Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 36
Filtrar
1.
Cancers (Basel) ; 15(14)2023 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-37509258

RESUMO

BACKGROUND: Given the dismal prognosis of small cell lung cancer (SCLC), novel therapeutic targets are urgently needed. We aimed to evaluate whether SSTR expression, as assessed by positron emission tomography (PET), can be applied as a prognostic image biomarker and determined subjects eligible for peptide receptor radionuclide therapy (PRRT). METHODS: A total of 67 patients (26 females; age, 41-80 years) with advanced SCLC underwent SSTR-directed PET/computed tomography (somatostatin receptor imaging, SRI). SRI-avid tumor burden was quantified by maximum standardized uptake values (SUVmax) and tumor-to-liver ratios (T/L) of the most intense SCLC lesion. Scan findings were correlated with progression-free (PFS) and overall survival (OS). In addition, subjects eligible for SSTR-directed radioligand therapy were identified, and treatment outcome and toxicity profile were recorded. RESULTS: On a patient basis, 36/67 (53.7%) subjects presented with mainly SSTR-positive SCLC lesions (>50% lesions positive); in 10/67 patients (14.9%), all lesions were positive. The median SUVmax was found to be 8.5, while the median T/L was 1.12. SRI-uptake was not associated with PFS or OS, respectively (SUVmax vs. PFS, ρ = 0.13 with p = 0.30 and vs. OS, ρ = 0.00 with p = 0.97; T/L vs. PFS, ρ = 0.07 with p = 0.58 and vs. OS, ρ = -0.05 with p = 0.70). PRRT was performed in 14 patients. One patient succumbed to treatment-independent infectious complications immediately after PRRT. In the remaining 13 subjects, disease control was achieved in 5/13 (38.5%) with a single patient achieving a partial response (stable disease in the remainder). In the sub-group of responding patients, PFS and OS were 357 days and 480 days, respectively. CONCLUSIONS: SSTR expression as detected by SRI is not predictive of outcome in patients with advanced SCLC. However, it might serve as a therapeutic target in selected patients.

3.
Clin Biochem ; 105-106: 35-43, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35483452

RESUMO

OBJECTIVE: Liquid chromatography tandem mass spectrometry (LC-MS/MS) is a highly selective and sensitive method for the quantification of kinase inhibitors, yet not widely available in clinical routine for therapeutic drug monitoring (TDM). To provide a more accessible alternative, a high-performance liquid chromatography method with ultraviolet/diode array detection (HPLC-UV/DAD) to quantify cabozantinib, dabrafenib, nilotinib and osimertinib, was developed and validated. Results were compared to LC-MS/MS. METHOD: After liquid-liquid-extraction and reconstitution of the residue in 20 mM potassium dihydrogen phosphate (KH2PO4) (pH4.6), acetonitrile and methanol (50:25:25,v/v/v), chromatographic separation was achieved in 20.0 min using a Luna® C18(2)-HST column (100 × 2 mm, 2.5 µm), protected by a C18 guard column (4 × 2 mm) (column temperature: 30 °C, autosampler: 10 °C). Mobile phase A and B consisted of 20 mM KH2PO4 (pH4.9) and acetonitrile (9:1,v/v) and acetonitrile:20 mM KH2PO4 (pH4.9) (7:3,v/v), respectively. Gradient elution was performed at 200 µL/min. Analytes were quantified at 250, 280 and 330 nm, using sorafenib as internal standard. RESULTS: Calibration curves were linear (35-2,000 ng/mL). Method validation assays met requirements by U.S. Food and Drug Administration and European Medicines Agency. Compared to the more sensitive and specific LC-MS/MS, HPLC-UV/DAD showed a good correlation and a strong positive association (Kendall's tau 0.811¬-0.963, p < 0.05). Bland-Altman-plots revealed 100% (cabozantinib), 98.6% (dabrafenib), 98.6% (nilotinib) and 96.2% (osimertinib) of relative differences inside the limits of agreement. Regulatory agency criteria for sample reanalysis and cross validation were met (±20%-criterion:100% (cabozantinib), 94.3% (dabrafenib), 92% (nilotinib) and 84.6% (osimertinib). CONCLUSION: The developed HPLC-UV/DAD method is "fit-for-TDM" in clinical routine and serves as a genuine alternative to LC-MS/MS.


