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BACKGROUND: Efficacy of necitumumab [recombinant human monoclonal antibody that blocks the ligand binding epidermal growth factor receptor (EGFR)] in patients with squamous (SQ) non-small-cell lung cancer (NSCLC) has been confirmed in two randomized clinical trials (SQUIRE and JFCM). This study evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM). MATERIALS AND METHODS: Data of 635 patients with SQ-NSCLC (intent-to-treat population) treated with necitumumab plus gemcitabine and cisplatin (N + GC) were pooled from two clinical trials (SQUIRE and JFCM). The relationship between skin toxicities developed by the end of the second cycle and efficacy was evaluated. Efficacy endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Univariate and multivariate analyses were carried out for these endpoints. RESULTS: OS and ORR were associated with skin toxicity, whereas PFS was not. Patients with grade ≥2 or grade 1 skin toxicity had significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; hazard ratio (HR) = 0.51 (grade ≥2 to grade 0); 95% confidence interval (CI) 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001]. In multivariate analysis, OS was significantly associated with skin toxicity. CONCLUSIONS: A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Gemcitabina , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Cisplatino/uso terapéutico , Cisplatino/farmacología , Cisplatino/efectos adversos , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Mature progression-free survival (PFS) data from the phase III J-ALEX study showed superiority for alectinib versus crizotinib [hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.26-0.52; median PFS 34.1 versus 10.2 months, respectively] in advanced ALK (anaplastic lymphoma kinase)-positive non-small-cell lung cancer (NSCLC). Overall survival (OS) data were immature (HR 0.80, 99.8799% CI 0.35-1.82) at the time of data cut-off (30 June 2018). We report final OS data after ≥5 years of follow-up. PATIENTS AND METHODS: ALK inhibitor naive Japanese patients who were chemotherapy naive or had received one prior chemotherapy regimen were enrolled. Patients were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was independent review facility-assessed PFS, with OS (not fully powered) as a secondary endpoint. RESULTS: Median duration of OS follow-up was 68.6 months with alectinib and 68.0 months with crizotinib. Treatment with alectinib did not prolong OS relative to crizotinib (HR 1.03, 95.0405% CI 0.67-1.58; P = 0.9105). Five-year OS rates were 60.9% (95% CI 51.4-70.3) with alectinib and 64.1% (95% CI 54.9-73.4) with crizotinib. In total, 91.3% (n = 95/104) of crizotinib-treated patients and 46.6% (n = 48/103) of alectinib-treated patients received at least one subsequent anticancer therapy. After study drug discontinuation, 78.8% of patients in the crizotinib arm switched to alectinib, while 10.7% of patients in the alectinib arm switched to crizotinib as a first subsequent anticancer therapy. Patients randomized to crizotinib tended to switch treatment earlier than those randomized to alectinib. CONCLUSION: Final OS analysis from J-ALEX did not show superiority of alectinib to crizotinib; this result was most likely confounded by treatment crossover. Alectinib remains a standard of care for the treatment of patients with advanced ALK-positive NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carbazoles , Crizotinib , Humanos , Japón , Piperidinas , Inhibidores de Proteínas Quinasas , Análisis de SupervivenciaRESUMEN
BACKGROUND: Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. PATIENTS AND METHODS: Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. RESULTS: Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. CONCLUSIONS: Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.
