RESUMEN
BACKGROUND: To investigate the feasibility of cerebrospinal fluid (CSF) CYFRA 21-1 levels as a therapeutic monitoring biomarker in leptomeningeal carcinomatosis (LMC) patients undergoing ventriculo-lumbar perfusion (VLP) chemotherapy. METHODS: The levels of CYFRA 21-1 in 42 CSF samples from 15 LMC patients were analyzed using an electrochemiluminescence immunoassay. Samples were collected at individual time points during VLP chemotherapy. Therapeutic outcomes were measured as improvements in the Karnofsky Performance Status (KPS) score and decreasing intracranial pressure (ICP) as the main endpoint of VLP chemotherapy. Changes in CSF CYFRA 21-1 levels, protein levels, and cytology results were also investigated. We subsequently evaluated whether these changes were correlated with KPS score and ICP. RESULTS: The CSF CYFRA 21-1 levels at individual time points were associated with KPS score and ICP. The KPS scores (p= 0.007) and ICP (p= 0.018) of patients with high CSF CYFRA 21-1 levels were significantly different from those of patients with low CSF CYFRA 21-1 levels. By contrast, CSF protein levels and cytological responses were not significantly associated with KPS scores and ICP. CONCLUSIONS: CSF CYFRA 21-1 may have utility as a therapeutic monitoring biomarker to design personalized therapeutic strategies in LMC patients undergoing VLP chemotherapy.
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Antígenos de Neoplasias/líquido cefalorraquídeo , Queratina-19/líquido cefalorraquídeo , Carcinomatosis Meníngea/líquido cefalorraquídeo , Biomarcadores de Tumor/líquido cefalorraquídeo , Neoplasias de la Mama/líquido cefalorraquídeo , Neoplasias de la Mama/diagnóstico , Femenino , Humanos , Masculino , Carcinomatosis Meníngea/diagnóstico , Persona de Mediana Edad , Neoplasias Ováricas/líquido cefalorraquídeo , Neoplasias Ováricas/diagnóstico , Proyectos PilotoRESUMEN
Galectin-3 binding protein (LGALS3BP or 90 K) is a secreted glycoprotein found in human body fluids. Deregulated levels were observed in cancer and infection and its study in neurological diseases is more recent. Here, we have investigated 90 K from human cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS, n = 35) and other neurological diseases (n = 23). CSF was fractionated by ultrafiltration/size-exclusion chromatography (SEC) and eluted fractions were analysed by complementary techniques including immunoblotting, electron microscopy and nano-liquid chromatography-tandem mass spectrometry. A fraction of 90 K appeared as nanoparticles of irregular shape with heterogeneous dimensions of 15-60 nm that co-eluted with extracellular vesicles in SEC. Median levels of 90 K quantified by ELISA were not different between ALS patients (215.8 ng/ml) and controls (213.3 ng/ml) in contrast with the benchmark biomarker for ALS phosphoneurofilament heavy chain (1750 and 345 pg/ml, respectively). A multiregression model supported age is the only independent predictor of 90 K level in both groups (p < 0.05). Significant correlation was found between 90 K levels and age for the ALS group (r = 0.366, p = 0.031) and for all subjects (r = 0.392, p = 0.003). In conclusion, this study unveils the presence of 90 K-containing nanoparticles in human CSF and opens novel perspectives to further investigate 90 K as potential aging marker.
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Antígenos de Neoplasias/líquido cefalorraquídeo , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/líquido cefalorraquídeo , Biomarcadores de Tumor/metabolismo , Líquido Cefalorraquídeo/metabolismo , Glicoproteínas/líquido cefalorraquídeo , Glicoproteínas/metabolismo , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Enfermedades del Sistema Nervioso/metabolismo , Adulto , Anciano , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/metabolismo , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Cromatografía Liquida/métodos , Vesículas Extracelulares/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Proteínas de Neurofilamentos/metabolismo , Proteoma/metabolismoRESUMEN
Fibromyalgia (FM) is a syndrome characterized by widespread muscular pain, fatigue and functional symptoms, which is known to be difficult to diagnose as the various symptoms overlap with many other conditions. Currently, there are no biomarkers for FM, and the diagnosis is made subjectively by the clinicians. We have performed shotgun proteomics on cerebrospinal fluid (CSF) from FM patients and non-pain controls to find potential biomarker candidates for this syndrome. Based on our multivariate and univariate analyses, we found that the relative differences in the CSF proteome between FM patients and controls were moderate. Four proteins, important to discriminate FM patients from non-pain controls, were found: Apolipoprotein C-III, Galectin-3-binding protein, Malate dehydrogenase cytoplasmic and the neuropeptide precursor protein ProSAAS. These proteins are involved in lipoprotein lipase (LPL) activity, inflammatory signaling, energy metabolism and neuropeptide signaling. SIGNIFICANCE: Fibromyalgia is present in as much as 2% of the population, causing pain, stiffness, and tenderness of the muscles. Upon accurate diagnostic, nonpharmacological and pharmacological therapies can be used to alleviate pain and manage other symptoms. However, lack of objective, universal applicable diagnostic criteria as well as vague and diffused symptoms, have made diagnosis difficult. In this context, our findings can shed light on potential value of CSF proteome for objectively diagnosing FM.