Assuntos
Monitoramento de Medicamentos , Espectrometria de Massas em Tandem , Acetonitrilas , Acrilamidas , Anilidas , Compostos de Anilina , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida , Humanos , Imidazóis , Indóis , Oximas , Piridinas , Pirimidinas , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
4.
J Pharm Biomed Anal ; 211: 114623, 2022 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-35121279

RESUMO

Personalized dosing of kinase inhibitors (KI) might be beneficial in oral anti-cancer therapy to overcome individual pharmacokinetic variability. Volumetric absorptive microsampling (VAMS) has emerged as an attractive alternative compared to conventional invasive sampling methods enabling remote and frequent specimen collection. Therefore, an LC-MS/MS VAMS method was developed and validated to monitor drug exposure of ten KI from 20 µL dried capillary blood. The assay includes the KI cabozantinib, dabrafenib, nilotinib, and osimertinib with a calibration range of 6-1500 ng/mL and afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib and trametinib within a range of 2-500 ng/mL. Using acetonitrile containing isotope labelled internal standards (IS) as solid-liquid extraction solvent, analytes and IS were detected by multiple reaction monitoring (MRM) after electro-spray ionization (ESI) in positive ionization mode after chromatographic separation using a phenyl-hexyl column. The method was validated according to the FDA and EMA guidelines for bioanalytical method validation and in accordance with the guideline of the International Association for Therapeutic Drug Monitoring and Clinical Toxicology for dried blood spot-based methods. The calibration model was linear and reproducible for all KI (R2> 0.994). Furthermore, the validation demonstrated that the VAMS method is accurate, precise, and sensitive. The method fulfilled the acceptance criteria for matrix effects, recovery, carry over, selectivity as well as for the haematocrit effect and all substances proved to be stable in dried condition for at least six weeks at room temperature. In vitro experiments using spiked venous blood were conducted to establish a VAMS-to-plasma conversion factor for each analyte for comparison of VAMS and plasma concentrations. The method was successfully used in a real-life setting demonstrating its applicability in clinical routine. VAMS concentrations of afatinib, cabozantinib, dabrafenib, nilotinib, ruxolitinib and trametinib were assessed in capillary blood samples collected from either trained healthcare professionals or patients at home.


Assuntos
Coleta de Amostras Sanguíneas , Espectrometria de Massas em Tandem , Coleta de Amostras Sanguíneas/métodos , Cromatografia Líquida/métodos , Teste em Amostras de Sangue Seco , Monitoramento de Medicamentos/métodos , Humanos , Espectrometria de Massas em Tandem/métodos
5.
Dtsch Med Wochenschr ; 146(5): 335-343, 2021 03.
Artigo em Alemão | MEDLINE | ID: mdl-33648003

RESUMO

Sarcoidosis occurs predominantly in younger adults and may involve multiple organ systems. Although classical features such as bihilar lymphadenopathy, low grade fever, fatigue, pulmonary opacities, ocular lesions and arthritis occur frequently it must be kept in mind that sarcoidosis is able to mimic virtually any other disease. A thorough and systematic diagnostic strategy is warranted since even the histological hallmark of non-caseating granulomas occurs in a variety of other granulomatous diseases and even malignancies. A firm diagnosis is based on a match of clinical features, imaging results and histopathological findings. The Scadding classification describes four different types, not stages, of thoracic sarcoidosis based on mediastinal lymph node and lung parenchyma involvement. Medical treatment of pulmonary sarcoidosis is indicated only in patients exhibiting progressive disease and/or organ function impairment. Cardiac sarcoidosis manifests itself by clinical signs of heart failure, impaired cardiac function and arrhythmias including ventricular tachycardia, ventricular fibrillation and AV-conduction abnormalities. Patients with symptomatic or suspected cardiac sarcoidosis require rapid and elaborate diagnostic testing including cardiac MRI and PET imaging. Referral to a specialized center should be considered to establish a firm diagnosis and to initiate medical treatment and eventual device implantation. Oral corticosteroids, as the initial medical treatment of choice, carry side effects that must be weighed carefully against clinical benefits. Immunosuppressive therapy with methotrexate, azathioprine or TNF-blockers is usually reserved for patients that are either not responsive or intolerant to systemic steroids or that require steroid maintenance therapy above the cushing threshold. Diagnosed early and treated correctly, pulmonary and cardiac sarcoidosis mostly carry a favorable prognosis.


