RESUMO
Precision medicine is an emerging approach for disease treatment and prevention that accounts for individual variability in genes, environment, and lifestyle. Cancer is a genomic disease; therefore, the dose-efficacy and dose-toxicity relationships for molecularly targeted agents in cancer most likely differ, based on the genomic mutation pattern. The individualized optimal dose - the maximal efficacious dose with a clinically acceptable safety profile - may vary depending on the genomic mutation patterns and should be determined prior to the use of these agents in precision medicine. In addition, genes that influence the individualized optimal doses should be identified in early-phase development. In this study, we propose a novel dose-finding approach to identify the individualized optimal dose for molecularly targeted agents in phase I cancer trials. Individualized optimal dose determination and gene selection were conducted simultaneously based on L1 and L2 penalized regression. Similar to most reported dose-finding approaches, this study considers non-monotonic patterns for dose-efficacy and dose-toxicity relationships, as well as correlations between efficacy and toxicity outcomes based on multinomial distribution. Our dose-finding algorithm is based on the predictive probability calculated with an estimated penalized regression model. We compare the operating characteristics between the proposed and existing methods by simulation studies under various scenarios.
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Ensaios Clínicos Fase I como Assunto/estatística & dados numéricos , Genômica/estatística & dados numéricos , Medicina de Precisão/estatística & dados numéricos , Projetos de Pesquisa/estatística & dados numéricos , Algoritmos , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/genética , Simulação por Computador , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Humanos , Modelos Estatísticos , Terapia de Alvo Molecular/estatística & dados numéricos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
BACKGROUND: Continuous infusion (CI) of recombinant FVIII (rFVIII) concentrates has been reported as an effective and safe method to achieve haemostasis during major surgeries or severe bleeding events. For more effective and safer CI, better understanding of in vivo recovery (IVR) and clearance (CL) issues is imperative. OBJECTIVE: We investigated the following factors affecting IVR and CL using univariate and multivariate regression analyses during 47 CIs in 34 patients: rFVIII concentrate type, haemophilia severity, blood type, the presence of hepatitis C virus (HCV) or human immunodeficiency virus (HIV), age and body mass index (BMI). RESULTS: The mean IVR was 1.64 ± 0.49 IU dL-1 per IU kg-1 , and the mean CL during CI was 3.56 ± 1.57 mL h-1 kg-1 . The univariate and multivariate regression analyses showed that the CL of octocog alfa was significantly lower than that of rurioctocog alfa (P = 0.043 and 0.0034, respectively). There was a significant difference in BMI in the univariate and multivariate regression analyses (P = 0.0403 and 0.0376, respectively). CONCLUSIONS: This study indicated that CL during CI was potentially affected by the type of rFVIII concentrate used and BMI.
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Fator VIII/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Fator VIII/farmacocinética , Humanos , Bombas de Infusão , Pessoa de Meia-Idade , Proteínas Recombinantes/farmacocinética , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: We aimed to analyse clinical and gene expression profiles to predict pathologic complete response and disease-free survival using two consecutive, prospective, preoperative chemotherapy trial cohorts. METHODS: Clinicopathological and gene expression data were evaluated in a cohort from two consecutive phase II preoperative studies that included patients with stage IIA-IIIC breast cancer of all subtypes. Analysed specimens were obtained before preoperative chemotherapy, and cDNA microarray analyses were performed using the Affymetrix Gene Chip U133 plus 2.0. RESULTS: Between December 2005 and December 2010, 122 patients were analysed. The pathologic complete response rate was significantly higher in HER2+ and HR-/HER2- cancers. Age, pathologic complete response, HR-/HER2- status, and lymph node positivity (⩾4) were significant poor prognostic factors for disease-free survival. For the cDNA microarray analyses, sufficient tumour samples were available from 78 of the 107 patients (73%). An 8-gene signature predictive of pathologic complete response and a 17-gene signature predictive of prognosis were identified. Patients were categorised into low-risk (n=45) and high-risk groups (n=33) (HR 70.0, P=0.004). CONCLUSIONS: This study yielded preliminary data on the expression of specific genes predicting pathologic complete response and disease-free survival in a cohort of chemonaïve breast cancer patients. Further validation may distinguish those who would benefit most from perioperative chemotherapy as well as those needing further intervention.