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Neoplasias Primarias Desconocidas , Nivolumab , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Inestabilidad de Microsatélites , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Nivolumab/efectos adversos , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores SólidosRESUMEN
BACKGROUND: Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL). PATIENTS AND METHODS: Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0-1 and adequate organ function were randomized to receive either oral S-1 80 mg/m(2)/day on days 1-21 plus cisplatin 60 mg/m(2) on day 8 every 4-5 weeks, or docetaxel 60 mg/m(2) on day 1 plus cisplatin 80 mg/m(2) on day 1 every 3-4 weeks, both up to six cycles. RESULTS: A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837-1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin. CONCLUSION: Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC. CLINICAL TRIAL NUMBER: UMIN000000608.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Grandes/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Calidad de Vida , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Administración Oral , Adulto , Anciano , Carcinoma de Células Grandes/mortalidad , Carcinoma de Células Grandes/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Docetaxel , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Ácido Oxónico/administración & dosificación , Pronóstico , Tasa de Supervivencia , Taxoides/administración & dosificación , Tegafur/administración & dosificaciónRESUMEN
Zoledronic acid (ZOL), a nitrogen-containing bisphosphonate, produced anti-tumor effects through apoptosis induction or S-phase arrest depending on human mesothelioma cells tested. An addition of isoprenoid, geranylgeraniol but not farnesol, negated these ZOL-induced effects, indicating that the ZOL-mediated effects were attributable to depletion of geranylgeranyl pyrophosphates which were substrates for prenylation processes of small guanine-nucleotide-binding regulatory proteins (small G proteins). ZOL-treated cells decreased a ratio of membrane to cytoplasmic fractions in RhoA, Cdc42 and Rab6 but less significantly Rac1 proteins, indicating that these proteins were possible targets for ZOL-induced actions. We further analyzed which small G proteins were responsible for the three ZOL-induced effects, caspase-mediated apoptosis, S-phase arrest and morphological changes, using inhibitors for respective small G proteins and siRNA for Cdc42. ZOL-induced apoptosis is due to insufficient prenylation of Rab proteins because an inhibitor of geranlygeranyl transferase II that was specific for Rab family proteins prenylation, but not others inhibitors, activated the same apoptotic pathways that ZOL did. ZOL suppressed an endogenous topoisomerase II activity, which was associated with apoptosis and S-phase arrest in respective cells because we detected the same cell cycle changes in etoposide-treated cells. Inhibitors for geranlygeranyl transferase I and for RhoA produced morphological changes and disrupted actin fiber structures, both of which were similar to those by ZOL treatments. These data demonstrated that anti-tumor effects by ZOL were attributable to inhibited functions of respective small G proteins and topoisomerase II activity, and suggested that cellular factors were involved in the differential cell cycle changes.
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Difosfonatos/farmacología , Regulación Neoplásica de la Expresión Génica , Imidazoles/farmacología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Fase S/efectos de los fármacos , Proteínas de Unión al GTP rab/antagonistas & inhibidores , Proteína de Unión al GTP rhoA/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo II/genética , ADN-Topoisomerasas de Tipo II/metabolismo , Difosfonatos/antagonistas & inhibidores , Diterpenos/farmacología , Farnesol/farmacología , Humanos , Imidazoles/antagonistas & inhibidores , Leucina/análogos & derivados , Leucina/farmacología , Mesotelioma/genética , Mesotelioma/metabolismo , Mesotelioma/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Prenilación de Proteína , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Fase S/genética , Transducción de Señal , Transferasas/genética , Transferasas/metabolismo , Ácido Zoledrónico , Proteína de Unión al GTP cdc42/antagonistas & inhibidores , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismo , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab/metabolismo , Proteína de Unión al GTP rac1/antagonistas & inhibidores , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rac1/metabolismo , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
Optical tweezers are often applied to control the dynamics of objects by scanning light. However, there is a limitation that objects fail to track the scan when the drag exceeds the trapping force. In contrast, Laguerre-Gaussian (LG) beams can directly control the torque on objects and provide a typical model for nonequilibrium systems such as Brownian motion under external fields. Although stable "mid-water" trapping is essential for removing extrinsic hydrodynamic effects in such studies, three-dimensional trapping by LG beams has not yet been clearly established. Here we report the three-dimensional off-axis trapping of dielectric spheres using high-quality LG beams generated by a special holographic method. The trapping position was estimated as ~ half the wavelength behind the beam waist. These results establish the scientific groundwork of LG trapping and the technical basis of calibrating optical torque to provide powerful tools for studying energy-conversion mechanisms and the nonequilibrium nature of biological molecules under torque.
