RESUMEN

BACKGROUND: Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. METHODS: We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. RESULTS: The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30-87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647-9.481; p = 0.002). CONCLUSIONS: Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.

RESUMEN

UNLABELLED: The goal of this study was to clarify whether binding potential (BP) images using (11)C-Pittsburgh compound B ((11)C-PiB) and dynamic PET can reliably detect cortical amyloid deposits for patients whose (11)C-PiB PET static images are ambiguous and whether visual ratings are affected by white matter retention. METHODS: Static and BP images were constructed for 85 consecutive patients with cognitive impairment after (11)C-PiB dynamic PET. Cortical uptake was visually assessed as positive, negative, or equivocal for both types of images. Quantitatively, the standardized uptake value ratio (SUVR) from the static image, the nondisplaceable BP from the dynamic image for mean gray matter uptake, and the ratio of gray matter uptake to white matter retention were compared among (11)C-PiB-positive, (11)C-PiB-equivocal, and (11)C-PiB-negative groups. RESULTS: Forty-three scans were visually assessed as (11)C-PiB-positive in both the static and the BP images. Ten scans were (11)C-PiB-equivocal in the static images. In 8 of them, the BP images were (11)C-PiB-positive, whereas the other 2 were (11)C-PiB-equivocal. Thirty-two scans were assessed as (11)C-PiB-negative in the static images. In the BP images, 4 were (11)C-PiB-positive and 2 were (11)C-PiB-equivocal. The mean gray matter uptake of (11)C-PiB in SUVR and nondisplaceable BP, respectively, showed statistically significant differences among the (11)C-PiB-positive, (11)C-PiB-equivocal, and (11)C-PiB-negative groups. The ratio of gray matter uptake to white matter retention was lower in the BP images than static images from the (11)C-PiB-negative and (11)C-PiB-equivocal groups, whereas it was higher in the (11)C-PiB-positive group. CONCLUSION: (11)C-PiB PET BP images can clarify visual interpretation of clinical static (11)C-PiB-equivocal images by reducing the interference of nonspecific white matter retention. We conclude that (11)C-PiB-equivocal PET findings on static images reflect cortical amyloid deposits, which can be verified using BP images. Furthermore, quantitative assessments, such as SUVR and nondisplaceable BP, are of no use for correctly rating equivocal visual findings.

Asunto(s)

Compuestos de Anilina/farmacocinética , Placa Amiloide/diagnóstico por imagen , Radiofármacos/farmacocinética , Tiazoles/farmacocinética , Anciano , Anciano de 80 o más Años , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Trastornos del Conocimiento/diagnóstico por imagen , Trastornos del Conocimiento/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismo

RESUMEN

OBJECTIVE: We have encountered occasional equivocal findings when assessing cerebral cortical amyloid retention with (11)C-Pittsburgh compound B (PiB) PET. We investigated the diagnostic significance of equivocal PiB PET findings. METHODS: This retrospective study included 101 consecutive patients complaining of cognitive disorders (30 Alzheimer's disease, 25 mild cognitive impairment, 8 Lewy body disease, 7 frontotemporal lobar degeneration, 31 others) who underwent both (11)C-PiB PET and (18)F-fluorodeoxy-D-glucose (FDG) PET. We visually classified PiB-positive, PiB-equivocal or PiB-negative ratings according to cortical uptake. For quantitative assessments of PiB PET, standard uptake values referred to cerebellar cortex (SUVR) were calculated in regional template volume of interests (frontal, temporoparietal, precuneus/posterior cingulate cortex, cerebral white matter and cerebellar cortex). The results of visual assessment were compared with the regional and mean cortical SUVRs and cortical-to-white matter ratio of PiB uptake, as well as clinical and FDG PET findings. RESULTS: Among the 101 scans, 41 were PiB negative, 11 were PiB equivocal, and 49 were rated PiB positive in the visual assessments. The mean cortical SUVR and cortical-to-white matter ratio were 0.97 ± 0.07 and 0.57 ± 0.21 in PiB-negative, 1.51 ± 0.17 and 0.75 ± 0.06 in PiB equivocal and 2.10 ± 0.33 and 0.97 ± 0.11 in PiB-positive group, respectively. Nine of 11 subjects with PiB-equivocal findings had cognitive impairments and FDG distribution compatible with Alzheimer's disease or dementia with Lewy bodies. CONCLUSIONS: We considered equivocal visual findings on PiB PET equivalent to PiB-positive with slight cortical uptake. In addition, slight cortical amyloid deposits were considered to cause cerebral metabolic abnormality and cognitive impairment. Although mean cortical SUVR was more sensitive than visual assessment because of low cortical-to-white matter contrast due to non-specific accumulation in white matter, it is important not to overlook small amounts of cortical uptake of PiB in visual inspection for exact diagnosis.

