RESUMO
Despite decades of effort in understanding pancreatic ductal adenocarcinoma (PDAC), there is still a lack of innovative targeted therapies for this devastating disease. Herein, we report the expression of apelin and its receptor, APJ, in human pancreatic adenocarcinoma and its protumoral function. Apelin and APJ protein expression in tumor tissues from patients with PDAC and their spatiotemporal pattern of expression in engineered mouse models of PDAC were investigated by immunohistochemistry. Apelin signaling function in tumor cells was characterized in pancreatic tumor cell lines by Western blot as well as proliferation, migration assays and in murine orthotopic xenograft experiments. In premalignant lesions, apelin was expressed in epithelial lesions whereas APJ was found in isolated cells tightly attached to premalignant lesions. However, in the invasive stage, apelin and APJ were co-expressed by tumor cells. In human tumor cells, apelin induced a long-lasting activation of PI3K/Akt, upregulated ß-catenin and the oncogenes c-myc and cyclin D1 and promoted proliferation, migration and glucose uptake. Apelin receptor blockades reduced cancer cell proliferation along with a reduction in pancreatic tumor burden. These findings identify the apelin signaling pathway as a new actor for PDAC development and a novel therapeutic target for this incurable disease.
Assuntos
Adenocarcinoma , Receptores de Apelina/metabolismo , Apelina/metabolismo , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/patologia , Animais , Carcinoma Ductal Pancreático/genética , Ciclina D1/metabolismo , Glucose , Humanos , Camundongos , Oncogenes , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Neoplasias PancreáticasRESUMO
Aims: Osteosarcoma represents the second most common cause of death in children and young adults. No biomaterial allowing local drug delivery has been specifically developed. However, a biocompatible bioactive implantable material could prevent some amputations, and the local release of an antitumor agent could limit risks of relapse and metastasis. Methods: We propose a proof of concept of a self-setting paste combining amorphous calcium phosphate and doxorubicin-loaded particles of bone-like carbonated nanocrystalline apatite, as a means of local release. Results: The cement formulation and doping, first with folic acid and then with doxorubicin, was successful. Its physicochemistry was scrutinized. Preliminary in vivo data on an invasive osteosarcoma rat model suggest a limiting effect on metastatic events in the lungs without signs of toxicity.
Assuntos
Cimentos Ósseos/química , Neoplasias Ósseas/tratamento farmacológico , Fosfatos de Cálcio/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias Pulmonares/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Apoptose , Materiais Biocompatíveis , Neoplasias Ósseas/patologia , Proliferação de Células , Doxorrubicina/química , Humanos , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Osteossarcoma/patologia , Ratos Nus , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Oral lichen planus (OLP) is a chronic inflammatory disease considered as a CD8+ T lymphocyte-mediated autoimmune reaction, which may be triggered by undetermined virus. Recent reports have described the detection of Merkel cell polyomavirus (MCPyV) DNA in oral samples from healthy patients and in patients with different forms of oral cancers. We therefore investigated in a prospective way whether MCPyV was detectable in oral lesions of patients with active OLP. Our preliminary results do not support the hypothesis that OLP may be triggered by MCPyV infection. Further studies are needed to evaluate the involvement of other human polyomaviruses in OLP pathogenesis.
Assuntos
Líquen Plano Bucal/virologia , Poliomavírus das Células de Merkel/genética , Poliomavírus das Células de Merkel/isolamento & purificação , Boca/virologia , Infecções por Polyomavirus/virologia , Adulto , Idoso , DNA Viral/isolamento & purificação , Feminino , Humanos , Líquen Plano Bucal/complicações , Masculino , Pessoa de Meia-Idade , Boca/patologia , Neoplasias Bucais/virologia , Infecções por Polyomavirus/complicações , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Mammary analog secretory carcinoma (MASC) of the salivary gland has been recently described according to morphological, immunohistochemical, and molecular (ETV6-NTRK3 translocation) similarities with the mammary secretory carcinoma. The most important differential diagnostic considerations of MASC are low-grade adenocarcinoma not otherwise specified (NOS), cystadenocarcinoma, and acinic cell carcinoma (AciCC). These tumors may share an overlapping morphology with MASC, and additional immunohistochemical studies are required to reinforce the diagnosis. Mammaglobin, GCDFP-15, and p63 staining have been reported in MASC. Our study was designed to check the specificity of these antibodies in MASC compared to other frequent tumors of salivary glands. METHODS: A series of 62 salivary gland tumors [10 MASCs, 5 adenocarcinomas NOS and 2 cystadenocarcinomas with MASC features and without ETV6 rearrangement, one low-grade cribriform cystadenocarcinoma (LGCCC), 9 AciCCs, 10 MECs, 10 adenoid cystic carcinomas (AdeCCs), 5 polymorphous low-grade adenocarcinomas (PLGAs), and 10 pleomorphic adenomas (PAs)] was analyzed by immunohistochemistry with mammaglobin, GCDFP-15, and p63 antibodies. RESULTS: Positivity for mammaglobin was observed in all MASCs, cystadenocarcinomas, LGCCC, and PLGAs, in some adenocarcinomas NOS, PAs, and MECs, rarely in AciCCs and never in AdeCCs. Positivity for GCDFP-15 was observed in most of the tumor types except in AdeCCs. Interestingly, cytoplasmic positivity for p63 was observed in most of MASCs and PLGAs while rarely in adenocarcinomas NOS and PAs, and never in the other tumor types. CONCLUSION: Our study revealed the usefulness of mammaglobin and p63 cytoplasmic staining to define which tumors are worth to be screened for ETV6 rearrangement.