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Fibromialgia/líquido cefalorraquídeo , Proteoma/análisis , Proteómica/métodos , Adulto , Anciano , Antígenos de Neoplasias/líquido cefalorraquídeo , Apolipoproteína C-III/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Biomarcadores de Tumor/líquido cefalorraquídeo , Estudios de Casos y Controles , Femenino , Fibromialgia/diagnóstico , Humanos , Malato Deshidrogenasa/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Neuropéptidos/análisis , Proteínas/análisisRESUMEN
Cerebrospinal fluid (CSF) cytology has low sensitivity for leptomeningeal metastasis (LM); thus, new markers are needed to improve the diagnostic accuracy of LM. We measured carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) in paired samples of CSF and serum from patients with LM and patients with nonmalignant neurological diseases (NMNDs) as controls. Receiver operating curve analysis was performed to assess their diagnostic accuracy for LM. In patients with NMNDs, CEA and CYFRA 21-1 levels in the CSF were significantly lower than the serum levels. In patients with LM, there was no significant difference between the CSF and serum CEA levels, whereas the CYFRA 21-1 levels were significantly higher in the CSF than the serum. CSF/serum quotients of CYFRA 21-1 were higher than those of CEA in patients with LM and patients with NMNDs. CSF CYFRA 21-1 and CSF/serum quotient of CYFRA 21-1 had high accuracy for differentiating LM from NMNDs that was similar to CSF CEA and CSF/serum quotient of CYFRA 21-1, whereas serum CYFRA 21-1 is of poor diagnostic value. Measurement of CSF CYFRA 21-1 should not be overlooked in patients with suspected LM, even if the serum CYFRA 21-1 level is within normal limits.
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Antígenos de Neoplasias/líquido cefalorraquídeo , Biomarcadores de Tumor/líquido cefalorraquídeo , Queratina-19/líquido cefalorraquídeo , Neoplasias Meníngeas/secundario , Adulto , Anciano , Femenino , Humanos , Masculino , Neoplasias Meníngeas/líquido cefalorraquídeo , Persona de Mediana EdadRESUMEN
The immune system exerts both tumor-destructive and tumor-protective functions. Mature dendritic cells (DCs), classically activated macrophages (M1), granulocytes, B lymphocytes, aß and ɣδ T lymphocytes, natural killer T (NKT) cells, and natural killer (NK) cells may be implicated in antitumor immunoprotection. Conversely, tolerogenic DCs, alternatively activated macrophages (M2), myeloid-derived suppressor cells (MDSCs), and regulatory T (Tregs) and B cells (Bregs) are capable of suppressing antitumor immune responses. Anti-cancer vaccination is a useful strategy to elicit antitumor immune responses, while overcoming immunosuppressive mechanisms. Whole tumor cells or lysates derived thereof hold more promise as cancer vaccines than individual tumor-associated antigens (TAAs), because vaccinal cells can elicit immune responses to multiple TAAs. Cancer cell-based vaccines can be autologous, allogeneic or xenogeneic. Clinical use of xenogeneic vaccines is advantageous in that they can be most effective in breaking the preexisting immune tolerance to TAAs. To potentiate immunotherapy, vaccinations can be combined with other modalities that target different immune pathways. These modalities include 1) genetic or chemical modification of cell-based vaccines; 2) cross-priming TAAs to T cells by engaging dendritic cells; 3) T-cell adoptive therapy; 4) stimulation of cytotoxic inflammation by non-specific immunomodulators, toll-like receptor (TLR) agonists, cytokines, chemokines or hormones; 5) reduction of immunosuppression and/or stimulation of antitumor effector cells using antibodies, small molecules; and 6) various cytoreductive modalities. The authors envisage that combined immunotherapeutic strategies will allow for substantial improvements in clinical outcomes in the near future.
