Assuntos
Adenocarcinoma/cirurgia , Colectomia/métodos , Neoplasias do Colo/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Cirurgia Vídeoassistida/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Estudos de Coortes , Colo Transverso/cirurgia , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/patologia , Linfonodos/cirurgia , Masculino , Mesocolo/cirurgia , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours. METHODS: This prospective multicentric study involved 251 stage I-III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CpG island methylation phenotype status, ploidy, S-phase, LOH. RESULTS: The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR. CONCLUSIONS: Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.
Assuntos
Adenocarcinoma/genética , Neoplasias Colorretais/genética , Di-Hidrouracila Desidrogenase (NADP)/metabolismo , Recidiva Local de Neoplasia/genética , Timidilato Sintase/metabolismo , Adenocarcinoma/enzimologia , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/mortalidade , Reparo de Erro de Pareamento de DNA , Análise Mutacional de DNA , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , França , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Polimorfismo Genético , Modelos de Riscos Proporcionais , Estudos ProspectivosRESUMO
BACKGROUND: In advanced colorectal cancer, K-Ras somatic mutations predict resistance to mAbs targeting epidermal growth factor receptor (EGFR). Relationships between K-Ras mutations and EGFR status have not been examined so far. We analyzed relationships between K-Ras mutations and EGFR tumoral status based on EGFR germinal polymorphisms, gene copy number and expression. METHODS: Eighty colorectal tumors (stage 0-IV) and 39 normal mucosas were analyzed. K-Ras mutations at codons 12 and 13 were detected by a sensitive enrichment double PCR-restriction fragment length polymorphism (RFLP) assay. EGFR gene polymorphisms at positions -216G>T, -191C>A and 497Arg>Lys were analyzed (PCR-RFLP), along with CA repeat polymorphism in intron 1 (fluorescent genotyping) and EGFR gene copy number (PCR amplification). EGFR expression was quantified by Scatchard binding assay. RESULTS: The number of EGFR high-affinity sites, dissociation constant (Kd), gene copy number, intron 1, -216G>T, -191C>A or 497Lys>Arg genotypes was not different between K-Ras-mutated or K-Ras-non-mutated tumors. No relationship was observed between any of the analyzed EGFR genotypes and EGFR expression. EGFR expression was not related to gene copy number. EGFR gene copy number in tumor and normal tissue was not correlated. The mean value of the tumor/normal mucosa gene copy number ratio was 1.16. CONCLUSIONS: Present data clearly show that EGFR status is independent of K-Ras mutations in colorectal tumors.
Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Receptores ErbB/metabolismo , Genes ras , Idoso , Idoso de 80 Anos ou mais , Feminino , Dosagem de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Estudos RetrospectivosRESUMO
BACKGROUND: Advances in the understanding of tumor biology have led to the development of targeted therapies allowing progress in colorectal cancer treatment. One of the most promising targets is the epidermal growth factor receptor (EGFR). METHOD: The presence and distribution of high- and low-affinity EGFR was investigated retrospectively in a group of 82 colorectal cancer samples (43 normal colon-colon cancer paired samples) using a specific ligand binding assay (Scatchard Analysis). FINDINGS: A large majority of tumor samples exhibited one class of high-affinity binding sites (78%). Eighteen cases (22%) exhibited both high- and low-affinity binding sites. A wide interpatient variability was observed for the site number, with physiologically-relevant high-affinity sites ranging from 7 to 310 fmol/mg protein in tumors and from 6 to 313 fmol/mg protein in normal mucosa. A significant positive correlation was demonstrated between tumor and normal mucosa for the high-affinity Kd values and for the number of high-affinity sites, suggesting a common regulation for both tumor and normal tissue. INTERPRETATION: These observations (i) could explain recently-reported clinically-active EGFR targeting in colorectal tumors apparently negative for EGFR, and (ii) may offer a plausible explanation for the link observed between toxicity in normal tissue (cutaneous rash) and clinical outcome of patients treated with anti-EGFR drugs. Present data extends our understanding of EGFR identity in colorectal cancer which could be useful in reconsidering the predictive tools for the identification of tumors putatively responsive to EGFR targeted therapy.