Assuntos
Cardiomiopatias , Sarcoidose Pulmonar , Adulto , Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia , Humanos , Masculino , Prognóstico , Sarcoidose/diagnóstico , Sarcoidose/terapia , Sarcoidose Pulmonar/diagnóstico , Sarcoidose Pulmonar/terapia , Taquicardia Ventricular
6.
Anal Bioanal Chem ; 413(2): 599-612, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33155133

RESUMO

A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib, cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for the application in daily clinical routine has been developed and validated according to the US Food and Drug Administration and European Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples with acetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5 µm (2.1 × 50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A and methanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400 µL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stable isotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min per run. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2-500 ng/mL for afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6-1500 ng/mL for cabozantinib, dabrafenib, nilotinib, and osimertinib (coefficients of correlation ≥ 0.99). Validation assays for accuracy and precision, matrix effect, recovery, carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughput and was successfully applied to monitor concentrations of kinase inhibitors in patients. Graphical abstract.


Assuntos
Cromatografia Líquida/métodos , Plasma/metabolismo , Inibidores de Proteínas Quinases/sangue , Espectrometria de Massas em Tandem/métodos , Calibragem , Técnicas de Química Analítica , Química Farmacêutica , Cromatografia , Monitoramento de Medicamentos/instrumentação , Monitoramento de Medicamentos/métodos , Humanos , Limite de Detecção , Espectrometria de Massas , Reprodutibilidade dos Testes , Razão Sinal-Ruído
7.
Sci Rep ; 8(1): 17631, 2018 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514933

RESUMO

In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated 18F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n = 6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, 18F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5 ± 4.2 vs. 59.4 ± 4.5%; HR: 331 ± 35 vs. 309 ± 24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1 ± 0.8 vs. 10.2 ± 1 Enddiastolic Volume/sec, P < 0.01). Investigating a diabetic rat model, ECG-gated 18F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent.


Assuntos
Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/patologia , Eletrocardiografia/métodos , Tomografia por Emissão de Pósitrons/métodos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/patologia , Animais , Diabetes Mellitus Tipo 2/complicações , Radioisótopos de Flúor/administração & dosagem , Ratos
8.
Theranostics ; 8(3): 644-649, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29344295

RESUMO

Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can involve virtually all organ systems. Whereas most patients present without symptoms, progressive and disabling organ failure can occur in up to 10% of subjects. Somatostatin receptor (SSTR)-directed peptide receptor radionuclide therapy (PRRT) has recently received market authorization for treatment of SSTR-positive neuroendocrine tumors. Methods: We describe the first case series comprising two patients with refractory multi-organ involvement of sarcoidosis who received 4 cycles of PRRT. Results: PRRT was well-tolerated without any acute adverse effects. No relevant toxicities could be recorded during follow-up. Therapy resulted in partial response accompanied by a pronounced reduction in pain (patient #1) and stable disease regarding morphology as well as disease activity (patient #2), respectively. Conclusion: Peptide receptor radionuclide therapy in sarcoidosis is feasible and might be a new valuable tool in patients with otherwise treatment-refractory disease. Given the long experience with and good tolerability of PRRT, further evaluation of this new treatment option for otherwise treatment-refractory sarcoidosis in larger patient cohorts is warranted.


Assuntos
Octreotida/análogos & derivados , Compostos Radiofarmacêuticos/uso terapêutico , Sarcoidose/radioterapia , Feminino , Humanos , Pessoa de Meia-Idade , Octreotida/administração & dosagem , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/efeitos adversos
9.
Oncotarget ; 8(57): 96732-96737, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29228566

RESUMO

C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [68Ga]Pentixafor in malignant pleural mesothelioma. Six patients with pleural mesothelioma underwent [68Ga]Pentixafor-PET/CT. 2'-[18F]fluoro-2'-deoxy-D-glucose ([18F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up. Whereas [18F]FDG-PET depicted active lesions in all patients, [68Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [68Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed. In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy.

10.
Sci Rep ; 7(1): 16795, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29196742

RESUMO

Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by 18F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic 18F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. 18F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased 18F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.


Assuntos
Tecido Adiposo Marrom/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Glucose/metabolismo , Obesidade/complicações , Tecido Adiposo Marrom/diagnóstico por imagem , Animais , Restrição Calórica , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Fluordesoxiglucose F18/metabolismo , Masculino , Obesidade/etiologia , Tomografia por Emissão de Pósitrons , Distribuição Aleatória , Ratos , Ratos Zucker
12.
Int J Cardiol ; 227: 257-260, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27839818