Asunto(s)

Benzotiazoles , Tomografía de Emisión de Positrones , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tiazoles

RESUMEN

PURPOSE: There is evidence that some cases of patients with dementia with Lewy bodies (DLB) can demonstrate Alzheimer disease (AD) like reduced glucose metabolism without amyloid deposition. The aim of this study was to clarify whether regional hypometabolism is related to amyloid deposits in the DLB brain and measure the degree of regional hypometabolism. METHODS: Ten consecutive subjects with DLB and 10 AD patients who underwent both Pittsburgh compound B (PiB)-PET and (18)F-fluoro-2-deoxyglucose (FDG)-PET were included in this study. Regional standardized uptake value ratio (SUVR)s normalised to cerebellar cortices were calculated in the FDG- and PiB-PET images. RESULTS: All AD patients and five DLB patients showed amyloid deposits (PiB positive). In the DLB group the parietotemporal and occipital metabolism were significantly lower than those in the AD group but there was no difference between the posterior cingulate hypometabolism between DLB and AD groups. There were no differences in regional glucose metabolism between PiB positive and negative DLB patients. CONCLUSIONS: In the DLB brain, it is suggested that decreased regional glucose metabolism is unrelated to amyloid deposits, although the hypometabolic area overlaps with the AD hypometabolic area and the degree of parietotemporal and occipital hypometabolism in DLB brain is much larger than that in AD brain.

Asunto(s)

Enfermedad de Alzheimer/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Glucosa/metabolismo , Enfermedad por Cuerpos de Lewy/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Compuestos de Anilina , Benzotiazoles , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Femenino , Fluorodesoxiglucosa F18 , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico por imagen , Masculino , Cintigrafía , Radiofármacos , Tiazoles

RESUMEN

BACKGROUND: Nephrotoxicity remains a problem for patients who receive cisplatin chemotherapy. We retrospectively evaluated potential risk factors for cisplatin-induced nephrotoxicity as well as the potential impact of intravenous magnesium supplementation on such toxicity. PATIENTS AND METHODS: We reviewed clinical data for 401 patients who underwent chemotherapy including a high dose (≥60 mg/m2) of cisplatin in the first-line setting. Nephrotoxicity was defined as an increase in the serum creatinine concentration of at least grade 2 during the first course of cisplatin chemotherapy, as assessed on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The severity of nephrotoxicity was evaluated on the basis of the mean change in the serum creatinine level. Magnesium was administered intravenously to 67 patients (17%). RESULTS: Cisplatin-induced nephrotoxicity was observed in 127 patients (32%). Multivariable analysis revealed that an Eastern Cooperative Oncology Group performance status of 2 (risk ratio, 1.876; P = 0.004) and the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) (risk ratio, 1.357; P = 0.047) were significantly associated with an increased risk for cisplatin nephrotoxicity, whereas intravenous magnesium supplementation was associated with a significantly reduced risk for such toxicity (risk ratio, 0.175; P = 0.0004). The development of hypomagnesemia during cisplatin treatment was significantly associated with a greater increase in serum creatinine level (P = 0.0025). Magnesium supplementation therapy was also associated with a significantly reduced severity of renal toxicity (P = 0.012). CONCLUSIONS: A relatively poor performance status and the regular use of NSAIDs were significantly associated with cisplatin-induced nephrotoxicity, although the latter association was marginal. Our findings also suggest that the ability of magnesium supplementation to protect against the renal toxicity of cisplatin warrants further investigation in a prospective trial.