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Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Inmunoterapia/métodos , Antígenos de Neoplasias/líquido cefalorraquídeo , Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas/inmunología , HumanosRESUMEN
Some patients with epithelial-cell cancers develop leptomeningeal carcinomatosis (LC), a severe complication difficult to diagnose and with an adverse prognosis. This study explores the contribution of flow cytometry immunophenotyping (FCI) to the diagnosis and prognosis of LC. Cerebrospinal fluid (CSF) samples from patients diagnosed with LC were studied using FCI. Expression of the epithelial-cell adhesion molecule (EpCAM) was the criterion used to identify the epithelial cells. To test the diagnostic precision, 144 patients (94 diagnosed with LC) were included. The prognostic value of FCI was evaluated in 72 patients diagnosed with LC and eligible for therapy. Compared with cytology, FCI showed greater sensitivity and negative predictive value (79.79 vs. 50%; 68.85 vs. 51.55%, respectively), but lower specificity and positive predictive value (84 vs. 100%; 90.36 vs. 100%, respectively). The multivariate analysis revealed that the percentage of CSF EpCAM+ cells predicted an increased risk of death (HR: 1.012, 95% CI 1.000-1.023; p=0.041). A cut-off value of 8% EpCAM+ cells in the CSF distinguished two groups of patients with statistically significant differences in overall survival (OS) (p=0.018). This cut-off value kept its statistical significance regardless of the absolute CSF cell-count. The FCI study of the CSF improved the sensitivity for diagnosing LC, but refinement of the technique is needed to improve specificity. Furthermore, quantification of CSF EpCAM+ cells was revealed to be an independent prognostic factor for OS in patients with LC eligible for therapy. An 8% cut-off value contributed to predicting clinical evolution before initiation of therapy.
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Antígenos de Neoplasias/líquido cefalorraquídeo , Moléculas de Adhesión Celular/líquido cefalorraquídeo , Líquido Cefalorraquídeo/citología , Inmunofenotipificación/métodos , Carcinomatosis Meníngea/diagnóstico , Anciano , Antígenos de Neoplasias/biosíntesis , Moléculas de Adhesión Celular/biosíntesis , Recuento de Células , Molécula de Adhesión Celular Epitelial , Células Epiteliales , Femenino , Citometría de Flujo , Humanos , Masculino , Carcinomatosis Meníngea/mortalidad , Persona de Mediana Edad , PronósticoAsunto(s)
Antígenos de Neoplasias/líquido cefalorraquídeo , Autoanticuerpos/líquido cefalorraquídeo , Biomarcadores de Tumor/líquido cefalorraquídeo , Neoplasias Pulmonares/líquido cefalorraquídeo , Mesotelioma/líquido cefalorraquídeo , Proteínas del Tejido Nervioso/líquido cefalorraquídeo , Neoplasias Pleurales/líquido cefalorraquídeo , Radiculopatía/líquido cefalorraquídeo , Humanos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/diagnóstico , Masculino , Mesotelioma/complicaciones , Mesotelioma/diagnóstico , Mesotelioma Maligno , Persona de Mediana Edad , Neoplasias Pleurales/complicaciones , Neoplasias Pleurales/diagnóstico , Radiculopatía/complicaciones , Radiculopatía/diagnósticoRESUMEN
PURPOSES: We aimed to investigate the concentration of CYFRA 21-1, NSE and CEA in cerebro-spinal fluid (CSF) and to explore their clinical value in the meningeal carcinomatosis (MC) of lung cancer. So that, sensitive and specificity of CSF examination can be improved in the initial diagnosis of MC. METHOD: A total of 35 lung cancer patients and 35 patients with benign brain tumor in the same period enrolled in this study. The concentrations of tumor markers CEA, CYFRA 21-1 and NSE in CSF and peripheral blood were examined. RESULT: The concentrations of three tumor markers of CYFRA 21-1, NSE and CEA in blood serum and CSF were obviously higher than that of benign disease group. In MC patients, the concentrations of three tumor markers of CYFRA 21-1, NSE and CEA in blood serum were significant lower than that in CSF. The maximum of Youden's index was identified as the cutoff value of indicator of MC in three tumor markers in CSF which were CEA > 4.7 µg/L, NSE > 14.6 µg/L and CYFRA21-1 > 5.5 µg/L respectively. Based on the cutoff values, the CEA had the highest sensitivity while the CYFRA21-1 had the highest specificitiy. Three tumor markers in the CSF had higher positive rate than those in blood serum. We combined the levels of CEA, NSE and CYFRA21-1 in CSF to diagnosis of MC. Positive of CEA or CYFRA21-1 had the greatest sensitivity of 100% while the specificity of 91.4%; the positive of both CEA and CYFRA21-1 had the highest specificity of 100% while the sensitivity of 74.3%. Both positive predictive value and negative predictive value were 100% when combination positive were confirmed when the all three markers were positive. CONCLUSION: The combination of CEA and CYFRA21-1 can be recommended in early screening of meningeal carcinoma. Especially, for the patient who was difficult to be diagnosed by CSF histology and MRI, it will be a useful auxiliary marker in diagnosis of MC. The combination of CEA, NSE and CYFRA21-1 can be an effective clinically confirmation and exclusively diagnose indictor of MC.
