RESUMO
BACKGROUND: Frequently, subjects offered colonoscopy due to symptoms of colorectal neoplasia are diagnosed with diverticula. The symptoms may, however, also be related to extra-colonic neoplasia. The present retrospective study evaluated a possible association between increased levels of predefined biomarkers in subjects diagnosed with diverticula and risk of developing a primary malignant disease. METHODS: During 2004/2005, about 4509 subjects were included in a multicenter study with collection of blood samples before bowel endoscopy. The aim was to evaluate a relation between the protein biomarkers CEA, TIMP-1, CA19-9 and YKL-40 and findings at endoscopy. Diverticula were diagnosed in 1021 subjects. By 31 December 2012, subjects who had developed primary malignancy were identified retrospectively and relation between biomarker levels at endoscopy and risk of developing primary malignancy was calculated. The relation with the four biomarkers was divided into three groups: 0 = none increased; 1 = one increased and 2 = two or more increased. RESULTS: In the observation period, 148 subjects developed a primary malignant disease. Univariable analyzes of the biomarker levels showed that CEA, TIMP-1 and CA19-9 were significantly associated with development of primary malignancy. A multivariable analysis showed that increased levels were associated with development of malignancy (p < 0.0001). The 1- and 5-year cumulative risks of being diagnosed with a primary malignancy were: group 0: 1.1%/5.5%; group 1: 4.2%/10.1% and group 2: 11.4%/18.8%, respectively. CONCLUSION: Increased levels of CEA, TIMP-1 and CA19-9 at endoscopy with findings of diverticula were associated with a significantly increased risk of being diagnosed with a subsequent primary malignant disease.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Colorretais/diagnóstico , Divertículo do Colo/diagnóstico , Neoplasias Intestinais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Glicosídicos Associados a Tumores/sangue , Proteína 1 Semelhante à Quitinase-3/sangue , Neoplasias Colorretais/sangue , Endoscopia Gastrointestinal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos , Inibidor Tecidual de Metaloproteinase-1/sangueRESUMO
OBJECTIVE: The combination of plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) and carcinoembryonic antigen (CEA) may be valuable biomarkers for early detection of colorectal cancer (CRC). A prospective, population based study was performed to validate this hypothesis. MATERIAL AND METHODS: Individuals (n = 4509) referred for large bowel endoscopy due to symptoms of CRC were prospectively included. Baseline data and concurrent diseases were recorded. The primary endpoint was detection of CRC and findings at examinations were recorded using International Classification of Diseases-10 codes. Plasma was obtained before endoscopy and TIMP-1 and CEA levels were determined after the inclusion of all individuals. RESULTS: Findings were based on sigmoidoscopy in 1766 and colonoscopy in 2743 individuals. Colon cancer (CC) was detected in 184 and rectal cancer in 110 individuals. Ten individuals with other cancers, 856 with adenomas and 1176 with non-neoplastic findings were also detected. The biomarker levels were increased in a variety of diseases including CRC compared to individuals without any findings at endoscopy. A multivariable analysis demonstrated that both markers were significant and independent detectors of CRC. Combining both biomarkers, independent contributions from each (TIMP-1, odds ratio (OR) = 1.8 (95% confidence interval (CI): 1.4-2.2), p < 0.0001; CEA < 5 ng/ml, OR = 1.6, 1.3-1.9, or ≥ 5 ng/ml, OR = 2.3, 95% CI: 1.9-2.7 (p < 0.0001)) were obtained. Subgroup analysis of individuals examined by colonoscopy with CC as the endpoint showed that combining both biomarkers, independent contributions from each (TIMP-1, OR = 2.5, 95% CI: 1.8-3.4, p < 0.0001; CEA < 5 ng/ml, OR = 1.4, 95% CI: 1.1-1.8, and CEA ≥ 5 ng/ml, OR = 2.3, 95% CI: 1.8-3.0 (p < 0.0001)) were obtained. CONCLUSIONS: This prospective validation study supports the use of the combination of plasma TIMP-1 and CEA protein measurements as a potential aid in early detection of CRC and specifically of CC.
