RESUMO
Microscopic colitis (MC) is a chronic inflammatory disease of the colon that presents with chronic, nonbloody watery diarrhea and only few or no endoscopic abnormalities. Histologic examination discriminates lymphocytic colitis (LyC; presence of ≥20 intraepithelial lymphocytes per 100 surface epithelial cells) and collagenous colitis (CC; colonic subepithelial collagen band >10 µm in diameter).1,2 MC not otherwise specified describes a subgroup of patients who do not fulfill the diagnostic criteria for either CC or LyC.1,2 Population-based epidemiologic data regarding MC are scarce. We aimed to evaluate the clinical presentation at diagnosis, incidence, and prevalence of MC in Cantons of Vaud and Fribourg, Switzerland.
Assuntos
Colite Colagenosa , Colite Linfocítica , Colite Microscópica , Colite , Estudos de Coortes , Colite Microscópica/diagnóstico , Colite Microscópica/epidemiologia , Humanos , Incidência , Suíça/epidemiologiaRESUMO
Despite the proven ability of immunization to reduce Helicobacter infection in mouse models, the precise mechanism of protection has remained elusive. In this study, we evaluated the role of inflammatory monocytes in the vaccine-induced reduction of Helicobacter felis infection. We first showed by using flow cytometric analysis that Ly6C(low) major histocompatibility complex class II-positive chemokine receptor type 2 (CCR2)-positive CD64(+) inflammatory monocytes accumulate in the stomach mucosa during the vaccine-induced reduction of H. felis infection. To determine whether inflammatory monocytes played a role in the protection, these cells were depleted with anti-CCR2 depleting antibodies. Indeed, depletion of inflammatory monocytes was associated with an impaired vaccine-induced reduction of H. felis infection on day 5 postinfection. To determine whether inflammatory monocytes had a direct or indirect role, we studied their antimicrobial activities. We observed that inflammatory monocytes produced tumor necrosis factor alpha and inducible nitric oxide synthase (iNOS), two major antimicrobial factors. Lastly, by using a Helicobacter in vitro killing assay, we showed that mouse inflammatory monocytes and activated human monocytes killed H. pylori in an iNOS-dependent manner. Collectively, these data show that inflammatory monocytes play a direct role in the immunization-induced reduction of H. felis infection from the gastric mucosa.
Assuntos
Vacinas Bacterianas/imunologia , Infecções por Helicobacter/imunologia , Helicobacter felis/imunologia , Monócitos/imunologia , Animais , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/genética , Feminino , Infecções por Helicobacter/genética , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/prevenção & controle , Helicobacter felis/genética , Humanos , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Monócitos/microbiologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: The criteria for choosing relevant cell lines among a vast panel of available intestinal-derived lines exhibiting a wide range of functional properties are still ill-defined. The objective of this study was, therefore, to establish objective criteria for choosing relevant cell lines to assess their appropriateness as tumor models as well as for drug absorption studies. RESULTS: We made use of publicly available expression signatures and cell based functional assays to delineate differences between various intestinal colon carcinoma cell lines and normal intestinal epithelium. We have compared a panel of intestinal cell lines with patient-derived normal and tumor epithelium and classified them according to traits relating to oncogenic pathway activity, epithelial-mesenchymal transition (EMT) and stemness, migratory properties, proliferative activity, transporter expression profiles and chemosensitivity. For example, SW480 represent an EMT-high, migratory phenotype and scored highest in terms of signatures associated to worse overall survival and higher risk of recurrence based on patient derived databases. On the other hand, differentiated HT29 and T84 cells showed gene expression patterns closest to tumor bulk derived cells. Regarding drug absorption, we confirmed that differentiated Caco-2 cells are the model of choice for active uptake studies in the small intestine. Regarding chemosensitivity we were unable to confirm a recently proposed association of chemo-resistance with EMT traits. However, a novel signature was identified through mining of NCI60 GI50 values that allowed to rank the panel of intestinal cell lines according to their drug responsiveness to commonly used chemotherapeutics. CONCLUSIONS: This study presents a straightforward strategy to exploit publicly available gene expression data to guide the choice of cell-based models. While this approach does not overcome the major limitations of such models, introducing a rank order of selected features may allow selecting model cell lines that are more adapted and pertinent to the addressed biological question.
