RESUMEN
BACKGROUND: In this study, we prepared and evaluated an injectable poloxamer (P407) hydrogel formulation for intratympanic (IT) delivery of dexamethasone (DEX). METHODS: DEX-loaded P407 hydrogels were characterized in terms of thermogelation, drug loading capacities, particle size, and drug release. The in vivo toxicity and drug absorption of the DEX-loaded P407 formulation after IT injection were evaluated using an animal model by performing histopathological analysis and drug concentration measurements. RESULTS: The P407 hydrogel effectively solubilized hydrophobic DEX and demonstrated a sustained release compared to the hydrophilic DEX formulation. The in vivo study showed that the hydrogel formulation delivered considerable drug concentrations to the inner ear and displayed a favorable safety profile without apparent cytotoxicity or inflammation. CONCLUSION: P407 hydrogel can be useful as an injectable inner ear delivery formulation for hydrophobic drugs due to their biocompatibility, drug-solubilizing capacity, thermogelation, and controlled release.
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Hidrogeles , Poloxámero , Animales , Poloxámero/química , Hidrogeles/química , Liberación de Fármacos , DexametasonaRESUMEN
PURPOSE: Although many studies have examined the efficiency of various protective devices for reducing the dose of radiation exposure to physicians during interventional pain procedures, no study has compared the protective effect of these devices when they are used in combination. The purpose of this prospective experimental study was to determine the best combination of radiation-shielding devices. MATERIALS AND METHODS: Using anthropomorphic phantoms of a physician and patient, we measured the radiation protection efficiency (RPE) of each of the following protection methods and in combination during C-arm-guided simulated lumbar epidural injection: (a) personal protective equipment (PPE), (b) bedside curtain shield (Curtain), (c) x-ray tube filter (Filter), and (d) fluoroscopic collimation method (Collimation). We measured exposure doses using personal electronic dosimeters at the eye, thyroid, and gonad levels for 1 minute. Each experiment was repeated 15 times. RESULTS: The radiation exposure dose and RPE with the best single-, double-, and triple-protection methods were as follows: PPE for the single-protection method (11.82 µSv/min, 80.04%), PPE + Collimation for the double-combination method (4.68 µSv/min, 92.09%), and PPE + Collimation + Curtain for the triple-combination method (3.08 µSv/min, 93.39%). Additionally, PPE + Collimation + Curtain + Filter for the quadruple-combination method resulted in a radiation exposure and RPE of 2.91 µSv/min and 93.61%, respectively, compared with nonprotection. CONCLUSIONS: The best single-, double-, and triple-protection method was PPE, PPE + Collimation, and PPE + Collimation + Curtain, respectively. While preparing protective equipment, we recommend prioritizing equipment in this order.
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Exposición Profesional , Exposición a la Radiación , Protección Radiológica , Humanos , Exposición Profesional/efectos adversos , Exposición Profesional/prevención & control , Estudios Prospectivos , Dosis de Radiación , Exposición a la Radiación/efectos adversos , Exposición a la Radiación/prevención & controlRESUMEN
Although previous studies continuously report an increased risk of hearing loss in diabetes patients, the impact of the disease on the inner ear remains unexplored. Herein, we examine the pathophysiology of diabetes-associated hearing impairment and cochlear synaptopathy in a mouse model of diabetes. Male B6.BKS(D)-Leprdb/J (db/db, diabetes) and heterozygote (db/+, control) mice were assigned into each experimental group (control vs. diabetes) based on the genotype and tested for hearing sensitivity every week from 6 weeks of age. Each cochlea was collected for histological and biological assays at 14 weeks of age. The diabetic mice exerted impaired hearing and a reduction in cochlear blood flow and C-terminal-binding protein 2 (CtBP2, a presynaptic ribbon marker) expression. Ultrastructural images revealed severely damaged mitochondria from diabetic cochlea accompanied by a reduction in Cytochrome c oxidase subunit 4 (COX4) and CR6-interacting factor 1 (CRIF1). The diabetic mice presented significantly decreased levels of platelet endothelial cell adhesion molecule (PECAM-1), B-cell lymphoma 2 (BCL-2), and procaspase-9, but not procaspase-8. Importantly, significant changes were not found in necroptotic programmed cell death markers (receptor-interacting serine/threonine-protein kinase 1, RIPK1; RIPK3; and mixed lineage kinase domain-like pseudokinase, MLKL) between the groups. Taken together, diabetic hearing loss is accompanied by synaptopathy, microangiopathy, damage to the mitochondrial structure/function, and activation of the intrinsic apoptosis pathway. Our results imply that mitochondrial dysfunction is deeply involved in diabetic hearing loss, and further suggests the potential benefits of therapeutic strategies targeting mitochondria.