Assuntos
Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Receptores ErbB/metabolismo , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Cinética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos RetrospectivosRESUMO
Tumoral thymidine phosphorylase (TP) appears to play a dual role by being involved in neoangiogenesis and by activating 5FU prodrugs at the tumoral target site. The aim of the study was to investigate more thoroughly these potential physiological and pharmacological roles of TP. A rat carcinoma cell line (PROb) was transfected with TP/PD-ECGF in order to study the effect of the overexpression of this enzyme (1) on the sensitivity of cells to 5'DFUR and 5FU in vitro and (2) on tumour growth in vivo by using a syngenic tumour model in the BDIX rat (hepatic tumours, sub-cutaneous tumours). Cytotoxic effects of 5'DFUR, and to a lesser extent those of 5FU, were enhanced in TP clones as compared to control cells: there was a highly significant correlation between TP activity and in vitro sensitivity to 5'DFUR (r2= 0.91, P = 0.0002, n = 8) and, to a lesser extent, to 5FU (r2= 0.49, P = 0.053, n = 8). The impact of TP transfection on tumour growth was relatively modest and concerned only the initial stages of tumour expansion. Staining of TP tumours for endothelial (factor VIII) cells was always higher than controls. The staining ratio (TP/controls) tended to be reduced as tumours increased in size. The stability of TP expression was checked both in vitro (TP activity measurement) and in vivo (RT-PCR determinations) and there was no loss of TP expression over time which could be advanced to explain the progressive weakening of the impact of TP overexpression on both tumour growth and neoangiogenesis.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias do Colo/irrigação sanguínea , Floxuridina/farmacologia , Fluoruracila/farmacologia , Neovascularização Patológica/enzimologia , Timidina Fosforilase/metabolismo , Animais , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Formazans , Transplante de Neoplasias , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Pentosiltransferases/metabolismo , Pirimidina Fosforilases , Ratos , Sais de Tetrazólio , Timidina Fosforilase/genética , Transfecção , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/enzimologiaRESUMO
In vitro and clinical studies have suggested that high-frequency microsatellite instability (MSI-H) phenotype, p53 and K-ras mutations might influence the response to chemotherapy in a variety of tumors, including primary colorectal cancers (CRC). Unresectable hepatic metastases from CRC are commonly treated with 5-fluorouracil (5FU) and folinic acid. Since several new active drugs are now used for treating CRC, molecular determinants predictive to response to 5FU would thus be crucial for optimizing indications of chemotherapy to those patients. MSI-H phenotype, p53 and K-ras status were characterized in a prospective study of 56 patients with CRC metastatic to the liver and treated with 5FU-based chemotherapy. The objective response rate after a 3-month treatment was 32.1%. The prevalence of p53 mutations, K-ras mutations and MSI-H phenotype was 62.5%, 30.3% and 1.8%, respectively. No significant association was found between response to chemotherapy and p53 mutations (78% mutated tumors in responders vs. 55% in nonresponders; p = 0.10) and K-ras mutations (39% mutated tumors in responders vs. 26% in nonresponders; p = 0.34). Survival was longer for patients with p53-mutated metastases than for patients with unresected wild-type p53 metastases (median survival 15 months vs. 17 months; p = 0.06). The determination of the MSI-H phenotype, p53 and K-ras status in hepatic metastases from CRC does not discriminate a group of patients that should preferentially benefit from 5FU-based chemotherapy. The prognosis of patients with treated liver metastases is better when p53 is mutated.
