RESUMEN
BACKGROUND: Cetuximab-induced skin toxicity (Cet-ST) is positively associated with outcome in metastatic colorectal cancer (mCRC). Besides its predictive relevance for targeted therapy, we investigated its prognostic impact with early tumor shrinkage (ETS) ≥20%, another on-treatment surrogate for clinical outcome in FIRE-3. PATIENTS AND METHODS: FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumors (i.e. wild-type in KRAS and NRAS exons 2-4). Retrospective data on Cet-ST that occurred during cycles 1-3 of treatment were correlated with efficacy endpoints, including ETS. To control for guarantee-time bias, only patients who had completed three or more treatment cycles were considered. RESULTS: Of 199 patients treated with FOLFIRI/Cet, 181 (91.0%) completed three or more treatment cycles. A significant survival benefit of FOLFIRI/Cet over FOLFIRI/Bev was only evident in patients developing Cet-ST grade 2-3 [41.0 versus 26.6 months; hazard ratio (HR) = 0.73; 95% confidence interval (CI): 0.61-0.87; P < 0.001] compared with Cet-ST grade 0-1 (HR = 0.90; 95% CI: 0.67-1.20; P = 0.48). Regarding prognosis, Cet-ST grade 2-3 (n = 75; 41.4%), compared with Cet-ST grade 0-1 (n = 106; 58.6%), was associated with prolonged overall survival (OS; HR = 0.62; 95% CI: 0.42-0.91; P = 0.01). In multivariate analysis, both Cet-ST (HR = 0.66; 95% CI: 0.50-0.87; P = 0.003) and ETS (HR = 0.55; 95% CI: 0.41-0.74; P < 0.0001) were independently prognostic for OS. Absence of both Cet-ST grade ≥2 and ETS identified a subgroup of patients with very poor prognosis (median OS 15.1 months). CONCLUSIONS: In FIRE-3, the addition of cetuximab to FOLFIRI was associated with superior OS compared with FOLFIRI/Bev only in patients developing Cet-ST grade ≥2. Regarding prognostic relevance, both Cet-ST and ETS were independent and early predictors of survival. The present analysis supports that a combined evaluation of on-treatment parameters such as Cet-ST and ETS may help to guide treatment of mCRC.
Asunto(s)
Camptotecina , Neoplasias Colorrectales , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Camptotecina/efectos adversos , Cetuximab/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/efectos adversos , Humanos , Leucovorina/efectos adversos , Metástasis de la Neoplasia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined. PATIENTS AND METHODS: In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method. RESULTS: CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n = 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS (P < 0.001), and OS (P < 0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy. CONCLUSIONS: CMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making.The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Biomarcadores de Tumor/genética , Camptotecina/análogos & derivados , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Camptotecina/farmacología , Camptotecina/uso terapéutico , Toma de Decisiones Clínicas/métodos , Colon/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN , Femenino , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Leucovorina/farmacología , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Supervivencia sin Progresión , Recto/patologíaRESUMEN
BACKGROUND: To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. PATIENTS AND METHODS: CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. RESULTS: Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. CONCLUSION: In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. CLINICAL TRIALS NUMBER: NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Camptotecina/análogos & derivados , Antígeno Carcinoembrionario/genética , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas Proto-Oncogénicas p21(ras)/genética , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Cetuximab/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Exones/genética , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
