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Doença de Crohn , Doenças Inflamatórias Intestinais , Doenças de Niemann-Pick , Animais , Antibacterianos , Autofagia , Criança , Doenças Genéticas Ligadas ao Cromossomo X , Gorilla gorilla , Humanos , Inflamação , Doenças Inflamatórias Intestinais/genética , Transtornos Linfoproliferativos , Mutação , Proteína Adaptadora de Sinalização NOD2/genética , Pirina/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo XRESUMO
Purpose: Quantitative measurement of minimal residual disease predicting recurrence in individual cancer patients is available only in very few indications, such as acute lymphoblastic leukemia, but is still missing in most solid tumors, including non-small cell lung cancer (NSCLC).Experimental Design: MAGE-A expression levels in blood and bone marrow determined as calibrator-normalized relative ratios by quantitative multimarker real-time RT-PCR for transcript amplification of MAGE-A1, -A2, -A3/6, -A4, -A10, and -A12 in 94 patients with completely resected NSCLC were correlated with survival in a clinical study.Results: Patients with MAGE-A expression levels ≥0.2 in at least one sample of bone marrow or blood at tumor surgery had a significantly reduced overall (P = 0.007), cancer-free (P = 0.002), and distant metastasis-free survival (P < 0.001) versus patients below 0.2 in all samples without significant difference in locoregional recurrence-free survival. The corresponding HRs (≥0.2 vs. <0.2) for death, cancer-related death, and development of distant metastasis were 2.56 [95% confidence interval (CI), 1.42-4.63], 3.32 (95% CI, 1.66-6.61), and 4.03 (95% CI, 1.77-9.18), respectively. Five-year Kaplan-Meier estimates of distant metastasis-free survival were 43% (MAGE-A ≥ 0.2) versus 87% (MAGE-A < 0.2).Conclusions: MAGE-A expression in blood or bone marrow at tumor surgery is an independent predictor of survival in resected NSCLC. The reliable prediction of distant metastasis in individual patients with a statistically proven impact on overall survival may help to refine patient selection for adjuvant therapy urgently needed, especially in the clinical management of elderly patients. Clin Cancer Res; 23(5); 1213-9. ©2016 AACR.
Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Antígenos Específicos de Melanoma/sangue , Recidiva Local de Neoplasia/sangue , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologiaRESUMO
BACKGROUND AND AIMS: Anemia is a frequent complication of inflammatory bowel disease (IBD). Hepcidin, a key mediator in this anemia, is up-regulated by high iron levels and inflammation, and serum levels are elevated in IBD. However, the extent of inflammatory activity and iron deficiency for the regulation of hepcidin is not known. This study aimed to evaluate serum hepcidin levels in anemic and non-anemic IBD patients, with iron or non-iron deficiency, and active or inactive disease. METHODS: This retrospective, observational study analyzed serum hepcidin levels from 247 patients with IBD (130 Crohn's patients and 117 with ulcerative colitis) recruited at Swiss Inflammatory Bowel Disease Cohort Study centers. Patients were divided into 5 different groups using criteria of active and inactive diseases (C-reactive protein, and CDAI/MTWAI=disease activity-index), anemia (hemoglobin) and iron deficiency (ferritin) and compared to healthy controls with no signs of anemia and normal ferritin levels. Hepcidin was measured using enzyme-linked immunosorbent assay. RESULTS: Independent of inflammatory activity, all patients with decreased ferritin (<30µg/L) had significantly lower hepcidin levels when compared to patients and healthy controls having normal ferritin (>30µg/L). A significant correlation between serum ferritin levels and serum hepcidin was found (Spearman's Rho=0.491; p<0.001). A backward multi-linear stepwise regression analysis showed that only ferritin, and none of the inflammatory markers or age and sex correlated significantly (p=0.005) with hepcidin. CONCLUSION: This retrospective analysis suggests that iron deficiency is the key trigger for hepcidin regulation in IBD patients with anemia.