Assuntos
Neoplasias Colorretais/genética , Genes ras , Neoplasias Hepáticas/genética , Repetições de Microssatélites/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Prospectivos , Taxa de SobrevidaRESUMO
UNLABELLED: Suicide gene therapy consists of transferring into tumor cells a viral or bacterial gene encoding for an enzyme which converts a non-toxic product into a lethal drug. STUDY AIM: To analyze the therapeutic potential of vaccination with tumor cells expressing the bacterial cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) treatment in a rat liver metastasis model. MATERIAL AND METHOD: We used a rat colon carcinoma cell line which, after subcapsular or intraportal injection in syngenic animals, generates single or multiple experimental liver metastases, respectively. We have shown that introduction of a vector expressing the CD gene in this colon carcinoma cell line results in 5-FC sensitivity (PRObCD). RESULTS: Intrahepatic subcapsular injection of PRObCD tumor cells, followed by 5-FC treatment, induces total regression of a wild-type tumor pre-established in the contralateral liver lobe in 45% of animals with a 96% decrease in mean volume (p < 0.0001), demonstrating the existence of a distant bystander effect. This vaccination significantly increased the survival of rats with single (log-rank p < 0.0001) or multiple (log-rank p = 0.01) liver metastasis CONCLUSIONS: These results suggest that suicide gene-modified tumor cells can act as potent therapeutic vaccines against liver metastasis from colon carcinoma.
Assuntos
Antimetabólitos/uso terapêutico , Neoplasias do Colo/patologia , Flucitosina/uso terapêutico , Terapia Genética , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Nucleosídeo Desaminases/uso terapêutico , Animais , Antimetabólitos/administração & dosagem , Citosina Desaminase , Modelos Animais de Doenças , Flucitosina/administração & dosagem , Neoplasias Hepáticas/genética , Masculino , Nucleosídeo Desaminases/administração & dosagem , Ratos , Vacinação/veterináriaRESUMO
Supernumerary ring and large marker chromosomes are a characteristic of atypical lipomas and well-differentiated liposarcomas (ALP-WDLPS) and are composed of amplified 12q14-15 sequences in association with variable segments from other chromosomes. Although stably transmitted, these chromosomes contain centromeric alterations, showing no detectable alpha-satellite sequences. We performed C-banding, fluorescence in situ hybridization, and immunostaining with anti-centromere antibodies in 8 cases of liposarcomas with supernumerary rings and large markers, including 5 ALP-WDLPS and 3 dedifferentiated-LPS and high-grade LPS. Our results with alpha-satellite probes and anti-CENPB antibodies confirm the lack of detectable alpha-satellite sequences in the five ALP-WDLPS supernumerary chromosomes, whereas centromeric activity was proved by the detection of kinetochores by using anti-CENPC antibodies. In contrast, the high grade and dedifferentiated liposarcomas showed a different pattern. In 2 cases, amplified chromosome 12 sequences, including amplification of alpha-satellite 12 sequences in 1 case, were present on chromosomes with typical centromeres. In another case, the rings were similar to WDLPS-ALP rings, but a large marker contained a chromosome 5 centromere and amplified alpha-satellite sequences from chromosome 8. ALP-WDLPS is the first example of a tumor class for which the presence of stable analphoid chromosomes is a constant and specific abnormality. Formation of newly derived centromeres, so-called neocentromeres, could be an original and effective way to maintain a selective advantage in neoplastic cells by conferring stability to the supernumerary chromosomes of ALP-WDLPS. The activation of normally non-centromeric sequences might be obtained by an epigenetic mechanism due to the peculiar chromatin conformation of these highly complex chromosomes.
