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1.
Mol Ther ; 25(12): 2620-2634, 2017 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-28967558

RESUMO

Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first phase I/IIa clinical trial of an oncolytic parvovirus in recurrent glioblastoma patients. H-1PV (escalating dose) was administered via intratumoral or intravenous injection. Tumors were resected 9 days after treatment, and virus was re-administered around the resection cavity. Primary endpoints were safety and tolerability, virus distribution, and maximum tolerated dose (MTD). Progression-free and overall survival and levels of viral and immunological markers in the tumor and peripheral blood were also investigated. H-1PV treatment was safe and well tolerated, and no MTD was reached. The virus could cross the blood-brain/tumor barrier and spread widely through the tumor. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. Markers of virus replication, microglia/macrophage activation, and cytotoxic T cell infiltration were detected in infected tumors, suggesting that H-1PV may trigger an immunogenic stimulus. Median survival was extended in comparison with recent meta-analyses. Altogether, ParvOryx01 results provide an impetus for further H-1PV clinical development.


Assuntos
Terapia Genética , Vetores Genéticos/genética , Glioblastoma/genética , Glioblastoma/terapia , Parvovirus H-1/genética , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Expressão Gênica , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/imunologia , Glioblastoma/mortalidade , Glioblastoma/patologia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Radioterapia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Transgenes , Resultado do Tratamento
2.
BMC Cancer ; 17(1): 576, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28851316

RESUMO

BACKGROUND: Metastatic pancreatic cancer has a dismal prognosis, with a mean six-month progression-free survival of approximately 50% and a median survival of about 11 months. Despite intensive research, only slight improvements of clinical outcome could be achieved over the last decades. Hence, new and innovative therapeutic strategies are urgently required. ParvOryx is a drug product containing native parvovirus H-1 (H-1PV). Since H-1PV was shown to exert pronounced anti-neoplastic effects in pre-clinical models of pancreatic cancer, the drug appears to be a promising candidate for treatment of this malignancy. METHODS: ParvOryx02 is a non-controlled, single arm, open label, dose-escalating, single center trial. In total seven patients with pancreatic cancer showing at least one hepatic metastasis are to be treated with escalating doses of ParvOryx according to the following schedule: i) 40% of the total dose infused intravenously in equal fractions on four consecutive days, ii) 60% of the total dose injected on a single occasion directly into the hepatic metastasis at varying intervals after intravenous infusions. The main eligibility criteria are: age ≥ 18 years, disease progression despite first-line chemotherapy, and at least one hepatic metastasis. Since it is the second trial within the drug development program, the study primarily explores safety and tolerability after further dose escalation of ParvOryx. The secondary objectives are related to the evaluation of certain aspects of anti-tumor activity and clinical efficacy of the drug. DISCUSSION: This trial strongly contributes to the clinical development program of ParvOryx. The individual hazards for patients included in the current study and the environmental risks are addressed and counteracted adequately. Besides information on safety and tolerability of the treatment after further dose escalation, thorough evaluations of pharmacokinetics and intratumoral spread as well as proof-of-concept (PoC) in pancreatic cancer will be gained in the course of the trial. TRIAL REGISTRATION: ClinicalTrials.gov-ID: NCT02653313 , Registration date: Dec. 4th, 2015.


Assuntos
Parvovirus H-1/fisiologia , Terapia Viral Oncolítica/métodos , Neoplasias Pancreáticas/tratamento farmacológico , Administração Intravenosa , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Intralesionais , Masculino , Metástase Neoplásica , Terapia Viral Oncolítica/efeitos adversos , Vírus Oncolíticos/fisiologia , Tamanho da Amostra , Análise de Sobrevida , Resultado do Tratamento
3.
Diagnostics (Basel) ; 13(17)2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37685260

