoras Naturais/imunologia , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Imunidade Adaptativa/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Humanos , Imunidade Inata/efeitos dos fármacos , Imunofenotipagem , Células Matadoras Naturais/efeitos dos fármacos , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Indução de Remissão , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Preclinical data have indicated a synergistic interaction between docetaxel and capecitabine by means of taxane-induced up-regulation of thymidine phosphorylase (TP). On the basis of such premises, we conducted a phase II trial to determine the activity and tolerability of weekly docetaxel plus capecitabine in patients with metastatic breast cancer (MBC). Furthermore, we explored the relationship between TP tumor expression and benefit from this regimen. PATIENTS AND METHODS: Patients received docetaxel 36 mg/m(2) i.v. on days 1, 8, and 15 and capecitabine orally 625 mg/m(2) b.i.d. from days 8 to 21. Cycles were repeated every 4 weeks. In the correlative study, we evaluated the TP expression by immunohistochemistry and the TP messenger RNA expression by real-time RT-PCR in the primary tumor. RESULTS: Forty-seven women were enrolled. In the intention-to-treat analysis, objective responses were achieved in 24 patients (51%). Fourteen additional patients (30%) had stable disease. The median time to progression (TTP) was 6 months (range 1-44 months). Median survival was 17 months (range 1-48 months). Overall, the treatment was well tolerated. The most common clinical adverse events (all grades) were alopecia (55%), nail changes (53%), fatigue/asthenia (51%), nausea/vomiting (51%), neutropenia (49%), and neuropathy (49%). A significantly higher TTP was observed in patients with TP-positive tumors (log-rank test, P = 0.009). Interestingly, a subgroup analysis confirmed this TTP benefit in patients with TP-positive tumors obtaining a tumor response (log-rank test, P = 0.03), whereas the statistical significance was lost in nonresponders (log-rank test, P = 0.3). CONCLUSIONS: This study indicates that a regimen with low doses of capecitabine plus weekly docetaxel is active against MBC. The correlative analysis provides preliminary evidence that TP expression may be a predictive marker for therapeutic benefit.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Carcinoma Ductal/secundário , Carcinoma Lobular/secundário , Timidina Fosforilase/metabolismo , Administração Oral , Adulto , Idoso , Alopecia/induzido quimicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais/análise , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Progressão da Doença , Docetaxel , Relação Dose-Resposta a Droga , Esquema de Medicação , Sinergismo Farmacológico , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Intravenosas , Neoplasias Hepáticas/secundário , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Medição de Risco , Sensibilidade e Especificidade , Análise de Sobrevida , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Timidina Fosforilase/análise , Resultado do Tratamento , Regulação para CimaRESUMO
Primary effusion lymphoma (PEL) represents a peculiar type of B cell lymphoma which associates with HHV-8 infection and preferentially grows in liquid phase in the serous body cavities. In this report, we provide the detailed characterization of a newly established PEL cell line, termed CRO-AP/6. The cell line was obtained from the pleural effusion of a HIV-positive patient with PEL. Its derivation from the tumor clone was established by immunogenotypic analysis. Detailed phenotypic investigations defined that CRO-AP/6 reflects pre-terminally differentiated B cells expressing the CD138/syndecan-1 antigen. Karyotypic studies of CRO-AP/6 identified several chromosomal abnormalities, whereas genotypic studies ruled out the involvement of molecular lesions associated with other types of B cell lymphoma. Both CRO-AP/6 and the parental tumor sample harbored infection by HHV-8. Conversely, EBV infection was present in the parental tumor sample although not in CROAP/6, indicating that CRO-AP/6 originated from the selection of an EBV-negative tumor subclone. The pattern of viral (HHV-8 v-cyclin) and cellular (p27Kip1) regulators of cell cycle expressed by CRO-AP/6, together with the results of growth fraction analysis, point to abrogation of the physiological inverse relationship between proliferation and p27Kip1 expression. Also, both CRO-AP/6 and the parental tumor sample display biallelic inactivation of the DNA repair enzyme gene O6-methylguanine-DNA methyltransferase (MGMT) by promoter methylation. Overall, the CRO-AP/6 cell line may help understand cell cycle control of PEL cells, may clarify the relative contribution of HHV-8 and EBV to the disease growth and development and may facilitate the identification of recurrent cytogenetic abnormalities highlighting putative novel cancer related loci relevant to PEL.