Assuntos
Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Inibidor Tecidual de Metaloproteinase-1/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: Golgi protein-73 (GP73) and fucosylated proteins have been proposed as potential serum markers for liver disease and/or hepatocellular carcinoma (HCC). The purpose of this study was to compare the sensitivity and specificity of serum GP73 and fucosylated hemopexin (Fuc-HPX) with α-fetoprotein (AFP) and with protein induced by the absence of vitamin K or antagonist-II (PIVKA-II) for diagnosing chronic hepatitis, cirrhosis, and HCC. METHODS: The concentration of GP73 in human sera was determined using an enzyme-linked immunosorbent assay employing mouse monoclonal and rabbit polyclonal GP73 antibodies. Fuc-HPX was detected using a lectin chemiluminescence-linked immunosorbent assay using a mouse monoclonal anti-hemopexin antibody and Aleuria aurantia lectin. A total of 229 serum samples from patients with chronic hepatitis, cirrhosis, and HCC, as well as from normal individuals were evaluated using these four markers. RESULTS: GP73 and Fuc-HPX showed significantly higher values in samples from patients with cirrhosis and HCC than in samples from patients with hepatitis and from normal individuals. The areas under the curves (AUCs) for GP73, Fuc-HPX, AFP, and PIVKA-II were 0.90, 0.77, 0.74, and 0.88, respectively, for liver cirrhosis and HCC samples vs. hepatitis and normal samples. The AUCs of GP73, Fuc-HPX, AFP, and PIVKA-II were 0.78, 0.72, 0.81, and 0.90, respectively, for HCC samples vs. all other samples. CONCLUSIONS: PIVKA-II showed superior sensitivity and specificity for HCC compared with the other three markers. GP73 may be useful for detecting cirrhosis as a risk factor for HCC. Fuc-HPX showed inferior sensitivity and specificity compared to the other markers.
Assuntos
Análise Química do Sangue/métodos , Carcinoma Hepatocelular/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Hepatite Crônica/sangue , Neoplasias Hepáticas/sangue , Proteínas de Membrana/sangue , Animais , Biomarcadores/sangue , Análise Química do Sangue/normas , Carcinoma Hepatocelular/diagnóstico , Ensaio de Imunoadsorção Enzimática/normas , Fibrose , Hemopexina/análise , Hemopexina/química , Hepatite Crônica/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico , Medições Luminescentes , Precursores de Proteínas/sangue , Protrombina , Curva ROC , Padrões de Referência , alfa-Fetoproteínas/análiseRESUMO
BACKGROUND: Pro-gastrin releasing peptide (ProGRP) concentrations in blood play an important role in the diagnosis and treatment of patients with small cell lung cancer (SCLC). The automated quantitative ARCHITECT ProGRP assay was developed to aid in the differential diagnosis and in the management of SCLC. The purpose of this study was to evaluate the analytical performance of this chemiluminescent microparticle immunoassay at multiple sites. METHODS: ARCHITECT ProGRP measures ProGRP using a two-step sandwich using monoclonal anti-ProGRP antibodies coated on paramagnetic microparticles and labeled with acridinium. Analytical performance of the assay was evaluated at four sites: Abbott Japan, Denka Seiken, the Johns Hopkins University, and the University of Munich. RESULTS: Total precision (%CV) for nine analyte concentrations was between 2.2 and 5.7. The analytical sensitivity of the assay was between 0.20 pg/mL and 0.88 pg/mL. The functional sensitivity at 20% CV was between 0.66 pg/mL and 1.73 pg/mL. The assay was linear up to 50,000 pg/mL using a 1:10 autodilution protocol. The calibration curve was stable for 30 days. Comparison with the Fujirebio microtiter plate enzyme-linked immunosorbent assay (EIA) ProGRP assay gave a slope of 0.93 and a correlation coefficient (r) of 0.99. CONCLUSIONS: These results demonstrate that the ARCHITECT ProGRP assay has excellent sensitivity, precision, and correlation to a reference method. This assay provides a convenient automated method for ProGRP measurement in serum and plasma in hospitals and clinical laboratories.