RESUMO

T-cell immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a central role in the control of the virus. In this study, we evaluated the performance of T-Track® SARS-CoV-2, a novel CE-marked quantitative reverse transcription-polymerase chain reaction (RT-qPCR) assay, which relies on the combined evaluation of IFNG and CXCL10 mRNA levels in response to the S1 and NP SARS-CoV-2 antigens, in 335 participants with or without a history of SARS-CoV-2 infection and vaccination, respectively. Of the 62 convalescent donors, 100% responded to S1 and 88.7% to NP antigens. In comparison, of the 68 naïve donors, 4.4% were reactive to S1 and 19.1% to NP. Convalescent donors <50 and ≥50 years of age demonstrated a 100% S1 reactivity and an 89.1% and 87.5% NP reactivity, respectively. T-cell responses by T-Track® SARS-CoV-2 and IgG serology by recomLine SARS-CoV-2 IgG according to the time from the last immunisation (by vaccination or viral infection) were comparable. Both assays showed a persistent cellular and humoral response for at least 36 weeks post immunisation in vaccinated and convalescent donors. Our results demonstrate the very good performance of the T-Track® SARS-CoV-2 molecular assay and suggest that it might be suitable to monitor the SARS-CoV-2-specific T-cell response in COVID-19 vaccinations trials and cross-reactivity studies.

4.
BMC Cancer ; 12: 99, 2012 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-22436661

RESUMO

BACKGROUND: The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. METHODS: ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months. DISCUSSION: This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application of an oncolytic virus. Due to its study design the trial will not only generate data on the local effect of H-1PV but it will also investigate the penetration of H-1PV into the tumor after systemic delivery and obtain safety data from systemic delivery possibly supporting clinical trials with H-1PV in other, non-CNS malignancies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01301430.


Assuntos
Neoplasias Encefálicas/terapia , Vetores Genéticos/administração & dosagem , Glioblastoma/terapia , Parvovirus H-1/genética , Vírus Oncolíticos/genética , Administração Intravenosa , Neoplasias Encefálicas/patologia , Protocolos Clínicos , Progressão da Doença , Feminino , Glioblastoma/patologia , Humanos , Injeções Intralesionais , Masculino , Terapia Viral Oncolítica , Recidiva
5.
Clin Cancer Res ; 27(20): 5546-5556, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34426438

RESUMO

PURPOSE: To investigate the safety, clinical efficacy, virus pharmacokinetics, shedding, and immune response after administration of an oncolytic parvovirus (H-1PV, ParvOryx) to patients with metastatic pancreatic ductal adenocarcinoma (PDAC) refractory to first-line therapy. PATIENTS AND METHODS: This is a noncontrolled, single-arm, open-label, dose-escalating, single-center clinical trial. Seven patients with PDAC and at least one liver metastasis were included. ParvOryx was administered intravenously on 4 consecutive days and as an intralesional injection, 6 to 13 days thereafter. Altogether, three escalating dose levels were investigated. In addition, gemcitabine treatment was initiated on day 28. RESULTS: ParvOryx showed excellent tolerability with no dose-limiting toxicities. One patient had a confirmed partial response and one patient revealed an unconfirmed partial response according to RECIST criteria. Both patients showed remarkably long surivial of 326 and 555 days, respectively. Investigation of pharmacokinetics and virus shedding revealed dose dependency with no excretion of active virus particles in saliva or urine and very limited excretion in feces. H-1PV nucleic acids were detected in tumor samples of four patients. All patients showed T-cell responses to viral proteins. An interesting immunologic pattern developed in tumor tissues and in blood of both patients with partial response suggesting immune activation after administration of ParvOryx. CONCLUSIONS: The trial met all primary objectives, revealed no environmental risks, and indicated favorable immune modulation after administration of ParvOryx. It can be considered a good basis for further systematic clinical development alone or in combination with immunomodulatory compounds.


Assuntos
Adenocarcinoma/secundário , Adenocarcinoma/terapia , Carcinoma Ductal Pancreático/secundário , Carcinoma Ductal Pancreático/terapia , Parvovirus H-1 , Sistema Imunitário/imunologia , Terapia Viral Oncolítica , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Idoso , Humanos , Pessoa de Meia-Idade , Terapia Viral Oncolítica/efeitos adversos
6.
Eur J Pharm Biopharm ; 68(2): 390-9, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17686618