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BACKGROUND: MicroRNAs (miRNAs) are involved in essential biological activities, and have been reported to exhibit differential expression profiles in various cancers. Our previous study demonstrated that intercellular adhesion molecule-2 (ICAM2) inhibition induces radiosensitisation in oral squamous cell carcinoma (OSCC) cells. Thus, we hypothesised that certain miRNAs play crucial roles in radioresistance in OSCC by regulating ICAM2 expression. METHODS: Because predicted target gene analyses revealed that microRNA-125b (miR-125b) potentially regulates ICAM2 mRNA expression, we examined the association between miR-125b and radioresistance. The expression of miR-125b was investigated by real-time quantitative reverse transcriptase-PCR. For a functional analysis, miR-125b was transfected to OSCC-derived cells. RESULTS: A downregulated expression of miR-125b was found in OSCC-derived cell lines and OSCC samples. The miR-125b-transfected cells showed a decreased proliferation rate, enhanced radiosensitivity to X-ray irradiation and diminished ICAM2 mRNA expression. Moreover, miR-125b expression correlated with OSCC tumour staging and survival. CONCLUSION: These findings suggested that the downregulated miR-125b expression was associated with proliferation and radioresistance mechanisms, probably through ICAM2 signalling. Thus, controlling the expression or activity of miR-125b might contribute to suppressing proliferation and overcoming radioresistance in OSCC.
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Antígenos CD/metabolismo , Carcinoma de Células Escamosas/radioterapia , Moléculas de Adhesión Celular/metabolismo , MicroARNs/metabolismo , Neoplasias de la Boca/radioterapia , Tolerancia a Radiación/genética , Antígenos CD/biosíntesis , Carcinoma de Células Escamosas/genética , Moléculas de Adhesión Celular/biosíntesis , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , Neoplasias de la Boca/genética , Pronóstico , ARN Mensajero/biosíntesis , Transducción de Señal , Transfección , Rayos XRESUMEN
The majority of malignant mesothelioma possesses the wild-type p53 gene with a homologous deletion of the INK4A/ARF locus containing the p14(ARF) and the p16(INK4A) genes. We examined whether forced expression of p53 inhibited growth of mesothelioma cells and produced anti-tumor effects by a combination of cisplatin (CDDP) or pemetrexed (PEM), the first-line drugs for mesothelioma treatments. Transduction of mesothelioma cells with adenoviruses bearing the p53 gene (Ad-p53) induced phosphorylation of p53, upregulated Mdm2 and p21 expression levels and decreased phosphorylation of pRb. The transduction generated cleavage of caspase-8 and -3, but not caspase-9. Cell cycle analysis showed increased G0/G1- or G2/M-phase populations and subsequently sub-G1 fractions, depending on cell types and Ad-p53 doses. Transduction with Ad-p53 suppressed viability of mesothelioma cells and augmented the growth inhibition by CDDP or PEM mostly in a synergistic manner. Intrapleural injection of Ad-p53 and systemic administration of CDDP produced anti-tumor effects in an orthotopic animal model. These data collectively suggest that Ad-p53 is a possible agent for mesothelioma in combination with the first-line chemotherapeutics.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Genes p53 , Mesotelioma/tratamiento farmacológico , Mesotelioma/metabolismo , Proteína p53 Supresora de Tumor/biosíntesis , Adenoviridae/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Caspasas/metabolismo , Ciclo Celular/efectos de los fármacos , Ciclo Celular/fisiología , Cisplatino/administración & dosificación , Activación Enzimática , Femenino , Glutamatos/administración & dosificación , Guanina/administración & dosificación , Guanina/análogos & derivados , Humanos , Mesotelioma/genética , Mesotelioma/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Pemetrexed , Fosforilación , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high diagnostic value in sarcoidosis if the obtained histological specimen is indicative of a non-caseating epithelioid-cell granuloma. However, EBUS-TBNA in sacoidosis sometimes affords solely cytological specimens. OBJECTIVE: To investigate the relevance of EBUS-TBNA cytology specimens in diagnosing sarcoidosis. DESIGN: The study population comprised 72 patients with sarcoidosis and 116 patients who had thoracic malignancies and intrathoracic lymphadenopathy but were eventually proven to be metastasis-free (controls). The EBUS-TBNA samples obtained for these subjects were blindly evaluated for the presence of epithelioid cell clusters by 2 independent cytoscreeners and a pathologist. RESULTS: Interobserver variability in the specimen grading was minimal. The sensitivity and specificity were 65.3% and 94.0%, respectively. The sensitivity was high, at 87.5%, for the combined cytological and histological examinations. Of 7 controls whose cytological specimens showed epithelioid cell clusters, 3 were also deemed positive for sarcoidosis on histological examination, which indicated that they had sarcoid reaction to cancer. CONCLUSIONS: Cytological evaluation of the EBUS-TBNA specimens had higher sensitivity than histological evaluation alone for intrathoracic lymphadenopathy due to sarcoidosis. It should be recognized, however, that up to 6% of patients with thoracic malignancy may have sarcoid reaction in non-metastatic lymph nodes.