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Diabetes Mellitus Experimental/complicaciones , Pérdida Auditiva/fisiopatología , Mitocondrias/ultraestructura , Receptores de Leptina/genética , Animales , Apoptosis , Biomarcadores/metabolismo , Cóclea/irrigación sanguínea , Cóclea/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Modelos Animales de Enfermedad , Regulación hacia Abajo , Pérdida Auditiva/etiología , Pérdida Auditiva/genética , Pérdida Auditiva/metabolismo , Humanos , Masculino , Ratones , Microscopía Electrónica de Transmisión , Mitocondrias/metabolismoRESUMEN
For a biosimilar to gain regulatory approval, a comprehensive comparability exercise must demonstrate that it is highly similar to its originator biologic, or reference product. Once biosimilarity has been shown, it is possible to approve the biosimilar for additional indications held by the reference product, without clinical trials in these indications. Extrapolation of clinical data is permitted by regulatory agencies as long as it is scientifically justified. CT-P10, a biosimilar of rituximab, was recently approved in Europe for all indications held by its reference product, incorporating both autoimmune diseases and hematological cancers. Here, we review the scientific rationale for extrapolation in biosimilar development using the example of CT-P10 as a case study.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Biosimilares Farmacéuticos/farmacología , Biosimilares Farmacéuticos/normas , Aprobación de Drogas , Humanos , Neoplasias/patología , Rituximab/farmacología , Rituximab/uso terapéutico , Resultado del TratamientoRESUMEN
Biosimilars are highly similar versions of approved biologic drugs that may confer equivalent efficacy at a reduced cost. Patents for several biological cancer therapeutics are past or approaching expiry, presenting an opportunity to increase affordability and global accessibility of key drugs through the development of biosimilars. To receive approval, a biosimilar must show no clinically meaningful differences from the reference product in terms of efficacy or safety. The first monoclonal antibody biosimilar cancer therapeutic to gain approval was CT-P10, a biosimilar of rituximab. Here, we review the oncology clinical development program for CT-P10, providing insights into the rationale for, and design of, CT-P10 clinical trials in patients with cancer. Trials of biosimilar cancer therapeutics in development are also discussed.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Descubrimiento de Drogas , Neoplasias/tratamiento farmacológico , Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biosimilares Farmacéuticos/farmacología , Ensayos Clínicos como Asunto , Humanos , Neoplasias/mortalidad , Neoplasias/patología , Resultado del TratamientoRESUMEN
As the patents for many biologic anticancer drugs expire, significant growth in the use of biosimilars is predicted, offering an opportunity to help combat the rising costs of treatment and increase patient access to biologic therapy. Attainment of regulatory approval, involving numerous nonclinical and clinical comparative studies versus each reference product, is only one of several barriers to realize the potential gains offered by biosimilars. It is important to understand the current perceptions and informational needs of different stakeholders if biosimilars are to be accepted and widely used in the clinic. We discuss these considerations and refer to recent experiences with CT-P13, a biosimilar of the TNF inhibitor infliximab used to treat rheumatoid arthritis and other inflammatory disorders.
