RESUMEN
The Hippo pathway is involved in colorectal cancer (CRC) development and progression. The Hippo regulator Rassf1a is also involved in the Ras signaling cascade. In this work, we tested single nucleotide polymorphisms within Hippo components and their association with outcome in CRC patients treated with cetuximab. Two cohorts treated with cetuximab plus chemotherapy were evaluated (198 RAS wild-type (WT) patients treated with first-line FOLFIRI plus Cetuximab within the FIRE-3 trial and 67 Ras WT patients treated either with first-line mFOLFOX6 or SOX plus Cetuximab). In these two populations, Rassf1a rs2236947 was associated with overall survival (OS), as patients with a CC genotype had significantly longer OS compared with those with CA or AA genotypes. This association was stronger in patients with left-side CRC (hazard ratio (HR): 1.79 (1.01-3.14); P=0.044 and HR: 2.83 (1.14-7.03); P=0.025, for Fire 3 and JACCRO cohorts, respectively). Rassf1a rs2236947 is a promising biomarker for patients treated with cetuximab plus chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Proteínas Supresoras de Tumor/genética , Anciano , Cetuximab/administración & dosificación , Estudios de Cohortes , Femenino , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
We analyzed associations between CXCR4/CXCL12 single-nucleotide polymorphisms and outcomes in metastatic colorectal cancer (mCRC) patients who underwent first-line bevacizumab-based chemotherapy. A total of 874 patients were included in this study: 144 treated with bevacizumab and FOLFOX or XELOX (training cohort), 653 treated with bevacizumab and FOLFIRI or FOLFOXIRI (validation cohort A or B) and 77 treated with cetuximab- and oxaliplatin-based regimens (control cohort). One CXCR4 polymorphism (rs2228014) and two CXCL12 polymorphisms (rs1801157 and rs3740085) were analyzed by PCR-based direct sequencing. Patients with a C/C genotype had a prolonged progression-free survival (PFS) compared with those with any T allele (P=0.030) in the training cohort. Similarly, patients with the C/C genotype had a superior PFS in the validation cohorts, but not in the control cohort. Our findings suggest that a common genetic variant, CXCR4 rs2228014, could predict PFS and may guide therapeutic decisions in mCRC patients receiving first-line bevacizumab-based chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Polimorfismo de Nucleótido Simple , Receptores CXCR4/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Estudios de Cohortes , Neoplasias Colorrectales/tratamiento farmacológico , Supervivencia sin Enfermedad , Femenino , Genotipo , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Valor Predictivo de las PruebasRESUMEN
BACKGROUND: In Asians, the risk of irinotecan-induced severe toxicities is related in part to UGT1A1*6 (UGT, UDP glucuronosyltransferase) and UGT1A1*28, variant alleles that reduce the elimination of SN-38, the active metabolite of irinotecan. We prospectively studied the relation between the UGT1A1 genotype and the safety of irinotecan-based regimens in Japanese patients with advanced colorectal cancer, and then constructed a nomogram for predicting the risk of severe neutropenia in the first treatment cycle. METHODS: Safety data were obtained from 1312 patients monitored during the first 3 cycles of irinotecan-based regimen in a prospective observational study. In development of the nomogram, multivariable logistic regression analysis was used to test the associations of candidate factors to severe neutropenia in the first cycle. The final nomogram based on the results of multivariable analysis was constructed and validated internally using a bootstrapping technique and externally in an independent data set (n=350). RESULTS: The UGT1A1 genotype was confirmed to be associated with increased risks of irinotecan-induced grade 3 or 4 neutropenia and diarrhoea. The final nomogram included type of regimen, administered dose of irinotecan, gender, age, UGT1A1 genotype, Eastern Cooperative Oncology Group performance status, pre-treatment absolute neutrophil count, and total bilirubin level. The model was validated both internally (bootstrap-adjusted concordance index, 0.69) and externally (concordance index, 0.70). CONCLUSIONS: Our nomogram can be used before treatment to accurately predict the probability of irinotecan-induced severe neutropenia in the first cycle of therapy. Additional studies should evaluate the effect of nomogram-guided dosing on efficacy in patients receiving irinotecan.