Assuntos
Centrômero/genética , Lipossarcoma/genética , Southern Blotting , Diferenciação Celular/genética , Feminino , Marcadores Genéticos/genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Cariotipagem , Lipossarcoma/classificação , Lipossarcoma/patologia , Masculino , Células Tumorais CultivadasRESUMO
BACKGROUND: The cytosine deaminase gene of Escherichia coli converts the nontoxic compound 5-fluorocytosine into 5-fluorouracil (5-FU), thereby acting as a suicide gene when introduced into cancer cells, killing the cells when they are exposed to 5-fluorocytosine. We analyzed the efficacy of using cytosine deaminase-bearing cancer cells as an autologous tumor vaccine in a rat model that mimics liver metastasis from colon carcinoma. METHODS: We introduced a plasmid vector containing the E. coli cytosine deaminase gene into a BDIX rat colon carcinoma cell line. Intrahepatic injection of the modified cells in syngeneic animals generates a single experimental liver "suicide tumor." We then analyzed the effect of 5-fluorocytosine treatment in terms of regression of cytosine deaminase-expressing cells in vivo as well as protection against wild-type cancer cells. RESULTS: Treatment with 5-fluorocytosine induced regression of cytosine deaminase-expressing (CD+) tumors, with seven of 11 treated animals being tumor free at the end of 30 days and a statistically significant difference in tumor volumes between treated and control animals (two-sided P<.0001). Intrahepatic injection of CD+ cells followed by 5-fluorocytosine treatment rendered the treated animals resistant to challenge with wild-type tumor cells, with no (zero of seven) treated animals developing wild-type tumors in contrast to all (four of four) control animals. Moreover, in animals with established wild-type liver tumors, injection of CD+ tumor cells followed by 5-fluorocytosine treatment produced a statistically significant increase in survival time (two-sided P<.0001). In vivo immunodepletion and immunohistologic analysis of experimental tumors indicate that natural killer cells are the major immune component involved in this antitumor effect. CONCLUSIONS AND IMPLICATIONS: Taken together, these results suggest the potential use of suicide gene-modified tumor cells as therapeutic vaccines against liver metastasis from colon carcinoma.
Assuntos
Antifúngicos/farmacologia , Antimetabólitos/farmacologia , Vacinas Anticâncer , Flucitosina/farmacologia , Terapia Genética , Neoplasias Hepáticas/terapia , Nucleosídeo Desaminases/genética , Animais , Antineoplásicos , Vacinas Anticâncer/farmacologia , Neoplasias do Colo/patologia , Citosina Desaminase , Escherichia coli/enzimologia , Citometria de Fluxo , Fluoruracila , Células Matadoras Naturais , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Masculino , Ratos , Transfecção , Células Tumorais CultivadasRESUMO
The cytotoxic effects of Tomudex (TX) were investigated on a panel of 15 human tumor cell lines expressing a spontaneous sensitivity to the tested agent. We determined the basal cellular amount of relevant cellular factors potentially related to the cytotoxic efficacy of or resistance to TX. We selected thymidylate synthase (TS) as the target for TX, basal reduced folates (RF), because RF may compete with TX for a common site on the TS molecule. We also tested folylpolyglutamate synthetase (FPGS) because this is the enzyme which transforms the drug into its active polyglutamated form. Results were as follows. There was a wide inter-cell line variability in IC50 values for TX and there were marked differences between cell lines for all tested biochemical parameters. No link was observed between basal cellular TS activity and TX cytotoxic efficacy. There was an inverse relationship between reduced folate cellular content and TX IC50 values; this relationship did not, however, reach statistical significance. The only significant relationship was found between basal cellular FPGS activity and TX IC50r = -0.56, p = 0.03. Tumor cells with a relatively high FPGS activity were more sensitive to TX cytotoxic effects and vice versa. Along with previous results which showed that acquired resistance to TX is accompanied by a decrease in FPGS activity, the present data are strongly indicative of a prominent role played by FPGS activity in the intrinsic sensitivity to TX. Means to up-regulate FPGS activity with pharmacological or tumor-specific genetic approaches are recommended so as to optimize TX antitumor activity.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Peptídeo Sintases/metabolismo , Quinazolinas/farmacologia , Tiofenos/farmacologia , Timidilato Sintase/antagonistas & inibidores , Animais , Humanos , Ratos , Células Tumorais CultivadasRESUMO