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Antineoplásicos/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Percepción , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/farmacología , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Biosimilares Farmacéuticos/farmacología , Personal de Salud , Humanos , Pacientes , Guías de Práctica Clínica como AsuntoRESUMEN
Monoclonal antibodies and other biologic drugs play important roles in the treatment of various hematological malignancies and solid tumors. However, such drugs are intrinsically more expensive to develop than small molecules and their clinical benefits are often accompanied by challenges relating to affordability and access. Patent expiry for 'originator' biologics is providing opportunities for a new generation of biosimilar drugs, potentially capable of relieving pressure on healthcare budgets. This article discusses key characteristics of biosimilars, distinguishes them from generics and noncomparable biologics and outlines the robust regulatory requirements that must be followed to establish biosimilarity with a reference product. The path to approval is discussed with reference to the rituximab biosimilar CT-P10, the first licensed monoclonal antibody biosimilar cancer therapeutic.
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Antineoplásicos/uso terapéutico , Biosimilares Farmacéuticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/química , Antineoplásicos/farmacología , Biosimilares Farmacéuticos/química , Biosimilares Farmacéuticos/farmacología , Estudios Clínicos como Asunto , Aprobación de Drogas , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Humanos , Legislación de Medicamentos , Resultado del TratamientoRESUMEN
BACKGROUND: The aim of this study is to evaluate the associations between vascular endothelial growth factor (VEGF) Single-nucleotide polymorphisms (SNPs) and clinical outcome in advanced gastric cancer patients treated with oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). METHODS: Genomic DNA was isolated from whole blood, and six VEGF (-2578C/A, -2489C/T, -1498 T/C, -634 G/C, +936C/T, and +1612 G/A) gene polymorphisms were analyzed by PCR. Levels of serum VEGF were measured using enzyme-linked immunoassays. RESULTS: Patients with G/G genotype for VEGF -634 G/C gene polymorphism showed a lower response rate (22.2%) than those with G/C or C/C genotype (32.3%, 51.1%; P = 0.034). Patients with the VEGF -634 G/C polymorphism G/C + C/C genotype had a longer progression free survival (PFS) of 4.9 months, compared with the PFS of 3.5 months for those with the G/G (P = 0.043, log-rank test). By multivariate analysis, this G/G genotype of VEGF -634 G/C polymorphism was identified as an independent prognostic factor (Hazard ratio 1.497, P = 0.017). CONCLUSION: Our data suggest that G/G genotype of VEGF -634 G/C polymorphism is related to the higher serum levels of VEGF, and poor clinical outcome in advanced gastric cancer patients.
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Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/genética , Polimorfismo de Nucleótido Simple , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Factor A de Crecimiento Endotelial Vascular/genética , Adenocarcinoma/sangre , Adenocarcinoma/patología , Adulto , Anciano , Biomarcadores de Tumor/sangre , Distribución de Chi-Cuadrado , Supervivencia sin Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Fluorouracilo/administración & dosificación , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Análisis Multivariante , Compuestos Organoplatinos/administración & dosificación , Fenotipo , Reacción en Cadena de la Polimerasa , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Neoplasias Gástricas/sangre , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Factores de Tiempo , Resultado del Tratamiento , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/sangre , Adulto JovenRESUMEN
BACKGROUND: Traditionally, tinnitus accompanied by hemifacial spasm has been considered a type of hyperactive neurovascular compression syndrome that is similar to hemifacial spasm alone because of the anatomically close relationship between the facial nerve and cochlear nerve as well as the hyperactive clinical nature. METHODS: Participants were 29 subjects who presented with hemifacial spasm and neuroradiological evidence of vascular compression of the cranial (facial/cochlear) nerve. We used magnetoencephalography (MEG) to estimate the activity of the cochlear nerve in patients with and without tinnitus on the ipsilateral side. We compared the difference in the latency and the ratio of the equivalent current dipole (ECD) strength between the ipsilateral and contralateral sides of the spasm and tinnitus. RESULTS: Cochlear nerve activity in patients with tinnitus was increased with a shorter latency (p = 0.016) and stronger ECD strength (p = 0.028) compared with patients without tinnitus. CONCLUSION: The MEG results from normal-hearing patients who had tinnitus accompanied by hemifacial spasm suggest that the hyperactivity of the auditory central nervous system may be a crucial pathophysiological factor in the generation of tinnitus in these patients. The neurovascular compression that causes sensory input from the pathologic facial nerve activity may contribute to this hyperactivity of the central auditory nervous system.
