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ABSTRACT: It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.
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Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos de Boro , ADN Tumoral Circulante , Dexametasona , Glicina , Lenalidomida , Mieloma Múltiple , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Femenino , Glicina/análogos & derivados , Glicina/administración & dosificación , Glicina/uso terapéutico , Masculino , Anciano , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Pronóstico , Dexametasona/administración & dosificación , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Compuestos de Boro/uso terapéutico , Compuestos de Boro/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Mutación , Adulto , Estudios Prospectivos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Biomarcadores de Tumor/genéticaRESUMEN
Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .
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Neoplasias del Colon , Neoplasias Colorrectales , Neoplasias del Recto , Humanos , Panitumumab/uso terapéutico , Bevacizumab/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Recto/tratamiento farmacológico , Biomarcadores , Receptores ErbB/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)RESUMEN
Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were "frail" according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4-19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.
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Compuestos de Boro , Fragilidad , Glicina/análogos & derivados , Mieloma Múltiple , Humanos , Anciano , Lenalidomida , Japón , Estudios Prospectivos , Fragilidad/diagnóstico , Fragilidad/epidemiología , Dexametasona , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
This nationwide, multicenter, open-label, single-arm study evaluated the efficacy and safety of the oral proteasome inhibitor (PI), ixazomib plus lenalidomide (LEN) and dexamethasone (DEX) (IRd) following injectable PI-based therapy for relapsed/refractory multiple myeloma (RRMM). Of 45 patients enrolled, 36 patients received IRd after achieving at least a minor response to 3 cycles of bortezomib or carfilzomib plus LEN + DEX (VRd, n=6; KRd, n=30). At median follow-up of 20.8 months, the 12-month event-free survival rate (primary endpoint) was 49% (90% CI: 35.9-62.0), counting 11 events of progressive disease/death, 8 dropouts and 4 missing response data. The 12-month progression-free survival (PFS) rate by Kaplan-Meier analysis (dropouts as censoring) was 74% (95% CI: 56-86). Median PFS and time to next treatment (95% CI) were 29.0 (21.3-NE) and 32.3 (14.9-35.4) months, respectively; median OS was not evaluable. The overall response rate was 73%, and 42% of patients had a very good partial response or better. Frequent (≥10% incidence) grade ≥3 treatment emergent adverse events were decreased neutrophil and platelet counts (n=7 [16%] each). Two deaths occurred (one during KRd treatment and one during IRd treatment), both due to pneumonia. IRd following injectable PI-based therapy was tolerable and efficacious in RRMM patients. TRIAL REGISTRATION NUMBER: NCT03416374; Date of registration: January 31, 2018.
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Mieloma Múltiple , Humanos , Lenalidomida/efectos adversos , Dexametasona , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Fasiglifam, a potent and highly selective agonist of G protein-coupled receptor 40, was developed for the treatment of type 2 diabetes mellitus. However, phase III clinical programs were terminated owing to liver safety concerns. Fasiglifam-related liver toxicity was also observed in repeat-dose dog toxicology studies, characterized by granulomatous inflammation with crystal formation in the liver and/or bile ducts. These histopathological changes were not observed in rat toxicology studies. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of dog liver sections obtained from a repeat-dose toxicology study indicated that the crystalline material in the affected dog liver contained fasiglifam and fasiglifam glucuronide (fasiglifam-G). Nonclinical mechanistic studies indicated that after 14 days of repeated oral dosing with [14C]fasiglifam at 200 mg/kg per day to dogs, the concentrations of fasiglifam and fasiglifam-G in the bile exceeded the solubility limit of these compounds in the bile (approximately 3000 µg/ml). After single oral 2- and 200-mg/kg doses administered to rats and dogs, fasiglifam and fasiglifam-G concentrations in dog bile were 5- to 10-fold higher than those in rat bile for the same dose of fasiglifam, while the bile flow rate adjusted by body weight was 4- to 8-fold lower in dogs than in rats. High fasiglifam and fasiglifam-G concentrations in dog bile together with lower bile flow rate could cause crystal formation in dog bile, resulting in secondary granulomatous inflammation in the dog liver.