Asunto(s)
Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neutropenia/inducido químicamente , Neutropenia/genética , Nomogramas , Anciano , Alelos , Pueblo Asiatico/genética , Bilirrubina/metabolismo , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Glucuronosiltransferasa/genética , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Neutropenia/metabolismo , Neutropenia/patología , Neutrófilos/metabolismo , Neutrófilos/patología , Estudios ProspectivosRESUMEN
BACKGROUND: In Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC. PATIENTS AND METHODS: Patients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40-60 mg/m(2)) on days 1-14 and intravenous irinotecan (150 mg/m(2)) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS). RESULTS: From February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78-1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group. CONCLUSION: The consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy. ClinicalTrials.gov ID: NCT00639327.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Ácido Oxónico/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Tegafur/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Supervivencia sin Enfermedad , Esquema de Medicación , Combinación de Medicamentos , Resistencia a Antineoplásicos , Femenino , Humanos , Irinotecán , Masculino , Persona de Mediana Edad , Ácido Oxónico/efectos adversos , Neoplasias Gástricas/mortalidad , Tegafur/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Background Elpamotide is an HLA-A*24:02-restricted epitope peptide of vascular endothelial growth factor receptor 2 (VEGFR-2) and induces cytotoxic T lymphocytes (CTLs) against VEGFR-2/KDR. Given the high expression of VEGFR-2 in biliary tract cancer, combination chemoimmunotherapy with elpamotide and gemcitabine holds promise as a new therapy. Patients and Methods Patients with unresectable advanced or recurrent biliary tract cancer were included in this single-arm phase II trial, with the primary endpoint of overall survival. Survival analysis was performed in comparison with historical control data. The patients concurrently received gemcitabine once a week for 3 weeks (the fourth week was skipped) and elpamotide once a week for 4 weeks. Results Fifty-five patients were registered, of which 54 received the regimen and were included in the full analysis set as well as the safety analysis set. Median survival was 10.1 months, which was longer than the historical control, and the 1-year survival rate was 44.4%. Of these patients, injection site reactions were observed in 64.8%, in whom median survival was significantly longer (14.8 months) compared to those with no injection site reactions (5.7 months). The response rate was 18.5%, and all who responded exhibited injection site reactions. Serious adverse reactions were observed in five patients (9%), and there were no treatment-related deaths. Conclusion Gemcitabine and elpamotide combination therapy was tolerable and had a moderate antitumor effect. For future development of therapies, it will be necessary to optimize the target population for which therapeutic effects could be expected.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/mortalidad , Vacunas contra el Cáncer/administración & dosificación , Desoxicitidina/análogos & derivados , Fragmentos de Péptidos/uso terapéutico , Receptor 2 de Factores de Crecimiento Endotelial Vascular/uso terapéutico , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/efectos adversos , Análisis de Supervivencia , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/efectos adversos , GemcitabinaRESUMEN
BACKGROUND: Chemotherapy in combination with anti-epidermal growth factor receptor (EGFR) antibody is considered a first-line treatment regimen for RAS wild-type and left-sided metastatic colorectal cancer (mCRC), whereas second-line treatment regimens have not yet been established. Few studies have prospectively evaluated second-line treatment with anti-vascular endothelial growth factor antibody after first-line anti-EGFR antibody therapy for RAS wild-type mCRC. PATIENTS AND METHODS: This non-randomized phase II trial investigated the clinical outcomes of second-line ramucirumab (RAM) plus fluorouracil, levofolinate, and irinotecan (FOLFIRI) after first-line anti-EGFR antibody in combination with doublet or triplet regimen in patients with RAS wild-type mCRC. The primary endpoint was the 6-month progression-free survival (PFS) rate. The secondary endpoints were PFS, overall survival (OS), objective response rate (ORR), rate of early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45%. Treatment was considered effective if the lower limit of the 90% confidence interval (CI) of the 6-month PFS rate was >0.30. RESULTS: Ninety-two patients were enrolled in the study. The primary tumor was located on the left side in 86 (95.6%) patients. Twenty (22.0%) patients had received triplet plus cetuximab as previous therapy. Six-month PFS rate was 58.2% (90% CI 49.3% to 66.2%) with a median PFS of 7.0 months (95% CI 5.7-7.6 months). Median OS was 23.6 months (95% CI 16.5-26.3 months). The ORR and ETS rate were 10.7% and 16.9%, respectively, in 83 patients with measurable lesions. The 6-month PFS rate was comparable between patients previously treated with doublet and triplet regimens; however, median PFS was longer for the doublet regimen (7.4 versus 6.4 months, P = 0.036). CONCLUSIONS: Our study demonstrated prospectively that RAM plus FOLFIRI is an effective second-line treatment after anti-EGFR antibody-containing first-line therapy in RAS wild-type and left-sided mCRC. Furthermore, the results were similar for patients who were previously treated with triplet regimen.