Assuntos
Bases de Dados Genéticas , Modelos Biológicos , Antineoplásicos/farmacologia , Células CACO-2 , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Células HT29 , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Análise de Componente PrincipalRESUMO
BACKGROUND & AIMS: Protective immunization limits Helicobacter infection of mice by undetermined mechanisms. Protease-activated receptor 2 (PAR2) signaling is believed to regulate immune and inflammatory responses. We investigated the role of PAR2 in vaccine-induced immunity against Helicobacter infection. METHODS: Immune responses against Helicobacter infection were compared between vaccinated PAR2-/- and wild-type (WT) mice. Bacterial persistence, gastric pathology, and inflammatory and cellular responses were assessed using the rapid urease test (RUT), histologic analyses, quantitative polymerase chain reaction, and flow cytometry, respectively. RESULTS: Following vaccination, PAR2-/- mice did not have reductions in Helicobacter felis infection (RUT values were 0.01±0.01 for WT mice and 0.11±0.13 for PAR2-/- mice; P<.05). The vaccinated PAR2-/- mice had reduced inflammation-induced stomach tissue damage (tissue damage scores were 8.83±1.47 for WT mice and 4.86±1.35 for PAR2-/- mice; P<.002) and reduced T-helper (Th)17 responses, based on reduced urease-induced interleukin (IL)-17 secretion by stomach mononuclear cells (5182 ± 1265 pg/mL for WT mice and 350±436 pg/mL for PAR2-/- mice; P<.03) and reduced recruitment of CD4+ IL-17+ T cells into the gastric mucosa of PAR2-/- mice following bacterial challenge (3.7%±1.5% for WT mice and 2.6%±1.1% for PAR2-/- mice; P<.05). In vitro, H felis-stimulated dendritic cells (DCs) from WT mice induced greater secretion of IL-17 by ovalbumin-stimulated OT-II transgenic CD4+ T cells compared with DCs from PAR2-/- mice (4298±347 and 3230±779; P<.04), indicating that PAR2-/- DCs are impaired in priming of Th17 cells. Adoptive transfer of PAR2+/+ DCs into vaccinated PAR2-/- mice increased vaccine-induced protection (RUT values were 0.11±0.10 and 0.26±0.15 for injected and noninjected mice, respectively; P<.03). CONCLUSIONS: PAR2 activates DCs to mediate vaccine-induced protection against Helicobacter infection in mice.
Assuntos
Vacinas Bacterianas/administração & dosagem , Infecções por Helicobacter/prevenção & controle , Helicobacter felis/imunologia , Helicobacter pylori/imunologia , Receptor PAR-2/metabolismo , Estômago/efeitos dos fármacos , Urease/administração & dosagem , Administração Intranasal , Transferência Adotiva , Animais , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Células Dendríticas/transplante , Modelos Animais de Doenças , Feminino , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/enzimologia , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor PAR-2/deficiência , Receptor PAR-2/genética , Baço/efeitos dos fármacos , Baço/imunologia , Baço/microbiologia , Estômago/imunologia , Estômago/microbiologia , Estômago/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/microbiologia , Vacinas Sintéticas/administração & dosagemRESUMO
Invariant NKT cells (iNKT cells) recognize glycolipid Ags via an invariant TCR alpha-chain and play a central role in various immune responses. Although human CD4(+) and CD4(-) iNKT cell subsets both produce Th1 cytokines, the CD4(+) subset displays an enhanced ability to secrete Th2 cytokines and shows regulatory activity. We performed an ex vivo analysis of blood, liver, and tumor iNKT cells from patients with hepatocellular carcinoma and metastases from uveal melanoma or colon carcinoma. Frequencies of Valpha24/Vbeta11 iNKT cells were increased in tumors, especially in patients with hepatocellular carcinoma. The proportions of CD4(+), double negative, and CD8alpha(+) iNKT cell subsets in the blood of patients were similar to those of healthy donors. However, we consistently found that the proportion of CD4(+) iNKT cells increased gradually from blood to liver to tumor. Furthermore, CD4(+) iNKT cell clones generated from healthy donors were functionally distinct from their CD4(-) counterparts, exhibiting higher Th2 cytokine production and lower cytolytic activity. Thus, in the tumor microenvironment the iNKT cell repertoire is modified by the enrichment of CD4(+) iNKT cells, a subset able to generate Th2 cytokines that can inhibit the expansion of tumor Ag-specific CD8(+) T cells. Because CD4(+) iNKT cells appear inefficient in tumor defense and may even favor tumor growth and recurrence, novel iNKT-targeted therapies should restore CD4(-) iNKT cells at the tumor site and specifically induce Th1 cytokine production from all iNKT cell subsets.