Asunto(s)

Cisplatino/efectos adversos , Suplementos Dietéticos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Magnesio/farmacología , Neoplasias/tratamiento farmacológico , Cisplatino/uso terapéutico , Creatinina/sangre , Análisis Mutacional de ADN , Humanos , Análisis Multivariante , Oportunidad Relativa , Estudios Retrospectivos , Factores de Riesgo

RESUMEN

Hiccups are often observed in patients treated with cisplatin(CDDP)-based chemotherapy. It has been reported that gender and specific dosages of CDDP and antiemetic drugs(e.g., dexamethasone and 5-HT3 receptor antagonist)using standard therapy are major risk factors in the onset of hiccups. Recently, aprepitant has been added to the antiemetic therapy in CDDP-based chemotherapy. However, it is not known how the onset of hiccups takes place in antiemetic therapy including aprepitant according to the guideline. In this study, we used cluster analysis to classify 229 patients treated with CDDP-based chemotherapy, to investigate the effect of antiemetic therapy on the onset of hiccups and chemotherapy-induced nausea and vomiting(CINV). Our analysis indicated that aprepitant was not a major risk factor for the onset of hiccups in the high CDDP dose group(≥70 mg/m(2)). However, an effect of antiemesis was confirmed in the standard therapy with aprepitant. In conclusion, we suggest that aprepitant is effective for CINV, without causing the onset of hiccups in patients treated with high-dose CDDP-based chemotherapy.

Asunto(s)

Antieméticos/uso terapéutico , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Dexametasona/uso terapéutico , Hipo/tratamiento farmacológico , Antagonistas del Receptor de Serotonina 5-HT3/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Análisis por Conglomerados , Femenino , Hipo/inducido químicamente , Hipo/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Receptores de Serotonina 5-HT3/metabolismo , Factores de Riesgo

RESUMEN

In team medicine, highly specialized pharmacists have recently been in demand. As one of the specialties, there is therapeutic drug monitoring (TDM). It is important for the optimal dosing of a wide range of drugs. In our hospital, a TDM service was started in 1987 at the clinical laboratory. A clinical laboratory technologist with the license of a pharmacist has performed administration plans for anti-methicillin-resistant Staphylococcus aureus (MRSA) drugs, vancomycin, teicoplanin, and arbekacin. In particular, the pharmacist in charge of TDM services, a TDM-specialized pharmacist, plays a central role in administration plans for anti MRSA drugs. Furthermore, we examined the active use of the TDM service to expand pharmaceutical care. Therefore, at first, we have worked in partnership with the clinical laboratory, as it is called the "Cooperation Support System", since September 2010. As a result, after the introduction of this system, from August 2011 to July 2012, the rate that the doctor referred to the administration plan was markedly improved by approximately 90%. We have been able to enhance TDM in practical training for pharmacology as an extension of this system. We thought that drug therapy can be performed more appropriately by increasing the number of executions of TDM in the future. For drug therapy to be done more appropriately, efforts made through cooperation with the clinical laboratory are essential for an effective TDM system. Naturally, an effective TDM process requires a collaborative, multidisciplinary approach with input from doctors, nurses, and clinical pharmacists.

Asunto(s)

Antibacterianos/uso terapéutico , Monitoreo de Drogas , Laboratorios de Hospital , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Farmacéuticos , Antibacterianos/administración & dosificación , Hospitales , Humanos , Servicios Farmacéuticos

RESUMEN

Zoledronic acid(ZA)dosage should be adjusted according to the risk it poses for renal impairment. The recommended dosage for patients with creatinine clearance(Ccr)of less than 60mL/min was established on the basis of an area under the curve analysis, but is doubted because it was calculated without performing a clinical trial. Creatinine secretion from the renal tubule affects Ccr; therefore, using Ccr as the basis for dosage adjustment may be inappropriate since this can cause an overestimation of the glomerular filtration rate(GFR). The Japanese Society of Nephrology recommends using the estimated GFR(eGFR)for evaluating renal function. Therefore, this study investigated the relationship between renal function before and adverse events(AEs)after ZA administration. The dosage of only 3 of the 47 patients with Ccr less than 60mL/min could be adjusted on the basis of Ccr. During ZA therapy(3 courses), the blood urea nitrogen level and occurrence of hypokalemia were higher in the non-adjusted group than in the adjusted group, but the total number of AEs was equivalent for both groups. For all the patients, Ccr and eGFR were used as parameters for investigating AEs; the total number of AEs was equivalent for patients with differing levels of renal function. Therefore, we suggest that AEs observed during ZA therapy did not depend on the renal function level before ZA administration.