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Antígenos de Neoplasias/líquido cefalorraquídeo , Biomarcadores de Tumor/líquido cefalorraquídeo , Antígeno Carcinoembrionario/líquido cefalorraquídeo , Queratina-19/líquido cefalorraquídeo , Neoplasias Pulmonares/líquido cefalorraquídeo , Carcinomatosis Meníngea/líquido cefalorraquídeo , Carcinomatosis Meníngea/diagnóstico , Fosfopiruvato Hidratasa/líquido cefalorraquídeo , Antígenos de Neoplasias/sangre , Biomarcadores de Tumor/sangre , Antígeno Carcinoembrionario/sangre , Humanos , Queratina-19/sangre , Neoplasias Pulmonares/patología , Carcinomatosis Meníngea/secundario , Fosfopiruvato Hidratasa/sangre , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
PURPOSE: To explore the contribution of flow cytometry immunophenotyping (FCI) in detecting leptomeningeal disease in patients with solid tumors. EXPERIMENTAL DESIGN: Cerebrospinal fluid (CSF) samples from 78 patients who received a diagnosis of epithelial-cell solid tumors and had clinical data suggestive of leptomeningeal carcinomatosis (LC) were studied. A novel FCI protocol was used to identify cells expressing the epithelial cell antigen EpCAM and their DNA content. Accompanying inflammatory cells were also described. FCI results (positive or negative for malignancy) were compared with those from CSF cytology and with the diagnosis established by the clinicians: patients with LC (n = 49), without LC (n = 26), and undetermined (n = 3). RESULTS: FCI described a wide range of EpCAM-positive cells with a hyperdiploid DNA content in the CSF of patients with LC. Compared with cytology, FCI showed higher sensitivity (75.5 vs 65.3) and negative predictive value (67.6 vs 60.5), and similar specificity (96.1 vs 100) and positive predictive value (97.4 vs 100). Concordance between cytology and FCI was high (Kp = 0.83), although misdiagnosis of LC did not show differences between evaluating the CSF with 1 or 2 techniques (P = .06). Receiver-operator characteristic curve analyses showed that lymphocytes and monocytes had a different distribution between patients with and without LC. CONCLUSION: FCI seems to be a promising new tool for improving the diagnostic examination of patients with suspicion of LC. Detection of epithelial cells with a higher DNA content is highly specific of LC, but evaluation of the nonepithelial cell compartment of the CSF might also be useful for supporting this diagnosis.
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Citometría de Flujo/métodos , Inmunofenotipificación/métodos , Carcinomatosis Meníngea/líquido cefalorraquídeo , Carcinomatosis Meníngea/diagnóstico , Neoplasias Glandulares y Epiteliales/líquido cefalorraquídeo , Neoplasias Glandulares y Epiteliales/diagnóstico , Anciano , Antígenos de Neoplasias/líquido cefalorraquídeo , Moléculas de Adhesión Celular/líquido cefalorraquídeo , ADN de Neoplasias/análisis , Molécula de Adhesión Celular Epitelial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios RetrospectivosRESUMEN
OBJECTIVES: CSF levels of Aß1-42, t-tau, and p-tau181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aß1-42, t-tau, p-tau181p, p-tau181p/Aß1-42, and t-tau/Aß1-42). METHODS: A total of 374 non-Hispanic Caucasian participants in the Alzheimer's Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p<0.01 (uncorrected p<3.10×10(-8)) and secondarily examined SNPs with uncorrected p values less than 10(-5) to identify potential candidates. RESULTS: Four SNPs in the regions of the APOE, LOC100129500, TOMM40, and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134, ABCG2, SREBF2, and NFATC4, although not reaching genome-wide significance, were identified as potential candidates. CONCLUSIONS: In addition to known candidate genes, APOE, TOMM40, and one hypothetical gene LOC100129500 partially overlapping APOE; one novel gene, EPC2, and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/genética , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/genética , Treonina/metabolismo , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Antígenos de Neoplasias/líquido cefalorraquídeo , Antígenos de Neoplasias/genética , Apolipoproteínas E/genética , Trastornos del Conocimiento/líquido cefalorraquídeo , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Estudios de Cohortes , Diagnóstico por Imagen , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Proteínas de Transporte de Membrana/líquido cefalorraquídeo , Proteínas de Transporte de Membrana/genética , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Fosforilación , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