BACKGROUND: The AIO KRK-0306 trial compares the efficacy of infusional 5-fluorouracil, folinic acid, irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC). In October 2008, an amendment terminated the inclusion of patients with KRAS-mutated tumours. This subgroup of patients is evaluated in the present analysis, while the study is ongoing for patients with KRAS wild-type tumours. METHODS: Patients were randomly assigned to FOLFIRI (Tournigand regimen) every 2 weeks plus cetuximab (400 mg/m2 day 1, followed by 250 mg/m2 weekly=arm A) or bevacizumab (5 mg/kg every 2 weeks=arm B). Among 336 randomised patients, KRAS mutation was demonstrated in 100 assessable patients. The primary study end point was objective response rate (ORR). RESULTS: ORR was 44% [95% confidence interval (CI) 29% to 59%] in arm A versus 48% (95% CI, 33% to 62%) in arm B. Progression-free survival was 7.5 versus 8.9 months (hazard ratio: 1.0) and overall survival was 22.7 versus 18.7 months (hazard ratio: 0.86) in arms A versus B, respectively. CONCLUSIONS: This is the first head to head comparison of cetuximab versus bevacizumab in first-line treatment of mCRC. In the present evaluation of patients with KRAS-mutated tumours, neither strategy demonstrated a clearly superior outcome.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cetuximab , Codón , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Alemania , Humanos , Irinotecán , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Mutación , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Proteínas Proto-Oncogénicas p21(ras) , Resultado del Tratamiento , Privación de TratamientoRESUMEN
Surgery has been the mainstay of therapy in patients with gastrointestinal perforations, leakage or fistulas. New techniques for endoscopic closure of gastrointestinal perforations provide tools for an effective treatment by less invasive procedures. Temporary placement of covered self-expanding stents is an established therapy for oesophageal perforations and anastomotic leaks. Using conventional endoclips small perforations and leaks in the oesophagus and gastrointestinal tract may be closed. With the new over-the-scope-clips a more effective endoscopic full wall closure is possible in the upper gastrointestinal tract and the rectum. Endoscopically guided endoluminal vacuum therapy using polyurethane sponges is an established method for treating rectal leaks and is now increasingly used also in oesophageal leaks. Biliary leakage following endoscopic or surgical interventions is effectively treated with temporary bile stenting in most cases, but closure using metal stents or coiling may be necessary. Pancreatic leaks are a major therapeutic problem and may require multimodal therapies.
Asunto(s)
Enfermedades de los Conductos Biliares/cirugía , Endoscopía del Sistema Digestivo/métodos , Endoscopía del Sistema Digestivo/tendencias , Enfermedades Gastrointestinales/cirugía , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Procedimientos Quirúrgicos Mínimamente Invasivos/tendencias , Enfermedades Pancreáticas/cirugía , Enfermedades de los Conductos Biliares/patología , Enfermedades Gastrointestinales/patología , Humanos , Enfermedades Pancreáticas/patologíaRESUMEN
PURPOSE: Increased baseline carcinoembryonic antigen (CEA) serum level is associated with inferior overall survival (OS) in metastatic colorectal cancer (mCRC). However, limited data exist on its predictive relevance for targeted therapies. Therefore, we analysed its relevance in FIRE-3, a randomised phase III study. EXPERIMENTAL DESIGN: FIRE-3 evaluated first-line FOLFIRI plus cetuximab (FOLFIRI/Cet) versus FOLFIRI plus bevacizumab (FOLFIRI/Bev) in mCRC patients with RAS-WT tumour (i.e. wild-type in KRAS and NRAS exons 2-4). Herein, the impact of CEA on patient outcome was investigated. RESULTS: Of 400 patients, 356 (89.0%) were evaluable for CEA. High CEA (>10 ng/ml; N = 237) compared to low CEA (≤10 ng/ml; N = 119) was associated with shorter OS in the FOLFIRI/Bev arm (hazard ratio [HR] = 1.50; P = 0.036), while no significant OS difference was observed in the FOLFIRI/Cet arm (HR = 1.07; P = 0.74). In patients with high CEA, FOLFIRI/Cet compared to FOLFIRI/Bev showed a greater OS benefit (HR = 0.56; P < 0.001) than in patients with low CEA (HR = 0.78; P = 0.30). Furthermore, FOLFIRI/Cet exhibited significantly superior objective response rate in patients with high CEA (odds ratio = 2.21; P = 0.006) in contrast to patients with low CEA (odds ratio = 0.90; P = 0.85). CONCLUSION: In patients with RAS-WT mCRC receiving first-line chemotherapy with FOLFIRI/Cet versus FOLFIRI/Bev, elevated CEA was associated with inferior survival in the bevacizumab arm, while this was not the case when cetuximab was applied. Comparison of OS and objective response rate according to treatment arms indicated that cetuximab was greatly superior to bevacizumab in patients with elevated CEA, while this effect was markedly lower and lost statistical significance in patients with low CEA.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Camptotecina/análogos & derivados , Antígeno Carcinoembrionario/sangre , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Cetuximab/efectos adversos , Ensayos Clínicos Fase III como Asunto , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Regulación hacia ArribaRESUMEN