Asunto(s)
Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Cetuximab/farmacología , Cetuximab/uso terapéutico , Receptores ErbB , RamucirumabAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/inmunología , Cetuximab/administración & dosificación , Cetuximab/inmunología , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/inmunología , Receptores ErbB/inmunología , Humanos , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Few prospective studies have used liquid biopsy testing in RAS-mutant metastatic colorectal cancer (mCRC), and its clinical significance remains unknown. Therefore, this study aimed to carry out a biomarker analysis by liquid biopsy using updated data of the phase II trial of FOLFOXIRI plus bevacizumab as first-line chemotherapy for RAS-mutant mCRC. MATERIALS AND METHODS: A total of 64 patients who received modified FOLFOXIRI regimen (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2) plus bevacizumab biweekly were enrolled. The primary endpoint was the objective response rate (ORR). Plasma samples were collected at pre-treatment, 8 weeks after treatment, and progression in participants included in the biomarker study. The levels of circulating tumour DNA (ctDNA) and specific KRAS and NRAS variants were evaluated using real-time PCR assays. RESULTS: There were 62 patients (median age: 62.5 years, 92% performance status 0, 27% right side) who were assessable for efficacy and 51 for biomarker analysis. ORR was 75.8% (95% confidence interval 65.1% to 86.5%). The median progression-free survival was 12.1 months, and the median overall survival (OS) was 30.2 months. In 78% of patients, RAS mutations disappeared in the ctDNA at 8 weeks after treatment; these patients tended to have better outcomes than those with RAS mutations. Interestingly, RAS mutations remained undetectable during progression in 62% of patients. Survival analysis indicated that the median OS from progression was significantly longer in patients with RAS mutation clearance than in those with RAS mutation in the ctDNA at disease progression (15.1 versus 7.3 months, hazard ratio: 0.21, P = 0.0046). CONCLUSIONS: Our biomarker study demonstrated no RAS mutations in ctDNA at disease progression in 62% of patients with RAS-mutant mCRC. Both OS and post-progression survival were better in patients with clearance of RAS mutations in ctDNA after triplet-based chemotherapy.
Asunto(s)
ADN Tumoral Circulante , Neoplasias del Colon , Neoplasias Colorrectales , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Camptotecina/análogos & derivados , ADN Tumoral Circulante/genética , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Fluorouracilo , Genes ras , Humanos , Leucovorina , Persona de Mediana Edad , Compuestos Organoplatinos , Estudios ProspectivosRESUMEN
BACKGROUND: S-1 is an oral anticancer agent that combines tegafur (FT) with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate. The recommended initial dose of S-1 is 120 mg/day for patients with a body surface area (BSA) of > or =1.5 m(2) in Japan. METHODS: We examined the effects of using this fixed dose on the pharmacokinetics of FT, CDHP, and active 5-fluorouracil (5-FU) on the basis of actual BSA. The pharmacokinetics was compared between patients with a BSA of 1.5-1.75 m(2) and those with a BSA of > or =1.75 m(2). RESULTS: The median areas under the time-concentration curves (AUCs) of 5-FU and CDHP were significantly lower in patients with a BSA of > or =1.75 m(2) than in those with a BSA of 1.5-1.75 m(2) (P = 0.005 and 0.006, respectively; Mann-Whitney U-test). There was no difference between the groups in the median AUC of FT. CONCLUSION: Systemic exposure to 5-FU is significantly lower in Japanese cancer patients with a large BSA of >1.75 m(2) who received the recommended fixed dose of S-1.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Superficie Corporal , Neoplasias/tratamiento farmacológico , Ácido Oxónico/administración & dosificación , Ácido Oxónico/farmacocinética , Tegafur/administración & dosificación , Tegafur/farmacocinética , Administración Oral , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Combinación de Medicamentos , Cálculo de Dosificación de Drogas , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Neoplasias/etnología , Resultado del TratamientoRESUMEN
S-1 is an oral anticancer agent that combines tegafur, a prodrug of 5-fluorouracil (5-FU), and 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase. We examined the effects of aging on the pharmacokinetics of the components of S-1. The median area under the concentration-time curve (AUC) of active 5-FU did not significantly differ between 10 patients 75 years or older and 53 patients younger than 75 years (P = 0.598, Mann-Whitney U test). It is interesting to note that the median oral clearance of tegafur in patients 75 years or older was significantly lower than that in patients younger than 75 years (P = 0.011). Furthermore, the median AUC of CDHP was significantly higher in patients 75 years or older than in those younger than 75 years (P = 0.004). This effect was caused by reduced renal function in the elderly, because CDHP is excreted in the urine by glomerular filtration. The opposing effects of aging on the oral clearance of tegafur and the AUC of CDHP may offset each other, leading to unchanged systemic exposure of 5-FU.