OBJECTIVE: To assess the diagnostic value of tumor markers in the cerebrospinal fluid (CSF) for meningeal carcinomatosis (MC). METHODS: Twenty-one MC patients (including 13 adenocarcinoma and 8 non-adenocarcinoma patients), 72 patients with tuberculous meningitis (TBM) and 23 with primary intracerebral tumors (PIT) were enrolled in this study. Blood and CSF tumor markers including CEA, CA125, CA15-3, CA19-9, CA72-4, CYFRA21-1, AFP and NSE were measured by Roche E170 electrochemiluminescence analyzer and sandwich assay. RESULTS: CSF tumor markers CEA, CA125, CA199 and CYFRA21-1 and the serum tumor markers CEA, CA125, CA153, CA199 and AFP were significantly higher in MC group than in the other two groups. CSF CEA and CA15-3 were significantly higher in adenocarcinoma MC than in non-adenocarcinoma MC patients, but no significant differences were found in the serum tumor markers between the two groups (P>0.05). CSF tumor markers including CEA, CA125, CA15-3, CA72-4 and CYFRA21-1 were positively correlated to the serum tumor markers (P<0.05). CA199 was positively correlated to the disease course (P<0.05), and age was not correlated to any of the indexes (P>0.05). CONCLUSION: Detection of the tumor markers in the CSF, especially CEA, CA125, CA19-9 and CYFRA21-1, may help in the early diagnosis of MC. CEA and CA15-3 can serve as indicators for differential diagnosis of adenocarcinoma and non-adenocarcinoma.
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Biomarcadores de Tumor/líquido cefalorraquídeo , Neoplasias Meníngeas/líquido cefalorraquídeo , Neoplasias Meníngeas/diagnóstico , Adenocarcinoma/líquido cefalorraquídeo , Adenocarcinoma/diagnóstico , Adulto , Anciano , Antígenos de Neoplasias/líquido cefalorraquídeo , Antígeno Ca-125/líquido cefalorraquídeo , Antígeno CA-19-9/líquido cefalorraquídeo , Antígeno Carcinoembrionario/líquido cefalorraquídeo , Femenino , Humanos , Queratina-19/líquido cefalorraquídeo , Masculino , Proteínas de la Membrana/líquido cefalorraquídeo , Persona de Mediana Edad , Adulto JovenRESUMEN
Diagnosis of meningeal localization of lymphoid malignancies by means of cytologic examination of the cerebrospinal fluid (CSF) can be difficult. Thus far no reliable CSF tumor markers have been identified. CD27 is a transmembrane disulfide-linked 55-kD homodimer present on most peripheral blood T cells and on a subset of B cells. CD27 is also expressed on human malignant B cells and high levels of soluble CD27 can be present in the serum of patients with B-cell malignancies. The aim of this study is to determine prospectively the diagnostic value of CSF sCD27 as a tumor marker in patients with meningeal localization of lymphoid malignancies. CSF sCD27 levels were determined by sandwich enzyme-linked immunosorbent assay. The optimal cut-off value using receiver operator characteristics curves was found to be 10 U/mL. sCD27 levels were normal in all 50 control patients (lumbar disc protrusion) and in 39 of 40 samples obtained from patients with either solid tumors or acute myeloid leukemia. Of 104 CSF samples from 70 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL) undergoing routine central nervous system (CNS) staging, sCD27 was false positive and false negative in only one sample each. In 70 samples from 45 patients suspected of meningeal localization of ALL or NHL, the sCD27 test had an excellent sensitivity (100%) and specificity (82%). In 7 patients with positive CSF studied longitudinally, sCD27 levels correlated very well with remission and relapse. sCD27 levels were not nonspecifically increased by the administration of cytostatic drugs. Finally, sCD27 was also elevated in the 4 patients studied with primary central nervous system lymphoma (PCNSL). CSF sCD27 is a promising tumor marker in patients with either meningeal localization of lymphoid malignancies or PCNSL, and can be useful in the differential diagnosis of CNS involvement by either lymphoid malignancies or solid tumors.
