RESUMO
OBJECTIVES: The aim of this prospective study was to compare the diagnostic performance of 64-row MDCT and gadoxetic-acid-enhanced MRI at 3.0 T in patients with colorectal liver metastases in correlation with histopathological findings. METHODS: Lesions detected at MDCT and MRI were interpreted by three blinded readers and compared with histopathological workup as the term of reference. Two subgroups of lesions were additionally evaluated: (1) metastases smaller than 10 mm and (2) lesions in patients with and without steatosis of the liver, assessed histopathologically. RESULTS: Surgery and histopathological workup revealed 81 colorectal liver metastases in 35 patients and diffuse metastatic involvement in 3 patients. In a lesion-by-lesion analysis, significant sensitivity differences could only be found for reader 1 (P = 0.035) and reader 3 (P = 0.003). For segment-based evaluation, MRI was more sensitive only for reader 3 (P = 0.012). The number of false-positive results ranged from 3 to 12 for MDCT and 8 to 11 for MRI evaluation. In the group of small lesions, the sensitivity differed significantly between both methods (P = 0.003). In patients with hepatic steatosis, MRI showed a trend toward better performance than MDCT, but without statistical performance. CONCLUSIONS: The 3.0-T MRI with liver-specific contrast agents is the preferred investigation in the preoperative setting, especially for the assessment of small colorectal liver metastases. KEY POINTS: ⢠Potential surgical treatment requires accurate radiological assessment of colorectal liver metastases ⢠Magnetic resonance imaging with gadoxetic acid is the preferred imaging investigation. ⢠MRI is better than multidetector CT for detecting small liver metastases.
Assuntos
Neoplasias Colorretais/diagnóstico por imagem , Meios de Contraste , Gadolínio DTPA , Neoplasias Hepáticas/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Tomografia Computadorizada Multidetectores/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/patologia , Reações Falso-Positivas , Feminino , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Variações Dependentes do Observador , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
STUDY PURPOSE: The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. METHODS: The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. RESULTS: Not applicable. CONCLUSION: DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04272931 (February 17, 2020). Toestingonline.nl: NL71535.068.19 (September 20, 2019).
Assuntos
Embolização Terapêutica , Neoplasias Hepáticas , Acreditação , Embolização Terapêutica/métodos , Hepatectomia/métodos , Veias Hepáticas/patologia , Hepatomegalia , Humanos , Hipertrofia/etiologia , Hipertrofia/patologia , Hipertrofia/cirurgia , Fígado/cirurgia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Estudos Multicêntricos como Assunto , Veia Porta/patologia , Estudos Prospectivos , Resultado do TratamentoRESUMO
AIM: Endo-sponge assisted treatment (endo-sponge) represents a novel approach to treat patients with anastomotic dehiscence following anterior resection for rectal cancer. Yet, limited data are available to predict success, compatibility with radiotherapy and/or chemotherapy as well as acceptance by the patients. METHOD: Between September 2007 and June 2008, nine patients suffering from anastomotic leakage after anterior rectal resection (n = 6) or suffering from leakage of rectal stump following Hartmann's procedure (n = 3) were treated by endo-sponge. We recorded clinical outcome and patient's comfort using a 10-point visual analogue scale (VAS). RESULTS: Median time of endo-sponge treatment was 3 weeks (range: 2-8). There were no minor or major complications. In 6 (66.6%) patients, the anastomotic leakage healed successfully. Three patients showed no response and needed further surgical intervention. The lack of success was due to complexity of the leakages, which comprised either more than 270 degrees of the circumference or consisted of two distant fistulas. Formation of granulation tissue was unaffected by chemotherapy. For the question 'alteration in daily life activity', a median score of 5 (range: 1-9) was found. Measuring 'pain sensation' during endo-sponge treatment patients scored a median of 3 (range: 0-6). CONCLUSIONS: Endo-sponge treatment can be recommended as an alternative approach to treat pelvic sepsis following anastomotic dehiscence or rectal stump insufficiency. Extended leakages should be treated by different approaches having little probability of successful healing, but can lead to discomfort for the patient. Radiochemotherapy does not cause a problem for application of the endo-sponge.