BACKGROUND: RAS and BRAF mutations have been identified as negative prognostic factors in metastatic colorectal cancer. Efficacy of 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) plus bevacizumab in patients with RAS-mutant tumours needs to be further evaluated. Whether to treat patients with BRAF-mutant tumours with either bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies remains unclear. METHODS: Patients treated within the FIRE-3 trial were retrospectively tested for BRAF and RAS mutations using formalin fixated paraffin embedded (FFPE) tumour material applying pyrosequencing for KRAS and NRAS exon 2, 3 and 4 mutations as far as for BRAF mutations. Survival analysis was done using Kaplan-Meier estimation and differences were expressed using the log-rank test. Overall response rate (ORR) was compared using Fisher's exact test. Data from a central independent radiological response evaluation were used to calculate early tumour shrinkage (ETS) and depth of response (DpR). RESULTS: Overall, 188 patients with RAS-mutant tumours and 48 with BRAF-mutant tumours were identified. In BRAF-mutant patients, ORR was numerically higher in the cetuximab versus the bevacizumab arm (52% versus 40%), while comparable results were achieved for progression-free survival (PFS; hazard ratio [HR] = 0.84, p = 0.56) and overall survival (OS; HR 0.79, p = 0.45). RAS mutation was associated with a trend towards lower ORR (37% versus 50.5%, p = 0.11) and shorter PFS (7.4 versus 9.7 months; HR 1.25; p = 0.14) in patients receiving FOLFIRI plus cetuximab versus bevacizumab, but OS was comparable (19.1 versus 20.1 months; HR 1.05; p = 0.73), respectively. ETS identified subgroups sensitive to cetuximab-based treatment in both BRAF- (9/17) and RAS-mutant (18/48) patients and was associated with significantly longer OS. DpR was comparable between both treatment arms in RAS- and BRAF-mutant patients, respectively. CONCLUSIONS: In BRAF- and RAS-mutant patients, cetuximab- and bevacizumab-based treatment had comparable survival times. ETS represents an early parameter associated with the benefit from anti-EGFR, while this was not the case with vascular endothelial growth factor A blockade.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/genética , Mutación/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cetuximab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Exones/genética , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: We explored the impacts of sequential application of various treatment lines on survival kinetics. Therefore, differences in overall survival (OS) observed in FIRE-3 were investigated in the context of time and exposure to applied treatment. PATIENTS AND METHODS: OS analyses (stratified by treatment with FOLFIRI plus either cetuximab or bevacizumab) were performed according to time intervals as well as using a Cox model to define changes of hazard ratio (HR) over time. RESULTS: The fraction of patients with systemic treatment and time on treatment markedly decreases over treatment lines and time. OS evaluation by a Cox model indicated a trend towards a non-proportional hazard between treatment arms (P = 0.12/P = 0.09 for KRAS-intention-to-treat (ITT)/all-RAS wild-type populations, respectively). To improve the fit of the model, a change-point (point of curve separation) was estimated at 22.6 months (day 687) after randomisation. The HR between the two arms before 22.6 months was not significantly different from one. However, markedly different survival kinetics in favour of the cetuximab arm were apparent after the change-point (KRAS-ITT: P = 0.0018; HR, 0.60 [95% confidence interval [CI], 0.44-0.83] and RAS: P = 0.0006; HR, 0.51 [95% CI, 0.35-0.75]). CONCLUSION: The differences in OS favouring the cetuximab arm become apparent about 22.6 months after randomisation, indicating that only those patients who survive 22.6 months after randomisation benefit from the superiority of the cetuximab arm. When OS curves separate, only few patients receive active systemic treatment in short courses, suggesting that earlier treatment effects are responsible for later kinetics of survival curves.