BACKGROUND: Electrochemotherapy, which consist of local or systemic administration of a cytotoxic agent followed by application of electric pulses to a tumor, has proved effective for various types of tumors in animals and for cutaneous and head and neck cancers in human beings. This is the first study to investigate the efficacy of electrochemotherapy for treatment of hepatic metastases of colorectal cancer in the rat. METHODS: After induction of a solitary hepatic metastasis in 36 male BDIX rats, the animals were randomized to one of four groups: B-E-(no treatment), B+E-(intratumoral bleomycin), B-E+ (application of electric pulses to the tumor), and B+E+ (electrochemotherapy: intratumoral bleomycin followed by application of electric pulses). RESULTS: Groups B-E and B-E+ had no tumor response. Group B+E had one partial response. Group B+E+ had seven partial responses and two complete responses. The difference in terms of response between group B+E+ and the other three groups was statistically significant (P < .05). Comparison of the mean posttherapy tumor volumes (B-E-, 50.6 mm3; B+E-, 58.7 mm3; B-E+, 46 mm3; and B+E+, 5.65 mm3) revealed a significantly smaller residual tumor in group B+E+ than in the other three groups (P < .05). CONCLUSIONS: Electrochemotherapy is an effective means to reduce the volume of hepatic metastases of colorectal cancer in the rat. Additional research is required to determine the optimum treatment duration, dose effects, volume of tumor that can be treated by electrochemotherapy, and impact on survival. Such experimental studies are indispensable prerequisites for clinical trials.
Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Bleomicina/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Animais , Terapia Combinada , Terapia por Estimulação Elétrica , Masculino , Transplante de Neoplasias , Ratos , Ratos EndogâmicosRESUMO
The purpose of this study was to investigate folate-related predictors of 5-fluorouracil (5-FU) cytotoxicity in the presence or absence of l-folinic acid (l-FA). Intracellular concentrations of the reduced folates (tetrahydrofolate + 5,10-methylenetetrahydrofolate) and folylpolyglutamate synthetase (FPGS) activity were determined in 14 human cancer cell lines expressing a spontaneous sensitivity to 5-FU. On these 14 cell lines grown without l-FA supplementation, a significant positive correlation was demonstrated between basal intracellular folate concentration and FPGS activity. 5-FU sensitivity (IC50 range 0.6-25.4 microM) was not related to the basal intracellular folate concentration, whereas, significantly, it was linked to FPGS activity (range 2.5-11.1 pmol/min/mg protein): the higher the FPGS activity, the greater the 5-FU sensitivity. Under l-FA supplementation (0.01-300 microM), intracellular reduced folates increased continuously without evidence of saturation in all cell lines; the pattern of accumulation was independent of the FPGS activity. l-FA enhanced 5-FU cytotoxicity by a factor of 1.9-6.4 in 12 of the 14 cell lines. In the 12 FA-sensitive cell lines, the l-FA concentrations allowing 90% of maximum 5-FU potentiation [l-FA]90 ranged between 0.7 and 107.9 micro M (median 1.9); in contrast, the intracellular concentrations of reduced folates allowing 90% of maximum 5-FU potentiation were much less variable (range 7.6-38.3, median 24.8 pmol/mg protein). In the presence of [l-FA]90, 5-FU sensitivity remained significantly correlated to the basal FPGS activity. In addition, reduced folates were measured in 96 tumoral samples (50 head and neck, 16 colon, 30 liver metastases from colorectal cancer) taken before treatment. Almost all investigated tumours had folate concentrations below the median concentration required for optimal 5-FU potentiation in vitro: median levels (range, pmol/mg protein) were 3.8 (0-17.7) for head and neck, 5.8 (2.3-12.0) for colon and 12.1 (1.7-118.5) for liver metastases. Above all, these data establish the relevance of FPGS activity for predicting the efficacy of 5-FU modulated by FA or not and point to the potential clinical interest of FPGS determination in human tumours.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Fluoruracila/uso terapêutico , Ácido Fólico/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Peptídeo Sintases/metabolismo , Antídotos/uso terapêutico , Biópsia , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Leucovorina/uso terapêutico , Neoplasias/enzimologia , Células Tumorais CultivadasRESUMO