Asunto(s)

Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/efectos adversos , Imidazoles/efectos adversos , Riñón/efectos de los fármacos , Riñón/fisiología , Anciano , Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Creatina/sangre , Difosfonatos/uso terapéutico , Femenino , Humanos , Imidazoles/uso terapéutico , Masculino , Persona de Mediana Edad , Ácido Zoledrónico

RESUMEN

Multidrug resistance represents a major obstacle for the chemotherapy of a wide variety of human tumors. To investigate the underlying mechanisms associated with resistance to anti-cancer drugs, we established anti-cancer drug-resistant multiple myeloma (MM) cell lines RPMI8226/ADM, RPMI8226/VCR, RPMI8226/DEX, and RPMI8226/L-PAM, the 50% inhibitory concentration values of which were 77-, 58-, 79-, and 30-fold higher than their parental cell lines, respectively. The resistant cell lines overexpressed MDR1 and survivin, or showed decreased Bim expression. These results indicated that regulating these factors with inhibitors might be a viable approach to increasing the susceptibility of quiescent MM cells to chemotherapy.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas de la Membrana/metabolismo , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteína 11 Similar a Bcl2 , Western Blotting , Bloqueadores de los Canales de Calcio/farmacología , Caspasas/metabolismo , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas de la Membrana/genética , Mieloma Múltiple/genética , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Survivin , Células Tumorales Cultivadas , Verapamilo/farmacología

RESUMEN

BACKGROUND: Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol synthesis. The inhibition of this key enzyme in the mevalonate pathway leads to suppression of cell proliferation and induction of apoptosis. However, the molecular mechanism of apoptosis induction by statins is not well understood in glioblastoma. In the present study, we attempted to elucidate the mechanism by which statins induce apoptosis in C6 glioma cells. METHODS: The cytotoxicity of statins toward the C6 glioma cells were evaluated using a cell viability assay. The enzyme activity of caspase-3 was determined using activity assay kits. The effects of statins on signal transduction molecules were determined by western blot analyses. RESULTS: We found that statins inhibited cell proliferation and induced apoptosis in these cells. We also observed an increase in caspase-3 activity. The apoptosis induced by statins was not inhibited by the addition of farnesyl pyrophosphate, squalene, ubiquinone, and isopentenyladenine, but by geranylgeranyl-pyrophosphate (GGPP). Furthermore, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt. CONCLUSIONS: These results suggest that statins induce apoptosis when GGPP biosynthesis is inhibited and consequently decreases the level of phosphorylated ERK1/2 and Akt. The results of this study also indicate that statins could be used as anticancer agents in glioblastoma.

Asunto(s)

Apoptosis/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosfatos de Poliisoprenilo/biosíntesis , Proteínas Proto-Oncogénicas c-akt/metabolismo , Acilcoenzima A/metabolismo , Procesos de Crecimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Femenino , Glioblastoma/enzimología , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Masculino , Ácido Mevalónico/metabolismo , Fosforilación , Fosfatos de Poliisoprenilo/metabolismo

RESUMEN

Glomerular filtration rate (GFR) is an important factor when considering carboplatin dosage adjustment. The Japanese equation for estimating GFR (eGFR) was recommended as a guideline for evaluating GFR in 2009 by The Japanese Society of Nephrology. However, benefits in the field of cancer chemotherapy with the use of eGFR have not yet been shown. To clarify the clinical benefits of eGFR, we investigated the renal function of 100 patients with gynecologic cancer who were treated with carboplatin from 2003 through 2009, and the carboplatin dosage was calculated by the Calvert formula in which eGFR was substituted for GFR. To predict the clinical benefit on the basis of carboplatin dosage using eGFR, we retrospectively divided the patients into two groups so that carboplatin dosage was within dosage in using eGFR and one was not. We compared response rates and adverse effects of the two groups. Renal function using eGFR was lower than renal function calculated by using the other formulae. Carboplatin dosage using eGFR was significantly lower than the dosage calculated with the other formulae (p<0.01). Moreover, the patients group actually, administered the dosage calculated by eGFR showed less side effects than the group of patients not treated this way, but the efficacy did not change. Thus, using eGFR in planning carboplatin dosage suggested clinical application to patients with Japanese gynecologic cancer.