RESUMO

OBJECTIVES: Tissue photon attenuation is one of the essential artifacts requiring correction in clinical cardiac positron emission tomography (PET) imaging. However, due to small body size its impact on diagnostic accuracy in small rodents is considered to be limited or even ignorable. The present cardiac PET study compares lean and obese rats to determine the influence of tissue attenuation on quantitative assessment as well as regional tracer distribution. METHODS: A dedicated small animal PET system equipped with a 57Co rotating source for transmission was used. To assess the impact of tissue attenuation in rats with different body sizes, cardiac 18F-FDG -PET studies for Zucker diabetic fatty rats (obese rats) and Zucker lean rats (lean rats) were performed. The radiotracer activity reduction by attenuation was compared between the two groups. Regional tracer distribution calculated with and without attenuation correction was also assessed. RESULTS: The chest diameter was significantly longer in obese than in lean rats (5.6±0.3cm in obese and 4.5±0.2cm in lean rats, p<0.0001). Whereas the activity reduction by attenuation was significantly greater in obese than in lean rats (44.1±2.5% and 5.1±3.1%, p<0.0001), the regional variation of tissue attenuation among the ventricular walls was minimal in both lean (p=0.73) and obese rats (p=0.65). CONCLUSION: Attenuation correction is indispensable for accurate comparison of cardiac tracer activity between animals with different body size, whereas it can be omitted for evaluation of regional tracer distribution.


Assuntos
Coração/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Animais , Artefatos , Técnicas de Imagem Cardíaca , Fluordesoxiglucose F18 , Masculino , Obesidade/diagnóstico por imagem , Compostos Radiofarmacêuticos , Ratos , Ratos Zucker , Magreza/diagnóstico por imagem
14.
Oncotarget ; 7(47): 77807-77814, 2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27780922

RESUMO

Diagnosis of cardiac sarcoidosis is often challenging. Whereas cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) are most commonly used to evaluate patients, PET/CT using radiolabeled somatostatin receptor (SSTR) ligands for visualization of inflammation might represent a more specific alternative. This study aimed to investigate the feasibility of SSTR-PET/CT for detecting cardiac sarcoidosis in comparison to CMR.15 patients (6 males, 9 females) with sarcoidosis and suspicion on cardiac involvement underwent SSTR-PET/CT imaging and CMR. Images were visually scored. The AHA 17-segment model of the left myocardium was used for localization and comparison of inflamed myocardium for both imaging modalities. In semi-quantitative analysis, mean (SUVmean) and maximum standardized uptake values (SUVmax) of affected myocardium were calculated and compared with both remote myocardium and left ventricular (LV) cavity.SSTR-PET was positive in 7/15, CMR in 10/15 patients. Of the 3 CMR+/PET- subjects, one patient with minor involvement (<25% of wall thickness in CMR) was missed by PET. The remaining two CMR+/PET- patients displayed no adverse cardiac events during follow-up.In the 17-segment model, PET/CT yielded 27 and CMR 29 positive segments. Overall concordance of the 2 modalities was 96.1% (245/255 segments analyzed). SUVmean and SUVmax in inflamed areas were 2.0±1.2 and 2.6±1.2, respectively. The lesion-to-remote myocardium and lesion-to-LV cavity ratios were 1.8±0.2 and 1.9±0.2 for SUVmean and 2.0±0.3 and 1.7±0.3 for SUVmax, respectively.Detection of cardiac sarcoidosis by SSTR-PET/CT is feasible. Our data warrant further analysis in larger prospective series.


Assuntos
Cardiomiopatias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Receptores de Somatostatina/metabolismo , Sarcoidose/diagnóstico por imagem , Adulto , Idoso , Cardiomiopatias/metabolismo , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Estudos Prospectivos , Sarcoidose/metabolismo , Sensibilidade e Especificidade
15.
Hypertension ; 67(5): 1000-5, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27045032

RESUMO

Chronic thromboembolic pulmonary hypertension (CTEPH) is an entity of PH that not only limits patients quality of life but also causes significant morbidity and mortality. The treatment of choice is pulmonary endarterectomy. However numerous patients do not qualify for pulmonary endarterectomy or present with residual vasculopathy post pulmonary endarterectomy and require specific vasodilator treatment. Currently, there is no available specific small animal model of CTEPH that could serve as tool to identify targetable molecular pathways and to test new treatment options. Thus, we generated and standardized a rat model that not only resembles functional and histological features of CTEPH but also emulates thrombi fibrosis. The pulmonary embolism protocol consisted of 3 sequential tail vein injections of fibrinogen/collagen-covered polystyrene microspheres combined with thrombin and administered to 10-week-old male Wistar rats. After the third embolism, rats developed characteristic features of CTEPH including elevated right ventricular systolic pressure, right ventricular cardiomyocyte hypertrophy, pulmonary artery remodeling, increased serum brain natriuretic peptide levels, thrombi fibrosis, and formation of pulmonary cellular-fibrotic lesions. The current animal model seems suitable for detailed study of CTEPH pathophysiology and permits preclinical testing of new pharmacological therapies against CTEPH.