Thymidylate synthase (TS) is the main target for fluorouracil (FU). Optimal cellular concentrations of reduced folates in polyglutamated forms [via folylpolyglutamate synthetase (FPGS)] are necessary for achieving maximal TS inhibition. The aim of this multicentric prospective study was to analyze the link between clinical response to FU therapy for liver metastases of colorectal carcinoma and tumoral TS and FPGS activities. Forty-four advanced colorectal cancer patients (15 women and 29 men; median age 63, range, 27-78 years) receiving a standard FU-folinic acid protocol were included. A single hepatic tumoral biopsy was obtained systematically at the time of diagnosis. For 24 patients, a biopsy in the primary colon tumor was available. TS and FPGS activities were measured by radioenzymatic assays. Clinical response on hepatic metastases was 1 complete response, 12 partial responses, 14 stabilizations, and 17 progressions. In hepatic biopsies, TS activity (median, 185; range, <10-3111 fmol/min/mg protein) and FPGS activity (median, 1270; range, <400-3730 fmol/min/mg protein) exhibited a wide variability. TS activity in primary tumors (median, 461; range, 35-2565 fmol/min/mg protein) was significantly higher than in hepatic metastases. No difference was observed between primaries and metastases for FPGS. FPGS activity expressed in liver metastases was significantly correlated to that expressed in primaries. The distribution of TS activity in liver metastases was not significantly different between responsive and nonresponsive patients. However, FPGS activity measured in liver metastases was significantly higher in responsive patients (median, 1550 fmol/min/mg protein) than in nonresponsive patients (median, 1100 fmol/min/mg protein). A discriminant analysis revealed that 24 of the 25 patients exhibiting a liver FPGS activity =1100 fmol/min/mg protein and/or a liver TS >320 fmol/min/mg protein were nonresponding patients. These data establish for the first time the potential importance of tumoral FPGS activity for assessing FU-folinic acid responsiveness in the clinical setting.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/cirurgia , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Peptídeo Sintases/metabolismo , Adulto , Idoso , Biópsia , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Análise Discriminante , Feminino , Humanos , Neoplasias Hepáticas/enzimologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Timidilato Sintase/metabolismoRESUMO
The aim of this study was to examine the results of a policy in the treatment of acute pancreatitis (AP): initial abstention, management in intensive care unit, surgery in cases of complication (infection and/or failure of medical treatment). The modalities of the surgical treatment were guided by CT scan findings: transperitoneal approach for diffuse lesions, posterior approach for localized lesions. From 1986 to 1994, 57 patients (32 males, 25 females, mean age 59.2 years) were referred to our department for AP. Etiology was gallstones in 29 cases, alcohol in 14 cases (Ranson < 3), moderate in 27 cases (Ranson < or = 5) and serious in 12 cases (Ranson > or = 6). According to the initial CT scan findings (56 cases), 9 patients were classified grade A, 11 grade B, 13 grade C, 8 grade D ans 15 grade E. Thirty eight patients were managed conservatively (mean Ranson stage 3.3), while 19 patients underwent surgical treatment (mean Ranson stage 4.6), in emergency for misdiagnosis (4 cases), or secondarily because of failure of medical management (15 cases). Surgery consisted in necrosectomy with active drainage in 13 cases and drainage alone in 6 cases. Associated maneuvers included: cholecystectomy in 8 cases, cholecystostomy in 2 cases, jejunostomy in 7 cases and colic resection for necrosis in 3 cases. Two patients (5%) managed conservatively died (multiple organ failure and cardiac insufficiency) while 4 patients (21%: NS) who underwent surgery died (2 multiple organ failures, 1 septic shock, 1 myocardic infarction). Mortality was correlated with the Ranson score: 42% for serious AP, 3.7% for moderate AP and nil for mild AP (p < 0.01). It was not correlated with CT scan grade, the onset or the type of operation. These results allow us to conclude that surgical treatment should be indicated only in cases of failure of conservative management, the best indication being uncontrolled sepsis. In this situation, active drainage provides good results since only one sepsis recurred among the 14 patients who underwent this procedure.