Asunto(s)

Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Tasa de Filtración Glomerular/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Pueblo Asiatico , Carboplatino/efectos adversos , Carboplatino/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos

RESUMEN

Mangiferin, 1,3,6,7-tetrahydroxyxanthone-C2-ß-D: -glucoside (C-glucosylxanthone), is a xanthone derivative that is widely distributed in higher plants. Recently, mangiferin was found to exhibit potential antitumor effects. However, the molecular mechanisms of this effect have not been elucidated. In the present study, we attempt to clarify the mechanism of mangiferin-induced apoptosis in the human acute myeloid leukemia cell line HL-60; mangiferin was found to induce apoptosis. We also observed a concurrent increase in caspase-3 activity and DNA fragmentation. Furthermore, on examining the survival signals expressed during apoptotic induction, we observed that mangiferin caused a remarkable decrease in the nuclear entry of NF-κB p65. However, there were no changes in the expression of other survival signals, such as extracellular signal-regulated kinase 1/2, protein kinase B, and p38 mitogenactivated protein kinase. In addition, mangiferin suppressed the expressions of Bcl-xL and XIAP; however, we did not note any changes in the levels of Bcl-2, Bax, and Bim. These results indicate that mangiferin induces apoptosis by suppressing NF-κB activation and expressions of Bcl-xL and XAIP. These findings suggest that mangiferin may be useful as an anticancer agent and can be used in combination therapy with other anticancer drugs for the treatment of acute myeloid leukemia.

Asunto(s)

Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Núcleo Celular/efectos de los fármacos , FN-kappa B/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/antagonistas & inhibidores , Xantonas/farmacología , Proteína bcl-X/antagonistas & inhibidores , Western Blotting , Caspasa 3/metabolismo , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HL-60 , Humanos , Transporte de Proteínas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Proteína Inhibidora de la Apoptosis Ligada a X/biosíntesis , Proteína bcl-X/biosíntesis

RESUMEN

PURPOSE: To clarify the change in the fluorodeoxyglucose (FDG) uptake by the bone marrow over time after administration of granulocyte colony-stimulating factor (G-CSF), we evaluated the correlation between the interval from the last day of administration of G-CSF to positron emission tomography/computed tomography (PET/CT) study and spinal bone marrow accumulation in patients with non-Hodgkin's lymphoma. METHODS: A total of 127 patients with confirmed non-Hodgkin's lymphoma who underwent FDG PET within 60 days from the last administration of G-CSF were retrospectively reviewed. Thirty age-matched and sex-matched healthy controls were also included to evaluate physiological FDG uptake. PET/CT examinations were retrospectively reviewed, and maximum standardized uptake value (SUVmax) was measured by placing volumetric regions of interest over each thoracic and lumbar vertebra on PET images referring to CT images. Bone marrow SUV was defined as the mean SUVmax of the vertebra. The correlation between the interval after G-CSF and the bone marrow SUV was plotted and analyzed with polynomial approximation. RESULTS: In controls, physiological bone marrow SUV of the spine was determined. In patients with lymphoma, bone marrow SUV decreased over time and reached a plateau at about 14 days after G-CSF administration, and this was higher by 5% than the plateau at 10 days. SUV declined to the 'physiological range', that is, mean+1 standard deviation of patients, at about 7 days. CONCLUSION: For a PET/CT study, an interval of 10 days after G-CSF administration is recommended to minimize the influence of G-CSF on the bone marrow when evaluating treatment response in patients with non-Hodgkin's lymphoma.