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Espasmo Hemifacial/complicaciones , Magnetoencefalografía , Síndromes de Compresión Nerviosa/complicaciones , Acúfeno/diagnóstico , Acúfeno/etiología , Estimulación Acústica , Adulto , Anciano , Electroencefalografía , Potenciales Evocados Auditivos/fisiología , Femenino , Lateralidad Funcional/fisiología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Tiempo de Reacción/fisiologíaRESUMEN
BACKGROUND: Although 30-50 % of patients with brain tumors experience epileptic seizure as the presenting clinical symptom, and another 10-30 % are at risk for developing epilepsy in the later stages of the disease, the mechanisms of tumor-related epileptogenesis are poorly understood. We used magnetoencephalography (MEG) to investigate sensory evoked fields (SEFs) in patients with frontal lobe brain tumors as a means of evaluating the neuronal activity of peri-tumoral cortex. METHODS: Twelve patients with frontal lobe brain tumors underwent MEG. We calculated the equivalent current dipole strength of two components of the primary sensory cortical response (N20m and P35m) and compared the P35m/N20m ratio in the tumor hemisphere vs. the normal hemisphere. There were two subsets of patients: group I, in which P35m/N20m was higher in the tumor hemisphere (n= 7), and group II, in which P35m/N20m was higher in the normal hemisphere (n=5). We looked for associations between clinical factors and P35m/N20m within each group. RESULTS: All patients with seizure presentation were in group I, whereas only two patients without seizure presentation were in group I (Fisher exact test, p=0.028). No other clinical factors were related to P35m/N20m. The mean ratio of P35m/N20m equivalent current dipole strength in patients with seizure presentation was 4.07 ± 2.38 in the tumor hemisphere and 2.00 ± 0.55 in the normal hemisphere. This difference was statistically significant (Mann-Whitney test, p=0.030). CONCLUSION: The paradoxical increase in P35m/N20m in patients with seizure presentation suggests that decreased inhibitory neuronal activity is a potential cause of tumorrelated epilepsy.
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Neoplasias Encefálicas/fisiopatología , Potenciales Evocados Somatosensoriales/fisiología , Lóbulo Frontal/fisiopatología , Magnetoencefalografía , Convulsiones/fisiopatología , Corteza Somatosensorial/fisiopatología , Adulto , Anciano , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/patología , Estimulación Eléctrica/métodos , Femenino , Humanos , Masculino , Nervio Mediano/fisiopatología , Persona de Mediana Edad , Convulsiones/etiología , Convulsiones/patología , Convulsiones/terapia , Corteza Somatosensorial/patología , Corteza Somatosensorial/fisiología , Adulto JovenRESUMEN
BACKGROUND: Obesity is an independent risk factor for hearing loss. Although attention has focused on major obesity comorbidities such as cardiovascular disease, stroke, and type 2 diabetes, the impact of obesity on sensorineural organs, including the auditory system, is unclear. Using a high-fat diet (HFD)-induced obese mouse model, we investigated the impact of diet-induced obesity on sexual dimorphism in metabolic alterations and hearing sensitivity. METHODS: Male and female CBA/Ca mice were randomly assigned to three diet groups and fed, from weaning (at 28 days) to 14 weeks of age, a sucrose-matched control diet (10 kcal% fat content diet), or one of two HFDs (45 or 60 kcal% fat content diets). Auditory sensitivity was evaluated based on the auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and ABR wave 1 amplitude at 14 weeks of age, followed by biochemical analyses. RESULTS: We found significant sexual dimorphism in HFD-induced metabolic alterations and obesity-related hearing loss. Male mice exhibited greater weight gain, hyperglycemia, increased ABR thresholds at low frequencies, elevated DPOAE, and lower ABR wave 1 amplitude compared to female mice. The hair cell (HC) ribbon synapse (CtBP2) puncta showed significant sex differences. The serum concentration of adiponectin, an otoprotective adipokine, was significantly higher in female than in male mice; cochlear adiponectin levels were elevated by HFD in female but not male mice. Adiponectin receptor 1 (AdipoR1) was widely expressed in the inner ear, and cochlear AdipoR1 protein levels were increased by HFD, in female but not male mice. Stress granules (G3BP1) were significantly induced by the HFD in both sexes; conversely, inflammatory (IL-1ß) responses were observed only in the male liver and cochlea, consistent with phenotype HFD-induced obesity. CONCLUSIONS: Female mice are more resistant to the negative effects of an HFD on body weight, metabolism, and hearing. Females showed increased peripheral and intra-cochlear adiponectin and AdipoR1 levels, and HC ribbon synapses. These changes may mediate resistance to HFD-induced hearing loss seen in female mice.