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Neoplasias Hepáticas/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD1d/imunologia , Complexo CD3/imunologia , Clonagem Molecular , Feminino , Células HeLa , Saúde , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND & AIMS: Despite the proven ability of immunization to reduce Helicobacter infection in mouse models, the precise mechanism of protection has remained elusive. This study explores the possibility that interleukin (IL)-17 plays a role in the reduction of Helicobacter infection following vaccination of wild-type animals or in spontaneous reduction of bacterial infection in IL-10-deficient mice. METHODS: In mice, reducing Helicobacter infection, the levels and source of IL-17 were determined and the role of IL-17 in reduction of Helicobacter infection was probed by neutralizing antibodies. RESULTS: Gastric IL-17 levels were strongly increased in mice mucosally immunized with urease plus cholera toxin and challenged with Helicobacter felis as compared with controls (654 +/- 455 and 34 +/- 84 relative units for IL-17 messenger RNA expression [P < .01] and 6.9 +/- 8.4 and 0.02 +/- 0.04 pg for IL-17 protein concentration [P < .01], respectively). Flow cytometry analysis showed that a peak of CD4(+)IL-17(+) T cells infiltrating the gastric mucosa occurred in immunized mice in contrast to control mice (4.7% +/- 0.3% and 1.4% +/- 0.3% [P < .01], respectively). Gastric mucosa-infiltrating CD4(+)IL-17(+) T cells were also observed in IL-10-deficient mice that spontaneously reduced H felis infection (4.3% +/- 2.3% and 2% +/- 0.6% [P < .01], for infected and noninfected IL-10-deficient mice, respectively). In wild-type immunized mice, intraperitoneal injection of anti-IL-17 antibodies significantly inhibited inflammation and the reduction of Helicobacter infection in comparison with control antibodies (1 of 12 mice vs 9 of 12 mice reduced Helicobacter infection [P < .01], respectively). CONCLUSIONS: IL-17 plays a critical role in the immunization-induced reduction of Helicobacter infection from the gastric mucosa.
Assuntos
Vacinas Bacterianas/farmacologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Memória Imunológica/fisiologia , Interleucina-17/metabolismo , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/prevenção & controle , Imuno-Histoquímica , Interleucina-10/deficiência , Interleucina-10/imunologia , Interleucina-17/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo , Reação em Cadeia da Polimerase , Probabilidade , Distribuição Aleatória , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Células Th1/imunologiaRESUMO
BACKGROUND: Family history is a known risk factor for breast cancer, but its prognostic value and the prognostic value of tumour characteristics in relation to family history has not been clearly established. In addition, studies of intra-familial tumour characteristics and prognosis in population-based settings are very rare. Two previous studies have suggested that breast cancer prognosis clusters within families. However, both studies lack information on HER2 expression status, which is a strong prognostic factor and could contribute to the observed results. METHODS: We conducted a population-based study on 145 mother-daughter and sister-sister affected pairs using data extracted from the Geneva Cancer Registry. Histopathological characteristics were determined in archived tumour blocks by immunochemistry techniques. Breast cancer survival among family members was studied according to patient and tumour characteristics. RESULTS: No significant intra-familial agreement of pathological characteristic features was observed. We found that relatives of breast cancer patients experienced a much higher risk of breast cancer death compared to the general population. However, we did not find significant concordance in good and poor breast cancer-specific survival between pairs. The small number of family pairs and deaths from breast cancer may partly explain our results. CONCLUSIONS: Large-scale studies with accurate data on strong prognosticators are still needed to confirm the possibility of familial inheritance of breast cancer prognosis.  .