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Anemia Ferropriva/sangue , Colite Ulcerativa/sangue , Doença de Crohn/sangue , Hepcidinas/sangue , Adolescente , Adulto , Idoso , Anemia Ferropriva/etiologia , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Colite Ulcerativa/complicações , Doença de Crohn/complicações , Feminino , Ferritinas/sangue , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto JovemRESUMO
Inflammatory Bowel Disease (i. e. Crohn's Disease and Ulcerative Colitis) show a rising incidence throughout Switzerland. An early and individualized therapy usually enables the effective treatment of both diseases and prevents structural gastrointestinal damage or surgical interventions. The goal of medical therapy is not only the relief of symptoms but rather the control of the disease's activity leading to mucosal healing and "deep" remission. Patients with unfavorable predictive parameters should receive a prompt intensification of medical therapy (as "early step-up" or even "top-down") with established immunosuppressive agents. Several updated practice guidelines respond to the most important medical questions, however, distinct clinical experience as well as a special dedication to these challenging patients are still a prerequisite for the effective and sustained therapy of inflammatory bowel disease.
Les maladies inflammatoires du tube digestif (la maladie de Crohn et la colite ulcéreuse) ont une incidence en augmentation partout en Suisse. Un traitement précoce et individualisé permet habituellement de prévenir de manière efficace les atteintes structurales de la paroi gastro-intestinale ainsi que le besoin au recours de la chirurgie, ceci pour les deux maladies. Le but du traitement médical n'est pas seulement de diminuer les symptômes, mais plus encore de contrôler l'activité de la maladie pour guérir la muqueuse et obtenir une rémission en profondeur. Les patients ayant des paramètres prédictifs défavorables devraient avoir leur traitement médical rapidement intensifié avec des agents immunosuppresseurs bien établis. Quelques recommandations pratiques récentes répondent aux questions médicales les plus importantes. Néanmoins il y a encore besoin d'une expérience clinique plus étendue pour traiter de manière efficace et prolongée les affections inflammatoires du tube digestif.
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Anti-Inflamatórios/uso terapêutico , Doença de Crohn/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Algoritmos , Anti-Inflamatórios/efeitos adversos , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Esquema de Medicação , Drogas em Investigação/efeitos adversos , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Guias de Prática Clínica como Assunto , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Esophagectomy with gastric pull-up is a standard procedure for patients with esophageal cancer. Despite growing surgical experience, anastomotic leakage can still occur and cause significant morbidity. We report a case of anastomotic leakage with concomitant spondylodiscitis and describe the endoscopical appearance and closure of an unusual posterior fistula to the spine.
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Discite/etiologia , Fístula Esofágica/etiologia , Esofagectomia/efeitos adversos , Fístula/etiologia , Meningite/etiologia , Doenças da Coluna Vertebral/etiologia , Carcinoma de Células Escamosas/cirurgia , Discite/tratamento farmacológico , Endoscopia do Sistema Digestório , Fístula Esofágica/complicações , Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Fístula/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Coluna Vertebral/complicaçõesRESUMO
PURPOSE: MAGE-A gene expression in humans is mostly restricted to tumor cells, and the role of MAGE-A transcripts and peptides as diagnostic markers and therapeutic targets is currently under investigation. Thus far, the clinical relevance of MAGE-A transcripts as marker for disseminated tumor cells in bone marrow of patients with operable lung cancer without overt metastases is still unclear. EXPERIMENTAL DESIGN: Preoperative bone marrow aspirates from 50 consecutive patients with operable non-small-cell lung cancer free of distant metastases (i.e., pT(1-4) pN(0-2) M(0) R(0)) were admitted to the study. Each bone marrow sample was divided and examined using multimarker MAGE-A reverse transcription-PCR (RT-PCR) and immunocytochemical staining with the anti-pancytokeratin antibody A45-B/B3. Multimarker MAGE-A RT-PCR consisted of multiple subtype-specific nested RT-PCRs with primers for MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, and MAGE-A12. The median follow-up duration was 92 months (range, 18-110 months). RESULTS: Twenty-six (52%) lung cancer patients harbored MAGE-A transcripts in their bone marrow, as opposed to none of the 30 healthy controls tested. In all 7 patients with immunocytochemically positive bone marrow, MAGE-A transcripts were also detected. All different MAGE-A subtypes (MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, and MAGE-A12) were observed. Sixty-five percent of patients with MAGE-A transcripts in bone marrow exhibited only one subtype. Univariate (P = 0.03, log-rank-test) and multivariate survival analysis showed that MAGE-A transcripts in bone marrow were associated with poor outcome in pN(0) patients (P = 0.02; relative risk, 7.6). CONCLUSIONS: Detection of MAGE-A transcripts in bone marrow predicts an unfavorable outcome in patients with early-stage operable lung cancer. This finding indicates that MAGE-A transcripts are clinically relevant markers of micrometastatic spread in lung cancer and supports further investigation of MAGE-A as potential future therapeutic target.