Assuntos
Proteínas de Transporte/análise , Glicoproteínas/análise , Mamoglobina A/análise , Carcinoma Secretor Análogo ao Mamário/diagnóstico , Neoplasias das Glândulas Salivares/química , Neoplasias das Glândulas Salivares/diagnóstico , Fatores de Transcrição/análise , Proteínas Supressoras de Tumor/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ/métodos , Masculino , Carcinoma Secretor Análogo ao Mamário/química , Carcinoma Secretor Análogo ao Mamário/patologia , Proteínas de Membrana Transportadoras , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-ets/análise , Proteínas Repressoras/análise , Neoplasias das Glândulas Salivares/patologia , Adulto Jovem , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
PURPOSE: The aim of the study was to analyse greater tuberosity's (GT) micro-vascularization in the context of rotator cuff tear and to identify factors that could affect the rate and distribution of micro-vessels. METHODS: Eighty-seven patients with supraspinatus and/or infraspinatus tendon tears were included in a prospective study. Mean age at surgery was 58 years (41-78) and clinical symptoms were lasting from an average of 20 months before surgery. A bone core of 1-cm depth was obtained from the GT during rotator cuff repair at two localizations, medial and lateral within tuberosity. Micro-vascularization was then analysed with an immunohistochemistry technique based on CD34 antigen tracking endothelial cells at two levels of depth for each sample (more and less than 5 mm). Epidemiologic and pathologic data were correlated with the rate of micro-vascularization measured. RESULTS: Median rate of GT's micro-vascularization was 9.8 %, which ranged from 0.13 % to 33.4 %. This rate decreased with preoperative steroid injection (7.4 % vs 11.2) and with localization close to the cartilage of the humeral head (8.7 % vs 11.9 %). However, it remains almost homogenous along the depth's core. Moreover, no significant correlation was found regarding age at surgery, gender, context of previous trauma, smoking habits, duration of symptoms, and specific data regarding the tendon tear. CONCLUSIONS: This study highlighted the variability of GT's micro-vascularization in case of rotator cuff tear. A greater rate was observed at the lateral part of the footprint, whereas medical history of steroid injection has a negative influence on micro-vascularization.
Assuntos
Lesões do Manguito Rotador , Manguito Rotador/cirurgia , Tendões/irrigação sanguínea , Adulto , Idoso , Antígenos CD34/metabolismo , Feminino , Humanos , Cabeça do Úmero/lesões , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica , Estudos Prospectivos , Manguito Rotador/patologia , RupturaRESUMO
BACKGROUND: Many anesthetic drugs interact with the NMDA receptor and may therefore alter the clinical presentation of anti-NMDA-R encephalitis. CASE PRESENTATION: A 24-year-old woman was admitted to hospital for decreased consciousness and hyperthermia. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis, and elevated protein. Cultures were negative. Patient state worsened with agitation, facial dyskinesia, ocular deviation, and limb dystonia. Diagnosis of anti-NMDA-R encephalitis was evidenced by specific antibodies. High doses of methylprednisolone were administered. CT scan disclosed an ovarian teratoma and tumor resection was scheduled under anesthesia with propofol, sufentanil, atracurium and sevoflurane. Sedation after surgery was maintained with propofol. Rapidly after surgery, patient's condition deteriorated with increase of dyskinesias, and two tonic-clonic generalized seizure events. CONCLUSION: In patients with anti-NMDA-R encephalitis, anesthesia using benzodiazepines, opiates and curares, which fail to interfere with the NMDA pathway, should be preferred.