Assuntos
Colectomia/efeitos adversos , Colonoscopia/métodos , Neoplasias Colorretais/cirurgia , Reto/cirurgia , Tampões de Gaze Cirúrgicos , Deiscência da Ferida Operatória/terapia , Idoso , Anastomose Cirúrgica/efeitos adversos , Colectomia/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Retrospectivos , Deiscência da Ferida Operatória/etiologia , Resultado do Tratamento , CicatrizaçãoRESUMO
A human acute lymphoblastic leukemia (ALL) cell line that was transplanted into immune-deficient SCID mice proliferated in the hematopoietic tissues, invaded various organs, and led to the death of the mice. The distribution of leukemic cells in SCID mice was similar to the course of the disease in children. A-1 cells marked with a retrovirus vector showed clonal evolution after the transplant. SCID mice that were injected with bone marrow from three patients with non-T ALL had leukemic cells in their bone marrow and spleen. This in vivo model of human leukemia is an approach to understanding leukemic growth and progression and is a novel system for testing new treatment strategies.
Assuntos
Síndromes de Imunodeficiência/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Encéfalo/patologia , Linhagem Celular , Células Clonais , DNA de Neoplasias/isolamento & purificação , Humanos , Rim/patologia , Fígado/patologia , Camundongos , Camundongos Mutantes , Transplante de Neoplasias , Transplante HeterólogoRESUMO
Characterization studies were performed on the malignant peripheral blood cells from three patients with juvenile chronic myelogenous leukemia (JCML) by allowing the cells to increase numerically in liquid cultures. JCML cells proliferated rapidly and excessively in the absence of an added humoral growth factor, whereas control peripheral blood cells declined in number when cultured under identical conditions. Clonality of JCML cells was proven by cytogenetic analysis of the proliferating population. JCML cells were exclusively of monocytic lineage as determined by morphology, staining characteristics, and monoclonal antibody identification of cell-specific surface antigens, but cytochemical and functional studies identified aberrant properties indicating defective differentiation. Striking differences from control cells in ultrastructure and topography were also observed by transmission and scanning electron microscopy. These data provide new information on the cellular origin of JCML and form the basis for further study of leukemic cell biology in this disease.
Assuntos
Leucemia Mieloide/sangue , Macrófagos/patologia , Monócitos/patologia , Pré-Escolar , Feminino , Humanos , Lactente , Leucemia Mieloide/patologia , Macrófagos/ultraestrutura , Masculino , Microscopia Eletrônica , Monócitos/ultraestruturaRESUMO
We have previously demonstrated the engraftment of human pre-B acute lymphoblastic leukemia (ALL) cells injected intravenously into irradiated scid mice. We now report on the ability of the reconstituted extracellular matrix, Matrigel, to promote the formation of subcutaneous tumors in non-irradiated scid mice by a CD10- pre-B ALL cell line termed G2. Lymphatic tumors infiltrating the dermis were seen in all eight mice sacrificed 10-13 weeks after the co-injection of G2 cells and Matrigel but in only 2/8 mice injected with leukemic cells alone. Infiltration of bone marrow, spleen, thymus, lung and liver was observed earlier and was more extensive in the Matrigel-treated group. The tumor cells derived from Matrigel-treated mice could be passaged in vitro and their colony-forming ability was higher than that of the original G2 line. When re-injected intravenously into non-irradiated scid mice, the tumor cells invaded the thymus earlier than did the G2 cells. The expression of CD10/neutral endopeptidase was induced at high levels in all tumors, in Matrigel or non Matrigel-treated animals. This up-regulation was transient as the tumor variants grown in vitro or in vivo lost expression of CD10. However, 6-8 weeks later, induction of CD10 was observed on both tumor variants and parental G2 cells growing in the thymus and at a lower level on cells in bone marrow and spleen. Culturing G2 cells in vitro at high density or in the presence of documented growth-promoting cytokines such as IL-3, IL-6, IL-7, and GM-CSF did not stimulate the expression of CD10 mRNA. The induction of this surface endopeptidase was thus associated with growth of leukemic cells in the specific microenvironments provided by the lymphoid tumors and the thymus in scid mice. The function of CD10 might be related to the hydrolysis of peptides which are critical in regulating interactions between adjacent pre-B cells, the stromal microenvironment and the transduction of growth and/or differentiation signals.