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Diabetes Mellitus Tipo 2 , Pérdida Auditiva , Femenino , Animales , Ratones , Masculino , Caracteres Sexuales , Adiponectina , ADN Helicasas , Ratones Endogámicos CBA , Proteínas de Unión a Poli-ADP-Ribosa , ARN Helicasas , Proteínas con Motivos de Reconocimiento de ARN , Pérdida Auditiva/etiología , Dieta Alta en Grasa , ObesidadRESUMEN
BACKGROUND: Palliative chemotherapy has been shown to have a survival benefit for patients with recurrent or metastatic gastric cancer. 5-fluorouracil (5-FU) and cisplatin have been widely used in a variety of combinations. We conducted a phase II study of combination chemotherapy with new agents, S-1 and oxaliplatin (SOx), in advanced gastric cancer patients in an effort to evaluate the efficacy and toxicity of this regimen. METHOD: Histologically confirmed recurrent or metastatic gastric cancer were treated by the oral administration of S-1 80 mg/m(2)/day on days 1-28, and oxaliplatin 85 mg/m(2) administered as a 90-min intravenous infusion on days 1, 15, and 29. Treatment courses were repeated every 6 weeks. Patients received a maximum of four cycles. RESULTS: From Feb 2006 to May 2008, 41 patients were enrolled in this study. The ratio of males to females was 28 to 13. The median patient age was 61 years (range, 36-74 years), and 85.4% (35/41) of the patients had a performance status (ECOG) of 1. The median number of chemotherapy cycles administered was 3 (range, 1-4). According to the results of our Intent-to-Treat analysis, 22 patients (53.7%) achieved a partial response (95% CI, 38-70%). 15 patients (36.6%) evidenced a stable disease, and 1 patient (2.4%) progressed during the course of the treatment. 3 patients were lost to follow-up prior to evaluation. The median time to progression and overall survival time were 4.6 months (95% CI, 3.4-5.8 months) and 7.8 months (95% CI, 6.9-8.7 months) from the start of the chemotherapy, respectively. A total of 114 cycles were assessed for toxicity. The major hematologic toxicities included grade 2 anemia (41.2%), grade 1-2 neutropenia (28.1%), and grade 1 thrombocytopenia (23.7%). Only 1 cycle of neutropenic fever occurred. The non-hematological toxicities observed were grade 3 vomiting (12.2%) and grade 3 diarrhea (4.9%). No treatment-related deaths occurred in our patient population during the study period. CONCLUSION: The SOx regimen evidenced a relatively high response rate and was well tolerated as a first-line therapy for advanced gastric cancer.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Administración Oral , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Distribución de Chi-Cuadrado , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Ácido Oxónico/administración & dosificación , Estudios Prospectivos , República de Corea , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Tegafur/administración & dosificación , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Gemcitabine has been recognized as a standard chemotherapy in advanced pancreas cancer(APC). We conducted a phase II study of a triple combination regimen (GPT) consisting of gemcitabine (G), cisplatin(P) and erlotinib (T) in patients with APC. PATIENTS AND METHODS: Chemotherapy-naïve patients with locally advanced or metastatic, histologically confirmed adenocarcinoma of the pancreas were treated with erlotinib 100 mg daily, 1,000 mg/m2 of gemcitabine and 25 mg/m2 of cisplatin administered on days 1 and 8, respectively, every 3 weeks.The primary end point was objective response. Secondary end points included progression-free