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Antígenos de Neoplasias/líquido cefalorraquídeo , Biomarcadores de Tumor/líquido cefalorraquídeo , Proteínas del Líquido Cefalorraquídeo/análisis , Infiltración Leucémica/líquido cefalorraquídeo , Linfoma no Hodgkin/líquido cefalorraquídeo , Linfoma no Hodgkin/patología , Meninges/patología , Invasividad Neoplásica/diagnóstico , Neoplasias/líquido cefalorraquídeo , Neoplasias/patología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/líquido cefalorraquídeo , Adulto , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias Encefálicas/patología , Niño , Diagnóstico Diferencial , Ensayo de Inmunoadsorción Enzimática , Reacciones Falso Positivas , Humanos , Recurrencia Local de Neoplasia , Estudios Prospectivos , Curva ROC , Inducción de Remisión , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Microglobulina beta-2/líquido cefalorraquídeoRESUMEN
BACKGROUND: Central nervous system (CNS) metastases occur in approximately 35% of patients with breast cancer. Parenchymal brain metastases (MET) remain undetected in a large proportion of patients, and only 50% of patients with leptomeningeal carcinomatosis (MC) are diagnosed in vivo. METHODS: Cytology and activity of the tumor markers tissue polypeptide antigen (TPA) and creatine kinase-BB isoenzyme (CK-BB) were evaluated in the cerebrospinal fluid (CSF) in 71 consecutive patients with breast cancer suspected for CNS metastases. RESULTS: Forty-three patients had no CNS metastases, 12 patients had MET, 5 patients had both MET and MC, and 11 patients had MC alone. Seven of the patients with MC had an intracerebroventricular (ICV) reservoir inserted, and an additional 70 ICV CSF samples from these patients were obtained. In CSF obtained by lumbar puncture, 11% of the samples were classified as "suspicious for malignancy," but a very limited interobserver variability was demonstrated (Kappa test value, 0.81; 95% confidence limits, 0.67-0.95%). Fifty-one percent of the ICV CSF samples were classified as "suspicious for malignancy" (Kappa test value, 0.58; 95% confidence limits, 0.34-0.82%). TPA and CK-BB were both measured in 101 CSF specimens (61 from lumbar puncture and 40 ICV samples). The differences between patients with and without CNS metastases were significantly different according to TPA (P < 0.00001) and CK-BB (P < 0.00003; Mann-Whitney test). The sensitivity and predictive value of a negative test for having any CNS metastases (in case of elevated values of either TPA or CK-BB or both) were 85% (95% confidence limits, 65-96%) and 90% (95% confidence limits, 76-97%), respectively. In addition, a significant correlation between TPA and CK-BB was demonstrated in CSF from lumbar puncture (Spearmans-Rho, 0.49; P < 0.0001) and ICV (Spearmans-Rho, 0.37; P < 0.02). CONCLUSIONS: Cytologic evaluation of CSF obtained by lumbar punctures is a reliable procedure. In CSF from ICV reservoirs, cytologic evaluation is of limited use, but CK-BB and TPA is of potential value.
Asunto(s)
Neoplasias de la Mama/patología , Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/secundario , Antígenos de Neoplasias/líquido cefalorraquídeo , Biomarcadores de Tumor/líquido cefalorraquídeo , Neoplasias de la Mama/líquido cefalorraquídeo , Ventrículos Cerebrales , Líquido Cefalorraquídeo/citología , Creatina Quinasa/líquido cefalorraquídeo , Femenino , Humanos , Isoenzimas , Péptidos/líquido cefalorraquídeo , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Punción Espinal , Antígeno Polipéptido de TejidoRESUMEN
Tissue polypeptide antigen (TPpA) in the cerebrospinal fluid (CSF) was measured in 59 consecutive breast cancer patients with suspected central nervous system (CNS) metastases. Subsequently, we determined that 13 patients had parenchymal brain metastases, 10 had leptomeningeal carcinomatosis, and 36 had no CNS involvement. The concentration of TPpA, which is a nonspecific marker for cell proliferation, was significantly higher in patients with CNS metastases than in those without it (P less than .0001; Mann-Whitney test). A tentative cutoff value for CNS metastases was set at 95 U/L TPpA; the upper limit of values indicating absence of CNS metastases was 89 U/L. Given these cutoff points, the sensitivity of TPpA as a marker for CNS metastases was 74% and the specificity was 100%; the predictive values of positive and negative tests were 100% and 86%, respectively. In 16 patients with CNS metastases, no correlation was found between TPpA activity in corresponding CSF and blood samples (correlation coefficient, Spearman's rho = .4; P greater than .1). In three patients treated for leptomeningeal carcinomatosis, the measurements of CSF TPpA showed correlation between the presence of tumor cells in the CSF and neurological clinical function. TPpA concentrations decreased in parallel with the clinical response and increased prior to CNS disease progression. As a marker for CNS metastases, the level of TPpA in the CSF in breast cancer patients appears to be superior to the level of protein, lactate dehydrogenase, or glucose, which showed very low sensitivity (41%, 47%, and 8%, respectively). For quantitative evaluation of treatment for leptomeningeal carcinomatosis, the TPpA level appears to be valuable and superior to CSF cytology, because tumor cells are not always present in CSF samples from patients with this condition.