Assuntos
Colágeno/farmacologia , Laminina/farmacologia , Neprilisina/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Proteoglicanas/farmacologia , Animais , Citocinas/farmacologia , Combinação de Medicamentos , Humanos , Infiltração Leucêmica , Camundongos , Camundongos SCID , Transplante de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Timo/patologia , Células Tumorais CultivadasRESUMO
We have previously demonstrated the engraftment and dissemination of human pre-B acute lymphoblastic leukemia (ALL) cells into scid mice. In the current study, the temporal pattern of infiltration of a CD10- pre-B leukemia line (G2) in various murine tissues and the progression of the disease in the whole animal were monitored by quantifying human CD44 mRNA expression by the polymerase chain reaction (PCR). Irradiated scid mice were injected intravenously with 10(6) G2 cells and killed 3 days to 10 weeks later. After 2 weeks, leukemic cells were found mostly in bone marrow, but also in lung. At 6 to 7 weeks, spleen and lung contained 30% human RNA, while peripheral blood, liver, and kidney contained 2-3%. Infiltration to brain and thymus was observed at 8-9 weeks. In terms of the whole animal, spleen and liver were the major sites of tumor burden. The induction of CD10 expression was previously observed in transplanted CD10- G2 leukemic cells recovered from scid thymus at 10-12 weeks, which corresponds to the terminal stage of disease. In this study, the CD10 expression on the leukemic cells was monitored at earlier time points by flow cytometry and quantitative PCR. Induction of CD10 was first observed in bone marrow, spleen, peripheral blood, and liver at 6-7 weeks (10-fold), at the time of the onset of dissemination of the leukemia. Despite the presence of 30% human RNA in lung at 6-7 weeks, CD10 induction was not significant in that site before 10 weeks. Increased levels of CD10 were seen in all tissues between 8 and 10 weeks; the highest levels were observed in leukemic cells proliferating in thymus (113-fold) and in those found in circulation. These findings suggest that initial induction of CD10 occurs in hematopoietic tissues at the time of rapid proliferation of the leukemic cells and their infiltration of several tissues. At later time points, the increase in CD10 expression is seen on the leukemic cells found in all peripheral organs suggesting an association with disease progression.
Assuntos
Antígenos de Neoplasias/biossíntese , Neprilisina/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Animais , Antígenos de Neoplasias/genética , Sequência de Bases , Ciclo Celular/fisiologia , Fase G2/fisiologia , Expressão Gênica/genética , Humanos , Receptores de Hialuronatos , Infiltração Leucêmica , Camundongos , Camundongos SCID , Dados de Sequência Molecular , Estadiamento de Neoplasias , Neprilisina/genética , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Retorno de Linfócitos/genética , Células Tumorais CultivadasRESUMO
A pre-B acute lymphoblastic leukemia (ALL) cell line with monosomy 7 was established from a child with juvenile chronic myelogenous leukemia (JCML) in lymphoid blast crisis. Analysis of the growth properties of the cell line, termed 'W1' showed an interleukin-1 (IL-1) mediated autocrine pattern of cell proliferation with the following features: W1 colony growth without added growth factor was density-dependent and colony growth was augmented with serum-free autologous cell culture supernatant; exogenous IL-1 beta had a growth-promoting effect on W1 colony numbers when cells were seeded at low density; W1 cells constitutively expressed mRNA for IL-1 beta, and high levels of IL-1 beta were measured in W1 cell lysates; anti-IL-1 beta antibodies as well as IL-1 receptor antagonist markedly suppressed W1 colony growth when either was added to cultures of cells seeded without growth factors at low density; anti-GM-CSF antibodies and anti-IL-3 antibodies had no inhibitory effect on W1 colony growth. Whereas W1 colony growth was also augmented by adding IL-3, IL-4, IL-6, IL-7, GM-CSF, Steel factor and erythropoietin individually to the cultures, W1 cells did not constitutively express mRNA for any of these cytokines. W1 colony growth was markedly suppressed by exogenous TNF-alpha which contrasts sharply with the autocrine growth promoting effect of TNF-alpha on myelomonocytic elements of JCML in 'chronic' phase. The inhibitory effect of TNF-alpha on W1 cells was not due to downregulation of IL-1 production. The IL-1-dependent growth of W1 cells appeared to be unique because none of five other pre-B lineage ALL cell lines established as controls showed an autocrine growth loop via IL-1. W1 cells provide a valuable opportunity to examine the relationship of monosomy 7, B-lineage acute lymphoblastic leukemia, aberrant genetic expression of cytokines and their receptors, and IL-1 mediated autocrine cell growth in cancer.