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Benzofuranos/efectos adversos , Benzofuranos/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hígado/efectos de los fármacos , Sulfonas/efectos adversos , Sulfonas/metabolismo , Animales , Bilis/metabolismo , Perros , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: The purpose of this study is the development of novel fluorine-18-fluorodeoxyglucose (F-FDG)-PET and Tc-hexamethylpropylene amine oxime (HMPAO) SPECT methods with free-moving apparatus on conscious rats to investigate brain activity without the effects of anesthesia and tactual stimulation. We also assessed the sensitivity of the experimental system by an intervention study using fluoxetine as a reference drug. MATERIALS AND METHODS: A catheter was inserted into the femoral vein and connected to a free-moving cannula system. After fluoxetine administration, the rats were given an injection of F-FDG or Tc-HMPAO via the intravenous cannula and released into a free-moving cage. After the tracer was trapped in the brain, the rats were anesthetized and scanned with PET or SPECT scanners. Then a volume of interest analysis and statistical parametric mapping were performed. RESULTS: We could inject the tracer without touching the rats, while keeping them conscious until the tracers were distributed and trapped in the brain using the developed system. The effects of fluoxetine on glucose uptake and cerebral blood flow were perceptively detected by volume of interest and statistical parametric mapping analysis. CONCLUSION: We successfully developed free-moving F-FDG-PET and Tc-HMPAO-SPECT imaging systems and detected detailed glucose uptake and cerebral blood flow changes in the conscious rat brain with fluoxetine administration. This system is expected to be useful to assess brain activity without the effects of anesthesia and tactual stimulation to evaluate drug effect or animal brain function.
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Circulación Cerebrovascular/efectos de los fármacos , Glucosa/metabolismo , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Transporte Biológico/efectos de los fármacos , Fluorodesoxiglucosa F18/metabolismo , Fluoxetina/farmacología , Inyecciones , Masculino , Tomografía de Emisión de Positrones/instrumentación , Ratas , Ratas Wistar , Tomografía Computarizada de Emisión de Fotón Único/instrumentaciónRESUMEN
Recent studies in RAS wild-type (WT) metastatic colorectal cancer (mCRC) suggest that the survival benefits of therapy using anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies combined with chemotherapy are maximized when the anti-EGFR antibody is given as first-line, followed by subsequent anti-VEGF antibody therapy. We report reverse-translational research using LIM1215 xenografts of RAS WT mCRC to elucidate the biologic mechanisms underlying this clinical observation. Sequential administration of panitumumab then bevacizumab (PB) demonstrated a stronger tendency to inhibit tumor growth than bevacizumab then panitumumab (BP). Cell proliferation was reduced significantly with PB (Pâ¯<â¯.01) but not with BP based on Ki-67 index. Phosphoproteomic analysis demonstrated reduced phosphorylation of EGFR and EPHA2 with PB and BP compared with control. Western blotting showed reduced EPHA2 expression and S897-phosphorylation with PB; RSK phosphorylation was largely unaffected by PB but increased significantly with BP. In quantitative real-time PCR analyses, PB significantly reduced the expression of both lipogenic (FASN, MVD) and hypoxia-related (CA9, TGFBI) genes versus control. These results suggest that numerous mechanisms at the levels of gene expression, protein expression, and protein phosphorylation may explain the improved clinical activity of PB over BP in patients with RAS WT mCRC.