Assuntos
Carcinoma de Células Pequenas/sangue , Imunoensaio/métodos , Neoplasias Pulmonares/sangue , Fragmentos de Peptídeos/sangue , Anticorpos Monoclonais/imunologia , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/terapia , Humanos , Imunoensaio/normas , Luminescência , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Fragmentos de Peptídeos/imunologia , Proteínas Recombinantes/sangue , Proteínas Recombinantes/imunologia , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: Linifanib, a potent and selective inhibitor of the tyrosine kinase activity of vascular endothelial growth factor and platelet-derived growth factor receptors, has clinical activity in advanced non-small cell lung cancer (NSCLC) both as monotherapy in the relapsed setting or with carboplatin and paclitaxel in the first-line setting. Though benefit was observed in unselected patient populations, identification of predictive biomarkers is critical for further development of this novel agent. MATERIALS AND METHODS: Data from 4 randomized studies in relapsed NSCLC with linifanib (n=116) or other treatments (n=125) were examined in an exploratory analysis to identify a biomarker profile predictive of favorable survival. RESULTS: A signature combining the established tumor markers carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) was predictive of a favorable outcome. This signature was associated with improved survival in patients receiving linifanib monotherapy (hazard ratio [HR]=0.51 vs signature negative; p=0.002), but not in those receiving other anti-cancer treatments (p=0.716). This signature was validated on baseline plasma samples from patients enrolled in a randomized trial of daily linifanib 7.5 mg, linifanib 12.5 mg, or placebo added to first-line carboplatin and paclitaxel chemotherapy for advanced, nonsquamous NSCLC. Only linifanib-treated signature-positive patients had significant improvement in progression-free survival (PFS). Median PFS with placebo was 5.2 months versus 10.2 months (HR=0.49, p=0.049) for those receiving linifanib 7.5mg, and 8.3 months (HR=0.38, p=0.029) for linifanib 12.5 mg. Overall survival for signature-positive patients was 11.3 months with placebo, 12.5 months with linifanib 7.5mg (HR=1.02, p=0.758), and 17.4 months with linifanib 12.5 mg (HR=0.54, p=0.137). CONCLUSION: This baseline plasma biomarker signature is associated with improved outcome in advanced NSCLC patients receiving linifanib. Utility of the biomarker signature in patient selection for linifanib therapy in NSCLC merits evaluation in larger, prospective trials that are powered to detect a survival benefit.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Antígenos de Neoplasias/metabolismo , Carboplatina/administração & dosagem , Antígeno Carcinoembrionário/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Feminino , Humanos , Indazóis/administração & dosagem , Queratina-19/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Compostos de Fenilureia/administração & dosagemRESUMO
BACKGROUND: A new ARCHITECT® alpha fetoprotein (AFP) assay was developed to improve the linearity at the upper end of the calibration curve and to enhance other performance characteristics. In addition, this reformulation eliminated the possibility of falsely depressed samples at high AFP concentrations. The purpose of this study was to evaluate its analytical performance at multiple sites. METHODS: The assay configuration, the diluent formulation, and the manufacturing process were redesigned. Analytical performance was evaluated at Abbott Laboratories, Sapporo Medical University, VU University Medical Center, and Johns Hopkins University. RESULTS: The limit of quantitation of the assay was 1.00-1.30 ng/mL. Total precision (%CV) across the assay range varied between 1.41 and 3.52. The assay was linear from 1.19 to 2535 ng/mL, and the range of the assay was expanded from 200 ng/mL to 2000 ng/mL. Comparison of this assay with the on-market ARCHITECT, AxSYM, ADVIA Centaur, DxI, AIA-1800, and E 170 systems yielded regression slopes of 0.91-1.08 and correlation coefficients of =0.99 for serum samples. No falsely depressed results were observed in 174 serum samples with AFP concentrations of 2018-1,196,856 ng/mL and in a spiked sample containing up to 10 mg/mL of purified AFP. CONCLUSIONS: The new AFP assay has improved an issue of the on-market ARCHITECT AFP assay and demonstrated excellent assay performance.