Assuntos
Linfócitos B/patologia , Crise Blástica , Interleucina-1/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Linfócitos B/metabolismo , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Criança , Citocinas/genética , Citocinas/farmacologia , Expressão Gênica , Substâncias de Crescimento/biossíntese , Humanos , Interleucina-1/antagonistas & inibidores , Interleucina-1/biossíntese , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores de Citocinas/genética , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/genética , Células Tumorais CultivadasRESUMO
We studied a patient with juvenile chronic myelogenous leukemia (JCML) whose terminal course was characterized by transformation to acute lymphoblastic leukemia. Karyotypic studies identified monosomy 7 in leukemic myelomonocytic marrow cells during the chronic phase and in the lymphoblasts during the transformation phase. Our ability to sustain the transformed lymphoblasts in culture allowed us to characterize them further. CD19, HLA-DR, and CD10 were present, consistent with a pre-B acute lymphoblastic leukemia phenotype. CD14 (My-4) and CD13 (My-7) were negative. Rearrangement of immunoglobulin heavy- and light-chain genes identified monoclonal populations of cells of the B lineage. This case provides further evidence that JCML is a clonal disease of pluripotent stem-cell origin.
Assuntos
Crise Blástica/patologia , Cromossomos Humanos Par 7 , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Monossomia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Crise Blástica/genética , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Rearranjo Gênico de Cadeia Leve de Linfócito B , Humanos , Imunofenotipagem , Lactente , Cariotipagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genéticaRESUMO
The sensitivity of the scid mouse model was assessed by comparing the growth of two pre-B acute lymphoblastic leukemia (ALL) cell lines, A1 and G2, established from patients at relapse. When cell numbers varying from 10(4) to 10(7) were injected intravenously into scid mice, advanced growth and dissemination of leukemia was observed at 10-12 weeks with the G2 cells. Bone marrow, spleen and thymus contained high levels of human leukemic cells and infiltration into lung, kidney, liver, and brain was observed. Two of three mice grafted with only 100 cells showed high levels of infiltration at 15 weeks, suggesting that 100 G2 cells was near the limiting cell number that could produce disseminated leukemia. With the A1 line, a minimum of 10(5) cells was needed to obtain dissemination to liver, lung, brain, and kidney; a low level of spleen infiltration occurred and thymus invasion was not observed. In vitro, both lines showed a density dependent growth in clonogenic assays but the cloning efficiency of the A1 line was 10-fold higher than for G2 cells. These results indicate that G2 and A1 lines have a dissimilar aggressiveness in vivo which does not correlate with clonogenic assay in vitro. Neither G2 nor A1 lines, growing in vitro, expressed CD10/CALLA on their surface, despite low levels of antigen on the freshly obtained relapse samples. Although A1 cells remained CD10-negative in the scid mice, G2 cells showed detectable levels of CD10, particularly on those cells found in the thymus. Several subclones of the G2 line were derived from isolated colonies in vitro; they were found to be CD10- in vitro, but to become CD10+ when proliferating into scid mouse thymus, suggesting the induction of CD10 by the murine microenvironment.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Antígenos de Diferenciação/metabolismo , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/análise , Criança , DNA de Neoplasias/análise , Citometria de Fluxo , Humanos , Cinética , Camundongos , Invasividade Neoplásica , Transplante de Neoplasias/patologia , Neprilisina , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Retorno de Linfócitos/análise , Células Tumorais Cultivadas/patologia , Ensaio Tumoral de Célula-TroncoRESUMO
Multidetector-row CT (MDCT) scanners have dramatically improved liver imaging. With the newest generation of 40-64 row scanners, true isotropic imaging with a z-axis resolution of 0.3-0.6 mm has become possible. Acquisition time for the scan has been shortened to a few seconds. To fully exploit the advantages of MDCT scanners in liver imaging, the examination protocols have to be optimized with regard to contrast material flow rate, scan delay, and the number of scans performed. The possible advantages of double arterial phase scans in the detection of HCC are discussed. The clinical value of 3D reconstructions, such as multiplanar reconstructions and curved planar reconstructions, for assessment of the vascular and biliary duct infiltration is demonstrated. Optimized MDCT imaging improves detection and characterization of focal liver lesions.