survival, overall survival and toxicity. The study was designed according to the optimal two-stage design. RESULTS: Twenty-two patients were enrolled between June 2009 and August 2010. No complete response was achieved and partial response was observed in 5 patients (26%), Stable disease in 7 (37%), and progressive disease in 7 (37%). The median time to progression was 4.0 months (95% CI: 2.95.1 months), and the median overall survival 6.8 months (95% CI: 3.79.9 months). The response rate in stage I reached the target (≥3/22,p0010%) established for movement to stage II but this study was determined to close earlier than planned because of unexpected treatment-related deaths (3 patients). CONCLUSION: The triple regimen of GPT is effective for APC. Treatment related mortalities factored early closure of this GPT protocol. Considering effect and toxicity, this triple regimen seems to offer few benefits to the patients compared with gemcitabine based doublets. (ClinicalTrials.gov number, NCT00922896).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Clorhidrato de Erlotinib , Femenino , Humanos , Masculino , Persona de Mediana Edad , Quinazolinas/administración & dosificación , GemcitabinaRESUMEN
The objective of this study was to clarify whether the neutrophil-lymphocyte ratio (NLR) and the platelet-lymphocyte ratio (PLR) are significant prognostic markers in patients with resectable colorectal cancer (CRC). A total of 200 patients who underwent curative resection for CRC were enrolled. The NLR and PLR were positively correlated (p < 0.001). Both the NLR and PLR were shown to be good prognostic biomarkers of overall survival (OS) (p=0.002 and p=0.001, respectively). The PLR was an independent prognostic factor of OS based on multivariate analysis (hazard ratio, 1.971; 95% confidence interval, 1.102-3.335; p=0.021).
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Neoplasias Colorrectales/patología , Linfocitos/patología , Neutrófilos/patología , Neoplasias Colorrectales/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
PURPOSE: To assess the efficacy of imatinib for different tumor genotypes in Korean patients with advanced gastrointestinal stromal tumors (GIST). MATERIAL AND METHODS: Clinical data were collected from 370 consecutive patients with locally advanced unresectable, metastatic, or recurrent GIST treated with imatinib 400 mg/day between August 2001 and December 2007 at 20 Korean institutions. Tumor genotypes were determined for 290 patients by direct DNA sequencing of KIT exons 9, 11, 13, and 17, and PDGFRA exons 12, 14, and 18. RESULTS: Of 290 patients assessed for genotype, 261 (90.0%) had mutations in KIT: 222 (76.6%) in exon 11, 35 (12.1%) in exon 9 and two each (0.7%) for exons 13 and 17. Four patients (1.4%) had mutations in the PDGFRA gene: one in exon 12, and three in exon 18. Twenty-five patients (8.6%) had no detectable mutations. The best responses of the 235 patients with measurable lesions were: 15 complete response (6.4%), 126 partial response (53.5%), 86 stable disease (36.6%), and eight progressive disease (3.4%). Patients with KIT exon 9 mutations, compared with patients with KIT exon 11 mutations, had a lower objective response rate (36.7% vs. 63.6%, p = 0.007) and a shorter progression-free survival (median 28.7 months vs. 49.4 months, p = 0.001). No statistical difference in overall survival was observed between these genotypes. CONCLUSION: This study confirms that imatinib efficacy is dependent on genotype in Korean GIST patients, consistent with results demonstrated by Western patients with GIST.