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Células da Medula Óssea/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias , Feminino , Humanos , Masculino , Antígenos Específicos de Melanoma , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
INTRODUCTION: Distant metastases of solid tumors are usually associated with fatal outcome. Disseminated cancer cells are considered early indicators of metastasis. Their sensitive detection and quantification would be a valuable tool for staging of disease and as guidance for therapeutic decisions. EXPERIMENTAL DESIGN: We established a highly sensitive and quantitative multimarker real-time RT-PCR assay for amplification of cancer-related genes MAGE-A1, -A2, -A3/6, -A4, -A10 and -A12 using SYBR green I to detect one single tumor cell in 2 mL of blood or bone marrow. The feasibility of the assay was tested in a large cohort of 177 patients with locally confined prostate carcinoma. RESULTS: Analysis revealed frequent MAGE expression in venous blood and bilateral bone marrow samples (25.5% of all cases) and yielded the first quantitative profile of MAGE expression with a broad range of transcript concentrations for individual markers in the minimal systemic tumor load of patients with localized cancer. CONCLUSIONS: Rare transcripts of different MAGE-A genes can be quantified in clinical samples of cancer patients by a sensitive multimarker real-time RT-PCR. Because of frequent expression of MAGE genes in various types of cancer the multimarker MAGE real-time RT-PCR may be generally useful for detection, quantification and characterization of the individual disseminated tumor load in cancer patients.
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Biomarcadores Tumorais/genética , Proteínas de Neoplasias/genética , Neoplasias da Próstata/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Carga Tumoral , Idoso , Antígenos de Neoplasias/genética , Expressão Gênica , Humanos , Masculino , Antígenos Específicos de Melanoma , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/análise , RNA Neoplásico/análise , Sensibilidade e Especificidade , Transcrição GênicaAssuntos
Transtornos de Deglutição/etiologia , Divertículo Esofágico/etiologia , Eosinofilia/complicações , Esofagite/complicações , Adulto , Divertículo Esofágico/diagnóstico , Endoscopia Gastrointestinal , Eosinofilia/diagnóstico , Estenose Esofágica/diagnóstico , Estenose Esofágica/etiologia , Esofagite/diagnóstico , Humanos , Masculino , Ruptura Espontânea/diagnóstico , Ruptura Espontânea/etiologiaRESUMO
Systemically disseminated tumor cells have become the subject of intensive research as the presumed seminal precursors of later distant metastasis. We describe here a novel sensitive multimarker nested reverse transcription (RT)-PCR capable of detecting the individual expression of human MAGE-A genes MAGE-1, -2, -3/6, -4, and -12 by rare, disseminated tumor cells in bone marrow and blood of patients with many different types of cancer. We analyzed bone marrow aspirates from 106 patients with breast, lung, colorectal, and prostate cancer and with different sarcomas. Heterogeneous expression of the different MAGE genes was found frequently in all those kinds of malignancies, in sharp contrast to 30 bone marrow and 20 blood samples from healthy donors, which were completely MAGE negative. Expression of at least one MAGE gene in bone marrow was more frequent than cytokeratin-positive tumor cells detected by immunocytochemistry, although the results of both tests overlapped considerably. In 30 patients with clinically localized prostate cancer, analysis by the multimarker MAGE RT-PCR of bilateral bone marrow aspirates from the right and left iliac crest revealed a positivity rate of 60%, which was twice as high as that obtained with either an established prostate-specific antigen RT-PCR or by cytokeratin-based immunocytochemistry. Analysis of primary prostate cancer revealed MAGE expression patterns considerably concordant with those found in the corresponding bone marrow aspirates. Prostate cancer patients carrying an exceptionally high risk of metastatic relapse, as defined by clinical prognostic factors, were significantly more often MAGE positive than patients with a distinctly lower risk (P = 0.02, Fisher's exact test). More frequent MAGE expression in the peripheral blood of patients with metastatic prostate cancer compared with those with clinically localized disease added further evidence for the prognostic impact of the multimarker MAGE RT-PCR. Moreover, MAGE-positive bone marrow samples from a small group of seven sarcoma patients demonstrated the relevance of our multimarker RT-PCR in nonepithelial tumors. Because MAGE antigens can induce autologous cytolytic T lymphocytes in vivo, the determination of individual MAGE expression patterns in cancer patients may furthermore identify candidate vaccine targets for adjuvant immunotherapy.