Asunto(s)
Antígenos de Neoplasias/líquido cefalorraquídeo , Biomarcadores de Tumor/líquido cefalorraquídeo , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/líquido cefalorraquídeo , Neoplasias Meníngeas/secundario , Péptidos/líquido cefalorraquídeo , Autopsia , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias de la Mama/inmunología , Femenino , Humanos , Neoplasias Meníngeas/líquido cefalorraquídeo , Antígeno Polipéptido de TejidoRESUMEN
Quantitative determination of human glioma-associated antigen in cerebrospinal fluids (CSFs) obtained from 66 patients with a variety of neurological diseases was performed by solid-phase radioimmunoassay with a monoclonal antibody (G-22). In this system, the minimum detectable amount of the antigen in the CSF was 8 ng/ml. It was demonstrated that CSF diagnosis of glioblastoma might be possible in the case of small tumors with a diameter of less than 2 cm. CSFs obtained from all 18 patients with glioma were positive and the level varied from 11.2 to 186.1 ng/ml. The antigen level in the cystic fluid of the tumor was higher than that in CSF. There was a tendency for the antigen level in CSF to be correlated with the tumor size and the type of histology. The malignant types of glioblastoma or medulloblastoma showed higher levels than the benign type of ependymoma and astrocytoma. Most types of non-gliomatous brain tumor were negative except immature teratoma, meningioma with central neurofibromatosis, and metastatic brain tumor from lung cancer. We also noted that tumor progression or regression of malignant glioma could be predicted by the monitoring of the antigen in the CSF.
Asunto(s)
Antígenos de Neoplasias/líquido cefalorraquídeo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Radioinmunoensayo , Adulto , Anticuerpos Monoclonales , Neoplasias Encefálicas/diagnóstico , Línea Celular , Niño , Femenino , Glioma/diagnóstico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Carcinomatous meningitis is a devastating metastatic complication of systemic carcinoma, which may occur insidiously, accompanied by a confusing spectrum of clinical symptoms and signs. In the absence of reliable diagnostic tumour markers, the diagnosis is established by the demonstration of malignant cells within the cerebrospinal fluid (CSF). Cytological techniques requiring skillful interpretation are occasionally negative in the presence of established disease, and when positive may indicate leptomeningeal malignancy of such advanced nature that effective palliation is difficult. Biochemical tumour marker technology offers the potential of reliable diagnosis in early disease states, prior to the appearance of exfoliated malignant cells. In a series of 100 patients, we assayed for an epithelial associated glycoprotein (HMFGI antigen) in CSF obtained at lumbar puncture. In 18 of 20 patients with carcinomatous meningitis, this high-molecular-weight glycoprotein was detectable in the CSF. The antigen was also present in 2 patients with neoplastic meningitis complicating lymphoma and medulloblastoma, but was not detected in the CSF of the remaining 78 patients.