Assuntos
Neoplasias da Mama , Neoplasias da Mama/genética , Análise por Conglomerados , Feminino , Humanos , Mães , Prognóstico , Sistema de RegistrosRESUMO
AIMS: To compare the molecular profile of a series of sessile serrated adenomas (SSAs) and hyperplastic polyps (HPs), in order to distinguish these lesions, SSAs having a potential role in the genesis of serrated adenocarcinomas through a serrated pathway in which methylation plays a key role. METHODS AND RESULTS: Twelve HPs and sixteen SSAs of the right and left colon were investigated for microsatellite instability, DNA mismatch repair genes, p53, p16, and beta-catenin expression, MLH1 and p16 (CDKN2A) gene methylation, and KRAS and BRAF mutations. Both SSAs and HPs were microsatellite stable. MLH1 and MSH2 protein silencing, aberrant cytoplasmic expression and methylation of p16 were found to be exclusive to right-sided SSAs. The MLH1 promoter gene was frequently methylated in right-sided SSAs in contrast with HPs. Abnormal p53 and beta-catenin expression was present in both SSAs and HPs. BRAF and KRAS mutation were mutually exclusive, but KRAS mutation was present only in left-sided SSAs and HPs. CONCLUSIONS: HPs and SSAs may be related lesions. However, at least right-sided SSAs differ from left-sided SSAs and HPs in the occurrence of MLH1 and p16 methylation, supporting the hypothesis that SSAs could be precursors of serrated adenocarcinomas.
Assuntos
Adenoma/genética , Pólipos do Colo/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenoma/metabolismo , Adenoma/patologia , Colo/metabolismo , Colo/patologia , Pólipos do Colo/metabolismo , Pólipos do Colo/patologia , Reparo de Erro de Pareamento de DNA , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , Genes p16 , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Imuno-Histoquímica , Intestino Grosso/metabolismo , Intestino Grosso/patologia , Metilação , Repetições de Microssatélites , Proteína 1 Homóloga a MutL , Mutação , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , beta Catenina/genética , beta Catenina/metabolismo , Proteínas ras/genéticaRESUMO
BACKGROUND: Anal condylomata acuminata (ACA) are caused by human papilloma virus (HPV) infection which is transmitted by close physical and sexual contact. The result of surgical treatment of ACA has an overall success rate of 71% to 93%, with a recurrence rate between 4% and 29%. The aim of this study was to assess a possible association between HPV type and ACA recurrence after surgical treatment. METHODS: We performed a retrospective analysis of 140 consecutive patients who underwent surgery for ACA from January 1990 to December 2005 at our tertiary University Hospital. We confirmed ACA by histopathological analysis and determined the HPV typing using the polymerase chain reaction. Patients gave consent for HPV testing and completed a questionnaire. We looked at the association of ACA, HPV typing, and HIV disease. We used chi, the Monte Carlo simulation, and Wilcoxon tests for statistical analysis. RESULTS: Among the 140 patients (123 M/17 F), HPV 6 and 11 were the most frequently encountered viruses (51% and 28%, respectively). Recurrence occurred in 35 (25%) patients. HPV 11 was present in 19 (41%) of these recurrences, which is statistically significant, when compared with other HPVs. There was no significant difference between recurrence rates in the 33 (24%) HIV-positive and the HIV-negative patients. CONCLUSIONS: HPV 11 is associated with higher recurrence rate of ACA. This makes routine clinical HPV typing questionable. Follow-up is required to identify recurrence and to treat it early, especially if HPV 11 has been identified.