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Anticuerpos Monoclonales/farmacología , Antineoplásicos/farmacología , Bevacizumab/farmacología , Neoplasias Colorrectales/patología , Animales , Biomarcadores , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/mortalidad , Modelos Animales de Enfermedad , Receptores ErbB/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Hipoxia/genética , Hipoxia/metabolismo , Ratones , Panitumumab , Fosforilación , Proteoma , Receptor EphA2/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: One of the major causes of diabetes and obesity is abnormality in glucose metabolism and glucose uptake in the muscle and adipose tissue based on an insufficient action of insulin. Therefore, many of the drug discovery programs are based on the concept of stimulating glucose uptake in these tissues. Improvement of glucose metabolism has been assessed based on blood parameters, but these merely reflect the systemic reaction to the drug administered. We have conducted basic studies to investigate the usefulness of glucose uptake measurement in various muscle and adipose tissues in pharmacological tests using disease-model animals. METHODS: A radiotracer for glucose, 18F-2-deoxy-2-fluoro-D-glucose (18F-FDG), was administered to Wistar fatty rats (type 2 diabetes model), DIO mouse (obese model), and the corresponding control animals, and the basal glucose uptake in the muscle and adipose (white and brown) tissues were compared using biodistribution method. Moreover, insulin and a ß3 agonist (CL316,243), which are known to stimulate glucose uptake in the muscle and adipose tissues, were administered to assess their effect. 18F-FDG uptake in each tissue was measured as the radioactivity and the distribution was confirmed by autoradiography. RESULTS: In Wistar fatty rats, all the tissues measured showed a decrease in the basal level of glucose uptake when compared to Wistar lean rats. On the other hand, the same trend was observed only in the white adipose tissue in DIO mice, while brown adipose tissue showed increments in the basal glucose uptake in this model. Insulin administration stimulated glucose uptake in both Wistar lean and fatty rats, although the responses were inhibited in Wistar fatty rats. The same tendency was shown also in control mice, but clear increments in glucose uptake were not observed in the muscle and brown adipose tissue of DIO mice after insulin administration. ß3 agonist administration showed the similar trend in Wistar lean and fatty rats as insulin, while the responses were inhibited in the adipose tissues of Wistar fatty rats. CONCLUSION: A system to monitor tissue glucose uptake with 18F-FDG enabled us to detect clear differences in basal glucose uptake between disease-model animals and their corresponding controls. The responses in the tissues to insulin or ß3 agonist could be identified. Taken as a whole, the biodistribution method with 18F-FDG was confirmed to be useful for pharmacological evaluation of anti-diabetic or anti-obesity drugs using disease-model animals.
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Tejido Adiposo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Glucosa/metabolismo , Insulina/farmacología , Músculos/metabolismo , Obesidad/metabolismo , Tejido Adiposo/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Diabetes Mellitus Experimental/patología , Modelos Animales de Enfermedad , Masculino , Ratones , Músculos/efectos de los fármacos , Obesidad/patología , Ratas , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
CONTEXT: Drug-induced phospholipidosis is one of the significant concerns in drug development, especially in safety assessment and noninvasive diagnostic tool is highly desirable. OBJECTIVE: The objective of this study is to explored novel biomarkers for phospholipidosis using a metabolomic approach. METHOD: NMR spectrometry and LC/MS/MS analyses were applied to urine and plasma of rats administrated cationic amphiphilic drugs. RESULTS: The phenylacetylglycine to hippuric acid ratio in plasma was increased in time and dose-dependent manners; and it was well correlated with histopathological observation. CONCLUSION: The plasma phenylacetylglycine to hippuric acid ratio is a potential marker in monitoring drug-induced phospholipidosis.