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Neoplasias da Mama/genética , Carcinoma/genética , RNA Mensageiro/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Carcinoma/patologia , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Prognóstico , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxoides/administração & dosagem , Análise Serial de Tecidos , Transcriptoma , Trastuzumab/administração & dosagem , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Dosage adjustment is very important to perform continuous infusion (CI) of recombinant factor IX (rFIX) concentrates more effectively and economically, and clearance (CL) is strongly related to the infusion rate. However, previous reports have shown that the CL of rFIX concentrates varies widely (4.2-11.4 mL kg(-1) h(-1) ). AIM: The goal of this study was to gain a better understanding of the CL of the rFIX concentrate (BeneFIX(®) ) to precisely set the infusion rate of rFIX concentrates. METHODS: We estimated CLs by five different calculation approaches: from area under the blood concentration-time curve (AUC), from in vivo recovery (IVR) and half-life, from actual FIX activity value during CI, and from the simulation by one-compartment model in seven patients with haemophilia B. RESULTS: The mean CL calculated from AUC was 3.8 ± 0.4 mL kg(-1) h(-1) (range = 3.3-4.3 mL kg(-1) h(-1) ). CONCLUSION: The mean CL calculated from IVR and distribution half-life was 4.4 ± 0.4 mL kg(-1) h(-1) (range = 4.0-5.1 mL kg(-1) h(-1) ). The mean CL calculated from IVR and terminal half-life was 2.1 ± 0.5 mL kg(-1) h(-1) (range = 1.7-2.8 mL kg(-1) h(-1) ). The mean CL during CI was 4.9 ± 0.6 mL kg(-1) h(-1) (range = 4.2-5.6 mL kg(-1) h(-1) ). In addition, when we simulated the theoretical CL using a one-compartment model, the adjusted mean CL during CI was 4.8 ± 0.5 mL kg(-1) h(-1) (range = 4.0-5.4 mL kg(-1) h(-1) ). The CL obtained from distribution half-life was comparable to the CL during CI, while the CL calculated from terminal half-life did not reflect actual CL. Further, the rFIX concentrate was characterized by a one-compartment model under certain conditions.
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Fator IX/farmacocinética , Proteínas Recombinantes/farmacocinética , Adulto , Idoso , Área Sob a Curva , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Prediction of prognosis is important for patients so that they can make the most of the rest of their lives. Oncologists could predict survival, but the accuracy of such predictions is unclear. METHODS: In this observational prospective cohort study, 14 oncologists treating 9 major adult solid malignancies were asked to complete questionnaires predicting survival based on performance status, oral intake, and other clinical factors when patients experienced progressive disease after standard chemotherapies. Clinically predicted survival (cps) was calculated by the oncologists from the date of progressive disease to the predicted date of death. Actual survival (as) was compared with cps using Kaplan-Meier survival curves, and factors affecting inaccurate prediction were determined by logistic regression analysis. The prediction of survival time was considered accurate when the cps/as ratio was between 0.67 and 1.33. RESULTS: The study cohort consisted of 75 patients. Median cps was 120 days (interquartile range: 60-180 days), and median as was 121 days (interquartile range: 40-234 days). The participating oncologists accurately predicted as within a 33% range 36% of the time; the survival time was overestimated 36% of time and underestimated 28% of the time. The factors affecting the accuracy of the survival estimate were the experience of the oncologist, patient age, and information given about the palliative care unit. CONCLUSIONS: Prediction of cps was accurate for just slightly more than one third of all patients in this study. Additional investigation of putative prognostic factors with a larger sample size is warranted.