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Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Camptotecina/análogos & derivados , Cetuximab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de la Angiogénesis/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Biomarcadores de Tumor/genética , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Cetuximab/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Mutación , Metástasis de la Neoplasia , Modelos de Riesgos Proporcionales , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
The potential of cationic liposomes as nonviral vectors for in vivo gene delivery to the liver and to intrahepatic hepatocellular carcinoma (HCC) was investigated. Mice were injected via the tail vein or portal vein with a cationic lipid complexed to plasmid DNA (pDNA) encoding the chloramphenicol acetyltransferase (CAT) reporter gene at various cationic lipid:pDNA molar ratios to analyze the efficiency of gene delivery after intravenous administration. Tail vein injection resulted in high CAT expression levels in lung and spleen and low levels in the liver. Portal vein injection, by comparison, significantly enhanced hepatic reporter gene expression but also resulted in pronounced hepatic toxicity. Gene delivery to intrahepatic tumors produced by intrahepatic injection of human HCC cells was analyzed in nude mice. Tail vein injection as well as portal vein injection resulted in low levels of gene expression in intrahepatic tumors. By comparison, high levels of gene expression were achieved by direct, intratumoral injection of liposome-pDNA complexes, with only minimal expression in the surrounding normal liver. Therefore, direct liposome-pDNA complex injection appears far superior to systemic or portal intravenous administration for gene therapy of localized intrahepatic tumors, and may be a useful adjunct in the treatment of human HCCs.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Liposomas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Cationes/administración & dosificación , Cationes/efectos adversos , Cationes/metabolismo , Cloranfenicol O-Acetiltransferasa/genética , Cloranfenicol O-Acetiltransferasa/metabolismo , Sistemas de Liberación de Medicamentos/efectos adversos , Sistemas de Liberación de Medicamentos/métodos , Expresión Génica , Genes Reporteros/genética , Terapia Genética/efectos adversos , Vectores Genéticos/efectos adversos , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Inyecciones , Inyecciones Intravenosas , Liposomas/administración & dosificación , Liposomas/efectos adversos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos BALB C , Vena Porta/fisiología , Transgenes/genéticaRESUMEN
This report reviews the effects of CCK on the pancreas and in particular analyzes recent studies in which CCK antagonists were used to evaluate the physiological role of CCK in modulating pancreatic function and morphology. CCK is released from endocrine cells of the small intestine in response to a meal. In various animal species there are CCK receptors on pancreatic acinar cells with two sites; occupation of the high affinity site is thought to mediate pancreatic secretion and growth, whereas occupation of the low affinity site by high CCK concentrations is thought to be responsible for supramaximal inhibition of secretion and pancreatitis. Recently, CCK receptors were also found on postganglionic cholinergic neurons in the gastrointestinal tract. Administration of CCK agonists stimulates pancreatic secretion and growth. Although in some previous studies CCK was given at doses that mimic its postprandial increase in plasma, these studies did not prove that the actions of exogenous CCK were physiologically important. In addition, it was unclear if CCK primarily acts as a true hormone or as a neurotransmitter. The development of specific CCK receptor antagonists made it possible to better evaluate the physiological role of CCK. In humans, CCK-A antagonists like loxiglumide or L-364,718 at doses that completely inhibited the action of supraphysiological doses of exogenous CCK reduced meal-stimulated pancreatic enzyme secretion only by approximately 50%. On the other hand, atropine abolished the postprandial increase in pancreatic secretion and in addition markedly reduced the increase in pancreatic secretion due to