Assuntos
Neoplasias dos Ductos Biliares/diagnóstico por imagem , Ductos Biliares Intra-Hepáticos/diagnóstico por imagem , Carcinoma Hepatocelular/diagnóstico por imagem , Colangiocarcinoma/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Hepatopatias/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Fígado/lesões , Tomografia Computadorizada Espiral , Meios de Contraste/administração & dosagem , Diagnóstico Diferencial , Humanos , Fígado/diagnóstico por imagem , Ruptura , Sensibilidade e Especificidade , Tomografia Computadorizada Espiral/instrumentaçãoRESUMO
The effect on marrow myeloblast colony formation in blood from nine patients with acute myeloid leukemia was studied by using three recombinant-DNA-derived human leukocyte interferons (IFN alpha 2, IFN alpha-A, and IFN alpha-C). In preliminary experiments, a brief exposure of leukemic marrow cells to IFN alpha resulted in a sharp increase in the IFN-induced enzyme 2-5A synthetase, indicating the expression of IFN cell receptors as well as the ability of leukemia cells to respond metabolically. Dose-response studies showed a dose-dependent suppression of myeloblast colony formation in all experiments using concentrations of 10(2)-10(5) U/ml of the three IFN subtypes. In self-renewal assays derived from the primary cultures that initially contained IFN alpha 2, a "carryover" antiproliferative effect was observed with a dose-dependent decline in secondary growth. In comparison studies of IFN alpha-A and IFN alpha-C, the suppressive effect on primary myeloblast growth was much more pronounced with IFN alpha-C at concentrations of 10(3) U/ml and higher; in self-renewal assays, the antiproliferative effect of IFN alpha-C on secondary growth was no longer observed, whereas that of IFN alpha-A persisted. These three subtypes of gene-cloned IFN have antileukemic properties in vitro, with differences in degree of suppression of primary myeloblast growth and of self-renewal.
Assuntos
Interferon Tipo I/farmacologia , Leucemia Mieloide Aguda/patologia , 2',5'-Oligoadenilato Sintetase/metabolismo , Adolescente , Medula Óssea/patologia , Divisão Celular , Células Cultivadas , Criança , Ensaio de Unidades Formadoras de Colônias , DNA Recombinante , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucemia Mieloide Aguda/enzimologia , MasculinoRESUMO
The type of a biomarker - whether it is prognostic or predictive - is frequently not known, although such information is crucial for assessing the clinical value of a marker. In order to evaluate the type of marker TP53 is, we identified a cohort of 76 patients with colorectal liver metastases (CLM), homogeneously staged as resectable, who had been treated either with or without fluorouracil-based neoadjuvant chemotherapy. The TP53 genotype was assessed retrospectively from paraffin-embedded, diagnostic tumour biopsies using a standardised, p53 gene-specific sequencing protocol (mark53(®) kit). The overall median survival was 44.2 months, and the overall TP53 mutation frequency was 55%. A significant interaction was observed between chemotherapy and TP53 status (P = 0.045). To illustrate this effect, the 51 patients with and the 25 patients without neoadjuvant chemotherapy were described separately. In patients with neoadjuvant chemotherapy, mutated TP53 was significantly associated with poor survival (P = 0.0025), resulting in five-year survival rates of 22%, compared to 60% in patients with normal TP53. The hazard ratio was 3.12 (95% confidence intervals (CI): 1.46-6.95) to the disadvantage of TP53-mutated patients and 5.49 (P = 0.0001; 95% CI: 2.28-13.24) after adjustment for known prognostic factors. In patients treated with surgery alone, a mutated TP53 did not have a negative effect on survival (P = 0.54). A mutated TP53 status independently predicted survival disadvantage in CLM patients in the presence, but not in the absence, of neoadjuvant chemotherapy. Our data suggest that TP53 might be a pure predictive marker.
