RESUMO
BACKGROUND: EndoFaster® analyzes gastric juice in real time during gastroscopy allowing the detection of hypo-achlorhydric conditions, like corpus atrophic gastritis. Narrow-band imaging (NBI) endoscopy allows to accurately detect and perform target biopsies in areas of intestinal metaplasia, a histological change often associated to corpus atrophic gastritis. AIMS: To compare the diagnostic accuracy of EndoFaster® with histological evaluation for corpus atrophic gastritis through high-resolution (HR) NBI targeted biopsies. METHODS: Prospective study on consecutive adult patients undergoing gastroscopy between April and November 2018. Patients in therapy with proton pump inhibitors, previous gastric surgery, and/or known gastric neoplasia were excluded. At the beginning of gastroscopy, gastric juice was aspirated and analyzed by EndoFaster® in 15 seconds. Endoscopists were blinded to the report of EndoFaster®. Evaluation of gastric mucosa in HR-white light was firstly performed, then with HR-NBI allowing to perform targeted biopsies on areas suspected for intestinal metaplasia; otherwise, biopsies were performed according to the updated Sydney System protocol and sent for histopathological evaluation. RESULTS: Overall, 124 patients were included [64% F; 56 (18-85) years]. Corpus atrophic gastritis was present in 41.9% of patients. EndoFaster® showed an accuracy for corpus atrophic gastritis diagnosis, compared to histopathological evaluation as gold standard, of 87.1% and a sensitivity, specificity, PPV, and NPV of 78.8%, 93.1%, 89.1%, and 85.9%, respectively. pH showed a positive correlation with the severity score of atrophy (r = 0.67, 95% CI: 0.73-0.81, and p < 0.0001). EndoFaster® allowed to diagnose corpus atrophic gastritis in 3.7% of patients negative to NBI (corpus atrophic gastritis without intestinal metaplasia). CONCLUSION: EndoFaster® seems a promising tool to diagnose corpus atrophic gastritis. The evaluation of hypo-achlorhydria during gastroscopy can address bioptic sampling in corpus atrophic gastritis patients without intestinal metaplasia.
RESUMO
PURPOSE: This study aims to identify in patients with neuroendocrine neoplasia (NEN) the potential correlation between FDG-PET findings and responses to everolimus therapy to identify predictors of long-term efficacy. METHODS: Retrospective analysis of patients with sporadic, advanced, progressive NEN treated with everolimus was performed based on the available data on FDG-PET patients obtained before commencing therapy. Data are expressed as the median (25-75th IQR). Risk factor analysis and survival analysis were performed by logistic regression and Cox proportional hazard regression and the determination of Kaplan-Meier curves, as appropriate. RESULTS: Sixty-six patients were evaluated (NET G1 19.7%, NET G2 75.7%, and NET G3 4.6%), including 45.4% with positive FDG-PET findings. Overall, disease stabilization and a partial response were achieved for 71.2% and 6% of patients, respectively. A long-term response (> 24 months) was observed in 33% of patients. Ki67 was the only predictor of tumor progression (p = 0.03). No significant difference in clinical outcomes was observed between patients with positive or negative FDG-PET findings (median PFS was 24 months and 18 months, respectively, p = 0.337; the disease control rate was 83.3% and 70%, respectively, p = 0.245). CONCLUSIONS: Everolimus is a valid therapeutic option for advanced, progressive, well-differentiated NEN, even in patients with positive FDG-PET findings.
Assuntos
Monitoramento de Medicamentos/métodos , Everolimo , Antígeno Ki-67/análise , Tumores Neuroendócrinos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Progressão da Doença , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Feminino , Humanos , Itália/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Retrospectivos , TempoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy.