Assuntos
Infecções por Herpesviridae/patologia , Herpesvirus Humano 8/patogenicidade , Linfoma Relacionado a AIDS/patologia , Linfoma de Células B/virologia , Proteínas de Neoplasias/fisiologia , O(6)-Metilguanina-DNA Metiltransferase/deficiência , Derrame Pleural Maligno/patologia , Células Tumorais Cultivadas/virologia , Infecções Tumorais por Vírus/patologia , Adulto , Antígenos Virais/biossíntese , Antígenos Virais/genética , Ciclo Celular , Aberrações Cromossômicas , Células Clonais/patologia , Células Clonais/virologia , Ciclinas/biossíntese , Ciclinas/genética , Metilação de DNA , Ativação Enzimática , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Genes Supressores de Tumor , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/virologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/imunologia , Herpesvirus Humano 8/isolamento & purificação , Humanos , Imunofenotipagem , Linfoma Relacionado a AIDS/etiologia , Linfoma Relacionado a AIDS/genética , Linfoma Relacionado a AIDS/virologia , Linfoma de Células B/genética , Linfoma de Células B/patologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , O(6)-Metilguanina-DNA Metiltransferase/genética , O(6)-Metilguanina-DNA Metiltransferase/fisiologia , Derrame Pleural Maligno/genética , Derrame Pleural Maligno/virologia , Regiões Promotoras Genéticas , Proto-Oncogenes , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/virologia , Proteínas Virais/biossíntese , Proteínas Virais/genética , Latência ViralRESUMO
Primary effusion lymphoma (PEL) is a novel lymphoma entity consistently infected by HHV-8 that occurs predominantly in immunodeficient patients and is characterized by liquid growth in the serous body cavities. In order to facilitate the understanding of PEL pathogenesis and histogenesis, we have established three PEL cell lines termed CRO-AP/2, CRO-AP/3 and CRO-AP/5. All cell lines have been derived from HIV positive homosexual men affected by PEL with (in the case of CRO-AP/2 and CRO-AP/5) or without (in the case of CRO-AP/3) a previous history of Kaposi's sarcoma. The cell lines are representative of both virologic variants of PEL, i.e. HHV-8+ EBV+ PEL (CRO-AP/2 and CRO-AP/5) and HHV-8+ EBV- PEL (CRO-AP/3). Morphologic and phenotypic features of CRO-AP/2, CRO-AP/3 and CRO-AP/5 are typical of PEL, and include morphology bridging immunoblastic and anaplastic features as well as an indeterminate (non B- non T-cell) phenotype. The B-cell nature of the cell lines is documented by the presence of rearranged immunoglobulin genes. The detailed analysis of the molecular and phenotypic features of CRO-AP/2, CRO-AP/3 and CRO-AP/5 has allowed the identification of recurrent chromosomal abnormalities of PEL and has contributed to the definition of PEL as a lymphoma of post-germinal center, pre-terminally differentiated B-cells.
Assuntos
Herpesvirus Humano 8/isolamento & purificação , Linfoma/virologia , Células Tumorais Cultivadas , Humanos , Linfoma/patologia , MasculinoRESUMO
We describe a patient with primary Hodgkin's disease (HD) of the vagina presenting with stage IEB. To our knowledge, this is the first case reported so far. Based on morphological and immunophenotypic features, the HD was classified as nodular sclerosis subtype, "syncytial" variant. The patient, a 64-year old woman, received chemotherapy followed by radiation therapy. She is still disease-free 14 months after diagnosis.