Assuntos
Anestesia/efeitos adversos , Encefalite Antirreceptor de N-Metil-D-Aspartato/diagnóstico , Discinesia Induzida por Medicamentos/diagnóstico , Éteres Metílicos/efeitos adversos , Propofol/efeitos adversos , Anestesia/métodos , Anestésicos Inalatórios , Anestésicos Intravenosos , Encefalite Antirreceptor de N-Metil-D-Aspartato/complicações , Encefalite Antirreceptor de N-Metil-D-Aspartato/terapia , Quimioterapia Combinada/efeitos adversos , Discinesia Induzida por Medicamentos/complicações , Feminino , Humanos , Éteres Metílicos/administração & dosagem , Propofol/administração & dosagem , Sevoflurano , Adulto JovemAssuntos
Paraproteinemias/terapia , Transplante de Células-Tronco , Macroglobulinemia de Waldenstrom/terapia , Adulto , Bronquiectasia/diagnóstico , Bronquiectasia/diagnóstico por imagem , Bronquiectasia/terapia , Enfisema/diagnóstico , Enfisema/diagnóstico por imagem , Enfisema/terapia , Feminino , Volume Expiratório Forçado , Humanos , Cadeias Leves de Imunoglobulina/imunologia , Imunoglobulina M/imunologia , Pulmão/patologia , Paraproteinemias/diagnóstico , Paraproteinemias/diagnóstico por imagem , Testes de Função Respiratória , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/diagnóstico por imagemAssuntos
Carcinoma de Células Escamosas/secundário , Neoplasias do Ceco/complicações , Hemorragia Gastrointestinal/etiologia , Neoplasias do Jejuno/complicações , Neoplasias Orofaríngeas/patologia , Neoplasias Gástricas/complicações , Idoso , Anemia Ferropriva/etiologia , Neoplasias do Ceco/secundário , Colonoscopia , Gastroscopia , Humanos , Neoplasias do Jejuno/patologia , Neoplasias do Jejuno/secundário , Masculino , Neoplasias Gástricas/secundárioRESUMO
Neurofibromas involving airways are rare and their management is usually surgical. Herein, we report the case of an endotracheal polypoid neurofibroma successfully treated by multimodal interventional bronchoscopy and cryotherapy.
Assuntos
Broncoscopia/métodos , Crioterapia/métodos , Neurofibroma/terapia , Neoplasias da Traqueia/terapia , Feminino , Humanos , Pessoa de Meia-Idade , Neurofibroma/diagnóstico por imagem , Neurofibroma/cirurgia , Tomografia Computadorizada por Raios X/métodos , Traqueia/diagnóstico por imagem , Traqueia/cirurgia , Neoplasias da Traqueia/diagnóstico por imagem , Neoplasias da Traqueia/cirurgiaRESUMO
Glomus tumors of the trachea are particularly rare, and their management is usually based on sleeve resection with end-to-end anastomosis. Glomangiomyoma represents the rarest histologic subtype and has been observed only once in the trachea. We describe the first case of tracheal glomangiomyoma treated by multimodal interventional bronchoscopy.
Assuntos
Broncoscopia/métodos , Tumor Glômico/cirurgia , Neoplasias da Traqueia/cirurgia , Feminino , Seguimentos , Tumor Glômico/diagnóstico por imagem , Tumor Glômico/patologia , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Doenças Raras , Medição de Risco , Tomografia Computadorizada por Raios X/métodos , Neoplasias da Traqueia/diagnóstico por imagem , Neoplasias da Traqueia/patologia , Resultado do Tratamento , Adulto JovemRESUMO
In contrast to long bone osteosarcoma, mandibular osteosarcoma is highly heterogeneous and morphologically overlaps with benign tumors, obscuring diagnosis and treatment selection. Molecular characterization is difficult due to the paucity of available specimens of this rare disease. We aimed to characterize the spectrum of mandibular osteosarcoma using immunohistochemistry and molecular techniques (quantitative polymerase chain reaction and sequencing) and compare them with benign fibro-osseous lesions. Forty-nine paraffin-embedded mandible osteosarcoma tissue samples were collected retrospectively and compared with 10 fibrous dysplasia and 15 ossifying fibroma cases. These were analyzed for molecular markers thought to differ between the different diseases and subtypes: MDM2 (murine double-minute type 2) overexpression, GNAS (guanine nucleotide-binding protein/α subunit) mutations, and amplification of MDM2 and/or RASAL1 (RAS protein activator like 1). Five fibroblastic high-grade osteosarcoma subtypes showed MDM2 amplification, including 2 with a microscopic appearance of high-grade osteosarcoma with part low-grade osteosarcoma (differentiated/dedifferentiated osteosarcoma) and MDM2 overexpression. The other 3 contained a coamplification of MDM2 and RASAL1, a signature also described for juvenile ossifying fibroma, with no overexpression of MDM2. These were of the giant cell-rich high-grade osteosarcoma, with areas mimicking juvenile ossifying fibroma (ossifying fibroma-like osteosarcoma). Our results show that some diagnosed high-grade osteosarcomas are differentiated/dedifferentiated osteosarcomas and harbor an overexpression and amplification of MDM2. In addition, juvenile ossifying fibromas can potentially evolve into giant cell-rich high-grade osteosarcomas and are characterized by a RASAL1 amplification (osteosarcoma with juvenile ossifying fibroma-like genotype). Thus, the presence of a RASAL1 amplification in ossifying fibroma may indicate a requirement for closer follow-up and more aggressive management.