Assuntos
Processamento Alternativo/fisiologia , Antimetabólitos Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Ribonucleoproteínas Nucleares Heterogêneas/fisiologia , Neoplasias Pancreáticas/tratamento farmacológico , Proteína de Ligação a Regiões Ricas em Polipirimidinas/fisiologia , Piruvato Quinase/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , GencitabinaRESUMO
Tyrosine kinase inhibitors (TKIs) have shown strong activity against non-small-cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. However, a fraction of EGFR wild-type (WT) patients may have an improvement in terms of response rate and progression-free survival when treated with erlotinib, suggesting that factors other than EGFR mutation may lead to TKI sensitivity. However, at present, no sufficiently robust clinical or biological parameters have been defined to identify WT-EGFR patients with greater chances of response. Therapeutics validation has necessarily to focus on lung cancer stem cells (LCSCs) as they are more difficult to eradicate and represent the tumor-maintaining cell population. Here, we investigated erlotinib response of lung CSCs with WT-EGFR and identified EGFR phosphorylation at tyrosine1068 (EGFRtyr1068) as a powerful biomarker associated with erlotinib sensitivity both in vitro and in preclinical CSC-generated xenografts. In contrast to the preferential cytotoxicity of chemotherapy against the more differentiated cells, in EGFRtyr1068 cells, erlotinib was even more active against the LCSCs compared with their differentiated counterpart, acquiring potential value as CSC-directed therapeutics in the context of WT-EGFR lung cancer. Although tumor growth was inhibited to a similar extent during erlotinib or chemotherapy administration to responsive tumors, erlotinib proved superior to chemotherapy in terms of higher tolerability and reduced tumor aggressiveness after treatment suspension, substantiating the possibility of preferential LCSC targeting, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumors. We conclude that EGFRtyr1068 may represent a potential candidate biomarker predicting erlotinib response at CSC-level in EGFR-WT lung cancer patients. Finally, besides its invariable association with erlotinib sensitivity in EGFR-WT lung CSCs, EGFRtyr1068 was associated with EGFR-sensitizing mutations in cell lines and patient tumors, with relevant diagnostic, clinical and therapeutic implications.
Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/genética , Cloridrato de Erlotinib/farmacologia , Regulação Neoplásica da Expressão Gênica , Células-Tronco Neoplásicas/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Farmacológicos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Receptores ErbB/metabolismo , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais , Tirosina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Metastatic growth in breast cancer (BC) has been proposed as an exclusive property of cancer stem cells (CSCs). However, formal proof of their identity as cells of origin of recurrences at distant sites and the molecular events that may contribute to tumor cell dissemination and metastasis development are yet to be elucidated. In this study, we analyzed a set of patient-derived breast cancer stem cell (BCSC) lines. We found that in vitro BCSCs exhibit a higher chemoresistance and migratory potential when compared with differentiated, nontumorigenic, breast cancer cells (dBCCs). By developing an in vivo metastatic model simulating the disease of patients with early BC, we observed that BCSCs is the only cell population endowed with metastatic potential. Gene-expression profile studies comparing metastagenic and non-metastagenic cells identified TAZ, a transducer of the Hippo pathway and biomechanical cues, as a central mediator of BCSCs metastatic ability involved in their chemoresistance and tumorigenic potential. Overexpression of TAZ in low-expressing dBCCs induced cell transformation and conferred tumorigenicity and migratory activity. Conversely, loss of TAZ in BCSCs severely impaired metastatic colonization and chemoresistance. In clinical data from 99 BC patients, high expression levels of TAZ were associated with shorter disease-free survival in multivariate analysis, thus indicating that TAZ may represent a novel independent negative prognostic factor. Overall, this study designates TAZ as a novel biomarker and a possible therapeutic target for BC.
Assuntos
Neoplasias da Mama/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metástase Neoplásica/genética , Recidiva Local de Neoplasia/genética , Animais , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Camundongos , Metástase Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas , Transativadores , Fatores de Transcrição , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Adequate gluten-free diet (GFD) is the only treatment for coeliac disease (CD). However, no agreement has been reached on either how and when to assess patient adherence to GFD or its effectiveness on villous atrophy. AIM: To assess, in a prospective study, patient adherence to and efficacy of GFD on histological recovery after 1-year of GFD. METHODS: Between 2009 and 2012, we enrolled 65 consecutive newly-diagnosed adult patients (median age 38 years, 18-70) with biopsy-proven atrophic CD. Patients were re-evaluated after 1 year of GFD with duodenal histology, serological assays, symptoms and a dietary interview based on a validated questionnaire. Complete histological recovery was defined as the absence of villous atrophy and ≤30/100 intraepithelial lymphocytes. RESULTS: Overall, 81.5% of patients had adequate adherence (ADA) to GFD, whereas 18.5% had an inadequate adherence (IADA); 66% of ADA patients and no IADA patients achieved complete histological recovery (P < 0.00001). Among ADA patients, antibody seroconversion and symptoms were not significantly different between patients who achieved complete histological recovery and those who achieved partial histological recovery with P = 0.309 and P = 0.197, respectively. Multivariate analysis showed that Marsh 3C was a risk factor for incomplete histological recovery in ADA patients (OR 8.74, 95% CI: 1.87-40.83). CONCLUSIONS: This study shows that complete histological recovery after 1-year of GFD in adult patients, who are assessed as adherent to the GFD, can be obtained in 66% of patients. Patients with severe histological damage at diagnosis are at risk for incomplete histological recovery 1 year later.