Asunto(s)

Médula Ósea/efectos de los fármacos , Médula Ósea/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/farmacología , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Transporte Biológico/efectos de los fármacos , Reacciones Falso Positivas , Femenino , Humanos , Linfoma no Hodgkin/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Estudios Retrospectivos , Columna Vertebral/inmunología , Factores de Tiempo , Adulto Joven

RESUMEN

The tumor microenvironment plays a critical role in modulating malignant behavior and can dramatically influence cancer treatment strategies. We investigated whether statins inhibit the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and transforming growth factor-ß (TGF-ß) mRNA in the mouse osteosarcoma cell line LM8. We found that statins significantly inhibited mRNA expressions of bFGF, HGF, and TGF-ß, and bFGF, HGF, and TGF-ß secretions at concentrations that did not have antiproliferative effects on LM8 cells, but had no effect on the mRNA expression and secretion of VEGF. The inhibition of bFGF, HGF, and TGF-ß mRNA expression, and bFGF, HGF, TGF-ß secretions was reversed when geranylgeranyl pyrophosphate (GGPP), an intermediate in the mevalonate pathway, was used in combination with statins. Furthermore, statins reduced the membrane localization of K-Ras, phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated Akt. Our research indicates that statins inhibit GGPP biosynthesis in the mevalonate pathway, and then inhibit signal transduction in the Ras/ERK and Ras/Akt pathways, thereby inhibiting bFGF, HGF, TGF-ß expression in LM8 cells. These results suggest that statins are potentially useful as anti-angiogenic agents for the treatment of osteosarcoma.

Asunto(s)

Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Regulación Enzimológica de la Expresión Génica , Factor de Crecimiento de Hepatocito/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Neovascularización Patológica , Osteosarcoma/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/metabolismo , Proteínas ras/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Ácido Mevalónico/metabolismo , Ratones , Fosforilación , Fosfatos de Poliisoprenilo/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

BACKGROUND: Oxaliplatin is a third-generation platinum compound and a key agent for the management of colorectal cancer. Patients treated with oxaliplatin are at risk for hypersensitivity reactions. We designed a modified premedication regimen to prevent oxaliplatin-related hypersensitivity reactions and assessed if this approach is effective. METHODS: A retrospective cohort study of patients with advanced colorectal cancer who received modified FOLFOX6 (mFOLFOX6) was performed. Patients received routine premedication with dexamethasone 8 mg and granisetron 3 mg for the first five cycles of mFOLFOX6. From the sixth cycle onward, cohort 1 received the same premedication, and cohort 2 received modified premedication (diphenhydramine 50 mg orally, followed by dexamethasone 20 mg, granisetron 3 mg, and famotidine 20 mg). We compared the incidence of hypersensitivity reactions, duration of treatment, and reasons for treatment withdrawal between the two cohorts. RESULTS: A total of 181 patients were studied (cohort 1, 81; cohort 2, 100). Hypersensitivity reactions developed in 16 patients (20%) in cohort 1 and 7 (7.0%) in cohort 2 (P = 0.0153). The median number of cycles increased from 9 in cohort 1 to 12 in cohort 2. Apart from progressive disease, neurotoxicity was the reason for discontinuing treatment in 20% of the patients in cohort 1, as compared with 53% in cohort 2. CONCLUSION: Increased doses of dexamethasone and antihistamine significantly reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive FOLFOX, allowing treatment to be completed as planned.

Asunto(s)

Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Hipersensibilidad a las Drogas/tratamiento farmacológico , Antagonistas de los Receptores Histamínicos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Antialérgicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios de Cohortes , Desensibilización Inmunológica , Dexametasona/administración & dosificación , Hipersensibilidad a las Drogas/etiología , Hipersensibilidad a las Drogas/prevención & control , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Premedicación , Estudios Retrospectivos

RESUMEN

OBJECTIVE: Faint brain [(18)F]fluoro-2-deoxyglucose (FDG) uptake has sporadically been reported in patients with FDG-avid large or diffusely extended tumors. The purpose of this study was to investigate whether there is a correlation between massive tumor uptake and decreased brain uptake on FDG positron emission tomography/computed tomography (PET/CT). METHODS: Sixty-five patients with histologically confirmed non-Hodgkin's lymphoma who underwent FDG-PET/CT were enrolled. Thirty control subjects were also included to evaluate normal brain FDG uptake. PET/CT examinations were retrospectively reviewed. The volumetric regions of interest were placed over lesions by referring to CT and PET/CT fusion images to measure mean standardized uptake value (SUVavg). The products of SUVavg and tumor volume were calculated as total glycolytic volume (TGV). The maximum SUV (SUVmax) and SUVavg were measured in the cerebrum and cerebellum. The values of TGV and brain FDG uptake were plotted and analyzed with a linear regression method. RESULTS: In the lymphoma patients, there were statistically significant negative correlations between TGV and brain SUVs. CONCLUSION: Demonstrating a significant negative correlation between TGV and brain uptake validated the phenomenon of decreased brain FDG uptake. Diversion of FDG from the brain to the lymphoma tissue may occur during the FDG accumulation process. Recognition of this phenomenon prevents unnecessary further neurological examinations in such cases.