Assuntos
Pancreatite/terapia , Centro Cirúrgico Hospitalar , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Colecistectomia , Cuidados Críticos , Desbridamento , Drenagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Necrose , Pancreatite/etiologia , Pancreatite/mortalidade , Complicações Pós-Operatórias , Reoperação , Resultado do TratamentoRESUMO
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluorouracil (FU) catabolism, which occurs mainly in the liver. Several cases of severe FU-related toxicity have been reported in patients exhibiting a marked DPD deficiency measured in peripheral blood mononuclear cells (PBMCs). In addition, it has been shown that PBMC-DPD activity correlates to systemic FU clearance. The purpose of the present study was to closely evaluate the link between DPD activity measured in PBMCs and in liver samples obtained from the same patients. This prospective study was conducted on 27 patients (18 men and 9 women) who underwent laparotomy for various pathologies. Liver biopsies were performed in normal liver and immediately stored in liquid nitrogen. Biological liver function tests were within normal values for all patients. Concomitantly to the liver biopsy, a blood sample was taken and PBMCs were immediately isolated and stored at -80 degreesC. Liver-DPD and PBMC-DPD activities were measured by a radioenzymatic assay using 14C-FU as substrate (sensitivity limit, 5 pmol/min/mg protein; interassay reproducibility, 10%). Liver-DPD (mean, 178; median, 186; range, 54-290 pmol/min/mg protein) and PBMC-DPD (mean, 196; median, 205; range, 80-275 pmol/min/mg protein) exhibited the same pattern of distribution. Neither liver-DPD nor PBMC-DPD was significantly different between men and women. A significant linear correlation was demonstrated between liver- and PBMC-DPD activity (liver-DPD = 0.6 x PBMC-DPD + 59, r = 0.56, P = 0.002). Interestingly, the patient who exhibited the lowest PBMC-DPD activity (80 pmol/min/mg protein, at risk value for developing FU-related side effects) also had very low liver-DPD activity (98 pmol/min/mg protein). In conclusion, in patients with normal liver function, DPD activity measured in PBMCs reflects DPD activity expressed in the liver. The demonstrated link between liver- and PBMC-DPD activity reinforces the interest in DPD investigation in PBMCs for selecting, before FU-containing chemotherapy, patients at risk of developing severe toxicities due to impairment of FU clearance.
Assuntos
Leucócitos Mononucleares/enzimologia , Fígado/enzimologia , Oxirredutases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Di-Hidrouracila Desidrogenase (NADP) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
From January 1979 to May 1995, 18 patients (4 men, 14 women) with a mean age of 75.4 +/- 12.5 yr underwent surgery for a complicated paraesophageal hiatus hernia. In 5 patients, the complication was the first sign of the diagnosis. Thirteen patients had a history of digestive, respiratory, or cardiac symptoms (mean duration of symptoms 74 mo.; range 2-240 mo.); 9 of them were aware that they had a hiatus hernia. Ten patients presented with acute obstruction (associated with a perforation in 1 case, jaundice in 1 case, and righy lower lobe pneumonia in 1 case). Hemorrhage occurred in 6 patients (hematemesis 4 cases, melena 2 cases). One patient had a perforation and another had an abscess of the lower right lobe. Surgery was performed via a transabdominal approach in all cases (5 times as an emergency, 12 times as a delayed emergency procedure, and once as an elective procedure). The procedure was delayed in 13 cases because of successful nasogastric decompression. All patients underwent reintegration of the stomach, diaphragmatic repair and gastropexy. An antireflux procedure was performed in 14 cases. Seven patients had an ancillary procedure (including one splenectomy following decapsulation). There were no postoperative deaths. Two patients who underwent emergency surgery developed a benign complication. The outcome of 17 patients is known; none of them developed a recurrence. One patient who did not undergo an antireflux procedure presented with gastroesophageal reflux; another experienced pain during eructation. In conclusion, nearly two-thirds of all patients who present with an acute complication can benefit from medical preparation before surgery, a strategy that improves results.