Assuntos
Biomarcadores Tumorais/genética , Proteínas Ativadoras de GTPase/genética , Amplificação de Genes , Neoplasias Mandibulares/genética , Osteossarcoma/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Diferenciação Celular , Cromograninas , Análise Mutacional de DNA , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Masculino , Neoplasias Mandibulares/química , Neoplasias Mandibulares/classificação , Neoplasias Mandibulares/patologia , Pessoa de Meia-Idade , Mutação , Osteossarcoma/química , Osteossarcoma/classificação , Osteossarcoma/patologia , Fenótipo , Reação em Cadeia da Polimerase , Prognóstico , Proteínas Proto-Oncogênicas c-mdm2/análise , Estudos Retrospectivos , Adulto JovemRESUMO
Chordomas are slow-growing malignant neoplasms. Determination of histopathologic prognostic factors using a large cohort study has been limited by their low incidence. In this retrospective study, we investigated the clinical, histopathologic, and immunohistochemical prognostic factors in 287 chordomas from 111 patients assessed by central pathologic review. Expression patterns of a variety of markers, including vascular endothelial growth factor (VEGF), mTOR pathway, c-kit, HER2, epidermal growth factor receptor (EGFR) and STAT3, and KRAS, BRAF, EGFR, and PIK3CA mutations were analyzed. On univariate analysis, the results confirm surgery as the best treatment, as judged by patient progression-free survival (PFS) and overall survival (OS). Proton therapy, the presence of a dedifferentiated component, mitotic figures, and Ki67 and p53 labeling indices correlated with PFS . Necrosis and apoptosis correlated with OS. Based on these findings, we propose a histopathologic grading system that correlates with PFS and OS. On multivariate analysis, extent of resection, tumor grade, and proton therapy were independent prognostic factors of PFS; extent of resection, tumor location, and grade were independent prognostic factors of OS. Based on the expression of EGFR, pSTAT3, VEGF, and mTOR pathway proteins, (in 85.9%, 79.1%, 85.7%, and 46% of chordomas, respectively), and 2 new mutations in the PIK3CA gene, we also provide evidence for potential therapeutic targets.
Assuntos
Biomarcadores Tumorais/análise , Cordoma/diagnóstico , Cordoma/terapia , Adolescente , Adulto , Idoso , Apoptose , Criança , Pré-Escolar , Cordoma/patologia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Necrose , Gradação de Tumores , Neoplasia Residual/patologia , Prognóstico , Prótons , Estudos Retrospectivos , Análise de Sobrevida , Adulto JovemRESUMO
Primary sinonasal intestinal-type adenocarcinomas (ITAC) are defined on the basis of their morphological similarities to colorectal adenocarcinomas (CRA). Thus, differential diagnosis with sinonasal metastasis of CRA could be a real challenge. Neuroendocrine differentiation has been variably described in several types of adenocarcinomas and notably in ITACs and CRAs. In a series of 25 ITACs and 25 lymph node metastasis of CRAs (nmCRA), we analysed neuroendocrine differentiation by immunohistochemistry with anti-chromogranin A and synaptophysin antibodies. Neuroendocrine differentiation (chromogranin A and/or synaptophysin positivity) was significantly different (p=0.0002) in ITACs (72%) and in nmCRAs (20%). In conclusion, presence of neuroendocrine cells seems more in favour of a sinonasal intestinal-type adenocarcinoma, than metastatic CRA. This immunohistochemical study could be useful in difficult cases and should be an interesting complement in a clinical discussion.
Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/análise , Diferenciação Celular , Neoplasias Colorretais/patologia , Neoplasias dos Seios Paranasais/diagnóstico , Adenocarcinoma/secundário , Idoso , Idoso de 80 Anos ou mais , Cromogranina A/análise , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias dos Seios Paranasais/secundário , Sinaptofisina/análiseRESUMO
BACKGROUND: Sinonasal intestinal-type adenocarcinomas (ITACs) have a poor prognosis, and are defined on the basis of their morphological similarities to colorectal adenocarcinomas. MET signaling pathway is involved in oncogenesis in various cancers. Nothing is currently known about the role of MET in ITACs. METHODS: In a series of 72 ITACs, we investigated MET protein levels by immunohistochemistry (IHC) and gene copy number by in situ hybridization. These findings were analyzed as a function of clinical data, histological typing, and patient outcome. RESULTS: MET protein was overproduced in 64% of cases and chromosome 7 polysomy was observed in 52% of cases. No tumor displayed MET amplification. The presence of mucinous or solid histological components, T3/T4 tumors, and incomplete resection were associated with a poor outcome. CONCLUSION: MET is overproduced in about two third of ITACs, suggesting a role for the MET signaling pathway in the oncogenesis of these tumors.
Assuntos
Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Intestinais/mortalidade , Neoplasias Intestinais/patologia , Proteínas Proto-Oncogênicas c-met/genética , Adenocarcinoma/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização In Situ , Neoplasias Intestinais/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-met/metabolismo , Estudos Retrospectivos , Transdução de Sinais , Estatísticas não Paramétricas , Análise de SobrevidaRESUMO
Using a cancer profiling array, our laboratory has shown that apelin gene is up-regulated in half of colon adenocarcinomas. We have therefore postulated that apelin signalling might play a prominent role in the growth of colon tumours. We first confirmed by immunohistochemistry that apelin peptide is overexpressed in human colon adenomas and adenocarcinomas. We also observed a significant overexpression of apelin receptor (APJ) in adjacent sections. We then demonstrated that several colorectal cancer cell lines also expressed apelin and its receptor, the highest gene and peptide expression being detected in LoVo cells. In this cell line, the expression and functionality of apelin receptor were revealed by apelin-induced adenylyl cyclase inhibition and Akt phosphorylation. In addition, apelin clearly protected LoVo cells from apoptosis by inactivating a caspase-dependent pathway and decreasing the degradation of poly ADP ribose polymerase protein (PARP). Finally, treatment of these tumour cells by the (F13A)apelin13 receptor antagonist significantly reduced their proliferation rate. Altogether, these data suggest the existence of an autocrine loop by which constitutive activation of apelin signalling should participate in the growth of colon adenocarcinomas. Accordingly, apelin signalling is a promising pharmacological target for the treatment of human colon adenomas and adenocarcinomas.
Assuntos
Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Receptores Acoplados a Proteínas G/biossíntese , Adenocarcinoma/genética , Apelina , Receptores de Apelina , Apoptose/fisiologia , Comunicação Autócrina , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Perfilação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fosforilação , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de SinaisRESUMO
We report the case of a 17-year-old male admitted to our academic hospital with massive rectal bleeding. Since childhood he had reported recurrent gastrointestinal bleeding and had two exploratory laparotomies 5 and 2 years previously. An emergency abdominal computed tomography scan, gastroscopy and colonoscopy, performed after hemodynamic stabilization, were considered normal. High-dose intravenous proton pump inhibitor (PPI) therapy was initiated and bleeding stopped spontaneously. Two other massive rectal bleeds occurred 8 h after each cessation of PPI which led to a hemostatic laparotomy after negative gastroscopy and small bowel capsule endoscopy. This showed long tubular duplication of the right colon, with fresh blood in the duplicated colon. Obscure lower gastrointestinal bleeding is a difficult medical situation and potentially life-threatening. The presence of ulcerated ectopic gastric mucosa in the colonic duplication explains the partial efficacy of PPI therapy. Obscure gastrointestinal bleeding responding to empiric anti-acid therapy should probably evoke the diagnosis of bleeding ectopic gastric mucosa such as Meckel's diverticulum or gastrointestinal duplication, and gastroenterologists should be aware of this potential medical situation.