Assuntos
Doença de Hodgkin/patologia , Neoplasias Vaginais/patologia , Feminino , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/radioterapia , Doença de Hodgkin/cirurgia , Humanos , Pessoa de Meia-Idade , Esclerose , Neoplasias Vaginais/tratamento farmacológico , Neoplasias Vaginais/radioterapia , Neoplasias Vaginais/cirurgiaAssuntos
Hiperplasia do Linfonodo Gigante/virologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 8 , Linfoma não Hodgkin/virologia , Mieloma Múltiplo/virologia , Biomarcadores , Hiperplasia do Linfonodo Gigante/patologia , Diferenciação Celular , Citocinas/metabolismo , Infecções por Herpesviridae/patologia , Humanos , Linfoma Relacionado a AIDS/patologia , Linfoma Relacionado a AIDS/virologia , Linfoma de Células B/patologia , Linfoma não Hodgkin/patologia , Mieloma Múltiplo/patologiaRESUMO
Human herpesvirus-8/Kaposi sarcoma-associated herpesvirus-positive primary effusion lymphoma (PEL) is a recently identified B-cell non-Hodgkin lymphoma category characterized by liquid growth in the serous body cavities. Apart from viral infection, no genetic alteration is known to be associated with PEL and no recurrent cytogenetic abnormality has been identified in these lymphomas. Yet the consistent monoclonality of PEL indicates that the disease is not solely a virus-driven proliferation. Here we report that PEL is associated with a high frequency of mutations of BCL6 5' noncoding regions, and we identify karyotypic abnormalities that may be recurrently involved in these lymphomas. Mutations of BCL-6 5' noncoding regions occurred in 8/13 PEL. Mutations occurred in the absence of BCL6 gross rearrangements were often multiple in the same patient (7/8 mutated cases), and occurred in both HIV-positive and HIV-negative individuals. Since BCL6 mutations are regarded as a genetic marker of B-cell transition through the germinal center (GC), these data are consistent with histogenetic derivation of PEL from GC or post-GC B-cells. Cytogenetic and FISH analysis of seven PEL cell lines showed frequent occurrence of complete or partial trisomy 12 (7/7 cases), trisomy 7 (4/7 cases), and abnormalities of bands Iq21-25 (5/7 cases).
Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença/genética , Infecções por Herpesviridae/etiologia , Herpesvirus Humano 8/patogenicidade , Linfoma/etiologia , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Regiões 5' não Traduzidas/genética , Análise Mutacional de DNA , Infecções por Herpesviridae/patologia , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Linfoma/genética , Linfoma/patologia , Proteínas Proto-Oncogênicas c-bcl-6 , Células Tumorais CultivadasRESUMO
AIDS-related non-Hodgkin's lymphomas (AIDS-NHL) are classified into Burkitt's lymphoma, diffuse large cell lymphoma (DLCL), and body cavity based lymphoma. The molecular pathogenesis of AIDS-NHL is complex and involves the genetic alteration of several cancer related genes, including the BCL-6 proto-oncogene. BCL-6 encodes a zinc finger transcription factor which is selectively expressed by germinal center (GC) B-cells, but not by pre-GC or post-GC B-cells. Genetic alterations of BCL-6 occur frequently among B-cell NHL and comprise gross rearrangements as well as small mutations of the 5' noncoding region of the gene. Gross rearrangements of BCL-6 among AIDS-NHL cluster with 20% AIDS-DLCL. Conversely, mutations of the 5' noncoding region of BCL-6 occur at sustained frequency throughout the clinico-pathologic spectrum of AIDS-NHL and represent the most common genetic alteration presently detectable in these lymphomas. The frequency of BCL-6 mutations, as well as their location in the proximity of the BCL-6 regulatory regions, suggest that they may play a pathogenetic role in AIDS-related lymphomagenesis. Beside their pathogenetic implications, the occurrence of BCL-6 mutations among AIDS-NHL bears histogenetic relevance because BCL-6 mutations are regarded as a marker of B-cell transition through the GC. Thus, it is conceivable that a large fraction of AIDS-NHL is histogenetically related to GC or post-GC B-cells. This notion is further confirmed by the observation that AIDS-NHL frequently express the BCL-6 protein, which stains selectively GC B-cells throughout B-cell differentiation.
Assuntos
Linfoma Relacionado a AIDS/genética , Proto-Oncogenes , Rearranjo Gênico , Humanos , Mutação , Proto-Oncogene Mas , Fatores de Transcrição/genética , Dedos de ZincoAssuntos
Implante Mamário , Neoplasias da Mama/etiologia , Hemangiossarcoma/etiologia , Neoplasias Induzidas por Radiação/etiologia , Segunda Neoplasia Primária , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/terapia , Feminino , Hemangiossarcoma/patologia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Induzidas por Radiação/patologia , Segunda Neoplasia Primária/patologiaRESUMO
Patients with acquired immunodeficiency syndrome (AIDS) are at increased risk of developing non Hodgkin's lymphomas (NHL). Current estimates indicate that 5-10% of HIV-infected individuals develop AIDS-related NHL (AIDS-NHL). AIDS-NHL share several clinical features, including frequent extranodal presentation, aggressive clinical course and poor outcome. However, AIDS-NHL are a heterogeneous group of malignancies. They traditionally included systemic and primary brain lymphomas, but nowadays their updated clinicopathologic spectrum also comprises two novel entities, namely primary effusion lymphoma and plasmablastic lymphoma of the oral cavity. In the last few years, several studies have shown that the pathologic heterogeneity of AIDS-NHL correlates with the heterogeneity of the molecular lesions associated with these lymphomas. However, despite their pathologic and molecular heterogeneity, AIDS-NHL have a common B-cell origin, although the precise stage of B-cell differentiation reflected by the different tumor types has not been clarified yet.