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BACKGROUND: This study aimed to examine the quality in oncology registration trials for new drug application (NDA) or supplemental new drug application (sNDA) as extensions of the indications for use in Japan based on Good Clinical Practice (GCP) audit findings. MATERIALS AND METHODS: We collected audit reports of on-site GCP inspections for registration trials in 383 NDAs or sNDAs that were reviewed by the Pharmaceuticals and Medical Devices Agency between the fiscal years 2004 and 2009. RESULTS: Among the 40 audits for oncology drug applications, the frequencies at which one or more deficiencies ascribed to institution, investigator, sponsor, and institutional review board were found to be 15 (37.5%), 13 (32.5%), 21 (52.5%), and 10 (25.0%), respectively. The exclusion of patients from the review objective due to serious violations of GCP in 40 audits for oncology drug applications was observed in 2 (5.0%) cases, whereas that in the remaining 343 audits for other drug applications was observed in 40 (11.7%) cases. CONCLUSION: The overall compliance of GCP in oncology registration trials was moderately better than that in registration trials for other diseases, although there was no statistically significant difference between them.
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Comitês de Monitoramento de Dados de Ensaios Clínicos/normas , Ensaios Clínicos como Assunto/normas , Aprovação de Drogas , Neoplasias , Antineoplásicos/uso terapêutico , Auditoria Clínica , Comitês de Ética em Pesquisa , Humanos , Japão , Neoplasias/tratamento farmacológicoRESUMO
This study retrospectively compared long-term outcomes between two groups of breast cancer patients with malignant pleural effusion (MPE): those receiving only systemic therapy (ST) and those receiving ST following initial pleurodesis (P-ST). We identified 180 breast cancer patients from the National Cancer Center Hospital (Tokyo, Japan) database who had received ST and P-ST as an initial treatment for MPE between 1997 and 2008 for study inclusion. Pleural progression-free survival (PPFS) was defined as the time from ST in the ST group and from pleurodesis in the P-ST group to the first observation of pleural progression or death from any cause. Of the 180 patients, 78 received ST and 102 received P-ST after MPE diagnosis. Median duration of follow-up was 12.7 months (range 0.9-80.1 months). Median PPFS for the ST group and the P-ST group was 4.1 and 8.5 months, respectively. The difference in PPFS between the two groups was statistically significant (p < 0.001) and the hazard ratio after adjusting for prognostic factors in the P-ST group relative to the ST group was 0.24. Our results suggest that the efficacy of P-ST may be superior to that of ST alone with respect to local control of pleural effusions in breast cancer patients.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma/tratamento farmacológico , Derrame Pleural Maligno/terapia , Pleurodese , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Neoplasias da Mama/mortalidade , Carcinoma/mortalidade , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Derrame Pleural Maligno/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND/OBJECTIVES: The Japan-multimodal intervention trial for prevention of dementia (J-MINT) is intended to verify the effectiveness of multi-domain interventions and to clarify the mechanism of cognitive improvement and deterioration by carrying out assessment of dementia-related biomarkers, omics analysis and brain imaging analysis among older adults at high risk of dementia. Moreover, the J-MINT trial collaborates with partnering private enterprises in the implementation of relevant interventional measures. This manuscript describes the study protocol. DESIGN/SETTING: Eighteen-month, multi-centered, randomized controlled trial. PARTICIPANTS: We plan to recruit 500 older adults aged 65-85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the dynamic allocation method with all subjects stratified by age, sex, and cognition. INTERVENTION: The multi-domain intervention program includes: (1) management of vascular risk factors; (2) group-based physical exercise and self-monitoring of physical activity; (3) nutritional counseling; and (4) cognitive training. Health-related information will be provided to the control group every two months. MEASUREMENTS: The primary and secondary outcomes will be assessed at baseline, 6-, 12-, and 18-month follow-up. The primary outcome is the change from baseline to 18 months in a global composite score combining several neuropsychological domains. Secondary outcomes include: cognitive change in each neuropsychological test, incident dementia, changes in blood and dementia-related biomarkers, changes in geriatric assessment including activities of daily living, frailty status and neuroimaging, and number of medications taken. CONCLUSIONS: This trial that enlist the support of private enterprises will lead to the creation of new services for dementia prevention as well as to verify the effectiveness of multi-domain interventions for dementia prevention.