Asunto(s)
Antineoplásicos/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Mutación/genética , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Pirimidinas/uso terapéutico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas , Exones/genética , Femenino , Estudios de Seguimiento , Tumores del Estroma Gastrointestinal/mortalidad , Humanos , Mesilato de Imatinib , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Fascin is an actin-binding protein that provides mechanical support and cell motility, and involves cancer cell metastasis. We investigated fascin protein expression in gastric cancer and assessed their relationship with clinicopathologic parameters and survival rates. In addition, we researched galectin-3 protein expression to study fascin action mechanisms. We performed immunohistochemisty with fascin and galectin-3 antibodies in 471 gastric carcinomas, using tissue microarrays. Fascin was positive in 14.9% (70/471) of the samples, and fascin expression was related to worse survival rates (P < 0.001), high clinical stage (P < 0.001), high T stage (P < 0.001), nodal metastasis (P < 0.001), lymphovascular invasion (P= 0.001) and the intestinal type of Lauren classification (P= 0.015). Galectin-3 protein expression was positive in 83.9% (395/471) of the samples and was reversely correlated with fascin protein expression (P= 0.020). Galectin-3 expression was related to low clinical stage (P < 0.001), but not to survival rates in multivariate analysis. In multivariate analysis, fascin expression was related to worse survival rates (HR = 1.56, P= 0.036), and can be an independent poor prognostic factor in gastric cancer.
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Adenocarcinoma/metabolismo , Biomarcadores de Tumor/análisis , Proteínas Portadoras/biosíntesis , Proteínas de Microfilamentos/biosíntesis , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Portadoras/análisis , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Proteínas de Microfilamentos/análisis , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Matrices Tisulares , Adulto JovenRESUMEN
BACKGROUND: Tumor vascular endothelial growth factor (VEGF) is a key angiogenic factor and may have an impact on tumor progression and response to chemotherapy. The insulin-like growth factor (IGF) system is related to cell proliferation and tumor growth. However, there is limited available data regarding the clinical and prognostic significance of VEGF or IGF-1 in advanced gastric cancer. The aim of this study was to evaluate the prognostic significance of serum VEGF and IGF-1 levels in advanced gastric cancer patients who were treated with oxaliplatin/5-fluorouracil (FOLFOX). METHODS: The study population consisted of 100 advanced gastric cancer patients (median age 56 years). Patients were treated with oxaliplatin 85 mg/m(2) as a 2-hour infusion on day 1 plus leucovorin 20 mg/m(2) over 10 min, followed by a 5-fluorouracil (5-FU) bolus 400 mg/m(2) and 22 h of continuous infusion of 600 mg/m(2) on days 1-2. Treatment was repeated in 2-week intervals. The levels of serum VEGF and IGF-1 were measured using enzyme-linked immunoassays. RESULTS: There was a significant correlation between the serum level of VEGF and Lauren's classification (p = 0.030) and previous operations (p = 0.010). IGF-1 was associated with the number of metastases (p = 0.012). The median level of serum VEGF was decreased after FOLFOX chemotherapy (p = 0.034). However, none of the measured serum markers were significantly correlated with response. In univariate analysis, overall survival (p < 0.001) was significantly shorter in patients with high serum levels of VEGF. Multivariate analysis revealed that VEGF was an independent factor for overall survival (HR 2.221; 95% CI 1.377-3.583, p = 0.001). Furthermore, IGF-1 had no significant influence on the clinical outcome. CONCLUSION: A high level of serum VEGF is an independent prognostic factor in patients with advanced gastric cancer treated with chemotherapy. This may help to identify the patients who are more sensitive to the FOLFOX regimen.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/sangre , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Compuestos Organoplatinos/uso terapéutico , Pronóstico , Neoplasias Gástricas/patología , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: The aim of this study was to investigate the surgical and oncologic outcomes of laparoscopy-assisted gastrectomy (LAG) and open gastrectomy (OG) for advanced gastric cancer (AGC) using the case-control method with a sufficient follow-up period. PATIENTS AND METHODS: The authors retrospectively analyzed 89 patients who underwent LAG and 345 patients who underwent OG for AGC between August 1999 and June 2007. A total of 176 matched cases were included in the final analysis. RESULTS: Except for tumor size and reconstruction, there were no statistically significant differences in the clinicopathological parameters between the two groups. Although operation time was significantly longer for LAG than OG (228.3 vs. 183.6 min, p < 0.0001), first flatus time and postoperative hospital stay without complications were significantly shorter in the LAG group (3.2 vs. 3.7 days, p < 0.0001; 7.0 vs. 10.4 days, p < 0.0001, respectively). Operation-related complications occurred in 7 cases (8.0%) in both groups. 13 patients (14.8%) in the LAG group and 15 patients (17.1%) in the OG group had recurrence. There was no statistically significant difference in the 5-year and disease-free survival rates between LAG and OG. CONCLUSIONS: LAG for AGC might be considered to be a minimally invasive surgery in some selected cases, although a well-designed prospective study comparing LAG with OG for AGC is needed.