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Biopsia con Aguja Fina/métodos , Broncoscopía/métodos , Endosonografía/métodos , Pulmón/patología , Sarcoidosis Pulmonar/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Estudios de Factibilidad , Femenino , Humanos , Pulmón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Adulto JovenRESUMEN
The apoptosis-inducing Fas ligand (FasL) is expressed in a variety of human cancers and has been implicated in tumor immune evasion. Paradoxically, ectopic expression of FasL in experimental tumors triggers a neutrophil-mediated inflammatory response and tumor rejection. To resolve these conflicting findings, we have established B16 melanoma and P29 Lewis lung carcinoma lines expressing different levels of FasL and examined their tumorigenicity in vivo. While tumors with a high level of FasL were rapidly rejected as previously reported, those expressing a low level of FasL were not rejected but grew faster than did FasL-negative parental cells. The growth enhancement of FasL(low) tumors was not observed in T-cell-deficient nude mice, suggesting that FasL expressed in tumors at low levels counteracted against T-cell-dependent antitumor responses. In support of this notion, FasL(low) tumors were found to grow faster than parental cells in mice that had acquired tumor-specific immunity. Furthermore, histological examinations revealed apoptosis of lymphocytes in tissue sections of FasL(low) tumors. These results collectively suggest that FasL on tumors is a double-edged sword: at high levels it triggers tumor rejection whereas at low levels it facilitates tumor growth possibly by suppressing antitumor immune responses.
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Carcinoma Pulmonar de Lewis/patología , Proteína Ligando Fas/fisiología , Melanoma Experimental/patología , Linfocitos T/inmunología , Animales , Apoptosis , Ligando de CD40/farmacología , Carcinoma Pulmonar de Lewis/inmunología , Técnicas de Cocultivo , Citotoxicidad Inmunológica/genética , Femenino , Citometría de Flujo , Humanos , Etiquetado Corte-Fin in Situ , Inflamación/patología , Melanoma Experimental/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Neutrófilos/inmunología , Bazo/citología , Bazo/efectos de los fármacos , TransfecciónRESUMEN
Interleukin (IL)-22, a novel cytokine belonging to the IL-10 family, is secreted from activated T and natural killer cells and is possibly involved in inflammatory responses. We examined whether expression of the IL-22 gene in murine colon carcinoma Colon 26 cells (Colon 26/IL-22) could produce any antitumour effects in the inoculated mice. Although growth of Colon 26/IL-22 tumours in syngeneic mice was not different from that of parent tumours, survival of the mice that were subcutaneously or intraperitoneally inoculated with Colon 26/IL-22 tumours was significantly prolonged compared with the mice inoculated with parent tumours. Metastasis was not influenced by IL-22 expressed in tumours. Expression of the IL-22 receptor-specific gene, IL-22R, was not induced in spleen cells stimulated with concanavalin A, anti-CD3 or anti-CD40 antibody, despite constitutive expression of the IL-10R2 gene, which encodes another component of the heterodimeric IL-22 receptor complex. IL-22 thereby does not directly act on immunocompetent cells, and IL-22 expressed in tumours can favour apothanasia of inoculated hosts.
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Carcinoma/metabolismo , Interleucinas/metabolismo , Animales , Ratones , Receptores de Interleucina/metabolismo , Bazo/metabolismo , Linfocitos T/metabolismo , Células Tumorales Cultivadas , Interleucina-22RESUMEN
Bandwidth-enhanced chaos synchronization in strongly injection-locked semiconductor lasers with optical feedback is numerically studied based on laser rate equations. The bandwidth of the chaotic carrier frequency in a semiconductor laser with optical feedback is expanded roughly three times by strong optical injection compared with the bandwidth when there is no optical injection. Using a bandwidth-enhanced semiconductor laser as a chaotic transmitter and receiver, we synchronized transmitter and the receiver lasers in a complete chaos synchronization scheme.