Assuntos
Neoplasias Colorretais/patologia , Genes p53/genética , Neoplasias Hepáticas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Estudos de Coortes , Neoplasias Colorretais/mortalidade , Feminino , Fluoruracila/administração & dosagem , Marcadores Genéticos , Genótipo , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Mutação , Terapia Neoadjuvante , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Prognóstico , Modelos de Riscos Proporcionais , Taxa de SobrevidaRESUMO
L-Arginine plays an important role in protecting animals against ammonia intoxication, enhances immune function, stimulates wound healing, and is the precursor for the endothelium-derived relaxing factor, recently recognized as nitric oxide (NO). In this study, we investigated the influence of hepatic reperfusion on amino acid metabolism after human OLT. After 10 sec of reperfusion, the arterial plasma levels of L-arginine dropped from 105 +/- 12 mumol/L to 3.8 +/- 0.6 mumol/L (P < 0.001), whereas plasma ornithine increased from 40 +/- 5.5 mumol/L to 129 +/- 15 mumol/L (P < 0.001). The reduced L-arginine levels remained subnormal for several hours after OLT. This drop in plasma L-arginine was due to an arginase release from the implanted graft. Immediately after reperfusion, the plasma concentrations of arginase increased from pretransplantation values of 18 +/- 13 IU/L to 2384 +/- 1456 IU/L (P < 0.01). Measurement of plasma nitrite (NO2-) and nitrate (NO3-), which are the stable end products of NO, revealed that NO2- decreased about 50% after reperfusion (from 1.64 +/- 0.32 mumol/L to 0.80 +/- 0.17 mumol/L; P < 0.001), whereas NO3- levels remained unchanged (76 +/- 23 mumol/L vs. 63 +/- 8 mumol/L). We conclude that hepatic reperfusion causes L-arginine deficiency by liberating high amounts of arginase from the implanted graft. This L-arginine depletion may influence the NO synthesis in patients after OLT.
Assuntos
Arginina/deficiência , Transplante de Fígado , Adulto , Arginase/sangue , Arginase/metabolismo , Arginina/sangue , Feminino , Veia Femoral/química , Humanos , Transplante de Fígado/fisiologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Artéria Radial/químicaRESUMO
Several studies have shown that the postoperative course of cytokines such as TNF-alpha or IL-6 is predictive of rejection and infection after human orthotopic liver transplantation (OLT). The aim of this prospective clinical trial was to evaluate the impact of transhepatic metabolism of endotoxin (ET), tumor necrosis-factor-alpha (TNF-alpha), and interleukin-6 (IL-6) after hepatic ischemia/reperfusion on the postoperative graft function. In 13 consecutive elective adult OLT patients with primary grafts, we determined concentrations of ET, TNF-alpha, and IL-6 in the radial artery, portal vein, and right hepatic vein at 1, 4, 7, 10, and 13 min after reperfusion. Of the 13 patients, four had ET levels below the detection limit (< 10 ng/L), and one patient had extremely high ET concentrations (151 ng/L in the hepatic vein). In the remaining patients the mean ET levels were 26 +/- 14, 26 +/- 15, and 24 +/- 14 ng/L in the portal vein, hepatic vein, and in the radial artery, respectively. These values indicate that in patients with a moderately elevated ET level, no transhepatic concentration differences of ET exist. However, in the patient with severe endotoxemia, the liver was apparently an ET-producing organ (HV-P: 29 +/- 13 ng/L). TNF-alpha levels were not measurable in four patients, and varied between 15 and 72 pg/ml (portal vein) in the remaining patients. The transhepatic concentration differences (HV-P and HV-A, respectively) of patients with PNF or dysfunction were higher than in those with "good" or "excellent" graft function (HV-P: 160 +/- 122 pg/ml vs. 7.3 +/- 9.7 pg/ml; P < 0.01 and HV-A: 137 +/- 101 pg/ml vs. 3.9 +/- 12 pg/ml; P < 0.01, respectively). Arterial IL-6 levels were below 88 pg/ml (mean value: 31 +/- 20 pg/ml) at the beginning of the operation, and increased considerably in three patients during the anhepatic phase and after reperfusion. No clinical correlation was found with the transhepatic concentration differences of IL-6. We conclude that in OLT patients without infection no transhepatic ET exchange was documented. However, a stimulated hepatic TNF-alpha release seems to be predictive of the beginning of liver dysfunction.