Assuntos
Condiloma Acuminado/epidemiologia , Condiloma Acuminado/cirurgia , Papillomaviridae/classificação , Papillomaviridae/genética , Infecções por Papillomavirus/epidemiologia , Adulto , Canal Anal/virologia , Condiloma Acuminado/prevenção & controle , Condiloma Acuminado/virologia , Feminino , Genótipo , Hospitais Universitários , Papillomavirus Humano 11/classificação , Papillomavirus Humano 11/genética , Papillomavirus Humano 11/isolamento & purificação , Papillomavirus Humano 6/classificação , Papillomavirus Humano 6/genética , Papillomavirus Humano 6/isolamento & purificação , Humanos , Masculino , Método de Monte Carlo , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/cirurgia , Infecções por Papillomavirus/virologia , Recidiva , Inquéritos e Questionários , Suíça/epidemiologiaRESUMO
Considerable progress was realized these last years in the understanding of the molecular mechanisms and the treatment of the GIST. Their diagnosis remains based on the morphology and immunohistochemistry. The evaluation of GIST prognosis was till know difficult to establish but a new histopronostic classification currently used allows a better therapeutic approach. The search for KIT and PDGFRA mutations is recommended to adapt a targeted therapy by KIT inhibitors. The pathologist plays a crucial role in the management of the GIST because it is on him that is based the diagnosis, the evaluation of the prognosis and the treatment (surgery and kit inhibitors).
Assuntos
Tumores do Estroma Gastrointestinal/patologia , Tumores do Estroma Gastrointestinal/terapia , Tumores do Estroma Gastrointestinal/genética , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genéticaRESUMO
Recurrent fever is frequent among children and mostly associated with viral infections inoculated via social contacts with others of the same age. Rarely, severe conditions such as hematological malignancies, pediatric rheumatoid diseases, chronic infections, or inherited recurrent fever syndromes are causative. Herein, we present the case of an 11-year-old boy with frequently recurring high-fever episodes since early childhood, failure to thrive, and iron deficiency who was found to have classical celiac disease (CD) with highly elevated tissue transglutaminase and anti-gliadin antibodies and marked duodenal villous atrophy. Upon implementation of a gluten-free diet, the boy ceased to have fevers, antibodies decreased markedly, his iron status improved, and he significantly gained weight. Although infrequent, recurrent fever should be included into the polymorphic clinical picture of CD, and the threshold of testing for diagnostic antibodies should be low in such patients.
RESUMO
The maintenance of homeostasis in the gut is a major challenge for the immune system. Here we demonstrate that the transcription factor MAF plays a central role in T cells for the prevention of gastro-intestinal inflammation. Conditional knock out mice lacking Maf in all T cells developed spontaneous late-onset colitis, correlating with a decrease of FOXP3+RORγt+ T cells proportion, dampened IL-10 production in the colon and an increase of inflammatory TH17 cells. Strikingly, FOXP3+ specific conditional knock out mice for MAF did not develop colitis and demonstrated normal levels of IL-10 in their colon, despite the incapacity of regulatory T cells lacking MAF to suppress colon inflammation in Rag1-/- mice transferred with naïve CD4+ T cells. We showed that one of the cellular sources of IL-10 in the colon of these mice are TH17 cells. Thus, MAF is critically involved in the maintenance of the gut homeostasis by regulating the balance between Treg and TH17 cells either at the level of their differentiation or through the modulation of their functions.