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Biomarcadores/análisis , Glicina/análogos & derivados , Hipuratos/análisis , Lipidosis/diagnóstico , Animales , Biomarcadores/sangre , Biomarcadores/orina , Monitoreo de Drogas/métodos , Glicina/análisis , Glicina/sangre , Glicina/orina , Hipuratos/sangre , Hipuratos/orina , Lipidosis/inducido químicamente , Metabolómica/métodos , Fosfolípidos , RatasRESUMEN
Urinary hippuric acid (HA) and phenylacetylglycine (PAG) are biomarker candidates for drug-induced phospholipidosis (PLD). To confirm their utility in preclinical and clinical settings, it is essential to develop and validate their quantification method in advance. In this study, we have applied liquid chromatography-tandem mass spectrometry (LC/MS/MS) for simultaneous quantification of HA and PAG in rat urine, and matrix based ion suppression was assessed by post-column infusion assay. Effective sample dilution reduced matrix effect of urine to be negligible level and calibration curves showed good correlation between those in urine diluent and buffer alone. Reliability of this assay was confirmed by the assessments for intra- and inter-day precisions and accuracies of quality control samples. The method was applied to rat urine after multiple oral administrations of PLD-inducing drugs, and the changes in HA and PAG concentrations and their ratio were successfully detected as rat plasma in previous report. This is the first report to quantify HA and PAG easily and accurately as potential biomarkers to monitor PLD status. This assay would be useful tool for monitoring PLD in toxicological studies by non-invasive sampling.
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Cromatografía Liquida/métodos , Glicina/análogos & derivados , Hipuratos/orina , Espectrometría de Masa por Ionización de Electrospray/métodos , Animales , Glicina/orina , Ratas , Ratas Sprague-Dawley , Estándares de ReferenciaRESUMEN
OBJECTIVE: The aim of this study was to evaluate the potential of (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) for monitoring the therapeutic efficacy of TAK-733, an inhibitor of mitogen-activated protein kinase kinase, in nude rats bearing A549 (human lung carcinoma) xenografts. METHODS: TAK-733 was administered orally by gavage to nude xenograft rats for 2 weeks, at dosage levels of 0 (0.5% w/v methylcellulose solution), 1, 3, and 10 mg/kg/day (n = 8/dose). Tumor size was measured before treatment (day 0), and on days 1, 3, 7, 9, 11, and 14. PET scans were performed pretreatment (day 0), and on days 2, 4, 7, 10, and 14. Tracer accumulations in tumor tissue were quantified as the mean standard uptake value (SUVmean). RESULTS: No deaths or treatment-related body weight losses occurred during the study period. TAK-733 showed dose-dependent inhibition of tumor growth and (18)F-FDG uptake in tumor tissue. At a dosage of 10 mg/kg, TAK-733 treatment produced a statistically significant reduction in tumor weight from day 11 compared with the vehicle group (P < 0.05). Tumor growth was inhibited in the 10 mg/kg group with a treated/control value of 31% on day 14. The SUVmean on day 2 in this dosage group was statistically lower than that observed on day 0, and that seen in the vehicle group on day 2 (P < 0.05 for both comparisons). Furthermore, this reduction in SUVmean at 10 mg/kg was maintained over time. In the two lower dosage groups (1 and 3 mg/kg), SUVmean gradually increased over time. CONCLUSIONS: (18)F-FDG-PET enabled early determination of late anti-tumor activity in response to TAK-733 treatment.