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Cognição/fisiologia , Disfunção Cognitiva/terapia , Demência/prevenção & controle , Exercício Físico , Avaliação Geriátrica , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Exercício Físico/fisiologia , Feminino , Humanos , Japão , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Avaliação Nutricional , Fatores de RiscoRESUMO
BACKGROUND: The aim of this study was to develop a prediction model of progressive disease (PD) in breast cancer patients without measurable disease in first-line chemotherapy. METHODS: We developed a model to predict PD using carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 15-3 in metastatic breast cancer patients who were enrolled in a phase III trial. The model was determined using the area under the receiver operating characteristic curve (AUC) calculated by the bootstrap method as internal validation. We verified the model for those who received first-line chemotherapy in a clinical setting as external validation. We categorized patients without measurable disease into PD and non-PD groups and compared the time to progression (TTP). RESULTS: The model consisted of percent changes in CEA and CA 15-3 levels from second to third chemotherapy course and baseline abnormality of them. The AUC after external validation was 0.90. Patients without measurable disease were categorized into PD (N = 10) and non-PD groups (N = 53) by the model. The difference in TTP between the two groups was statistically significant (hazard ratio, 0.437; P = 0.021). CONCLUSION: The model may be useful to determine PD in metastatic breast cancer patients without measurable disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Antígeno Carcinoembrionário/sangue , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Mucina-1/sangue , Adulto , Idoso , Neoplasias Ósseas/sangue , Neoplasias Ósseas/secundário , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/secundário , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Progressão da Doença , Doxorrubicina/administração & dosagem , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/secundário , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: The objective of this study was to evaluate the age-based enrollment of cancer patients into registration trials of new drug applications or expanding the indications for use. MATERIALS AND METHODS: The data from 234 registration trials in Japan and overseas of 43 drugs, which were reviewed by the Pharmaceuticals and Medical Devices Agency and approved by the Ministry of Health, Labour and Welfare in Japan between 1999 and 2008, were retrospectively analyzed according to the age distribution of enrolled patients. The age distribution of the Japanese cancer population was derived from Cancer Statistics in Japan 2003 and Annual Report on Health, Labour and Welfare 2003-2004. RESULTS: In the Japanese cancer population, the estimated median age of cancer patients is 70 years, and 66% of cancer patients are aged 65 years or more. The estimated median age of cancer patients in all registration trials conducted in Japan was 59 years, whereas it was 55 years in the registration trials conducted overseas. The proportion of patients aged 65 years or more enrolled in registration trials conducted in Japan was 35%; this number was 28% in registration trials conducted overseas. CONCLUSION: Elderly patients are underrepresented in oncology registration trials in Japan.
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Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto/estatística & dados numéricos , Neoplasias/tratamento farmacológico , Seleção de Pacientes , Sujeitos da Pesquisa , Fatores Etários , Idoso , Feminino , Seguimentos , Humanos , Agências Internacionais , Japão , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/patologia , PrognósticoRESUMO
The cardiac conduction system was examined histologically in 12 canine cases of lymphocytic myocarditis with complete atrioventricular (AV) block. Histological analysis showed active myocarditis characterized by intense infiltration of mononuclear cells, primarily lymphoid, associated with degeneration and necrosis of the adjacent cardiomyocytes. Additionally, there was healing or healed myocarditis manifested by disappearance of cardiomyocytes and replacement fibrosis. This destructive inflammatory process of lymphocytic myocarditis involved the whole of the AV conduction system, resulting in loss and deletion of the conduction fibres, as well as the myocardium of all chambers. Such total or subtotal destruction of the AV conduction system caused by the inflammatory changes was thought to have set the stage for blocking AV conduction of cardiac impulses, but the aetiology of the lymphocytic myocarditis was not elucidated.