Assuntos
Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Duodeno/patologia , Adulto , Atrofia/dietoterapia , Atrofia/patologia , Biópsia , Doença Celíaca/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
AIM: Preoperative chemoradiation (CRT) for rectal cancer decreases the number of examined lymph nodes (NELN) found in the resected specimen. However, the prognostic role of lymph node evaluation including overall numbers and the lymph node ratio (LNR) in patients having preoperative CRT have not yet been defined. The study has assessed the influence of CRT on the NELN and on lymph node number and LNR on the survival of patients with rectal cancer. METHOD: Between 2003 and 2011, 508 patients with nonmetastatic rectal cancer underwent mesorectal excision. Of these 123 (24.2%) received preoperative CRT. Univariate and multivariate analysis was performed to define the role of NELN and LNR as prognostic indicators of survival. RESULTS: Neoadjuvant CRT significantly reduced the NELN (P < 0.0001). Disease-free survival (DFS) and overall survival (OS) of patients with fewer or more than 12 nodes retrieved did not differ statistically. Node-negative patients with six or fewer lymph nodes were significantly associated with a poor DFS and OS on univariate analysis (P = 0.03 and P = 0.03). LNR significantly influenced the DFS and OS on multivariate analysis [DFS, P = 0.0473, hazard ratio (HR) 2.4980, 95% confidence interval (CI) 1.2631-9.4097; OS, P = 0.0419, HR 1.1820, 95% CI 1.1812-10,710]. CONCLUSION: The cut-off of 12 lymph nodes does not influence survival and should not be considered for cancer-specific prediction of patients having neoadjuvant CRT. In contrast LNR is an independent prognostic predictor of DFS and OS in such patients.
Assuntos
Carcinoma/terapia , Quimiorradioterapia Adjuvante/métodos , Excisão de Linfonodo/métodos , Linfonodos/patologia , Neoplasias Retais/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Carcinoma/patologia , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Fatores de TempoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplastic disease. Gemcitabine, the currently used chemotherapeutic drug for PDAC, elicits only minor benefits, because of the development of escape pathways leading to chemoresistance. Herein, we aimed at investigating the involvement of the mitogen activating protein kinase interacting kinase (MNK)/eIF4E pathway in the acquired drug resistance of PDAC cells. Screening of a cohort of PDAC patients by immunohistochemistry showed that eIF4E phosphorylation correlated with disease grade, early onset of disease and worse prognosis. In PDAC cell lines, chemotherapeutic drugs induced MNK-dependent phosphorylation of eIF4E. Importantly, pharmacological inhibition of MNK activity synergistically enhanced the cytostatic effect of gemcitabine, by promoting apoptosis. RNA interference (RNAi) experiments indicated that MNK2 is mainly responsible for eIF4E phosphorylation and gemcitabine resistance in PDAC cells. Furthermore, we found that gemcitabine induced the expression of the oncogenic splicing factor SRSF1 and splicing of MNK2b, a splice variant that overrides upstream regulatory pathways and confers increased resistance to the drug. Silencing of SRSF1 by RNAi abolished this splicing event and recapitulated the effects of MNK pharmacological or genetic inhibition on eIF4E phosphorylation and apoptosis in gemcitabine-treated cells. Our results highlight a novel pro-survival pathway triggered by gemcitabine in PDAC cells, which leads to MNK2-dependent phosphorylation of eIF4E, suggesting that the MNK/eIF4E pathway represents an escape route utilized by PDAC cells to withstand chemotherapeutic treatments.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/metabolismo , Desoxicitidina/análogos & derivados , Fator de Iniciação 4E em Eucariotos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pancreáticas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/mortalidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Splicing de RNA , Proteínas de Ligação a RNA/metabolismo , Fatores de Processamento de Serina-Arginina , Transdução de Sinais , GencitabinaRESUMO