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Carcinoma de Pulmón de Células no Pequeñas/patología , Transformación Celular Neoplásica , Fluorodesoxiglucosa F18 , Neoplasias Pulmonares/patología , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Tomografía de Emisión de Positrones , Piridonas/farmacología , Pirimidinonas/farmacología , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , Ratas , Resultado del TratamientoRESUMEN
PURPOSE: Intravascular ultrasonography (IVUS) and (18)F-FDG PET have been used to evaluate the efficacy of antiatherosclerosis drugs. These two modalities image different characteristics of atherosclerotic plaques, and a comparison of IVUS and PET images with histology has not been performed. The aim of this study was to align IVUS and PET images using anatomic landmarks in Watanabe heritable hyperlipidaemic (WHHL) rabbits, enabling comparison of their depiction of aortic atherosclerosis. Cellular (18)F-FDG localization was evaluated by (3)H-FDG microautoradiography (micro-ARG). METHODS: A total of 19 WHHL rabbits (7 months of age) were divided into three groups: baseline (n = 6), 3 months (n = 4), and 6 months (n = 9). PET, IVUS and histological images of the same aortic segments were analysed. Infiltration by foamy macrophages was scored from 0 to IV using haematoxylin and eosin (H&E) and antimacrophage immunohistochemical staining, and compared with (3)H-FDG micro-ARG findings in two additional WHHL rabbits. RESULTS: IVUS images did not identify foamy macrophage deposition but revealed the area of intimal lesions (r = 0.87). (18)F-FDG PET revealed foamy macrophage distribution in the plaques. The intensity of (18)F-FDG uptake was correlated positively with the degree of foamy macrophage infiltration. Micro-ARG showed identical (3)H-FDG accumulation in the foamy macrophages surrounding the lipid core of the plaques. CONCLUSION: F-FDG PET localized and quantified the degree of infiltration of foamy macrophages in atherosclerotic lesions. IVUS defined the size of lesions. (18)F-FDG PET is a promising imaging technique for evaluating atherosclerosis and for monitoring changes in the composition of atherosclerotic plaques affecting their stability.
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Fluorodesoxiglucosa F18/farmacocinética , Células Espumosas/diagnóstico por imagen , Placa Aterosclerótica/diagnóstico por imagen , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Ultrasonografía Intervencional , Animales , Aorta/diagnóstico por imagen , Aorta/patología , Placa Aterosclerótica/patología , ConejosRESUMEN
UNLABELLED: Various noninvasive imaging methods have been developed to evaluate atherosclerotic plaques. Among them, (18)F-FDG PET and MR imaging with ultrasmall superparamagnetic iron oxide particles (USPIO) have been used to quantify plaque inflammation. Both methods are based on the efficient uptake of FDG and USPIO by macrophages in atherosclerotic lesions. Differently polarized macrophages have been reported to have different characteristics that are involved in the pathologic development of atherosclerosis. M1 polarized macrophages are considered the more proatherogenic phenotype than M2 polarized macrophages. However, little is known regarding the association between macrophage polarization and FDG or USPIO accumulation. In this study, we investigated intracellular FDG and USPIO accumulation in M1 and M2 polarized macrophages. METHODS: THP-1 macrophages were differentiated into M1 and M2 polarized macrophages. Under optimal glucose conditions, we investigated the (3)H-labeled FDG uptake in M1 and M2 polarized macrophages. We then investigated intracellular USPIO uptake by M1 and M2 macrophages. RESULTS: We found that M1 polarization, compared with M2 polarization, results in increased intracellular accumulation of FDG. To elucidate the mechanism by which FDG was preferentially accumulated in M1 macrophages, we examined messenger RNA expressions of glucose transporters (GLUTs) and hexokinases, which have pivotal roles in glucose uptake, and glucose-6-phosphatase (G6Pase), which catalyzes the reverse reaction of hexokinase. In M1 macrophages, GLUT-1, GLUT-3, hexokinase 1, and hexokinase 2 were upregulated and G6Pase was downregulated. In contrast to FDG, M1 polarization resulted in decreased intracellular accumulation of USPIO. We found that scavenger receptor A and CD11b, which are involved in USPIO binding and uptake, were significantly downregulated by M1 polarization. CONCLUSION: Compared with M2, proatherogenic M1 macrophages preferentially accumulated FDG but not USPIO, suggesting that FDG PET is a useful method for the detection of proinflammatory M1 macrophages.