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Bloqueio Atrioventricular/veterinária , Doenças do Cão/patologia , Miocardite/veterinária , Animais , Bloqueio Atrioventricular/etiologia , Bloqueio Atrioventricular/patologia , Cães , Feminino , Masculino , Miocardite/complicações , Miocardite/patologiaRESUMO
Balloon occlusion is a potential method for inducing hyperemia to measure post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR). The objective of this study was to determine the clinical usefulness of post-occlusional hyperemia. FFRs measured using post-occlusional hyperemia caused by 30 (FFRoccl30) and 60 s (FFRoccl60) of balloon occlusion after PCI were compared in 60 lesions from 60 patients. The duration of hyperemia was also measured. There was a strong correlation between FFRoccl30 and FFRoccl60 (r = 0.969, p < 0.01). The duration of hyperemia was significantly longer with FFRoccl60 than with FFRoccl30 (68 ± 23 vs. 37 ± 15 s, p < 0.01). The time required for pullback curve analysis was around 45 s. However, in 7 (12%) cases, the duration of hyperemia with FFRoccl60 was < 45 s, which was not enough for pull-back curve analysis. To predict the duration of hyperemia with FFRoccl60 ≥ 45 s, the receiver operating characteristic curve analysis revealed a cut-off value of 25 s of hyperemia with FFRoccl30. FFRoccl30 is sufficient for diagnostic purposes. FFRoccl60 is suitable for pull-back curve analysis in select cases based on predictions made using the duration of hyperemia with FFRoccl30.
Assuntos
Oclusão com Balão , Estenose Coronária/terapia , Reserva Fracionada de Fluxo Miocárdico , Hiperemia , Intervenção Coronária Percutânea , Trifosfato de Adenosina , Idoso , Oclusão com Balão/métodos , Cateterismo Cardíaco , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores de TempoRESUMO
BACKGROUND: To evaluate the impact of change in the hormone receptor (HR) status (HR status conversion) on the long-term outcomes of breast cancer patients treated with neoadjuvant chemotherapy (NAC). METHODS: We investigated 368 patients for the HR status of their lesions before and after NAC. On the basis of the HR status and the use/non-use of endocrine therapy (ET), the patients were categorised into four groups: Group A, 184 ET-administered patients with HR-positive both before and after NAC; Group B, 47 ET-administered patients with HR status conversion; Group C, 12 ET-naive patients with HR status conversion; Group D, 125 patients with HR-negative both before and after NAC. RESULTS: Disease-free survival in Group B was similar to that in Group A (hazard ratio, 1.16; P=0.652), but that in Group C was significantly lesser than that in Group A (hazard ratio, 6.88; P<0.001). A similar pattern of results was obtained for overall survival. CONCLUSION: Our results indicate that the HR status of tumours is a predictive factor for disease-free and overall survival and that ET appears to be suitable for patients with HR status conversion. Therefore, both the CNB and surgical specimens should be monitored for HR status.