RESUMO

The objective of this study was to establish and validate an ex vivo human cervical tissue model appropriate for transport studies of molecular and especially nucleic acid based drugs. For that purpose conditions had to be established for a standardized tissue handling and preparation following hysterectomy to allow an immediate experimental use of fresh tissue samples. Samples of the ectocervical, endocervical and the transition zone representing the entire cervix organ were characterized in Franz diffusion cells by the determination of the in vitro permeation of low and high molecular weight markers (propanolol, mannitol, dextran 4000, 10,000, 20,000 and 40,000Da). Additionally, the permeability of mannitol and dextran 4000 across fresh and frozen cervical tissue was compared. The apparent permeability coefficients (P(app)) of the various markers demonstrated (i) that with increasing molecular weight the marker permeability decreases, (ii) an upper permeability limit between 10,000 and 20,000Da, (iii) no significant difference of the permeability across the three cervical tissue zones, (iv) a statistically significant but effectively small variation of the permeability among different patient samples. A continuous difference of approximately two log values between the P(app) values of mannitol and dextran 4000 makes them suitable as an internal marker control pair for each biopsy. Moreover, the P(app) values of both markers across fresh and frozen tissue are comparable. According to the presented data we conclude that the human cervical tissue model has been well characterized and is therefore suitable for local delivery and permeation studies.


Assuntos
Ácidos Nucleicos/farmacocinética , Neoplasias do Colo do Útero/patologia , Feminino , Humanos , Técnicas In Vitro , Peso Molecular , Ácidos Nucleicos/química , Permeabilidade , Neoplasias do Colo do Útero/metabolismo
7.
Comp Med ; 65(1): 36-45, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25730755

RESUMO

The autonomous parvovirus H1 (H1PV) is transmitted in rodent populations. The natural host is the rat, in which H1PV infection is pathogenic only in fetuses and newborns. H1PV infection of human cancer cells leads to strong oncolytic effects in preclinical models. In preparation for a clinical trial of H1PV injection in patients with malignant brain tumors, H1PV had to be prepared to Good Manufacturing Practice standards, including extensive toxicology testing in rats. Because the trial involves direct intracerebral injection of H1PV into the tumor and around the resection cavity, possible toxicity to CNS tissue had to be investigated. In addition, quantitative blood levels and the tissue distribution of H1PV after single intracerebral or intravenous injection were measured. Direct injection of H1PV into rat brain at 3 dose levels (maximum, 7.96 × 107 pfu) did not cause any macroscopic or histologic pathology. Furthermore, H1PV infection of the brain did not alter central or autonomous nervous system function. H1PV DNA was detected in almost all organs at 6 h, 48 h, and 14 d after intravenous and intracerebral injection, with the highest levels in liver and spleen. H1PV concentrations in most organs were similar after intravenous and intracerebral injection, indicating high permeability of the blood-brain barrier for this small virus. The current results demonstrate wide organ distribution of H1PV after intravenous or intracerebral injection, confirm that H1PV is nonpathogenic in adult rats even after direct injection into the brain, and form the basis for the ongoing ParvOryx01 clinical trial.


Assuntos
Sistema Nervoso Central/virologia , Parvovirus H-1/patogenicidade , Terapia Viral Oncolítica/métodos , Animais , Disponibilidade Biológica , Sistema Nervoso Central/patologia , DNA Viral/metabolismo , Avaliação Pré-Clínica de Medicamentos , Injeções Intravenosas , Fígado/virologia , Terapia Viral Oncolítica/normas , Ratos , Baço/virologia , Fatores de Tempo , Carga Viral
8.
Comp Med ; 65(1): 23-35, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25730754

RESUMO

Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated.


Assuntos
Genoma Viral/genética , Parvovirus H-1/patogenicidade , Terapia Viral Oncolítica/métodos , Infecções por Parvoviridae/imunologia , Infecções por Parvoviridae/patologia , Animais , Análise Química do Sangue , Testes de Coagulação Sanguínea , Relação Dose-Resposta Imunológica , Avaliação Pré-Clínica de Medicamentos , Fezes/virologia , Parvovirus H-1/genética , Imunoglobulina G/imunologia , Injeções Intravenosas , Fígado/patologia , Reação em Cadeia da Polimerase , Ratos , Baço/patologia
9.
Recent Results Cancer Res ; 162: 135-40, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12790327