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Aterosclerosis/diagnóstico , Compuestos Férricos/química , Fluorodesoxiglucosa F18 , Macrófagos/citología , Imagen Molecular/métodos , Tamaño de la Partícula , Transporte Biológico , Línea Celular , Células Cultivadas , Medios de Contraste/química , Medios de Contraste/metabolismo , Compuestos Férricos/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Regulación de la Expresión Génica , Glucosa/metabolismo , Humanos , Macrófagos/metabolismo , Imanes/químicaAsunto(s)
Apolipoproteínas E/deficiencia , Aterosclerosis/diagnóstico , Aterosclerosis/patología , Dextranos , Imagen por Resonancia Magnética/métodos , Nanopartículas de Magnetita , Animales , Aorta Torácica/patología , Apolipoproteínas E/metabolismo , Aterosclerosis/diagnóstico por imagen , Angiografía por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , RadiografíaRESUMEN
PURPOSE: To evaluate the relationship between the degree of hydronephrosis and the detection rates of ureteral stones with ultrasonography (US). METHODS: Of 250 consecutive patients with suspected ureterolithiasis, 214 who were diagnosed with ureterolithiasis were enrolled in this study. First, both kidneys were observed by US to evaluate the intrarenal collecting systems. Thereafter, the possible course of the ureters and the bladder were searched to find any stones. RESULTS: Stones were clearly observed in 80 (73%) of 109 patients with caliceal dilatation, whereas stones were clearly observed in 46 (44%) of 105 patients without dilatation (P < 0.05). Of the former 80 patients, 31 (39%) had stones in the ureterovesical junction (UVJ), whereas 51 (64%) had stones in the more proximal ureter. Of the latter 46 patients, 37 (80%) had stones in the UVJ or the bladder, whereas 9 (20%) had stones in the more proximal ureter. CONCLUSION: The US detection rate of ureteral stones was high in patients with caliceal dilatation. The whole ureter should be scanned in patients with caliceal dilatation for detection of ureteral stones. Even when patients have no caliceal dilatation, it is still considered to be useful to scan the UVJ and the bladder.
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We retrospectively evaluated the outcome of oral low-dose dexamethasone (DXM) therapy for androgen-independent prostate cancer (AIPC). Between January 1999 and April 2006, 99 consecutive patients with AIPC were enrolled in this study. The median patient age was 70 years (range 46-86), and the median pretreatment prostate-specific antigen (PSA) level was 243 ng/ml (range 8.2-29600). Median follow-up was 41.9 months (range 11.4-170.4). Upon biochemical failure, patients were treated with oral low-dose DXM. A total of 40 of the 99 cases (40.4%) showed a ≥50% decrease in serum PSA levels (PSA responders). Twenty-five cases (25.2%) showed a <50% decrease in PSA, and the remaining 34 cases (34.3%) had increased PSA levels (PSA non-responders). The median PSA progression-free survival was 3.0 (range 0-27) and 8.0 months (range 2-27) for the entire cohort and PSA responders, respectively. The PSA responders had a significantly increased survival (median 30.1 months) compared to the non-responders (median 8.8 months, P<0.001). Of the 34 patients who were under pain control for bone metastases before the administration of DXM, 23 (67.6%) were able to discontinue the regular use of analgesics. The PSA responders also showed an increase in hemoglobin levels. The change in serum interleukin-6 levels was significantly associated with a response to DXM (P=0.0065). Severe adverse events of DXM were rare. Clinicopathological factors predicting the PSA response to DXM were age, time from initial androgen deprivation therapy to DXM and PSA velocity prior to DXM. In conclusion, oral low-dose DXM led to an acceptable PSA response in patients with AIPC. Thus, this therapy may be an effective and safe alternative for the treatment of AIPC, particularly for patients who are not favourable candidates for chemotherapy.