Assuntos
Colite/genética , Proteínas Proto-Oncogênicas c-maf/genética , Linfócitos T Reguladores/patologia , Células Th17/patologia , Animais , Células Cultivadas , Colite/imunologia , Colite/patologia , Feminino , Fatores de Transcrição Forkhead/análise , Fatores de Transcrição Forkhead/imunologia , Deleção de Genes , Interleucina-10/análise , Interleucina-10/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/análise , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Proteínas Proto-Oncogênicas c-maf/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologiaRESUMO
Despite the high prevalence of colon cancer in the world and the great interest in targeted anti-cancer therapy, only few tumor-specific gene products have been identified that could serve as targets for the immunological treatment of colorectal cancers. The aim of our study was therefore to identify frequently expressed colon cancer-specific antigens. We performed a large-scale analysis of genes expressed in normal colon and colon cancer tissues isolated from colorectal cancer patients using massively parallel signal sequencing (MPSS). Candidates were additionally subjected to experimental evaluation by semi-quantitative RT-PCR on a cohort of colorectal cancer patients. From a pool of more than 6000 genes identified unambiguously in the analysis, we found 2124 genes that were selectively expressed in colon cancer tissue and 147 genes that were differentially expressed to a significant degree between normal and cancer cells. Differential expression of many genes was confirmed by RT-PCR on a cohort of patients. Despite the fact that deregulated genes were involved in many different cellular pathways, we found that genes expressed in the extracellular space were significantly over-represented in colorectal cancer. Strikingly, we identified a transcript from a chromosome X-linked member of the human endogenous retrovirus (HERV) H family that was frequently and selectively expressed in colon cancer but not in normal tissues. Our data suggest that this sequence should be considered as a target of immunological interventions against colorectal cancer.
Assuntos
Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Regulação para Baixo , Retrovirus Endógenos/genética , HumanosRESUMO
Radiotherapy is one of the principal modalities of rectal cancer treatment, and the ability to predict radio resistance could potentially improve survival through a targeted treatment approach. Cyclooxygenase-2 (COX-2) may protect against damage by irradiation that would justify the use of COX-2 inhibitors. The purpose of this study was to investigate the potential role of COX-2 in tumor response and outcome of patients with rectal cancer treated preoperatively with radiotherapy. Using immunohistochemistry, we examined COX-2 expression in 88 surgical specimens of rectal cancer treated preoperatively and in 26 pretherapeutic biopsies. We tested whether COX-2 expression was correlated with clinico-pathologic parameters and with survival and local recurrence. COX-2 was expressed in 50% of the pretherapeutic tumor biopsies and in 88.6% of post-irradiated surgical samples. COX-2 expression was correlated only with enhanced tumor inflammation (p = 0.03) and with tumor volume exceeding 30 cc (p = 0.05). COX-2 was not significantly correlated with patient survival, but none of the patients with COX-2 negative tumors did recur locally, whereas 80% of patients with local recurrences have COX-2 positive tumors. We conclude that COX-2 expression is overexpressed in the majority of rectal cancers treated with radiotherapy and likely plays a role in local relapse.
Assuntos
Adenocarcinoma/enzimologia , Adenocarcinoma/radioterapia , Ciclo-Oxigenase 2/metabolismo , Cuidados Pré-Operatórios , Neoplasias Retais/enzimologia , Neoplasias Retais/radioterapia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/prevenção & controle , Prognóstico , Neoplasias Retais/patologia , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: In contrast to wild type, interleukin-10-deficient (IL-10(-/-)) mice are able to clear Helicobacter infection. In this study, we investigated the immune response of IL-10(-/-) mice leading to the reduction of Helicobacter infection. MATERIALS AND METHODS: We characterized the immune responses of Helicobacter felis-infected IL-10(-/-) mice by studying the systemic antibody and cellular responses toward Helicobacter. We investigated the role of CD4(+) T cells in the Helicobacter clearance by injecting H. felis-infected IL-10(-/-) mice with anti-CD4 depleting antibodies. To examine the role of mast cells in Helicobacter clearance, we constructed and infected mast cells and IL-10 double-deficient mice. RESULTS: Reduction of Helicobacter infection in IL-10(-/-) mice is associated with strong humoral (fivefold higher serum antiurease antibody titers were measured in IL-10(-/-) in comparison to wild-type mice, p < .008) and cellular (urease-stimulated splenic CD4(+) T cells isolated from infected IL-10(-/-) mice produce 150-fold more interferon-gamma in comparison to wild-type counterparts, p < .008) immune responses directed toward Helicobacter. Depletion of CD4(+) cells from Helicobacter-infected IL-10(-/-) mice lead to the loss of bacterial clearance (rapid urease tests are threefold higher in CD4(+) depleted IL-10(-/-) in comparison to nondepleted IL-10(-/-) mice, p < .02). Mast cell IL-10(-/-) double-deficient mice clear H. felis infection, indicating that mast cells are unnecessary for the bacterial eradication in IL-10(-/-) mice. CONCLUSION: Taken together, these results suggest that CD4(+) cells are required for Helicobacter clearance in IL-10(-/-) mice. This reduction of Helicobacter infection is, however, not dependent on the mast cell population.