Asunto(s)

Encéfalo/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Linfoma no Hodgkin/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Transporte Biológico , Encéfalo/diagnóstico por imagen , Femenino , Glucosa/metabolismo , Glucólisis , Humanos , Linfoma no Hodgkin/diagnóstico por imagen , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Carga Tumoral

RESUMEN

BACKGROUND: Melanomas are highly malignant and have high metastatic potential; hence, there is a need for new therapeutic strategies to prevent cell metastasis. In the present study, we investigated whether statins inhibit tumor cell migration, invasion, adhesion, and metastasis in the B16BL6 mouse melanoma cell line. METHODS: The cytotoxicity of statins toward the B16BL6 cells were evaluated using a cell viability assay. As an experimental model, B16BL6 cells were intravenously injected into C57BL/6 mice. Cell migration and invasion were assessed using Boyden chamber assays. Cell adhesion analysis was performed using type I collagen-, type IV collagen-, fibronectin-, and laminin-coated plates. The mRNA levels, enzyme activities and protein levels of matrix metalloproteinases (MMPs) were determined using RT-PCR, activity assay kits, and Western blot analysis, respectively; the mRNA and protein levels of vary late antigens (VLAs) were also determined. The effects of statins on signal transduction molecules were determined by western blot analyses. RESULTS: We found that statins significantly inhibited lung metastasis, cell migration, invasion, and adhesion at concentrations that did not have cytotoxic effects on B16BL6 cells. Statins also inhibited the mRNA expressions and enzymatic activities of matrix metalloproteinases (MMPs). Moreover, they suppressed the mRNA and protein expressions of integrin α2, integrin α4, and integrin α5 and decreased the membrane localization of Rho, and phosphorylated LIM kinase (LIMK) and myosin light chain (MLC). CONCLUSIONS: The results indicated that statins suppressed the Rho/Rho-associated coiled-coil-containing protein kinase (ROCK) pathways, thereby inhibiting B16BL6 cell migration, invasion, adhesion, and metastasis. Furthermore, they markedly inhibited clinically evident metastasis. Thus, these findings suggest that statins have potential clinical applications for the treatment of tumor cell metastasis.

Asunto(s)

Antineoplásicos/farmacología , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Neoplasias Pulmonares/prevención & control , Melanoma Experimental/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Proteínas de Unión al GTP rho/metabolismo , Quinasas Asociadas a rho/metabolismo , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Western Blotting , Supervivencia Celular/efectos de los fármacos , Proteínas de la Matriz Extracelular/metabolismo , Ácidos Grasos Monoinsaturados/farmacología , Femenino , Fluvastatina , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Indoles/farmacología , Integrinas/metabolismo , Quinasas Lim/metabolismo , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/secundario , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Melanoma Experimental/enzimología , Melanoma Experimental/secundario , Ratones , Ratones Endogámicos C57BL , Cadenas Ligeras de Miosina/metabolismo , Invasividad Neoplásica , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Simvastatina/farmacología , Factores de Tiempo , Quinasas Asociadas a rho/antagonistas & inhibidores

RESUMEN

The small GTPases of the Ras and Rho families are widely involved in tumorigenesis and metastasis. We recently showed that YM529/ONO-5920, a new developed bisphosphonate, inhibits the mevalonate pathway, is required for the prenylation of the small GTPases. In this study, we investigated whether YM529/ONO-5920 inhibits tumor cell migration, invasion, adhesion, and metastasis in B16BL6 cells, a mouse melanoma cell line. It was found that YM529/ONO-5920 significantly inhibited lung metastasis, cell migration, invasion, and adhesion at concentrations that did not show anti-proliferative effects on B16BL6 cells. YM529/ONO-5920 also inhibited the expression of matrix metalloproteinases (MMPs) and very late antigens (VLAs). Furthermore, YM529/ONO-5920 suppressed Rho activation, but not activation of Ras. The results indicate that YM529/ONO-5920 suppresses the Rho/ROCK pathways, thereby inhibiting B16BL6 cell migration, invasion, adhesion and metastasis. These findings suggest that YM529/ONO-5920 has potential clinical applications for the treatment of tumour cell metastasis.