Assuntos
Imunoensaio/métodos , Medições Luminescentes/métodos , alfa-Fetoproteínas/análise , Biomarcadores Tumorais/sangue , Carcinoma Hepatocelular/diagnóstico , Feminino , Humanos , Técnicas Imunológicas , Neoplasias Hepáticas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Gravidez , Sensibilidade e Especificidade , Neoplasias Testiculares , alfa-Fetoproteínas/químicaRESUMO
PURPOSE: Bcl-2 is a critical regulator of apoptosis that is overexpressed in the majority of small cell lung cancers (SCLC). Nativoclax (ABT-263) is a potent and selective inhibitor of Bcl-2 and Bcl-x(L). The primary objectives of this phase IIa study included safety at the recommended phase II dose and preliminary, exploratory efficacy assessment in patients with recurrent and progressive SCLC after at least one prior therapy. EXPERIMENTAL DESIGN: Thirty-nine patients received navitoclax 325 mg daily, following an initial lead-in of 150 mg daily for 7 days. Study endpoints included safety and toxicity assessment, response rate, progression-free and overall survival (PFS and OS), as well as exploratory pharmacodynamic correlates. RESULTS: The most common toxicity associated with navitoclax was thrombocytopenia, which reached grade III-IV in 41% of patients. Partial response was observed in one (2.6%) patient and stable disease in 9 (23%) patients. Median PFS was 1.5 months and median OS was 3.2 months. A strong association between plasma pro-gastrin-releasing peptide (pro-GRP) level and tumor Bcl-2 copy number (R = 0.93) was confirmed. Exploratory analyses revealed baseline levels of cytokeratin 19 fragment antigen 21-1, neuron-specific enolase, pro-GRP, and circulating tumor cell number as correlates of clinical benefit. CONCLUSION: Bcl-2 targeting by navitoclax shows limited single-agent activity against advanced and recurrent SCLC. Correlative analyses suggest several putative biomarkers of clinical benefit. Preclinical models support that navitoclax may enhance sensitivity of SCLC and other solid tumors to standard cytotoxics. Future studies will focus on combination therapies.
Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Trombocitopenia/induzido quimicamenteRESUMO
Tissue inhibitor of metalloproteinases-1 (TIMP-1) plays a pivotal role in tissue remodeling processes, such as inflammation, wound healing and cancer invasion. Experimental results have pointed to a role in angiogenesis, cell proliferation, apoptosis and in malignant transformation. In clinical investigations high tumor tissue or plasma levels of TIMP-1 have been shown to have a strong and independent association with shorter survival time for breast and colorectal cancer patients, respectively. The purpose of this study has been to develop and characterize new anti-TIMP-1 monoclonal antibodies that may be useful in future development of TIMP-1 immunoassays.Peptide-based epitope mapping reveals linear epitopes. Surface plasmon resonance was used to determine antibody affinity and ability of antibodies to sandwich with each other. Antigen recognition was tested using ELISA and a chemiluminescence microtiter immunoassay format. Three antibodies recognized linear peptides. Estimated antibody affinities for TIMP-1 ranged from 6.6 x 10(8) to>10(10) 1/M. Antibodies demonstrated different abilities in 'capture' and 'detection' positions in the sandwich experiment. All antibody pairs bound TIMP-1:ProMMP-9 complexes. TIMP-1:MMP-9 complexes were marginally reactive with five antibody pairs. The results suggest that the antibodies are unique. They may be useful in designing assays that recognize various forms of TIMP-1. Future studies will clarify whether the use of different combinations of antibodies will increase the clinical value of TIMP-1 measurements in the treatment of cancer patients.