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Helicobacter/imunologia , Interleucina-10/deficiência , Mastócitos/imunologia , Animais , Feminino , Citometria de Fluxo , Infecções por Helicobacter/genética , Interleucina-10/genética , Cinética , Masculino , Camundongos , Camundongos MutantesRESUMO
AIMS: Serrated polyps of the colorectum are a heterogenous group of mucosal lesions including hyperplastic polyps (HP) and sessile serrated adenomas (SSA), but their morphologic distinction is not always straightforward. However, it is important for the pathologist to identify SSA because recent data show that they might be the precursors of serrated adenocarcinomas which are probably involved in the serrated pathway. MATERIAL AND METHODS: We selected 102 serrated colorectal polyps resected by colonoscopy and evaluated the following parameters: location, size, number of biopsies per polyp, superficial or tangential biopsies, type of resection, location of the serrated feature, branching, horizontalisation, dilatation and herniation of crypts through the muscularis mucosae, cellular type, epithelial tufts, cytoplasmic eosinophilia and dysplasia. RESULTS: There were 81 HP (79%), seven SSA (7%) of which one showed foci of dysplasia, five traditional serrated adenomas (5%) and three mixed polyps (HP and tubulous adenoma: 3%). Only six serrated polyps could not be classified. The main architectural criterion for diagnosing SSA was a serrated pattern throughout the crypt axis and the rarity of undifferentiated cells at the base of the crypts. Moreover, clinical characteristics were also helpful, since sessile serrated adenomas were significantly more often located in the right colon and larger (median: 11mm versus 4mm) than HP. CONCLUSION: SSA can be distinguished morphologically from HP in a daily practice. The presence of foci of dysplasia in one case of SSA supports the hypothesis that these polyps have a carcinogenetic potential and should have the same clinical follow-up as traditional adenomas.
Assuntos
Adenoma/patologia , Pólipos do Colo/patologia , Hiperplasia/patologia , Pólipos/patologia , Doenças Retais/patologia , Adenoma/cirurgia , Biópsia , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Pólipos do Colo/classificação , Pólipos do Colo/cirurgia , Diagnóstico Diferencial , Humanos , Hiperplasia/cirurgia , Pólipos/classificação , Pólipos/cirurgia , Doenças Retais/classificação , Doenças Retais/cirurgia , Neoplasias Retais/patologia , Neoplasias Retais/cirurgiaRESUMO
UNLABELLED: In sentinel node (SN) biopsy, an interval SN is defined as a lymph node or group of lymph nodes located between the primary melanoma and an anatomically well-defined lymph node group directly draining the skin. As shown in previous reports, these interval SNs seem to be at the same metastatic risk as are SNs in the usual, classic areas. This study aimed to review the incidence, lymphatic anatomy, and metastatic risk of interval SNs. METHODS: SN biopsy was performed at a tertiary center by a single surgical team on a cohort of 402 consecutive patients with primary melanoma. The triple technique of localization was used-that is, lymphoscintigraphy, blue dye, and gamma-probe. Otolaryngologic melanoma and mucosal melanoma were excluded from this analysis. SNs were examined by serial sectioning and immunohistochemistry. All patients with metastatic SNs were recommended to undergo a radical selective lymph node dissection. RESULTS: The primary locations of the melanomas included the trunk (188), an upper limb (67), or a lower limb (147). Overall, 97 (24.1%) of the 402 SNs were metastatic. Interval SNs were observed in 18 patients, in all but 2 of whom classic SNs were also found. The location of the primary was truncal in 11 (61%) of the 18, upper limb in 5, and lower limb in 2. One patient with a dorsal melanoma had drainage exclusively in a cervicoscapular area that was shown on removal to contain not lymph node tissue but only a blue lymph channel without tumor cells. Apart from the interval SN, 13 patients had 1 classic SN area and 3 patients 2 classic SN areas. Of the 18 patients, 2 had at least 1 metastatic interval SN and 2 had a classic SN that was metastatic; overall, 4 (22.2%) of 18 patients were node-positive. CONCLUSION: We found that 2 of 18 interval SNs were metastatic: This study showed that preoperative lymphoscintigraphy must review all known lymphatic areas in order to exclude an interval SN.