AIM: Over the past 10 years, few authors reported the synchronous detection of gastrointestinal stromal tumors (GISTs) and other neoplasms in the 9-33% of GISTs series. The primary aim of the present study was of investigating the features of GISTs detected in patients with other malignancies. METHODS: From 1999 to 2010 the GISTs detected at surgical exploration or preoperative assessment for other malignancies plus primary-GISTs, were recorded and reviewed. RESULTS: All synchronous GISTs were positive for kit/CD34, resulting smaller in size, with a lower mitotic index and occurring in elderly patients, comparing with primary-GISTs (P<0.05). Moreover a prevalence of males and of lower-risk classifications were noted, not reaching, however, a statistical value. CONCLUSION: According with our findings, the synchronous GISTs are mainly asymptomatic/incidentally detected and display some of the low malignant features; we recommend, however, the surgical excision of GISTs occurring in patients with other malignancies in order to define the histology and risk features and since it might result in an incorrect management if misdiagnosed as a metastases.
Assuntos
Tumores do Estroma Gastrointestinal/patologia , Neoplasias Primárias Múltiplas/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Proteínas Quinases/metabolismo , Animais , Western Blotting , Carcinoma Pulmonar de Células não Pequenas/genética , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Cisplatino/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Inibidores Enzimáticos/farmacologia , Feminino , Imunofluorescência , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Quinases/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , GencitabinaRESUMO
BACKGROUND: Long-term observational studies assessing the incidence of type I gastric carcinoid (typeIGC) in patients with chronic atrophic gastritis are few. AIM: To evaluate the occurrence of typeIGC at diagnosis and during follow-up and to identify patient features associated with the presence of typeIGC in a cohort of chronic atrophic gastritis patients. METHODS: Three hundred and sixty-seven chronic atrophic gastritis patients [245 women, age 54 (18-79) years] underwent regular follow-up by gastroscopy. The incidence of typeIGC was determined in chronic atrophic gastritis patients with at least 2 years of follow-up (n = 214). Baseline clinical and histological features were analysed as factors associated with the presence of typeIGC by univariate analysis. RESULTS: Type I gastric carcinoid was diagnosed in nine (2.4%) patients at the moment when chronic atrophic gastritis was diagnosed. After 1463 person-years, six patients developed typeIGC with an annual incidence rate (person-year) of 0.4%. Patients with typeIGC had significantly higher levels of gastrin, chromogranin A and more frequently the presence of body polyps and ECL-dysplasia compared with chronic atrophic gastritis patients without typeIGC. CONCLUSIONS: This cohort study shows that typeIGC is a rare complication in patients with chronic atrophic gastritis, and the presence of body polyps and ECL-dysplasia at gastroscopic/histologic evaluation is strongly associated with the presence of typeIGC.