Assuntos
Linfoma Relacionado a AIDS/patologia , HumanosRESUMO
Primary lymphomatous effusions are represented by cases of non-Hodgkin's lymphoma (NHL) which grow in liquid phase in the serous body cavities in the absence of solid tumour masses. Based on morphologic, immunophenotypic, virologic and genotypic features, primary lymphomatous effusions are distinguished into body cavity-based lymphoma (BCBL), Burkitt's lymphoma (BL) and immunoblastic large-cell lymphoma. The histogenesis and pathogenesis of primary lymphomatous effusions are virtually unclarified. In this study, we have established 2 cell lines (CRO-AP/1 and CRO-AP/2) representative of 2 distinct categories of primary lymphomatous effusion, BCBL (CRO-AP/2) and BL (CRO-AP/1). Both CRO-AP/1 and CRO-AP/2 carry monoclonal re-arrangements of the immunoglobulin genes which are identical to those of the respective parental tumours. Consistent with its BCBL origin, CRO-AP/2 is characterised by a non-B, non-T phenotype and harbours infection by HHV-8 (approx. 100 viral copies/cell) and Epstein-Barr virus. Conversely, CRO-AP/1 expresses several B cell-associated antigens, lacks HHV-8 infection and carries the genetic hallmark of BL, i.e., a chromosomal breakpoint of band 8q24. CRO-AP/1 and CRO-AP/2 may be valuable for the biologic characterization of primary lymphomatous effusions, particularly since the number of available cell lines derived from such lymphomatous effusions is extremely limited.
Assuntos
Linfoma de Burkitt/patologia , Linfoma de Burkitt/virologia , Herpesvirus Humano 8 , Linfoma Relacionado a AIDS/patologia , Linfoma Relacionado a AIDS/virologia , Células Tumorais Cultivadas/patologia , Células Tumorais Cultivadas/virologia , Ascite/patologia , Linfoma de Burkitt/genética , DNA de Neoplasias/genética , Herpesvirus Humano 8/genética , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Derrame Pleural/patologiaRESUMO
Although the cellular origin of Reed-Sternberg (RS) cells of classical Hodgkin's disease (HD) has been a controversial issue for many years, recent immunophenotypic and molecular studies have suggested that RS cells of a subset of classical HD cases may be related to B cells. To further define the immunophenotypic features and the differentiation stage of RS cells, a series of 56 HD samples, including both nodular lymphocyte predominance (LP) (eight cases) and classical HD (nodular sclerosis [NS], 32 cases; mixed cellularity [MC], 16 cases) with a non-T-cell phenotype, were evaluated for the immunohistochemical expression of the B-B4 antigen, a specific marker for terminally differentiated B cells. Because the cDNA of the B-B4 antigen encodes syndecan-1, a member of a family of transmembrane heparan sulfate proteoglycans thought to be involved in binding cells of the B lineage to the interstitial matrix, the B-B4 immunoreactivity was correlated with the expression of syndecan-1 in HD-derived cell lines (L428, KM-H2), as detected by both reverse transcriptase polymerase chain reaction (RT-PCR) studies and Western blotting. Our results show that B-B4 reacts with RS cells and their morphological variants of all cases of classical HD, irrespective of their antigenic phenotype (B, undetermined), albeit at a varying degree of cellular expression. Notably, a high reactivity and staining intensity for the B-B4 monoclonal antibody (MoAb) was restricted to tumor cells from NS HD. In cases of the latter subtype, B-B4 positivity was also found in sclerosis-trapped spindle cells (fibrocytes/fibroblasts). Conversely, the putative tumor cells of nodular LP HD were consistently unreactive with the B-B4 MoAb. Finally, we have demonstrated by RT-PCR, flow cytometry, and Western blotting that cultured RS cells, of B and undetermined phenotype, express syndecan-1 mRNA and produce a form of syndecan-1, recognized by the B-B4 MoAb, which is predominantly associated with glycosaminoglycans and is present at the cell surface. Our detection of the plasma cell-specific antigen B-B4 (syndecan-1) on tumor cells of classical HD further supports that RS cell progenitors may be related to germinal/postgerminal center mature B cells and suggests that expression of syndecan-1 may contribute to some of the typical biologic and histopathologic features of classical HD, with a special regard to the NS subtype.