Assuntos
Endotoxinas/sangue , Interleucina-6/sangue , Circulação Hepática/fisiologia , Transplante de Fígado/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Adolescente , Adulto , Idoso , Feminino , Sobrevivência de Enxerto , Veias Hepáticas , Humanos , Masculino , Pessoa de Meia-Idade , Veia Porta , Estudos Prospectivos , Artéria Radial , ReperfusãoRESUMO
BACKGROUND: The release of liver arginase after orthotopic liver transplantation (OLT) causes a deficiency of L-arginine and nitrite in the plasma. This deficiency is possibly related to pulmonary hypertension and reduced hepatic blood flow, which are commonly observed in the immediate reperfusion period. The aim of this study was to evaluate the impact of L-arginine supplementation on metabolic and hemodynamic parameters during liver reperfusion after OLT in pigs. METHODS: Thirteen pig OLTs (control group, n=6; arginine group, n=7) were performed by a standard technique. Cold ischemic time was 20 hr. L-Arginine was infused at a dosage of 500 mg/kg body weight into the donor pigs (30 min before liver explantation) and also into the recipients (over a period of 3 hr from the beginning of the reperfusion period). At the end of the experimental study, the pigs were killed with an overdose of potassium. RESULTS: In the control group, liver revascularization increased plasma arginase concentrations (+615%) and reduced plasma levels of L-arginine (-87%), nitrite (-82%), and nitrate (-53%). Infusion of L-arginine increased plasma levels of L-arginine from 94+/-21 micromol/L to 1674+/-252 micromol/L (P<0.001), L-ornithine from 46+/-8 micromol/L to 2215+/-465 micromol/L (P<0.001), and L-citrulline from 58+/-8 micromol/L to 116+/-34 micromol/L (P<0.001), but had no effect on plasma levels of nitrite and nitrate. Administration of L-arginine in the donor pigs did not produce any systemic or organ-specific hemodynamic alterations. Infusion of L-arginine into the recipient pigs improved cardiac performance (increase in heart rate [+61%, P=0.017] and cardiac index [+53%, P=0.005], reduction in pulmonary capillary wedge pressure [-54%, P=0.014]). Moreover L-arginine infusion increased oxygen consumption (+65%, P=0.003), reduced pulmonary vascular resistance index (P=0.001), stimulated portal venous blood flow (P=0.014), and elevated body temperature during the reperfusion period (P=0.007). CONCLUSIONS: From these data, we conclude that the infusion of L-arginine during OLT improves the hemodynamic performance of the heart, lung, and liver.
Assuntos
Arginina/farmacologia , Débito Cardíaco/fisiologia , Hipertensão Pulmonar/tratamento farmacológico , Transplante de Fígado/efeitos adversos , Fígado/irrigação sanguínea , Resistência Vascular/efeitos dos fármacos , Animais , Arginina/sangue , Nitrogênio da Ureia Sanguínea , Feminino , Hemodinâmica/fisiologia , Humanos , Hipertensão Pulmonar/etiologia , Infusões Intravenosas , Circulação Hepática/efeitos dos fármacos , Circulação Hepática/fisiologia , Masculino , Nitratos/sangue , Nitritos/sangue , Oxigênio/sangue , Traumatismo por Reperfusão/tratamento farmacológico , SuínosRESUMO
BACKGROUND: A 35-year period of clinical development resulted in orthotopic liver transplantation (OLT) becoming a standardized surgical procedure. Despite this progress, the rate of technical complications is still high. Although the main problem in most analyses is vascular or bile duct failure, we observed a remarkable number of parenchymal liver injuries that led to intraoperative problems. Our aim, therefore, is to present an overall report on the incidence, treatment, and clinical course of parenchymal liver injuries in OLT. METHODS: Five hundred seventy-two consecutive OLT procedures performed between 1988 and 1998 were analyzed in a retrospective study. Parenchymal liver injury was diagnosed by means of examination of the surgical reports. Donor- and recipient-related data followed the medical report. The lesions were classified according to the Organ Injury Scale. RESULTS: Parenchymal liver injury was diagnosed in 23 patients (4%). The lesions were classified as grade Ia (13.1%), grade Ib (13.1%), grade IIb (52.1%), grade IIIa (17.1%), and grade IIIb (4.3%). In 19 patients (82.6%), the lesion was detected during OLT, and in four patients (17.4%), during relaparotomy. The latter group showed significantly higher-grade injuries. Treatment was suture or fibringlue alone, 17.4%; fibringlue and hemostyptics, 26.1%, mesh wrapping 30.4%, and mesh packing 26.1%. Seven patients (30.4%) underwent relaparotomy. Further active bleeding was not found in any of them. Statistical analysis found a correlation between injury grade and relaparotomy rate. No patients died as a result of parenchymal liver injury. CONCLUSIONS: Parenchymal liver injuries can be treated well, with no adverse effect on patient or graft survival. An early decision concerning the surgical procedure for controlling hemorrhage is required. A basically aggressive therapeutic approach might avoid further complications relating to reperfusion edema.