RESUMEN
Drug candidates under development by industry frequently show phospholipidosis as a side-effect in pre-clinical toxicity studies. This study sets up a cell-based assay for drug-induced phospholipidosis (PLD) and its performance was evaluated based on the in vivo PLD potential of compounds in 2-week toxicity studies in rats. When HepG2 cells were exposed simultaneously to PLD-inducing chemicals and a phospholipid having a fluorophore, an accumulation of phospholipids was detected as an increasing fluorescent intensity. Amiodarone, amitriptyline, fluoxetine, AY-9944, and perhexiline, which are common PLD-inducing chemicals, increased the fluorescent intensity, but acetaminophen, ampicillin, cimetidine, famotidine, or valproic acid, which are non-PLD-inducing chemicals, did not. The fluorescent intensity showed concordance with the pathological observations of phospholipid lamellar bodies in the cells. Then to confirm the predictive performance of the in vitro PLD assay, the 32 proprietary compounds characterized in 2-week toxicity studies in rats were evaluated with this in vitro assay. Because this in vitro assay was vulnerable to cytotoxicity, the innate PLD potential was calculated for each compound. A statistically significant increase in the in vitro PLD potential was seen for the compounds having in vivo PLD-inducing potential in the rat toxicity studies. The results suggest that the in vitro PLD potential could be appropriate to detect the appearance of PLD as a side effect in pre-clinical toxicity studies in rats.
Asunto(s)
Colorantes Fluorescentes/metabolismo , Lipidosis/inducido químicamente , Fosfatidiletanolaminas/metabolismo , Fosfolípidos/metabolismo , Pruebas de Toxicidad/métodos , Amiodarona/toxicidad , Alternativas a las Pruebas en Animales/métodos , Animales , Vesículas Citoplasmáticas/efectos de los fármacos , Inhibidores Enzimáticos/toxicidad , Femenino , Células Hep G2 , Humanos , Lipidosis/patología , Masculino , Microscopía Electrónica de Transmisión , Especificidad de Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Espectrometría de Fluorescencia , Factores de Tiempo , Pruebas de Toxicidad/economíaRESUMEN
OBJECTIVES: To examine the effect of alpha 1D/A adrenoceptor inhibitor naftopidil on health-related quality of life (QOL) in men with benign prostatic hyperplasia (BPH). METHODS: A total of 56 newly diagnosed patients with symptomatic BPH were prospectively enrolled and treated with 50 mg naftopidil daily for more than 12 weeks. All underwent pre-treatment documentation of lower urinary tract symptoms, QOL assessment using the international prostate symptom score (IPSS) and King's Health Questionnaire (KHQ), and uroflowmetry. A post-treatment assessment was performed at 12 weeks. RESULTS: IPSS scores as well as QOL index showed a significant improvement after naftopidil administration. Similarly, all seven domains except general health perceptions and social limitations in the KHQ questionnaire were significantly improved. When dividing the patients into overactive bladder (OAB) and non-OAB groups, only the OAB group showed significant improvement in almost all the domains of KHQ. Change ratios of the IPSS were not associated with those of KHQ domain scores in the OAB group. On the other hand, in the non-OAB group more domains presented improvements, which were associated with those of IPSS scores. CONCLUSIONS: Twelve-week treatment with naftopidil for symptomatic BPH patients is associated with significant improvement in the IPSS, QOL index, maximum urinary flow rate, post-void residual urine volume (PVR) and almost all domains in KHQ. KHQ is useful for the evaluation of clinical response in BPH patients, particularly in those with associated OAB.
Asunto(s)
Antagonistas Adrenérgicos alfa/uso terapéutico , Naftalenos/uso terapéutico , Piperazinas/uso terapéutico , Hiperplasia Prostática/tratamiento farmacológico , Calidad de Vida , Anciano , Humanos , Masculino , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
The human MrgX3 gene, belonging to the mrgs/SNSRs (mas related genes/sensory neuron specific receptors) family, was overexpressed in transgenic rats using the actin promoter. Two animal lines showed cataracts with liquification/degeneration and swelling of the lens fiber cells. The transient epidermal desquamation was observed in line with higher gene expression. Histopathology of the transgenic rats showed acanthosis and focal parakeratosis. In the epidermis, there was an increase in cellular keratin 14, keratin 10, and loricrin, as well as PGP 9.5 in innervating nerve fibers. These phenotypes accompanied an increase in the number of proliferating cells. These results suggest that overexpression of the human MrgX3 gene causes a disturbance of the normal cell-differentiation process.