Assuntos
Anticorpos Monoclonais/imunologia , Antígenos de Neoplasias/imunologia , Doença de Hodgkin/patologia , Glicoproteínas de Membrana/imunologia , Plasmócitos/imunologia , Proteoglicanas/imunologia , Células de Reed-Sternberg/metabolismo , Especificidade de Anticorpos , Antígenos de Diferenciação/análise , Antígenos de Neoplasias/biossíntese , Biomarcadores , Linhagem da Célula , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Doença de Hodgkin/imunologia , Humanos , Linfonodos/imunologia , Glicoproteínas de Membrana/biossíntese , Proteoglicanas/biossíntese , Células de Reed-Sternberg/imunologia , Células de Reed-Sternberg/patologia , Sindecana-1 , SindecanasRESUMO
Metastatic disease to the masticator space and to the jaws is a rare event. About a dozen cases are reported in the current literature. We describe the imaging findings of a rectal adenocarcinoma metastatic to the temporomandibular joint before and after radiotherapy.
Assuntos
Adenocarcinoma/secundário , Neoplasias Retais/patologia , Neoplasias Cranianas/secundário , Articulação Temporomandibular , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/radioterapia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Dosagem Radioterapêutica , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/radioterapia , Neoplasias Cranianas/diagnóstico por imagem , Neoplasias Cranianas/radioterapia , Articulação Temporomandibular/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Primary effusion lymphoma (PEL) represents a novel B-cell non-Hodgkin's lymphoma (NHL) type associated with Kaposi's sarcoma-associated herpesvirus infection and typically growing as lymphomatous effusions in the body cavities. The precise B-cell subset from which PEL originates as well as the biologic mechanisms responsible for its peculiar growth pattern are unclear. In this study, we have analyzed PEL for the expression status of CD138/syndecan-1, a molecule selectively associated with late stages of B-cell differentiation and implicated in cell-to-cell and cell-to-extracellular matrix interactions. PEL patient samples (n = 7) and cell lines (n = 5) were investigated by multiple approaches, including immunocytochemistry, flow cytometry, RNA analysis, and Western blot studies. For comparison, lymphomatous effusions other than PEL (n = 13) and tissue-based NHL (n = 103) were also tested. Expression of CD138/syndecan-1 associates at high frequency with PEL (5 of 7 patient samples and 5 of 5 cell lines), whereas it is consistently absent among other lymphomatous effusions (n = 13). The CD138/syndecan-1 isoform expressed by PEL has an average molecular weight of 420 kD, which is substantially different from that of CD138/syndecan-1 molecules generally expressed by plasma cells. These data, along with previous immunophenotypic evidence, unequivocally define that PEL cells represent a preterminal stage of B-cell differentiation and may bear implications for the peculiar growth pattern of this lymphoma.