Assuntos
Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Melanoma/diagnóstico , Melanoma/secundário , Biópsia de Linfonodo Sentinela/métodos , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia , Adulto , Idoso , Feminino , Humanos , Recém-Nascido , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Cintilografia , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
The distinction between serrated polyps of the colon is complex, particularly between hyperplastic polyps (HP) and sessile serrated adenomas (SSA). Recent data show that SSA might be the precursors of serrated colonic cancers, underlining the necessity of identifying them. We characterized the demographic and pathologic characteristics of 102 serrated lesions among 321 polyps of the colorectum and determined if SSA can be microscopically distinguished from HP in biopsy material of a daily practice. There were 81 HP (79%) and 7 SSA (7%) of which one displayed low-grade dysplasia. Only six serrated polyps (6%) could not be correctly classified. The main architectural criteria for distinguishing SSA from HP is the serrated feature along the crypt axis and the rarity of undifferentiated cells in the lower third of the crypts. SSA was significantly more often located in the right colon and larger (median, 11 vs 4 mm) than HP. SSA are rare serrated polyps that can be distinguished from HP based on their morphology, location in the right colon, and larger size. One SSA of our series showed low-grade dysplasia supporting the concept that this lesion might be a precursor of serrated adenocarcinoma.
Assuntos
Adenoma/patologia , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Pólipos Intestinais/patologia , Doenças Retais/patologia , Diagnóstico Diferencial , Feminino , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Distant metastases represent the major cause of death after curative surgery of colorectal cancer. The aim of this study was to evaluate the role of Smad4 and KRAS genetic alterations in colorectal metastases taking into account both the site (hepatic versus extrahepatic) and the time (synchronous versus metachronous) of recurrence. We examined the immunohistochemical expression of Smad4 and frequency of KRAS mutation in primary colorectal tumors and in their corresponding metastatic tissues. Loss of Smad4 expression was noted in 37% (26/71) of the primary tumors and the corresponding metastases. Absence of Smad4 protein was more frequently observed in hepatic metastases, whether they were metachronous or synchronous, than in extrahepatic metastases (p<0.005). The frequency of KRAS mutations was high in the synchronous and extrahepatic metachronous metastases (68-80%), but was significantly lower in the hepatic metachronous metastases (11%). Our results indicate that absence of Smad4 expression correlated significantly with liver metastases regardless of the time of their occurrence and represents a promising new biomarker to predict liver metastasis in colorectal cancer patients. Therefore, this group of patients could benefit from a specific and appropriate pre- and/or post-operative therapy.
Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundário , Proteína Smad4/deficiência , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Feminino , Genes ras , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Polimorfismo Conformacional de Fita Simples , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteína Smad4/biossíntese , Proteína Smad4/genética , Proteínas ras/genéticaRESUMO
Serrated polyps of the colon represent a large morphological spectrum of lesions. They comprise the hyperplastic polyp considered as an innocuous lesion for many years, the traditional serrated adenoma presenting a potential of cancerisation and the recently described the sessile serrated adenoma which seems to be a potential precursor of colonic cancer with microsatellite instability and which probably uses an alternate polyp-neoplasia pathway in addition to the classical adenoma-carcinoma sequence. The aims of this article intend to inform of new concept of colonic carcinogenesis, to be aware of a serrated colonic polyp entity recently described and to use a same nomenclature to facilitate the dialogue between pathologists and clinicians.