RESUMO

The presence of occult micrometastases in bone marrow (BM) of patients with early breast cancer increases the risk of relapse. Detection of circulation tumor cells in peripheral blood (PB) may also influence the patient's prognosis. Few data are available on the correlation between tumor cell dissemination in BM and PB in solid epithelial tumors. Twenty-milliliter blood samples were collected from PB of 42 patients with advanced breast cancer and centrifuged using the density gradient OncoQuick (OncoQuick Greiner BioOne, Frickenhausen, Germany). The BM aspirates available from 11 of the 42 patients were centrifuged using density centrifugation Ficoll. Tumor cell detection was performed by microscopy after cytospin preparation and immunocytochemical staining with the monoclonal antibody A45-B/B3. Cytokeratin-positive cells were detected in 23 patients (55%) in the PB and in three patients (27%) in the BM. A cohort with bone lesions as the only metastatic side showed a correlation as follows: 7 of the 11 patients (64%) had negative findings in BM and PB, whereas cytokeratin-positive cells in PB were present in 3 of these 11 patients (27%). The presence of visceral metastases was associated with the detection of cytokeratin-positive cells in the PB in 20 of the 31 patients (65%) in this subgroup. The density gradient OncoQuick in combination with immunocytochemical staining allows the detection of cytokeratin-positive cells in PB of patients with advanced breast cancer. The immunocytochemical detection of cytokeratin-positive cells in PB seems to be associated with the site of metastatic manifestation.


Assuntos
Neoplasias da Medula Óssea/secundário , Medula Óssea/patologia , Neoplasias da Mama/patologia , Células Neoplásicas Circulantes/patologia , Células da Medula Óssea , Neoplasias da Mama/sangue , Feminino , Humanos , Imuno-Histoquímica , Queratinas/metabolismo , Metástase Neoplásica , Pós-Menopausa , Prognóstico , Resultado do Tratamento
10.
Recent Results Cancer Res ; 162: 149-55, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12790329

RESUMO

The aim of the study was to compare the new density gradient centrifugation system OncoQuick with the standard density gradient centrifugation system Ficoll for improved tumor cell enrichment in blood of tumor patients. Evaluation of OncoQuick and Ficoll density gradient centrifugation was performed by flow-cytometry and immunocytochemistry using 10 ml unspiked and tumor cell-spiked blood samples of tumor-free probands. From 10 ml blood, OncoQuick density gradient centrifugation separated a cell fraction which consisted of a mean cell number of 9.5x10(4) mononuclear cells compared to 1.8x10(7) cells by Ficoll. Density gradient centrifugation of tumor cell-spiked blood samples with OncoQuick and Ficoll led to similar tumor cell recovery rates, between 70% and 90% for both methods. The improved depletion of mononuclear blood cells by OncoQuick simplified further immunocytochemical evaluation of the enriched cell fraction, which could be spun onto 1-2 glass slides by cytocentrifugation. In comparison, the mononuclear cells separated by Ficoll had to be spun onto more than 50 glass slides for complete immunocytochemical evaluation. Consequently, tumor cell density on each cytospin was higher after OncoQuick preparation compared to Ficoll. Density gradient centrifugation with OncoQuick results in higher relative tumor cell enrichment than Ficoll density gradient centrifugation. This simplifies further immunocytochemical tumor cell detection and is a promising tool for the detection of circulating tumor cells in blood of tumor patients.


Assuntos
Centrifugação com Gradiente de Concentração/métodos , Células Neoplásicas Circulantes/metabolismo , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Leucócitos Mononucleares/metabolismo , Células Tumorais Cultivadas
11.
Neurochem Int ; 62(8): 1029-38, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23562846

RESUMO

Alpha-motoneurons appear to be exceedingly affected in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Morphological and physiological degeneration of this neuronal phenotype is typically characterized by a marked decrease of neuronal markers and by alterations of cholinergic metabolism such as reduced choline acetyltransferase (ChAT) expression. The motoneuron-like cell line NSC-34 is a hybrid cell line produced by fusion of neuroblastoma with mouse motoneuron-enriched primary spinal cord cells. In order to further establish this cell line as a valid model system to investigate cholinergic neurodegeneration, NSC-34 cells were differentiated by serum deprivation and additional treatment with all-trans retinoic acid (atRA). Cell maturation was characterized by neurite outgrowth and increased expression of neuronal and cholinergic markers, including MAP2, GAP-43 and ChAT. Subsequently, we used differentiated NSC-34 cells to study early degenerative responses following exposure to various neurotoxins (H2O2, TNF-α, and glutamate). Susceptibility to toxin-induced cell death was determined by means of morphological changes, expression of neuronal marker proteins, and the ratio of pro-(Bax) to anti-(Bcl-2) apoptotic proteins. NSC-34 cells respond to low doses of neurotoxins with increased cell death of remaining undifferentiated cells with no obvious adverse effects on differentiated cells. Thus, the different vulnerability of differentiated and undifferentiated NSC-34 cells to neurotoxins is a key characteristic of NSC-34 cells and has to be considered in neurotoxic studies. Nonetheless, application of atRA induced differentiation of NSC-34 cells and provides a suitable model to investigate molecular events linked to neurodegeneration of differentiated neurons.