infusion of "physiological" doses of CCK (i.e., CCK doses that mimic its postprandial increase in plasma). The increase in pancreatic bicarbonate secretion was only slightly reduced by CCK blockade. CCK antagonists failed to reduce the postprandial increase in plasma insulin, but markedly reduced the postprandial PP release. CCK-A antagonists caused slight hypotrophy and hypoplasia of the exocrine pancreas. However, even after 9 months of effective blockade of the CCK-A-receptor, mice had normal body weight and an almost normal pancreas. CCK antagonists were unable to alter short-term changes in pancreatic growth due to feeding and fasting. In some species, CCK agonists induced development of pancreatic nodules and increased the growth of malignant tumors. Studies about the effects of CCK antagonists on induction and growth of pancreatic tumors showed controversial results. In conclusion, CCK may act on the pancreas by three pathways: (1) At low doses it serves as a neurotransmitter by acting on cholinergic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)
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Colecistoquinina/farmacología , Colecistoquinina/fisiología , Islotes Pancreáticos/fisiología , Páncreas/fisiología , Animales , Colecistoquinina/antagonistas & inhibidores , Ingestión de Alimentos , Vesícula Biliar/efectos de los fármacos , Vesícula Biliar/fisiología , Humanos , Islotes Pancreáticos/efectos de los fármacos , Páncreas/citología , Páncreas/efectos de los fármacos , Proglumida/análogos & derivados , Proglumida/farmacologíaRESUMEN
Hepatitis C Virus (HCV) is the major causative agent of chronic hepatitis. Since it has been difficult to obtain full-length cDNA clones of HCV including the 3' untranslated region (UTR) that give rise to replication competent virus, we generated the 3'UTR by a modified protocol of total chemical synthesis (TCS) with overlap-extension-PCR using four long oligodeoxynucleotides. A synthetic cDNA fragment of about 340 nucleotides (nt) in length was generated, subcloned and sequenced. This approach represents a rapid and easy alternative to RT-PCR from infectious serum and may be a highly valuable method to generate partial cDNA clones of HCV and other viruses including defined variants.
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Regiones no Traducidas 3'/síntesis química , ADN Viral/síntesis química , Hepacivirus/genética , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , OligodesoxirribonucleótidosRESUMEN
BACKGROUND/AIMS: The present analysis evaluates whether the type, dose, and duration of interferon treatment affect its short- and long-term responses, and also analyzes whether the presence of liver cirrhosis predicts response rates. MATERIAL AND METHODS: The present review analyzes 52 randomized clinical trials of a-interferon in chronic NANB and C hepatitis. Normalization of serum ALT during and 3-6 months after interferon treatment served to assess short- and long-term response rates. RESULTS: Interferon initially induced ALT normalization in 1499/2927 patients (51.2%); due to a high relapse rate (> 50%), only 482/2218 patients (21.7%) still had normal ALT values three months after interferon therapy had been stopped. Nevertheless, ALT normalization was increased more than 8-fold by a-interferon treatment (21.7%) when compared with the spontaneous normalization rate in untreated or placebo-treated controls (22/822 controls; 2.7%)(chi 2 = 156.1; p < or = 10(-15). The long-term response rate significantly increased with increasing weekly doses and with the duration of interferon therapy (r = 0.25 and 0.38 with p < 0.01, respectively). Correspondingly, the response rate was correlated most closely with the total dose of interferon given (r = 0.49, p < 0.001). Total interferon doses > 240 M.U. resulted in a threefold higher long-term response when compared with doses < 240 M.U. (X2 = 103.3; p < or = 10(-15). The presence of cirrhosis markedly reduced the response rate to almost 1/3 of noncirrhotic patients (chi 2 = 12.1; p = 0.00013). The response rate did not depend on the type of interferon used. CONCLUSIONS: The present data strongly suggest that future studies which evaluate effects of a-interferon in chronic hepatitis C should focus on higher doses and longer duration of therapy, preferably in noncirrhotic patients.