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Cancer chemotherapy for haemodialysis patients has never been established. To elucidate the feasibility of cisplatin-based combination chemotherapy for haemodialysis patients with lung cancer, a dose escalation study was conducted. Five haemodialysis patients with lung cancer were treated with cisplatin and etoposide. A starting dose of 40 mg m(-2) of cisplatin on day 1 and 50 mg m(-2) of etoposide on days 1, 3 and 5 were administered as the first course for the first patient. Membrane haemodialysis was regularly performed three times a week and soon after the completion of therapy. By monitoring toxicity and pharmacokinetics data, the dose was escalated course by course and patient by patient. Dose escalation was completed for the first two patients resulting in full-dose chemotherapy consisting of 80 mg m(-2) of cisplatin on day 1 and 100 mg m(-2) of etoposide on days 1, 3 and 5. Multiple courses of the full-dose chemotherapy were administered to the other three patients. Toxicity was manageable and tolerable for all. Pharmacokinetics data were comparable to those from patients with normal renal function, except for potential long-lasting higher levels of free platinum in the renal insufficiency group. In conclusion, this standard-dose combination chemotherapy was feasible even for haemodialysis patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Diálisis Renal , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/farmacocinética , Etopósido/administración & dosificación , Etopósido/efectos adversos , Etopósido/farmacocinética , Estudios de Factibilidad , Femenino , Humanos , Neoplasias Pulmonares/complicaciones , Masculino , Persona de Mediana Edad , Insuficiencia Renal/complicaciones , Resultado del TratamientoRESUMEN
To study the activation states and cytokine profiles of pulmonary T cells in corticosteroid-resistant and corticosteroid-sensitive interstitial pneumonitis (IP) in dermatomyositis (DM)/polymyositis (PM), we examined the activation markers and cytokine profiles of T cells in bronchoalveolar lavage fluids (BALF) from patients with IP in DM/PM before prednisolone therapy and then compared the activation states of T cells according to the therapeutic response of IP to prednisolone therapy. CD25+ CD4+ T cells in BALF were significantly increased in both corticosteroid-resistant and corticosteroid-sensitive IP in DM/PM as compared with those in controls without IP. Furthermore, CD25+ CD4+ T cells in BALF were significantly more increased in corticosteroid-resistant IP than those in cortico teroid- sensitive IP. Moreover, CD25+ CD8+ T cells in BALF were significantly increased only in corticosteroid-resistant IP, but not in corticosteroid-sensitive IP or controls without IP. IFN-gamma mRNA was detected in BALF T cells in corticosteroid-resistant and corticosteroid-sensitive IP but not in controls without IP, whereas IL-4 mRNA was virtually undetected in BALF T cells in both the IP groups. However, there were no significant differences in CD4/CD8 ratio of BALF T cells, HLA-DR+ BALF T cells or CD25+ and HLA-DR+ peripheral blood T cells between the two IP groups. These results indicate that activated Th1-type pulmonary T cells play an important role in the development of corticosteroid- resistant IP in DM/PM and that the increase in CD25+ CD8+ T cells in BALF is a useful indicator for corticosteroid-resistant IP in DM/PM and hence may be an indicator for early use of cyclosporin.
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Glucocorticoides/uso terapéutico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/inmunología , Polimiositis/tratamiento farmacológico , Polimiositis/inmunología , Prednisolona/uso terapéutico , Linfocitos T/inmunología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Dermatomiositis/tratamiento farmacológico , Dermatomiositis/inmunología , Resistencia a Medicamentos , Femenino , Antígenos HLA-DR/análisis , Humanos , Interferón gamma/biosíntesis , Interferón gamma/genética , Pulmón/inmunología , Activación de Linfocitos , Masculino , Persona de Mediana Edad , ARN Mensajero/biosíntesis , Receptores de Interleucina-2/análisis , Subgrupos de Linfocitos T/clasificación , Subgrupos de Linfocitos T/inmunologíaRESUMEN
The soil yeast Lipomyces starkeyi was tested for its ability to degrade triazine herbicides. Polyvinylalcohol (PVA) was employed as a solid medium in culture plates instead of agar. The cell sizes of the control (without nitrogen source) on the PVA gel plate were much smaller than those on the agar gel plate. The difference between the diameters of the sample and control colonies on the PVA gel plate were almost twice those of the colonies on the agar gel plate (1.9 and 1.0 mm, respectively). Thus, the PVA gel plate is much better than the agar plate for evaluating the degree of utilization of a sole nitrogen source. The yeast grew well (more than 4 mm in diameter) with 1,3,5-triazine or cyanuric acid as nitrogen source. In addition, melamine and thiocyanuric acid inhibited growth of the yeast, and the sizes of colonies were smaller than those of the control. All triazine herbicides tested (simazine, atrazine, cyanazine, ametryn, and prometryn) could be degraded and assimilated by L. starkeyi.