Assuntos
Tumor Carcinoide/patologia , Gastrite Atrófica/patologia , Lesões Pré-Cancerosas/patologia , Neoplasias Gástricas/patologia , Adolescente , Adulto , Idoso , Tumor Carcinoide/classificação , Estudos de Coortes , Feminino , Mucosa Gástrica/patologia , Gastroscopia/métodos , Humanos , Imuno-Histoquímica , Incidência , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/classificação , Adulto JovemRESUMO
Lung carcinoma is often incurable and remains the leading cancer killer in both men and women. Recent evidence indicates that tumors contain a small population of cancer stem cells that are responsible for tumor maintenance and spreading. The identification of the tumorigenic population that sustains lung cancer may contribute significantly to the development of effective therapies. Here, we found that the tumorigenic cells in small cell and non-small cell lung cancer are a rare population of undifferentiated cells expressing CD133, an antigen present in the cell membrane of normal and cancer-primitive cells of the hematopoietic, neural, endothelial and epithelial lineages. Lung cancer CD133(+) cells were able to grow indefinitely as tumor spheres in serum-free medium containing epidermal growth factor and basic fibroblast growth factor. The injection of 10(4) lung cancer CD133(+) cells in immunocompromised mice readily generated tumor xenografts phenotypically identical to the original tumor. Upon differentiation, lung cancer CD133(+) cells acquired the specific lineage markers, while loosing the tumorigenic potential together with CD133 expression. Thus, lung cancer contains a rare population of CD133(+) cancer stem-like cells able to self-renew and generates an unlimited progeny of non-tumorigenic cells. Molecular and functional characterization of such a tumorigenic population may provide valuable information to be exploited in the clinical setting.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Pequenas/patologia , Neoplasias Pulmonares/patologia , Células-Tronco Neoplásicas/patologia , Antígeno AC133 , Animais , Antígenos CD/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Pequenas/metabolismo , Diferenciação Celular , Resistencia a Medicamentos Antineoplásicos , Feminino , Glicoproteínas/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos SCID , Células-Tronco Neoplásicas/metabolismo , Peptídeos/metabolismo , Fenótipo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Expression of the autoimmune regulator gene (AIRE) and the presence of CD25(+)/forkhead box p3 (FoxP3)(+) T regulatory (T(reg)) cells were investigated in histologically normal adult thymi and in thymomas using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). In the normal thymus staining for AIRE was detected in the nucleus of some epithelial-like cells located in the medulla; in thymomas AIRE-positive cells were extremely rare and could be detected only in the areas of medullary differentiation of two B1 type, organoid thymomas. RNA was extracted from 36 cases of thymoma and 21 non-neoplastic thymi obtained from 11 myasthenic (MG(+)) and 10 non-myasthenic (MG(-)) patients. It was found that AIRE is 8.5-fold more expressed in non-neoplastic thymi than in thymomas (P = 0.01), and that the amount of AIRE transcripts present in the thymoma tissue are not influenced by the association with MG, nor by the histological type. A possible involvement of AIRE in the development of MG was suggested by the observation that medullary thymic epithelial cells isolated from AIRE-deficient mice contain low levels of RNA transcripts for CHRNA 1, a gene coding for acetylcholine receptor. Expression of human CHRNA 1 RNA was investigated in 34 human thymomas obtained from 20 MG(-) patients and 14 MG(+) patients. No significant difference was found in the two groups (thymoma MG(+), CHRNA1 = 0.013 +/- 0.03; thymoma MG-, CHRNA1 = 0.01 +/- 0.03). In normal and hyperplastic thymi CD25(+)/Foxp3(+) cells were located mainly in the medulla, and their number was not influenced by the presence of MG. Foxp3(+) and CD25(+) cells were significantly less numerous in thymomas. A quantitative estimate of T(reg) cells revealed that the levels of Foxp3 RNA detected in non-neoplastic thymi were significantly higher (P = 0.02) than those observed in 31 cases of thymomas. Our findings indicate that the tissue microenvironment of thymomas is defective in the expression of relevant functions that exert a crucial role in the negative selection of autoreactive lymphocytes.
Assuntos
Linfócitos T Reguladores/imunologia , Timoma/imunologia , Neoplasias do Timo/imunologia , Fatores de Transcrição/metabolismo , Adulto , Idoso , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/imunologia , Reação em Cadeia da Polimerase/métodos , Timo/imunologia , Fatores de Transcrição/genética , Proteína AIREAssuntos
Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Células Jurkat , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/patologia , Fatores de Tempo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Hypomethylation has been reported to be responsible for the activation of several oncogenes. The possibility that hypomethylation is involved in the regulation of MET transcription was investigated through the analysis of the methylation status of one CpG island containing 43 CpGs in six cases of papillary carcinoma, in the corresponding normal thyroid tissue, and in two cases of hyperplastic goitre. Evidence of methylation was not found in any of the analysed CpG.