Asunto(s)
Antígenos de Neoplasias/líquido cefalorraquídeo , Biomarcadores de Tumor/líquido cefalorraquídeo , Carcinoma/secundario , Glicoproteínas de Membrana/líquido cefalorraquídeo , Neoplasias Meníngeas/secundario , Antígeno Carcinoembrionario/líquido cefalorraquídeo , Carcinoma/líquido cefalorraquídeo , Carcinoma/diagnóstico , Humanos , Neoplasias Meníngeas/líquido cefalorraquídeo , Neoplasias Meníngeas/diagnóstico , Mucina-1 , Mucinas/líquido cefalorraquídeo , RadioinmunoensayoRESUMEN
This investigation evaluated the possibility that the occurrence of S-antigen in cerebrospinal fluid (CSF) might be used as a preoperative marker of pineal parenchymal tumors (pineoblastoma and pineocytoma). Such a marker could provide a means of preoperatively differentiating these neoplasms from pineal region tumors of other origin. The S-antigen, also known as the 48-kD protein or arrestin, is a highly antigenic protein originally found in the retina and pineal gland. In the retinal photoreceptors and submammalian pineal photoreceptors the protein is thought to be involved in phototransduction; its function in the mammalian pinealocyte is unknown. S-Antigen immunoreactivity also occurs in certain neoplastic cells of retinoblastomas, pineocytomas, pineoblastomas, and cerebellar medulloblastomas. This study included a group of 13 patients with tumors of the pineal region. Samples of CSF were obtained preoperatively and analyzed for the S-antigen using western blot technology. Tumor biopsy material was classified according to conventional neurohistological criteria and was also examined by immunocytochemical techniques for the presence of the S-antigen. S-Antigen immunoreactivity was found in the preoperative CSF of the one patient found to have pineocytoma; tumor tissue removed from this patient was the only neoplastic tissue examined in this study which contained S-Antigen immunoreactive tumor cells. Furthermore, hydroxyindole-O-methyltransferase activity was detectable in the pineocytoma but not in three other pineal tumors, and melatonin levels in the CSF of the pineocytoma patient were the highest in the patient group examined. These preliminary results suggest that testing for S-antigen in CSF might be useful in characterizing and treating tumors of the pineal region and, when identified in conjunction with other markers, it might also help to better define pineal parenchymal tumors. This study needs confirmation with a larger number of patients. If this approach is eventually found to be a reliable predictor of pineal cell tumors, it may supplant the need for surgical biopsies before initiating appropriate adjunctive therapy.
Asunto(s)
Antígenos de Diferenciación/líquido cefalorraquídeo , Antígenos de Neoplasias/líquido cefalorraquídeo , Antígenos/líquido cefalorraquídeo , Neoplasias Encefálicas/inmunología , Proteínas del Ojo/líquido cefalorraquídeo , Glándula Pineal , Pinealoma/inmunología , Arrestina , Humanos , InmunohistoquímicaRESUMEN
Immunocytochemical methods were applied to bone marrow aspirate and cerebrospinal fluid specimens to show cellular reactivity with the monoclonal antibody UJ13A, which recognises an antigen expressed by cells of neuroectodermal origin. The antigen remained stable after air drying and appropriate fixation. In five patients with various neuroectodermal tumours the diagnostic advantages of these techniques were clear; they can be performed even when only very small amounts of diagnostic material are available.
Asunto(s)
Neuroblastoma/diagnóstico , Adulto , Anticuerpos Monoclonales , Antígenos de Neoplasias/líquido cefalorraquídeo , Médula Ósea/inmunología , Preescolar , Femenino , Humanos , Técnicas para Inmunoenzimas , Lactante , Masculino , Meduloblastoma/diagnósticoRESUMEN
Monoclonal antibodies were produced by immunization of the human glioma cell line SK-MG-4. One of the antibodies, designated G-22, reacted with 18 of 20 glioma cell lines, two melanoma cell lines, and three lung cancer cell lines, but not with 39 cell lines derived from sarcoma, carcinoma, or hematopoietic tumors. The antigen was expressed in the brain of human fetuses in early gestation (9 weeks) but not in late gestation (8 months) or in normal adult brain, suggesting that the antibody recognizes neural differentiation antigens expressed by neuroectodermal origin. A high incidence of positive antigens has been observed in gliomas but not in the other neural tumors, such as ependymomas, meningiomas, and neuroblastomas. Thus, the antigen defined by the G-22 monoclonal antibody could be defined as glioma-associated antigen. Pulse-labeling with tritiated leucine and subsequent immunoprecipitation of the solubilized cell membrane revealed that the antigen recognized by this antibody had a molecular weight of 67 kD on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). It was shown by dot-blot enzyme-linked immunospecific assay (ELISA) that the antigen could be detected in the cerebrospinal fluid (CSF) from patients with gliomas. From analysis of affinity chromatography and SDS-PAGE, the antigen present in the CSF had a molecular weight similar to that of a 1% Nonidet P-40 (NP-40) extract from a glioma cell line. When the antigen in CSF was quantitatively assayed by ELISA, the mean antigen level (expressed as optical density at 450 nm) in the CSF of seven patients was 0.8 +/- 0.28 (mean +/- standard deviation), which was significantly higher than the 0.38 +/- 0.14 level observed in the CSF of 15 patients with nonglioma brain tumors and the 0.23 +/- 0.09 level in the CSF of four patients without brain tumors. These results indicate that the monoclonal antibody G-22 is useful for the diagnosis of glioma.