Asunto(s)

Difosfonatos/uso terapéutico , Imidazoles/uso terapéutico , Melanoma Experimental/tratamiento farmacológico , Metástasis de la Neoplasia/prevención & control , Quinasas Asociadas a rho/metabolismo , Animales , Secuencia de Bases , Western Blotting , Línea Celular Tumoral , Cartilla de ADN , Femenino , Melanoma Experimental/metabolismo , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa

RESUMEN

NF-kappaB acts as a signal transducer during tumor progression, cell invasion, and metastasis. Dimethylfumarate (DMF) is reported to inhibit tumor necrosis factor-alpha-induced nuclear entry of NF-kappaB/p65. However, only a few reports suggest that DMF inhibits tumor metastasis; also the molecular mechanisms underlying the inhibition of metastasis are poorly understood. We investigated the inhibition of tumor invasion and metastasis by DMF in a melanoma cell line, B16BL6. DMF inhibited B16BL6 cell invasion and metastasis by suppressing the expression and activities of MMPs. DMF also inhibited the nuclear entry of NF-kappaB/p65, thus inhibiting B16BL6 cell invasion and metastasis. These results suggest that DMF is potentially useful as an anti-metastatic agent for the treatment of malignant melanoma.

Asunto(s)

Fumaratos/uso terapéutico , Inmunosupresores/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Melanoma Experimental/tratamiento farmacológico , Melanoma/tratamiento farmacológico , FN-kappa B/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Dimetilfumarato , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Fumaratos/toxicidad , Inmunosupresores/toxicidad , Melanoma/enzimología , Melanoma/secundario , Melanoma Experimental/enzimología , Melanoma Experimental/secundario , Ratones , Ratones Endogámicos C57BL , FN-kappa B/antagonistas & inhibidores , Invasividad Neoplásica , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/patología , Factor de Transcripción ReIA/antagonistas & inhibidores , Factor de Transcripción ReIA/metabolismo

RESUMEN

In melanoma, several signaling pathways are constitutively activated. Among these, the protein kinase C (PKC) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Recently, it has been reported that tamoxifen, an anti-estrogen reagent, inhibits PKC signaling in estrogen-negative and estrogen-independent cancer cell lines. Thus, we investigated whether tamoxifen inhibited tumor cell invasion and metastasis in mouse melanoma cell line B16BL6. Tamoxifen significantly inhibited lung metastasis, cell migration, and invasion at concentrations that did not show anti-proliferative effects on B16BL6 cells. Tamoxifen also inhibited the mRNA expressions and protein activities of matrix metalloproteinases (MMPs). Furthermore, tamoxifen suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt through the inhibition of PKCalpha and PKCdelta phosphorylation. However, other signal transduction factor, such as p38 mitogen-activated protein kinase (p38MAPK) was unaffected. The results indicate that tamoxifen suppresses the PKC/mitogen-activated protein kinase kinase (MEK)/ERK and PKC/phosphatidylinositol-3 kinase (PI3K)/Akt pathways, thereby inhibiting B16BL6 cell migration, invasion, and metastasis. Moreover, tamoxifen markedly inhibited not only developing but also clinically evident metastasis. These findings suggest that tamoxifen has potential clinical applications for the treatment of tumor cell metastasis.

Asunto(s)

Neoplasias Pulmonares/secundario , Melanoma Experimental/patología , Proteínas Quinasas Activadas por Mitógenos/fisiología , Fosfatidilinositol 3-Quinasas/fisiología , Proteína Quinasa C/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiología , Tamoxifeno/farmacología , Animales , Antineoplásicos Hormonales/farmacología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Neoplasias Pulmonares/metabolismo , Melanoma Experimental/metabolismo , Ratones , Ratones Endogámicos C57BL , Invasividad Neoplásica , Trasplante de Neoplasias , Fosforilación , Transducción de Señal/efectos de los fármacos