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Herbicidas/metabolismo , Alcohol Polivinílico , Saccharomycetales/metabolismo , Microbiología del Suelo , Triazinas , Agar , Biodegradación Ambiental , Compuestos Heterocíclicos/metabolismoRESUMEN
We report a method for measuring the concentration of flecainide in hair. An animal study, in which flecainide (1, 5, and 10 mg/kg/day) was orally administered for 1, 2, and 3 weeks to pigmented rats, showed that flecainide concentration in rat hairs newly regrown after administration significantly correlated with both the daily dose and the dosing period. The part of hair containing flecainide continued to grow upward, retaining the drug within the hair structure that had been formed at the time of drug exposure. Flecainide was also determined in human scalp hairs collected from patients treated with flecainide. The drug content of white hairs was much less than that black hairs collected from the same rats and subjects, suggesting the determinant effect of hair pigment on flecainide accumulation in hair. These findings suggest that the analysis of flecainide in hair may be useful for assessing exposure to drug qualitatively.
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Antiarrítmicos/análisis , Flecainida/análisis , Cabello/química , Animales , Antiarrítmicos/farmacología , Relación Dosis-Respuesta a Droga , Flecainida/farmacología , Cabello/efectos de los fármacos , Humanos , Masculino , Ratas , Proyectos de InvestigaciónRESUMEN
Acetylcholine (Ach) has been considered a major neurotransmitter in the inner ear efferent nerve endings. A bioassay analysis has shown that the electrical stimulation of the crossed olivocochlear bundle increased the Ach-like activity in the perilymph. Applying in vivo microdialysis techniques and high-performance liquid chromatography to the perilymph, the change of Ach level was thus measured before and after alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), a glutamate receptor agonist, was added to the perfusate. Ach was only detectable when the perfusate contained an acetylcholinesterase inhibitor. The level of Ach increased 2-3-fold immediately after AMPA was administered. Our data suggest that the afferent stimulation, such as the administration of AMPA, may therefore induce the release of Ach from the efferent nerve endings.
Asunto(s)
Acetilcolina/metabolismo , Cóclea/efectos de los fármacos , Vías Eferentes/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Terminales Presinápticos/efectos de los fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Inhibidores de la Colinesterasa/farmacología , Cóclea/inervación , Cóclea/metabolismo , Nervio Coclear/efectos de los fármacos , Nervio Coclear/metabolismo , Vías Eferentes/metabolismo , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Cobayas , Masculino , Microdiálisis , Perfusión/métodos , Perilinfa/efectos de los fármacos , Perilinfa/metabolismo , Fisostigmina/farmacología , Terminales Presinápticos/metabolismo , Receptores de Glutamato/efectos de los fármacos , Receptores de Glutamato/metabolismoRESUMEN
Pulmonary capillary haemangiomatosis is a rare disorder characterised by multiple angiomatous lesions composed of proliferating capillary vessels in the lung parenchyma that usually progress rapidly to establish fatal pulmonary hypertension. The 29 year old man presented here, however, has been stable for 3.5 years since the diagnosis without symptoms of pulmonary hypertension. High resolution computed tomographic findings of the pulmonary lesions seemed specific to the disease.