Asunto(s)
Sinergismo Farmacológico , Fluorouracilo/farmacocinética , Neoplasias/metabolismo , Piridinas/farmacología , Tegafur/administración & dosificación , Anciano , Antimetabolitos Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Pueblo Asiatico , Dihidrouracilo Deshidrogenasa (NADP)/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales/métodos , Inhibidores Enzimáticos/farmacología , Humanos , Tasa de Depuración Metabólica , Neoplasias/tratamiento farmacológico , Piridinas/administración & dosificación , Piridinas/química , Tegafur/farmacologíaRESUMEN
Nonsteroidal anti-inflammatory drugs reduce the incidence and mortality of colorectal carcinoma. Their chemopreventive effects appear to be due to inhibition of cyclooxygenase (COX)-2. Here, we have studied the relationship between the COX-2 mRNA levels and pathological characteristics in 43 primary colorectal carcinomas. COX-2 levels were significantly higher in tumors with larger sizes and in those with deeper invasions but were not correlated with whether the patients had metastasis or not. These results suggest that larger carcinomas produce more COX-2 to support their own growth and that COX-2 inhibitors may be effective agents of carcinoma growth suppression.
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Neoplasias Colorrectales/enzimología , Inhibidores de la Ciclooxigenasa/uso terapéutico , Isoenzimas/biosíntesis , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/prevención & control , Ciclooxigenasa 1 , Femenino , Humanos , Isoenzimas/genética , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Datos de Secuencia Molecular , Invasividad Neoplásica , Prostaglandina-Endoperóxido Sintasas/genéticaRESUMEN
Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme for 5-fluorouracil catabolism. In this study, both the enzymatic activity and mRNA level of DPD were estimated in the tumor tissue and adjacent normal mucosa of 51 patients with colorectal cancer. Although no significant difference in enzymatic activity was observed between tumor tissue and normal mucosa (70.4 and 70.7 pmol/min/mg protein, respectively), the mRNA level in normal mucosa was significantly higher than that in tumor tissue (1.37 and 0.39, respectively; P<0.01). A linear relationship was noted between DPD activity and the DPD mRNA level in cancerous tissue (r(s) = 0.714, P<0.001). Thus, the DPD mRNA level as determined by reverse transcription-PCR can be used to indicate the DPD activity of colorectal cancers.
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Neoplasias Colorrectales/enzimología , Oxidorreductasas/metabolismo , ARN Mensajero/análisis , Dihidrouracilo Deshidrogenasa (NADP) , Femenino , Humanos , Mucosa Intestinal/enzimología , Masculino , Persona de Mediana Edad , Oxidorreductasas/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Germ-line mutation of the E-cadherin gene was reported in familial gastric cancer (FGC) kindreds from New Zealand. Therefore, we analyzed all of the exons of E-cadherin by PCR-single-strand conformational polymorphism analysis in 16 patients from 14 Japanese FGC kindreds. However, no germ-line mutation was detected, suggesting that a predisposition to FGCs by E-cadherin gene mutation is infrequent in Japanese cases.