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Neoplasias da Mama/tratamento farmacológico , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Adulto , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Receptor ErbB-2/análiseRESUMO
Carcinoma of unknown primary site (CUP) is rarely encountered in clinical practice and optimal chemotherapy has not yet been established. This phase II study was conducted to evaluate the efficacy and toxicity of combined irinotecan+carboplatin therapy in chemotherapy-naive patients with CUP. Irinotecan was administered at 60 mg m(-2) as a 90-min intravenous infusion on days 1, 8 and 15. Carboplatin was administered at an area-under-the curve of 5 mg ml(-1) min as a 60-min intravenous infusion on day 1. This cycle was repeated every 28 days for up to six cycles. Forty-five patients were enrolled in the study. An intent-to-treat analysis revealed an objective response rate to the treatment of 41.9% (95% confidence interval, 27.0-57.9%). The median time to progression was 4.8 months and the median survival was 12.2 months. The 1- and 2-year survival rates were 44 and 27%, respectively. The most frequent grade 3 or more severe adverse events were leukopaenia (21%), neutropaenia (33%), anaemia (25%) and thrombocytopaenia (20%). Thus, the combination of irinotecan plus carboplatin was found to be active in patients with CUP. Therefore, the regimen may be one of the potentially available chemotherapeutic options for community standard of care in patients with a good performance status.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Primárias Desconhecidas/tratamento farmacológico , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/análogos & derivados , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Desconhecidas/mortalidade , Taxa de SobrevidaRESUMO
Observations of Raman spectra of various molecules at different exciting laser wavelengths lead to an empirical rule. If a Raman line becomes stronger when the exciting frequency is brought closer to the frequency of an electronic band, this means that the equilibrium conformation of the molecule is distorted along the normal coordinate for the Raman line in the transition from the ground to the excited electronic state.
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This study reports pathological and molecular features in 41 cases of feline restrictive cardiomyopathy (RCM). Grossly, there were patchy or diffuse areas of endocardial thickening affecting the left ventricle. The more common patchy endocardial lesions occurred as large trabecular or irregular broad bands of fibrous tissue bridging the left ventricular free wall and ventricular septum. Microscopically, regardless of the gross pattern, the thickened endocardium contained various numbers of stellate, spindle-shaped or elongated mesenchymal cells surrounded by fibrous connective tissue. Immunohistochemical findings were indicative of smooth muscle differentiation in mesenchymal cells. These cells proliferated vigorously and produced alcian blue-positive ground substance and collagen fibres; it was considered that the mesenchymal cells contributed to the formation of the endocardial lesions. In addition, multiple left ventricular 'false tendons' were invariably included within the trabecular or broad fibrous bands, providing a framework for formation of those bands. Evidence of endocarditis or endomyocarditis was lacking in all 41 cases, and no viral genomes were detected in any of the DNA or RNA samples obtained from 14 of the hearts. These observations suggest that any relationship between feline RCM and a virus-induced inflammatory response seems unlikely.
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Cardiomiopatia Restritiva/veterinária , Doenças do Gato/patologia , Animais , Gatos , Imuno-Histoquímica , Miocárdio/patologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Intravascular large B-cell lymphoma (IVLBCL) is a distinct disease entity with the peculiar characteristic that tumor cells proliferate within vessels. Despite recent advances in understanding the disease from clinical aspects, the underlying pathogenesis remains unknown. Here we demonstrate analyses of IVLBCL biology using four xenograft mouse models established from primary IVLBCL samples. In all four models, the main characteristic of IVLBCL tumor cell proliferation within vessels was retained. Time-lapse engraftment analyses revealed that the tumor cells initially engrafted and proliferated in the sinusoids and vessels in the liver and then engrafted and proliferated in multiple organs. Intriguingly, serial passage of tumor cells from the adrenal gland of a transplanted mouse developed from primary patient bone marrow cells into a second mouse showed that the tumor cells mainly distributed into the adrenal gland in the second mouse, implying the existence of clonal selection and/or evolution at engraftment of a specific organ. Gene expression profiling analyses demonstrated that the gene set associated with cell migration was enriched for normal peripheral blood B cells, indicating that inhibition of cell migration might be involved in IVLBCL pathogenesis. In conclusion, the mouse xenograft models described here are essential tools for uncovering IVLBCL biology.