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Hepatitis C/terapia , Interferón-alfa/uso terapéutico , Alanina Transaminasa/sangre , Enfermedad Crónica , Hepatitis C/sangre , Hepatitis C/complicaciones , Humanos , Interferón-alfa/administración & dosificación , Cirrosis Hepática/sangre , Cirrosis Hepática/complicaciones , Análisis de RegresiónRESUMEN
BACKGROUND/AIMS: Polyunsaturated phospatidyl-choline (PPC) has been shown to reduce serum aminotransferases in experimental hepatitis. This multi-center, randomized, double-blind, placebo-controlled trial evaluated the effects of PPC in patients with chronic hepatitis B and C in combination with interferon alpha 2a or 2b. The diagnosis of chronic viral hepatitis was based on an abnormal serum alanine aminotransferase (ALT) value (more than twice the upper value of normal), viral replication and chronic hepatitis found on liver biopsy. METHODOLOGY: Patients received 5 million I.U. (Hepatitis B) and 3 million I.U. (hepatitis C) interferon s.c. thrice weekly for 24 weeks, respectively, and were randomly assigned to additional oral medication with either 6 capsules of PPC (total daily dose: 1.8 g) or 6 capsules of placebo per day for 24 weeks. Biochemical response to therapy was defined as a reduction of ALT by more than 50% of pre-treatment values. The responders were treated for further 24 weeks after cessation of interferon therapy with either PPC or placebo. RESULTS: 176 patients completed the study protocol (per-protocol population: 92 in the PPC and 84 in the placebo group). A biochemical response (> 50% ALT reduction) was seen in 71% of patients who were treated with PPC, but only in 56% of patients who received placebo (p < 0.05). PPC increased the response rate in particular in patients with hepatitis C: 71% of those patients responded in the PPC group versus 51% in the placebo group (p < 0.05). Prolonged PPC therapy given to responders beyond the cessation of interferon therapy tended to increase the rate of sustained responders at week 48 in patients with hepatitis C (41% versus 15% in the control group; p = 0.064). In contrast, PPC did not alter the biochemical response to interferon in patients with hepatitis B. PPC did not accelerate elimination of HBV-DNA, HBeAg and HCV-RNA. CONCLUSIONS: In conclusion, PPC may be recommended in patients with chronic hepatitis C in combination with interferon and after termination of interferon in order to reduce the high relapse rate. PPC may not be recommended for patients with chronic hepatitis B. In contrast to IFN and other antiviral agents PPC does not carry major risks and is tolerated very well.
Asunto(s)
Antivirales/uso terapéutico , Hepatitis B/tratamiento farmacológico , Hepatitis C/tratamiento farmacológico , Interferón Tipo I/uso terapéutico , Fosfatidilcolinas/administración & dosificación , Adulto , Anciano , Alanina Transaminasa/sangre , Biomarcadores/sangre , Método Doble Ciego , Quimioterapia Combinada , Estudios de Evaluación como Asunto , Estudios de Seguimiento , Hepatitis B/sangre , Hepatitis C/sangre , Hepatitis Crónica , Humanos , Hipolipemiantes/uso terapéutico , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Persona de Mediana Edad , Proteínas Recombinantes , Factores de TiempoRESUMEN
BACKGROUND/AIMS: Viral serum concentrations are considered to have a clinical, prognostic and epidemiological impact on patients with hepatitis C infection. The purpose of this study was to test whether quantitation of HCV-RNA is possible by PCR in combination with DNA-ELISA. METHODOLOGY: PCR with 25 to 35 cycles was performed with variable concentrations of cloned HCV-cDNA or the serum of patients with chronic hepatitis C. The amplified PCR-products were detected by agarose gel or by DNA-ELISA. RESULTS: The detection limit of PCR with DNA-ELISA or gel detection decreased with increasing numbers of PCR cycles. However, the correlation of the optical density of the DNA-ELISA with the HCV-cDNA concentration decreased with increasing numbers of PCR as well (r=0.8 vs. r=0.29; 25 vs. 35 PCR-cycles). HCV-RNA was found in the sera of 19 of 30 patients (63%) with chronic hepatitis C by gel detection and in 14 of 30 patients (47%) by DNA-ELISA subsequent to PCR with 35 cycles. CONCLUSIONS: The PCR/DNA-ELISA technique allows a semiquantitative determination of HCV-cDNA concentrations down to 103 genomes/ul. However, to obtain a reasonable sensitivity for HCV concentrations in the serum of patients with hepatitis C, the number of PCR cycles has to be increased to numbers too high to provide reliable quantification. Further studies should be done to evaluate whether the detection systems can be improved to obtain a sufficient sensitivity for quantitative HCV-PCR. A prerequisite for the use of PCR in combination with quantifiable detection systems is that a PCR-cycle number is chosen that keeps amplification within the logarithmic phase.