Assuntos
Diferenciação Celular , Modelos Biológicos , Neurônios Motores/citologia , Animais , Sequência de Bases , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Colina O-Acetiltransferase/metabolismo , Primers do DNA , Ácido Glutâmico/farmacologia , Peróxido de Hidrogênio/farmacologia , Camundongos , Neurônios Motores/enzimologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Necrose Tumoral alfa/farmacologia
12.
World J Surg ; 31(12): 2329-34, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17914651

RESUMO

Tumor cell dissemination appears to be an early event in tumor progression, and tumor cells can be detected in peripheral venous blood at the time of the operation. Although cytokeratin 20 (CK-20) is not specifically expressed by colorectal carcinomas, it represents a widely used marker for the detection of colorectal tumor cells. We used the combination of density centrifugation and CK-20 real-time reverse transcription polymerase chain reaction to detect CK-20-positive cells in the peripheral venous blood of 37 patients with colorectal carcinoma. Detection rates were compared to serum levels of the tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen CA 19-9, and cancer antigen CA 125. The prognostic impact was assessed by the overall survival and by univariate and multivariate analysis. Overall, CK-20-positive cells in peripheral venous blood were detected in 11 of 37 (29.7%) patients. CK-20-positive patients showed a significantly higher mean serum CEA level (90.3 ng/ml) than the 4.1 ng/ml found in the CK-20-negative group (p = 0.03). CEA levels also correlated with CK-20 copy numbers. No significant correlation was observed for CA 19-9 or CA 125. CK-20-negative patients showed a trend toward better survival (p = 0.08). In the univariate analysis, CA 19-9, CEA, tumor size, lymph node status, grading, the presence of distant metastases, and resection status reached significant prognostic levels, whereas the detection of CK-20-positive cells showed only a prognostic trend (p = 0.06). Multivariate analysis failed to identify independent prognostic parameters. Here we report the correlation of CK-20-positive cells in peripheral venous blood with the serum CEA level of patients with colorectal cancer, which may represent a potential marker of the tumor load.


Assuntos
Biomarcadores Tumorais/sangue , Antígeno Carcinoembrionário/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Queratina-20/sangue , Células Neoplásicas Circulantes/imunologia , Carga Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
World J Surg ; 29(4): 422-8, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15770378

RESUMO

Despite curative tumor resection, about 30%-50% of patients with locally advanced gastrointestinal (GI) carcinoma develop tumor recurrence which may be caused by pre- or intraoperative tumor cell dissemination. We examined the combination of optimized density gradient centrifugation with a CK-20 reverse transcriptase-polymerase chain reaction to detect and quantify circulating tumor cells in peripheral blood. Peripheral venous blood (20 ml) of patients with GI carcinomas was collected during primary tumor staging before and after the endoscopy procedure. CK-20 expression in peripheral venous blood was found in 22 of 82 patients (26.8%) with a nonsignificant difference between the upper GI tract (23.9%) and the lower GI tract (30.5%). The correlation with clinical outcome (24-month-survival) revealed a significantly worse prognosis (p < 0.05) of CK-20-positive patients with carcinoma of the upper GI tract and a trend toward a worse prognosis for patients with carcinoma of the lower GI tract. Quantification of CK-20 expression in peripheral blood showed a significantly higher circulating CK-20 copy number (median: 2816) in patients with metastatic tumors than in those with non-metastatic tumors (median: 983) (p < 0.05). For a subset of 42 primarily operated patients, we correlated the detection rate with UICC (International Union Against Cancer) staging categories. In contrast to the upper GI tract, the detection rate of patients with carcinoma of the lower GI tract showed a trend toward tumor size (pT) and a significant correlation with the presence of distant metastases (pM) (p < 0.01) and the postoperative residual tumor status (R) (p < 0.01). The endoscopy procedure did not lead to an increased detection of CK-20 expression.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Gastrointestinais/sangue , Proteínas de Filamentos Intermediários/metabolismo , Células Neoplásicas Circulantes/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Centrifugação com Gradiente de Concentração , Humanos , Queratina-20 , Masculino , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade
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