Assuntos
Carcinoma Papilar/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas/biossíntese , Receptores de Fatores de Crescimento , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Carcinoma Papilar/fisiopatologia , Ilhas de CpG , DNA de Neoplasias , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-met , Neoplasias da Glândula Tireoide/fisiopatologia , Transcrição GênicaRESUMO
BACKGROUND/AIMS: The p73 gene encodes a protein that shares structural and functional homology with the p53 gene product. The highest degree of homology is in the DNA binding domain, which is the region of p53 that is most frequently mutated in cancer. In contrast to p53 there is little evidence that p73 acts as a classic tumour suppressor gene. Because of the similarities between the p53 and p73 genes and the high frequency of mutation of p53, this study was designed to investigate the p73 gene in patients with gastric adenocarcinoma. METHODS: The mutational status of the p73 gene was investigated in a series of 13 cases of gastric adenocarcinoma from the antro-pyloric region and the gastro-oesophageal junction, using the polymerase chain reaction, single strand conformational polymorphism, and direct DNA sequencing. RESULTS: A glutamine to arginine mutation was detected in exon 5 of the p73 gene in a case of adenocarcinoma at the gastro-oesophageal junction. CONCLUSION: Although limited to a small series of cases, these results suggest that p73 may have a potential pathogenetic role in this tumour.
Assuntos
Adenocarcinoma/genética , Genes Neoplásicos/genética , Neoplasias Gástricas/genética , Idoso , Idoso de 80 Anos ou mais , Arginina/análise , Sequência de Bases , DNA de Neoplasias/análise , Junção Esofagogástrica , Glutamina/análise , Humanos , Pessoa de Meia-Idade , Mutação/genética , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita SimplesRESUMO
This study presents an examination of the Ig heavy chain (IgH) and T-cell receptor gamma (TCRgamma) genes in a series of 39 CD3-positive T-cell acute lymphoblastic leukaemia (ALL) cases with and without co-expression of CD79a; 30/39 cases had a rearrangement of the TCRgamma genes and two of these 30 cases also demonstrated an IgH rearrangement. No cases had solely an IgH rearrangement. The conclusion of the study is that lymphoblastic lymphoma cases that are positive for CD3 are of T-cell lineage, regardless of CD79a expression.
Assuntos
Rearranjo Gênico do Linfócito T , Leucemia-Linfoma de Células T do Adulto/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Antígenos CD/análise , Antígenos de Neoplasias/análise , Complexo CD3/análise , Antígenos CD79 , Criança , Pré-Escolar , Feminino , Rearranjo Gênico da Cadeia delta dos Receptores de Antígenos dos Linfócitos T , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imunofenotipagem , Lactente , Recém-Nascido , Leucemia-Linfoma de Células T do Adulto/classificação , Leucemia-Linfoma de Células T do Adulto/imunologia , Masculino , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Antígenos de Linfócitos B/análiseAssuntos
Leiomiossarcoma/patologia , Linfangioleiomiomatose/patologia , Esclerose Tuberosa/patologia , Neoplasias Uterinas/patologia , Biomarcadores Tumorais/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Leiomiossarcoma/metabolismo , Linfangioleiomiomatose/metabolismo , Pessoa de Meia-Idade , Esclerose Tuberosa/metabolismo , Neoplasias Uterinas/metabolismoRESUMO
Inflammatory pseudotumour of the lung is a lesion mainly composed of histiocytes. Histiocyte accumulation may arise from local proliferation of migratory cells, from cytokine induced recruitment of monocytes from the systemic circulation, or both. Cell proliferation was investigated with Ki-67 immunostaining and cytokine production with reverse transcriptase-polymerase chain reaction in two cases of inflammatory pseudotumour of the lung. It was found that the two lesions were composed mainly of non-proliferating (Ki-67 non-binding) macrophages that stained positive for CD68, CD14, CD4, and mannose receptor. Both cases contained mRNA transcripts for monocyte chemotactic protein-1 (MCP-1), a monocyte chemoattractant, and for interleukin 6 (IL-6), an inducer of plasma cell differentiation. One of the two cases also contained mRNA transcripts for IL-8, a neutrophil chemoattractant. These findings are consistent with the possibility that accumulation of non-proliferating histiocytes induced by MCP-1 is one of the pathogenic events occurring in inflammatory pseudotumour of the lung.