Assuntos
Perfuração Esofágica/cirurgia , Hemorragia Gastrointestinal/cirurgia , Hérnia Hiatal/cirurgia , Volvo Gástrico/cirurgia , Idoso , Idoso de 80 Anos ou mais , Medicina de Emergência , Perfuração Esofágica/etiologia , Feminino , Hemorragia Gastrointestinal/etiologia , Hérnia Hiatal/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Volvo Gástrico/etiologiaRESUMO
Between 1979 and May 1994, 42 patients (11 males, 31 females, mean age 72.8 +/- 12.4 years) underwent surgery for paraoesophageal hiatal hernia. In 37 cases, clinical signs had been observed for 64 months on the average: digestive (32), respiratory (15), cardiac (9). Nine patients had iron deficiency anaemia. Eighteen patients had a complication (acute obstruction: 10, haemorrhage: 6, perforation: 2, lung infection: 2). In 5 cases, the complication was the inaugural sign. Surgery was performed in a emergency situation in 5 cases and deferred emergency in 12 and surgery was elective in 25. An antireflux procedure was used in 36 cases (Lortat-Jacob (2), Toupet (5), Dor (2), Nissen-Rossetti (27)). Another procedure was also needed in 12 patients. There were no postoperative deaths and complications occurred in 6 patients (14.9%). Outcome was known in 40 patients with a mean follow-up of 40.5 months (range 3 to 140 months). Functional results was very good in 35 patients (87.5%), good in 3 (7.5%) and poor in 2 (5%). The most satisfactory immediate results were obtained for patients who had elective surgery and in those with a deferred emergency. Use of the Nissen-Rossetti procedure did not have any deleterious effect on these results and no long-term inconveniences.
Assuntos
Perfuração Esofágica/cirurgia , Hemorragia Gastrointestinal/cirurgia , Hérnia Hiatal/cirurgia , Estenose Pilórica/cirurgia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Medicina de Emergência , Perfuração Esofágica/etiologia , Feminino , Seguimentos , Hemorragia Gastrointestinal/etiologia , Hérnia Hiatal/complicações , Hérnia Hiatal/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estenose Pilórica/etiologiaAssuntos
Adenocarcinoma/patologia , Biópsia/métodos , Linfonodos/patologia , Neoplasias do Mediastino/patologia , Toracoscopia/métodos , Adenocarcinoma/diagnóstico por imagem , Humanos , Linfonodos/diagnóstico por imagem , Neoplasias do Mediastino/diagnóstico por imagem , Pessoa de Meia-Idade , Radiografia , Gravação de VideoteipeRESUMO
INTRODUCTION: Extra-cutaneous manifestations of neutrophilic dermatosis are rare. Symptomatic cases are usually multiform and confusing. We report a case with an aseptic lymph node abscess associated with pyoderma gangrenosum. CASE REPORT: A 28-year-old woman with past history of pyoderma gangrenosum was seen for abdominal symptoms and fever related to an epigastric mass. Due to signs indicating abscess formation, surgery was performed and led to total regression of the symptomatology. Recurrence was evidenced 3 months later with skin lesions which were negative on bacteriological examinations. The diagnosis of lymph node manifestations of pyoderma gangrenosum was retained. General corticotherapy was very effective. Relapse occurred again 6 years later and was treated with thalidomide. DISCUSSION: Lymph node involvement has been described in Sneddon-Wilkinson's disease associated with pyoderma gangrenosum. In neutrophilic dermatosis, pulmonary manifestations appear to be the least exceptional of the extra-cutaneous lesions. The pathophysiology has not been elucidated although recent hypotheses suggest that G-CSF could be involved. Corticotherapy is remarkably effective in most cases but thalidomide could be an interesting alternative treatment.