Assuntos
Transplante de Fígado/métodos , Transplante de Fígado/fisiologia , Fígado/patologia , Adulto , Cadáver , Causas de Morte , Feminino , Hemorragia , Humanos , Fígado/lesões , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/terapia , Reoperação , Estudos Retrospectivos , Doadores de Tecidos/estatística & dados numéricosRESUMO
The human leukemic cell line B1, is characterized by a specific 4;11 chromosomal translocation, immature myeloid/pre-B biphenotypic features, expression of multiple cytokine receptors and IL-1-dependent autocrine growth regulation [Cohen et al. (1991) Blood 78, 94]. Exposure of B1 cells to low concentrations of IL-6 abolished the leukemic cells ability to form colonies in semi-solid medium and slowed down their proliferation rate in suspension. Associated with these changes in growth characteristics, the B1 cells differentiated along the myeloid lineage as judged by the induction of the myeloid-specific surface antigens CD33, CD13 and CD11b, as well as histochemical and morphological changes characteristic of myeloid cells. The induction of differentiation was specific to IL-6 since none of the other cytokines which inhibited B1 cell growth (IL-7, gamma IFN and TNF alpha) were able to induce myeloid or lymphoid differentiation in these cells. The IL-6-induced differentiation was completed over a two week period and was essentially irreversible. Together with the phenotypic changes, IL-6 induced the expression of the protein tyrosine phosphatase (CD45) which may be associated with altered growth observed in IL-6-treated cells. Induction of terminal differentiation of leukemic cells by recombinant bioregulators has therapeutic implications and merits further study.
Assuntos
Interleucina-6/farmacologia , Leucemia Mieloide/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Medula Óssea/patologia , Diferenciação Celular , Divisão Celular , Humanos , Leucemia Mieloide/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/enzimologia , Proteínas Tirosina Fosfatases/metabolismo , Células Tumorais Cultivadas/enzimologia , Células Tumorais Cultivadas/patologiaRESUMO
BACKGROUND: In this study we compared the expression of selected monocyte surface antigens with the potential to transmigrate through an endothelial layer before and after surgery from breast cancer patients (CA) and patients with benign disease of the breast (BE). MATERIALS AND METHODS: Transmigration capacity of mononuclear cells was determined after isolation by Ficoll density gradient, layered over human umbilical vein endothelial cells and cultured in a two chamber plate added with fMLP as a chemotactic stimulus. We determined monocyte phenotye (HLA-DR, FcgRI/CD64, CR1/CD11b and LFA-1/CD11a) and the phagocytosis of E. coli by flow cytometry. RESULTS: Before surgery blood monocytes had an equal expression of the measured surface antigens, but were different in regard to their interaction with endothelial cells. Monocytes derived from CA had a higher transmigration potency than those of BE. Moreover, the migration through the endothelial cell layer created different populations of monocytes. Surgical stress modified transmigrated monocytes of BE into the direction of monocytes from CA. Phagocytic capacity of peripheral blood monocytes from CA was significantly diminished and was further reduced after surgery when measured in transmigrated cells. CONCLUSION: Our study shows that monocytes from CA and BE can be discriminated in regard to their interaction with endothelial cells.