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Ensayo de Inmunoadsorción Enzimática , Hepacivirus/genética , Hepatitis C Crónica/virología , Reacción en Cadena de la Polimerasa , ARN Viral/sangre , ADN Viral/análisis , Hepacivirus/aislamiento & purificación , Humanos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND/AIMS: The incidence of hepatitis C infection is increased in subjects with human immunodeficiency virus infection, although the relative frequency of hepatitis b infection is higher than that hepatitis c. The present study assessed the effect of IFN-a on chronic hepatitis C in HIV infected patients. MATERIAL AND METHODS: Twenty patients with chronic hepatitis C, nine positive for antibodies to the human immunodeficiency virus and eleven HIV-seronegative, were treated with interferon a-2b. RESULTS: Five HIV-positive patients responded to therapy with a complete (three) or partial (two) remission of hepatitis at the end of treatment. A sustained response was achieved in four patients. From the HIV-negative patients eight responded with a complete (six) or partial (two) remission. The response was sustained in six patients. Hepatitis C virus-RNA became at least temporarily undetectable in three HIV-positive and six HIV-negative patients. No severe toxicity of interferon treatment was seen in either the HIV-positive or the HIV-negative patients. CONCLUSION: The present results indicate that interferon treatment of chronic hepatitis C in HIV-positive patients is successful in a considerable number of individuals. However it might be inferior to the results in HIV-negative patients.
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Infecciones por VIH/complicaciones , Hepatitis C/terapia , Interferón-alfa/administración & dosificación , Adulto , Recuento de Linfocito CD4 , Enfermedad Crónica , Femenino , Proteína p24 del Núcleo del VIH/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/terapia , Hepacivirus/genética , Hepatitis C/complicaciones , Hepatitis C/inmunología , Humanos , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , ARN Viral/análisisRESUMEN
BACKGROUND: Since 3 years there is an effective enzyme replacement therapy for patients with Gaucher's disease which is the most prevalent sphingolipid storage disease. Also the diagnostic procedures have recently been improved. This study reports about the results of longterm enzyme replacement therapy and the diagnostic workup in 18 patients with Gaucher's disease. PATIENTS AND METHODS: Since June 1991, 18 patients with moderate to severe degree of Gaucher's disease were treated by administration of modified human glucocerebrosidase on regular bases in the University Hospital Düsseldorf. According to the severity of the disease, glucocerebrosidase infusion was performed every 2 weeks. The dosage was individually chosen according to the severity of the disease. RESULTS: Within 3 to 4 months all patients showed an improvement of laboratory findings, of hepatosplenomegaly and of their general well-being. CONCLUSIONS: The advances in our understanding of this disease need to be publicized because an early diagnosis and timely enzyme replacement guarantees almost all patients with the adult type of Gaucher's disease to live a normal life without complaints and complications.
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Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/administración & dosificación , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Enfermedad de Gaucher/diagnóstico , Glucosilceramidasa/deficiencia , Humanos , Infusiones Intravenosas , Cuidados a Largo Plazo , Masculino , Persona de Mediana EdadRESUMEN
How many patients with chronic viral hepatitis are suitable for interferon therapy? A prospective analysis of a university out-patient department. The present study prospectively analyzes 273 consecutive patients admitted to the outpatient-hepatology clinic for interferon therapy of chronic viral hepatitis from 1989 to 1991. 149/273 (54.6%) patients suffered from hepatitis-B viral infection (HBV). Of the 107 patients with NANB-hepatitis (39.2%) 103 patients finally proved to have hepatitis-C viral infection (HCV) (96.3%). In 17/273 patients (6.2%) the outside diagnosis of viral hepatitis was wrong. The percentage of men versus women was significantly greater in HBV (71.8% vs. 28.2%) than in HCV infection (52.4% vs. 47.5%) (p < 0.01; c2-test). The admittance of patients increased from 68 patients in 1989 to 88 patients in 1990 and 117 patients in 1991. The percentage of HCV-patients increased from 26.4% in 1989 to 38.6% in 1990 and 43.6% in 1991. The number of patients with HCV-infection admitted by non-university hospitals versus practitioners and internists was significantly greater in HCV-infection (48.5% vs. 51.5%) compared to HBV-infection (hospitals: 36.9%; practitioners: 63.1%) (p < 0.05). Interferon therapy was initiated in 131/252 patients (52%) with HBV- or HCV-infection. HCV-patients were treated with interferon significantly more frequently (59.2%) compared with HBV-patients (46.9%) (p = 0.05). Since interferon therapy was initiated in only about 50% of HBV- and HCV-patients, the selection criteria for such treatment need to be publicized more effectively. The marked increase in patients with HCV-infection suggests that recent improvements in serology of viral hepatitis are widely and appropriately used in clinical practice.