Assuntos
Herpesvirus Humano 8/isolamento & purificação , Linfoma/química , Linfoma/virologia , Glicoproteínas de Membrana/análise , Proteoglicanas/análise , Humanos , Linfoma/patologia , Glicoproteínas de Membrana/genética , Proteoglicanas/genética , RNA Mensageiro/análise , Sindecana-1 , Sindecanas , Células Tumorais CultivadasRESUMO
In order to obtain prognostic clinicopathological information, 49 cases of pure ductal carcinoma in situ of the breast (DCIS), were evaluated for the immunohistochemical expression of potential predictor markers including c-erbB-2 oncogene product, p53 protein, oestrogen (ER) and progesterone (PR) receptors, oestrogen-regulated proteins pS2 and cathepsin-D (cath-D), CD44 protein and 67-kDa laminin receptor (MLuC5). Immunohistochemical findings were compared with conventional pathological parameters, clinical findings, and the clinical outcome of the patients. When markers were matched to each other, statistical analyses provided a significant positive correlation between c-erbB-2 overexpression and p53 positivity (P < 0.01) and between ER and PR (P < 0.01), ER, PR and pS2 (P < 0.01), pS2 and MLuC5 (P < 0.05). Significant negative correlations between c-erbB-2 overexpression and ER (P < 0.05), PR (P < 0.01) and pS2 (P < 0.01) positivity was also observed. Data on the relationship between marker status and pathological findings revealed a significant positive trend between c-erbB-2, p53, and increased grade values (P < 0.05) and opposite results with PR receptor expression (P < 0.01). c-erbB-2 overexpression was further significantly associated with comedotype carcinoma (P < 0.05) and distribution of disease in confluent neoplastic ducts (P < 0.01). Although no statistically significant correlation among biological markers expression, clinical findings and outcome was demonstrated, overall this study indicates that tumour cells from a subset of DCIS, which includes comedotype carcinoma, express significantly unfavourable prognostic factors.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Carcinoma in Situ/química , Carcinoma Ductal de Mama/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma in Situ/patologia , Carcinoma Ductal de Mama/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , PrognósticoRESUMO
Six ovarian undifferentiated carcinomas (UCs) and 19 poorly differentiated serous (14 cases) and endometrioid (5 cases) carcinomas with areas of solid diffuse carcinomas have been considered for the study. Pathological findings were analyzed in conjunction with molecular analysis concerning the structure and expression of nm23-H1 gene. Differences in the frequency of loss of heterozigosity (LOH) of this gene have been observed between the two groups, UCs displaying lower percentage of LOH (1/5) as compared to poorly differentiated tumors (17/17). The remaining 3 cases (1 UC and 2 poorly differentiated carcinomas) were homozygotes, i.e., noninformative. UCs might occur as a consequence of cellular dedifferentiation, being at the end of the differentiation spectrum of epithelial ovarian tumors. Nevertheless, this study suggests that, in a fraction of cases, UCs could represent a distinct entity not involved in the malignant progression, associated with peculiar DNA anomalies, one possibly being that of the nm23-H1 deletion. In other words, a noticeable subset of UCs, not harboring nm23-H1 alterations, may be histologically uncommitted "ab initio". Moreover, nm23-H1 LOHs could be considered early events in the ovarian carcinogenesis, because similar molecular patterns were found both in primary and metastatic sites of the same tumor.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Endometrioide/patologia , Cistadenocarcinoma Seroso/patologia , Proteínas Monoméricas de Ligação ao GTP , Proteínas de Neoplasias/genética , Núcleosídeo-Difosfato Quinase , Neoplasias Ovarianas/patologia , Fatores de Transcrição/genética , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/química , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/genética , Diferenciação Celular , Cromossomos Humanos Par 17/genética , Cistadenocarcinoma Seroso/química , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/genética , DNA de Neoplasias/análise , Feminino , Deleção de Genes , Humanos , Metástase Linfática , Repetições de Microssatélites , Nucleosídeo NM23 Difosfato Quinases , Estadiamento de Neoplasias , Neoplasias Ovarianas/química , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Polimorfismo de Fragmento de Restrição , RNA Mensageiro/análise , RNA Neoplásico/análise , Estudos RetrospectivosRESUMO
Chromosome 1q abnormalities represent the second most frequent cytogenetic lesion of Burkitt lymphoma (BL) and acute lymphoblastic leukemia (ALL)-L3. The most frequent change is partial duplication of the long arm of chromosome 1, involving variable bands but consistently including 1q23. Among AIDS-related BL similar chromosome 1q abnormalities have also been found. We have now characterized in detail the chromosome 1q abnormalities of 4 AIDS-BL cell lines and compared them to other molecular features of the tumor clone, namely infection by Epstein Barr virus (EBV). Immunophenotypic characteristics were also assessed by conventional in situ immunocytochemical and flow cytometric procedures. The B-cell origin of all cell lines was demonstrated by the expression of B-cell-restricted markers (e.g., CD19). Analysis of Ig light chains confirmed their monoclonal nature. The t(8;14) was present in 3 of the 4 lines, whereas variant translocation t(8;22) was detected in the remaining cell line. Additional chromosomal changes were found in all cases, with chromosome 1 being involved in all. Structural changes encompassed in each case the 1q21-25 bands, in either duplication or partial trisomy. EBER ISH studies identified EBV association in 3 of the 4 AIDS-BL cell lines in contrast to previous studies of BL of immunocompetent individuals. Our findings of a high frequency of chromosome 1q abnormalities in EBV-infected AIDS-related BL cell lines demonstrate that such chromosomal abnormality and EBV positivity are not mutually exclusive and are possibly independent factors, whereas their close association in AIDS may be related to the immunodeficiency.