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Cadherinas/genética , Neoplasias Gástricas/genética , Adolescente , Adulto , Anciano , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Humanos , Japón , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
B16 melanoma cells were injected into the tail vein of young mice, old mice and parabiotic mice constructed between young and old mice, and the number and shape of pulmonary metastases were compared among three experimental groups. In unpaired mice, the number of metastatic colonies in the lungs was 10-fold larger in young than in old mice. In parabiotic mice, the number in young mice was almost comparable with that of unpaired young mice, but the number in old mice approached the level of young mice. Metastatic colonies on the pulmonary surface of young mice were mostly nodular in shape, while those of old mice were flat in shape. The shape of colonies reflecting the tumor growth rate did not change in parabiotic old mice in spite of an increase in number. In young parabiotic mice, the large and intermediate colonies decreased with a concomitant increase of small ones as compared with unpaired young mice. These results suggest that the implantation of metastatic colonies in the lung is mainly dependent on systemic humoral factors and their growth is mainly dependent on the host local factors in the microenvironment, and distinct age changes of both factors greatly influence the metastatic mode of tumors, respectively.
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Envejecimiento/fisiología , Metástasis de la Neoplasia/fisiopatología , Parabiosis , Animales , Femenino , Inmunidad/fisiología , Neoplasias Pulmonares/secundario , Melanoma Experimental/fisiopatología , Melanoma Experimental/secundario , Ratones , Ratones Endogámicos C57BL , Trasplante de NeoplasiasRESUMEN
Cyclooxygenase-2 (COX-2) is an important target for the suppression of colorectal tumorigenesis by non-steroidal anti-inflammatory drugs (NSAIDs). To evaluate the role of COX-2 in human sporadic colorectal adenomas, COX-2 mRNA expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) in 63 adenomas. COX-2 mRNA was detected in all the adenomas at higher levels than in normal colorectal mucosa (P<0.001). Levels of expression in the adenomas were correlated with their size (P=0.019), but no relationships were demonstrable between COX-2 expression and adenoma location, macroscopically observed configuration or microscopic degree of dysplasia. These findings suggest that COX-2 plays an important role in the growth of sporadic colorectal adenomas.
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Adenoma/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias del Colon/metabolismo , Isoenzimas/metabolismo , Proteínas de Neoplasias/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Neoplasias del Recto/metabolismo , Adenoma/patología , Neoplasias del Colon/patología , Ciclooxigenasa 2 , Regulación Neoplásica de la Expresión Génica , Humanos , Mucosa Intestinal/enzimología , Proteínas de la Membrana , ARN Mensajero/metabolismo , Neoplasias del Recto/patología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Thymidylate synthase (TS) expression has been identified as an important predictor of response to 5-fluorouracil (5-FU). However, there is relatively little information on the heterogeneity of TS mRNA expression between primary and metastatic tumors, as well as differential expression of TS mRNA in metastatic sites. In this study, TS mRNA expression was measured in primary colorectal cancer tumors and various metastatic tumors. The median TS/glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA ratio was 0.98 in primary tumors, 0.70 in liver metastases, 1.92 in lymph node metastases, and 3.42 in pulmonary metastases. A significantly higher expression of TS mRNA was observed in pulmonary and lymph node metastases compared with their respective primary tumors. In contrast, TS mRNA expression in hepatic metastases was significantly lower than in primary tumors. Similar results were observed in tumors obtained from the same patient. These results may explain the difference in the clinical response to 5-FU-based chemotherapy between various metastatic sites. The discordant TS expression between primary and metastatic tumors is a critical factor that must be taken into account when TS is being used as a predictive biomarker for the antitumor effect of 5-FU-based chemotherapy.