Asunto(s)
Gastrectomía/métodos , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/cirugía , Adulto , Anciano , Biopsia con Aguja , Estudios de Casos y Controles , Intervalos de Confianza , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Gastrectomía/efectos adversos , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Laparoscopía/métodos , Laparotomía/efectos adversos , Laparotomía/métodos , Ganglios Linfáticos/cirugía , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Seguridad del Paciente , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/fisiopatología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Neoplasias Gástricas/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Recently, laparoscopic resection for relatively small sized gastric gastrointestinal stromal tumors (GISTs) has been widely accepted as minimally invasive surgery. However, no report on the long-term safety and efficacy of this surgery for large sized gastric GISTs has been published to date. METHODS: Between July 1998 and January 2011, 104 consecutive patients who underwent resection for gastric GISTs were enrolled in this retrospective study. We assessed the clinicopathological characteristics, postoperative outcomes, patient survival, and tumor recurrence. RESULTS: Of the 104 patients with gastric GISTs who were included in the study, there were 47 males and 57 females whose mean age was 59.8 years. Sixty-four patients (61.5%) had symptoms associated with tumor. Ten patients included in the group 1, 49 in the group 2, 15 in the group 3a, 9 in the group 5, 14 in the group 6a, and 7 in the group 6b. There was one minor complication and no mortalities. Recurrence was noted in 5 patients, with a median follow-up period of 49.3 months (range, 8.4 to 164.4). The 5-year overall and disease free survival rates of 104 patients were 98.6% and 94.8%, respectively. When comparing large tumor (5-10 cm) between laparoscopic and open surgery, there were statistically differences in age, tumor size, tumor location, and length of hospitalization. There were no statistical differences in the 5-year survival rate between laparoscopic and open surgery for large tumor (5-10cm). CONCLUSION: Laparoscopic surgery is feasible and effective as an oncologic treatment of gastric GISTs. Moreover, laparoscopic surgery can be an acceptable alternative to open methods for gastric GISTs of size bigger than 5 cm.
Asunto(s)
Gastrectomía/métodos , Tumores del Estroma Gastrointestinal/cirugía , Laparoscopía/métodos , Neoplasias Gástricas/cirugía , Carga Tumoral , Anciano , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Tumores del Estroma Gastrointestinal/mortalidad , Tumores del Estroma Gastrointestinal/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Hemifacial spasm patients often suffer from non-motor symptoms such as tinnitus. These non-motor symptoms are known to be associated with changes in cortical activity. Magnetoencephalography (MEG) is a technique that can record brain activity noninvasively. To determine the usefulness of MEG in assessing changes in cortical activity associated with non-motor hearing symptoms in hemifacial spasm patients. METHODS: We used MEG to evaluate the reactivity of the auditory cortex in 26 hemifacial spasm patients. We divided patients into a subjective tinnitus group (n = 10) and a non-tinnitus group (n = 16). The latency and amplitude of the most prominent deflection, N100m, was compared between the two groups. RESULTS: There was a significant difference in the pure tone audiogram on the spasm side compared with the non-spasm side. After stimulation on the spasm side, the amplitude of the N100m peak in the contralateral hemisphere was lower in the subjective tinnitus group than in the non-tinnitus group. CONCLUSIONS: Our results indicate that MEG can detect differences in cortical activity between hemifacial spasm patients with and without tinnitus. This suggests that MEG can identify changes in cortical activity associated with non-motor symptoms.