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Hepatitis B/terapia , Hepatitis C/terapia , Hepatitis Crónica/terapia , Interferón-alfa/uso terapéutico , Adulto , Anciano , Estudios Transversales , Utilización de Medicamentos/tendencias , Femenino , Alemania/epidemiología , Hepatitis B/epidemiología , Hepatitis C/epidemiología , Hepatitis Crónica/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Derivación y Consulta/tendenciasAsunto(s)
Vacunas contra el SIDA/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Síndrome de Inmunodeficiencia Adquirida/prevención & control , Fármacos Anti-VIH/efectos adversos , Estudios Transversales , Farmacorresistencia Viral , Alemania , Humanos , Investigación , Resultado del TratamientoRESUMEN
Bile leak is a well-known complication of cholecystectomy. Endoscopic drainage and decompression of the biliary system including temporary insertion of a biliary stent is generally considered the treatment of choice. We report the successful obliteration of a bile leak using fibered platinum coils placed under fluoroscopic guidance after stent treatment had failed.
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Fístula Biliar/terapia , Colecistectomía , Colecistitis/cirugía , Embolización Terapéutica , Complicaciones Posoperatorias/terapia , Enfermedad Aguda , Anciano , Fístula Biliar/diagnóstico por imagen , Colangiopancreatografia Retrógrada Endoscópica , Colecistitis/diagnóstico por imagen , Conducto Cístico/diagnóstico por imagen , Conducto Cístico/cirugía , Duodenoscopía , Fluoroscopía , Humanos , Masculino , Complicaciones Posoperatorias/diagnóstico por imagen , Dehiscencia de la Herida Operatoria/diagnóstico por imagen , Dehiscencia de la Herida Operatoria/terapiaRESUMEN
Previous large multicentre trials reported sustained virological response (SVR) rates of 45-80% in chronically infected hepatitis C virus (HCV) patients. However, it is unclear whether such a treatment success is also achieved in daily routine and to what extent it depends on expert hepatological supervision. This was retrospectively analysed in patients presenting at our outpatient department during May 1997 and March 2004 and receiving at least one treatment dose. A total of 302 treatment-naive HCV patients [72% genotypes 1 or 4 (n = 215), 25% genotypes 2/3 (n = 78) and 3% undetermined genotype (n = 9)] were included in the analysis. Out of these, 196 patients consulted an expert hepatologist at least once every 3 months during treatment [regular visitors (RV)], whereas in 106 patients treatment was performed and supervised by a general practitioner (irregular visitors). Both patient groups did not differ in their baseline characteristics. However, the virological response rates at the end of treatment (ETR; 146/196, 74%vs 51/106, 48%, P < 0.001) and 6 months thereafter (SVR; 129/196, 66%vs 36/106, 34%, P < 0.001) were significantly higher in RV. In patients treated with pegylated-interferon (PEG-IFN)/ribavirin, this difference was statistically highly significant (P < 0.001) for HCV genotypes 1 and 4 (treated patients: SVR: 62/101, 61%vs 14/51, 27%, P < 0.001), but not for genotypes 2/3. SVR rates were also significantly better in RV with advanced liver damage [SVR 69% (22/32) vs 25% (5/20), P = 0.004]. In regular and irregular visitors treatment was discontinued in 7% (14/196) and 15% (16/106) respectively (P = 0.015). Patients with unfavourable genotypes 1 and 4 or with advanced liver damage benefit from HCV therapy supervision by a specialist, probably because of less frequent treatment interruptions or dose reductions.