Assuntos
Coristoma/tratamento farmacológico , Doenças do Colo/tratamento farmacológico , Mucosa Gástrica , Hemorragia Gastrointestinal/tratamento farmacológico , Inibidores da Bomba de Prótons/uso terapêutico , Administração Intravenosa , Adolescente , Coristoma/complicações , Coristoma/diagnóstico , Doenças do Colo/complicações , Doenças do Colo/diagnóstico , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Humanos , Masculino , Inibidores da Bomba de Prótons/administração & dosagem , Reto , Recidiva , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Sinonasal intestinal-type adenocarcinomas (ITACs) are uncommon tumors of poor prognosis defined by their similarities to colorectal adenocarcinomas. The involvement of the epidermal growth factor receptor (EGFR) pathway in colorectal adenocarcinoma oncogenesis is well established, and the same is expected to apply to ITACs. In a series of 39 ITACs, we investigated EGFR amplification and chromosome 7 polysomy by fluorescence in situ hybridization; EGFR, KRAS, and BRAF mutational status by polymerase chain reaction sequencing; EGFR variant messenger RNA expression by quantitative reverse transcriptase polymerase chain reaction; and EGFR protein expression by immunohistochemistry with antibodies targeting the extracellular domain, the intracellular domain, and the phosphorylated isoform. The findings were analyzed with respect to clinical data, histologic typing, and patient outcome. EGFR amplification was observed in 3 cases with a focal distribution. EGFR proteins were overexpressed in all these foci with both extracellular domain and intracellular domain antibodies, suggesting involvement of the whole receptor. Chromosome 7 polysomy was observed in 15 cases and was not associated with EGFR protein expression. EGFR, KRAS, or BRAF mutations were observed in 5 different cases. The EGFRvIII mutant was not detected. In all cases, EGFR variants were expressed. There was no association between these molecular features and patient survival. In conclusion, (1) our study revealed various EGFR expression patterns in ITACs, indicating tumor heterogeneity; (2) EGFR amplification should be distinguished from chromosome 7 polysomy; (3) fluorescence in situ hybridization analysis could be guided by immunohistochemistry; and (4) ITACs share common alterations of the EGFR pathway with colorectal adenocarcinomas, except for a lower frequency of KRAS and BRAF mutations.
Assuntos
Adenocarcinoma/genética , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Mutação , Neoplasias dos Seios Paranasais/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Aneuploidia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Terapia Combinada , Feminino , França/epidemiologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias dos Seios Paranasais/metabolismo , Neoplasias dos Seios Paranasais/mortalidade , Neoplasias dos Seios Paranasais/patologia , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Estudos Retrospectivos , Taxa de Sobrevida , Proteínas ras/metabolismoRESUMO
The EGFR (epidermal growth factor receptor) is involved in the oncogenesis of many tumors. In addition to the full-length EGFR (isoform a), normal and tumor cells produce soluble EGFR isoforms (sEGFR) that lack the intracellular domain. sEGFR isoforms b, c and d are encoded by EGFR variants 2 (v2), 3 (v3) and 4 (v4) mRNA resulting from gene alternative splicing. Accordingly, the results of EGFR protein expression analysis depend on the domain targeted by the antibodies. In meningiomas, EGFR expression investigations mainly focused on EGFR isoform a. sEGFR and EGFRvIII mutant, that encodes a constitutively active truncated receptor, have not been studied. In a 69 meningiomas series, protein expression was analyzed by immunohistochemistry using extracellular domain targeted antibody (ECD-Ab) and intracellular domain targeted antibody (ICD-Ab). EGFRv1 to v4 and EGFRvIII mRNAs were quantified by RT-PCR and EGFR amplification revealed by MLPA. Results were analyzed with respect to clinical data, tumor resection (Simpson grade), histological type, tumor grade, and patient outcome.Immunochemical staining was stronger with ECD-Ab than with ICD-Ab. Meningiomas expressed EGFRv1 to -v4 mRNAs but not EGFRvIII mutant. Intermediate or high ECD-Ab staining and high EGFRv1 to v4 mRNA levels were associated to a better progression free survival (PFS). PFS was also improved in women, when tumor resection was evaluated as Simpson 1 or 2, in grade I vs. grade II and III meningiomas and when Ki67 labeling index was lower than 10%. Our results suggest that, EGFR protein isoforms without ICD and their corresponding mRNA variants are expressed in meningiomas in addition to the whole isoform a. EGFRvIII was not expressed. High expression levels seem to be related to a better prognosis. These results indicate that the oncogenetic mechanisms involving the EGFR pathway in meningiomas could be different from other tumor types.