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Adenocarcinoma/enzimología , Adenocarcinoma/secundario , Biomarcadores de Tumor/biosíntesis , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/patología , Timidilato Sintasa/biosíntesis , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Antimetabolitos Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Fluorouracilo/uso terapéutico , Expresión Génica , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Metástasis Linfática , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Timidilato Sintasa/genéticaRESUMEN
This study explored the efficacy of hepatic arterial therapy, comparing both injection and infusion of 5-fluorouracil (5-FU) in prolonging the survival of 92 patients with recurrent unresectable hepatic metastasis from colorectal cancer. With respect to pretreatment carcinoembryonic antigen doubling time (CEA-DT), 56 patients were treated with intra-arterial injection, and 36 with intra-arterial infusion. In 21 patients with a CEA-DT of less than 40 days, the cumulative survival of patients treated with arterial injection was significantly longer than that of patients treated with arterial infusion. In 45 patients with a CEA-DT of 40-80 days, the survival curves of patients did not differ from each other. Of the remaining 26 patients with a CEA-DT of more than 80 days, those treated using arterial infusion had an excellent prognosis, in contrast to those treated using arterial injection, with statistical significance. CEA-DT may be useful when choosing a chemotherapy regimen, and may help to accurately establish the prognosis of patients with unresectable hepatic metastasis from colorectal cancer.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Antígeno Carcinoembrionario/metabolismo , Neoplasias del Colon/patología , Fluorouracilo/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias del Recto/patología , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antígeno Carcinoembrionario/análisis , Femenino , Fluorouracilo/administración & dosificación , Arteria Hepática , Humanos , Bombas de Infusión Implantables , Infusiones Intraarteriales , Inyecciones Intraarteriales , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pronóstico , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
This study was designed to clarify the contribution of IL-8 as a specific neutrophil chemotactic factor in the human respiratory tract in various pulmonary diseases. The neutrophil chemotactic activity (NCA), neutrophil counts and IL-8 concentration in the bronchoalveolar lavage fluid (BALF) obtained from normal volunteers (NV), control patients (CP), patients with diffuse panbronchiolitis (DPB) and patients with idiopathic pulmonary fibrosis (IPF) were examined. Neutrophil counts, NCA and IL-8 concentration in BALF obtained from patients with DPB or IPF was significantly higher than that from NV or CP. The IL-8 concentration correlated with neutrophil count and also correlated with NCA in BALF from patients with IPF, whereas there was no correlation between these factors in BALF from DPB. These results suggest that the contribution of IL-8 to neutrophil accumulation of the lower respiratory tract is different between IPF and DPB.
Asunto(s)
Interleucina-8/metabolismo , Neutrófilos/metabolismo , Fibrosis Pulmonar/metabolismo , Recuento de Células Sanguíneas , Lavado Broncoalveolar , Quimiotaxis , Humanos , Neutrófilos/inmunología , Neutrófilos/patología , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/patologíaRESUMEN
In the United States and Europe, the combination of oral UFT plus leucovorin has been reported to produce objective responses and survival rates similar to those achieved with standard intravenous 5-fluorouracil plus leucovorin in patients with metastatic colorectal cancer, with reduced toxicity. However, because knowledge and experience with UFT plus leucovorin are relatively limited in Japan, we conducted a phase II study to evaluate the safety and efficacy of this combination in Japanese patients with metastatic colorectal cancer. For the purposes of this study, 20 patients received oral UFT 400 mg/m2/day in two divided doses (q 12 h) and a 5-mg tablet of leucovorin (q 8 h). Treatment was administered for 5 days, followed by a 2-day rest period, for a 28-day cycle. There were six partial responses (30%) and one complete response (5%) (overall response rate, 35%; 95% confidence interval, 14.1% to 55.9%). Greater efficacy of UFT plus leucovorin was demonstrated in patients with lung metastases, with a response rate of 63% (five of eight patients). Patients received a median of 4.5 courses (range, 2 to 12) of therapy. The median duration of survival was 228+ days (range, 81 to 540; six patients remain alive). Grade 3 or 4 toxicities occurred in three patients: diarrhea in two and mucositis in one. No toxicity-related hospitalization was reported. In summary, this combination showed promising activity and an acceptable toxicity profile in the treatment of Japanese patients with metastatic colorectal cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Tegafur/administración & dosificación , Resultado del Tratamiento , Uracilo/administración & dosificaciónRESUMEN
The purpose of this investigation was to study the anatomy of the articular eminence of the temporomandibular joint. Direct angulation measurements of the lateral and midpoint inclined planes were made in 100 adult Asiatic Indian skulls using a headholder (craniophore) apparatus. The results showed that left and right side measurements did not differ significantly. The mean angulation of the midpoint inclined plane was significantly greater than that of the lateral inclined plane. The mean lateral inclined plane was 41.2 degrees +/- 10.7 degrees, with a range of 20 degrees-72 degrees; at the midpoint inclined plane, the mean was 54.2 degrees +/- 11.4 degrees, with a range of 17 degrees-77 degrees. Three morphologic articular eminence types were identified: (1) protuberant, (2) moderate, and (3) flat. These findings need to be considered when making clinical correlations.