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Xenoenxertos/patologia , Linfoma Difuso de Grandes Células B/patologia , Neoplasias Vasculares/patologia , Idoso , Animais , Movimento Celular , Proliferação de Células , Feminino , Sobrevivência de Enxerto , Humanos , Cadeias Pesadas de Imunoglobulinas/análise , Fígado/irrigação sanguínea , Masculino , Camundongos , Pessoa de Meia-Idade , Especificidade de ÓrgãosRESUMO
Effects of chronic treatment of normotensive Wistar rats with N(omega)-nitro-L-arginine methyl ester (L-NAME) on blood pressure and on endothelium-dependent relaxation of the aorta, carotid and iliac arteries were studied. The endothelium-dependent relaxation was compared in arteries from normotensive Wistar Kyoto rats (WKY) and genetically hypertensive rats (stroke-prone spontaneously hypertensive rats, SHRSP). Chronic treatment of normotensive Wistar rats with L-NAME caused an elevation of blood pressure. The elevated blood pressure at 15 weeks of age was significantly higher in these animals than that of untreated Wistar rats, but lower than that of SHRSP. Endothelium-dependent relaxation of the arteries induced by acetylcholine (ACh) was almost abolished by chronic treatment with L-NAME. The remaining small relaxation in arteries from L-NAME-treated rats was completely inhibited by application of L-NAME (10(-4) M). In such preparations, higher concentrations of ACh induced a contraction, which was abolished by removal of the endothelium or by an application of indomethacin (10(-5) M). Endothelium-independent relaxation induced by sodium nitroprusside was similar between preparations from untreated and L-NAME-treated Wistar rats. Endothelium-dependent relaxation was significantly impaired in preparations from SHRSP, when compared with that in those from WKY. However, the impairment was less prominent in preparations from SHRSP than in those from L-NAME-treated rats. These results suggest that the impairment of endothelium-dependent relaxation in the arteries from L-NAME-treated rats is not due to the elevated blood pressure resulting from the chronic treatment, and that impairment of NO synthesis by the endothelium does not play a major role in the initiation of hypertension in SHRSP.
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Endotélio Vascular/fisiologia , Hipertensão/metabolismo , Relaxamento Muscular/fisiologia , Óxido Nítrico/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Aorta/efeitos dos fármacos , Aorta/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/metabolismo , Artérias Carótidas/fisiologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Artéria Ilíaca/efeitos dos fármacos , Artéria Ilíaca/metabolismo , Artéria Ilíaca/fisiologia , Relaxamento Muscular/efeitos dos fármacos , NG-Nitroarginina Metil Éster/administração & dosagem , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Nitroprussiato/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vasodilatadores/farmacologiaRESUMO
The effects of ventilation at positive end-expiratory pressure (PEEP) on extravascular lung water (EVLW) and cardiopulmonary function were studied in dogs with experimental severe hydrostatic pulmonary edema, which was generated by inflating a left atrial balloon and simultaneously injecting warm 5% glucose solution into the pulmonary artery. The EVLW was measured by the double indicator dilution method using heat and sodium ions. All the dogs were ventilated at zero end-expiratory pressure (ZEEP) until the EVLW had increased by 200-300% (maximal edema), when they were divided into two groups, one of which (n = 6) was ventilated at a PEEP of 10 cm H2O throughout the 4 hr study period (PEEP group) and the other (n = 6) was maintained at ZEEP during their survival period (ZEEP group). All the dogs in the PEEP group survived ventilation for 4 hr, whereas all those in the ZEEP group died within 3 hr, (2 within 1 hr, 1 between 1 and 2 hr and 3 between 2 and 3 hr). The EVLW of the PEEP group remained unchanged throughout the 4 hr study period, whereas that of the ZEEP group showed a tendency to increase. The arterial oxygen tension (PaO2) increased significantly throughout the 4 hr period of ventilation in the PEEP group but tended to decrease in the ZEEP group. In conclusion, PEEP improves gaseous exchange, but does not decrease the EVLW in dogs with experimental severe hydrostatic edema.