Asunto(s)
Hemangioma Capilar/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Adulto , Progresión de la Enfermedad , Hemangioma Capilar/complicaciones , Hemangioma Capilar/fisiopatología , Humanos , Hipertensión Pulmonar/etiología , Pulmón/fisiopatología , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/fisiopatología , Masculino , Intensificación de Imagen Radiográfica , Factores de Tiempo , Tomografía Computarizada por Rayos X , Factor de TransferenciaRESUMEN
The importance of low-density lipoprotein (LDL) in the etiology of atherosclerosis is well recognized. We have established a reproducible stenosis model in hypercholesterolemic hamsters, and the process of arterial stenosis by thrombus or neointima was studied and compared with that in normal hamsters. The level of plasma LDL was 4.6 times higher in hamsters fed a high-cholesterol diet than in hamsters fed normal food. Endothelial injury in right common carotid arteries was induced using a modified catheter. Arterial blood flow was monitored continuously using a Doppler flow probe. Arterial patency after the initiation of injury in high-cholesterol hamsters was significantly changed as compared with that of normal hamsters. Neointima was observed 2 wk after the vascular injury. The neointimal area of high-cholesterol hamsters was significantly larger than that of normal hamsters. To characterize the stenosis in hypercholesterolemic hamsters, we measured platelet aggregation, thrombin time, activated partial thromboplastin time, and proliferating smooth muscle cells (SMC) in vitro and in vivo. The half-maximal inhibitory concentration value for platelet aggregation induced by thrombin or collagen, the DNA synthesis stimulated by platelet-derived growth factor (PDGF)-BB, and 5-bromo-2-deoxy-uridine labeling indices (proliferating index of SMC in vivo) in high-cholesterol hamsters were each significantly higher than the comparable value from normal hamsters. However, specific binding of PDGF-BB in SMC was not different between the two types of hamsters. Furthermore, we investigated the inhibitory effects of probucol or losartan on neointima formation using this model. Probucol, but not losartan, significantly reduced the neointimal area in hypercholesterolemic hamsters. These findings indicated that high levels of plasma LDL strongly contributed to the development of thrombus and neointima formation via both up-regulation of platelet aggregation and the enhancement of SMC proliferation. This stenosis model may be useful for the investigation of hypercholesterolemia-associated cardiovascular diseases.
Asunto(s)
Constricción Patológica/metabolismo , Hipercolesterolemia/metabolismo , Enfermedades Vasculares/metabolismo , Animales , Becaplermina , Velocidad del Flujo Sanguíneo , Arterias Carótidas/patología , Arterias Carótidas/ultraestructura , Trombosis de las Arterias Carótidas/sangre , Trombosis de las Arterias Carótidas/metabolismo , Trombosis de las Arterias Carótidas/patología , Células Cultivadas , Colesterol/sangre , Colesterol en la Dieta/administración & dosificación , Colesterol en la Dieta/farmacología , Constricción Patológica/sangre , Constricción Patológica/patología , Cricetinae , ADN/biosíntesis , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Hipercolesterolemia/sangre , Hipercolesterolemia/patología , Losartán/farmacología , Masculino , Mesocricetus , Microscopía Electrónica , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Agregación Plaquetaria , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Factor de Crecimiento Derivado de Plaquetas/farmacología , Probucol/farmacología , Proteínas Proto-Oncogénicas c-sis , Reproducibilidad de los Resultados , Túnica Íntima/efectos de los fármacos , Túnica Íntima/crecimiento & desarrollo , Túnica Íntima/ultraestructura , Enfermedades Vasculares/sangre , Enfermedades Vasculares/patologíaRESUMEN
The pathogenesis of severe pulmonary hypertension seems to be related to inflammatory response in diseased sites. Monocyte chemoattractant protein-1 (MCP-1) has been reported to play a role in the development of congestive heart failure. In this immunological response, activation and migration of leukocytes including macrophages to the inflammatory region are important factors. We hypothesized that the severity of pulmonary hypertension may be related to MCP-1, which is thought to be upregulated by blood pressure or shear stress in pulmonary vasculature as well as by immunological and inflammatory reactions in chronic thromboembolic pulmonary hypertension (CTEPH). Circulating levels of MCP-1, interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha) were measured by sandwich ELISA in 14 patients with CTEPH. The plasma level of MCP-1 was significantly correlated with pulmonary vascular resistance. In IL-1beta and TNF-alpha, on the other hand, there was no correlation between cytokines and pulmonary hemodynamics. Pathological specimens obtained from the patients with CTEPH undergoing thromboendarterectomy demonstrated immunoreactivity of MCP-1 in endothelium, smooth muscle cells, and macrophages within neointima in the hypertensive large elastic pulmonary artery. We conclude that MCP-1 is upregulated in the remodeling of pulmonary arteries in close association with increased pulmonary vascular resistance in CTEPH.