Assuntos
Endarterectomia/métodos , Hipertensão Pulmonar/fisiopatologia , Artéria Pulmonar/fisiopatologia , Embolia Pulmonar/cirurgia , Animais , Biópsia por Agulha , Doença Crônica , Modelos Animais de Doenças , Endarterectomia/mortalidade , Hipertensão Pulmonar/patologia , Imuno-Histoquímica , Masculino , Circulação Pulmonar/fisiologia , Embolia Pulmonar/mortalidade , Embolia Pulmonar/patologia , Distribuição Aleatória , Ratos , Ratos Wistar , Medição de Risco , Taxa de Sobrevida , Resultado do Tratamento , Remodelação Vascular/fisiologia
16.
Oncotarget ; 7(15): 20033-40, 2016 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-26936994

RESUMO

Despite initial responsiveness to both chemotherapy and radiotherapy, small cell lung cancer (SCLC) commonly relapses within months. Although neuroendocrine characteristics may be difficult to demonstrate in individual cases, a relevant expression of somatostatin receptors (SSTR) on the cell surface has been described. We aimed to evaluate the prognostic value of SSTR-expression in advanced SCLC. We further examined pre-requisites for successful peptide receptor radionuclide therapy (PRRT). 21 patients with extensive stage SCLC were enrolled. All patients underwent positron emission tomography/computed tomography (PET/CT) with 68Ga-DOTATATE to select patients for SSTR-directed therapy. PET scans were visually and semi-quantitatively assessed and compared to SSTR2a and SSTR5 expression in biopsy samples. Peak standardized uptake values (SUVpeak) of tumors as well as tumor-to-liver ratios were correlated to progression-free (PFS) and overall survival (OS). In 4/21 patients all SCLC lesions were PET-positive. 6/21 subjects were rated "intermediate" with the majority of lesions positive, the remaining 11/21 patients were PET-negative. PET-positivity correlated well with histologic SSTR2a, but not with SSTR5 expression. Neither PET-positivity nor SUVpeak were predictors of PFS or OS. In 4 patients with intensive SSTR2a-receptor expression, PRRT was performed with one partial response and one stable disease, respectively. SSTR-expression as detected by 68Ga-DOTATATE-PET and/or histology is not predictive of PFS or OS in patients with advanced SCLC. However, in patients exhibiting sufficient tracer uptake, PRRT might be a treatment option given its low toxicity and the absence of effective alternatives.


Assuntos
Neoplasias Pulmonares/metabolismo , Compostos Organometálicos/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Receptores de Somatostatina/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Adulto , Idoso , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/radioterapia , Carcinoma de Pequenas Células do Pulmão/secundário
17.
Oncotarget ; 7(8): 9288-95, 2016 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-26843617

RESUMO

Chemokine receptor CXCR4 is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging of small cell lung cancer (SCLC) with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine ligand [68Ga]Pentixafor. 10 patients with primarily diagnosed (n=3) or pre-treated (n=7) SCLC (n=9) or large cell neuroendocrine carcinoma of the lung (LCNEC, n=1) underwent [68Ga]Pentixafor-PET/CT. 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG, n=6) and/or somatostatin receptor (SSTR)-directed PET/CT with [68Ga]DOTATOC (n=5) and immunohistochemistry (n=10) served as standards of reference. CXCR4-PET was positive in 8/10 patients and revealed more lesions with significantly higher tumor-to-background ratios than SSTR-PET. Two patients who were positive on [18F]FDG-PET were missed by CXCR4-PET, in the remainder [68Ga]Pentixafor detected an equal (n=2) or higher (n=2) number of lesions. CXCR4 expression of tumor lesions could be confirmed by immunohistochemistry. Non-invasive imaging of CXCR4 expression in SCLC is feasible. [68Ga]Pentixafor as a novel PET tracer might serve as readout for confirmation of CXCR4 expression as prerequisite for potential CXCR4-directed treatment including receptor-radio(drug)peptide therapy.


Assuntos
Complexos de Coordenação/farmacologia , Radioisótopos de Gálio/farmacologia , Neoplasias Pulmonares/diagnóstico por imagem , Peptídeos Cíclicos/farmacologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Receptores CXCR4/análise , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Adulto , Idoso , Feminino , Fluordesoxiglucose F18/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Octreotida/análogos & derivados , Octreotida/farmacologia , Receptores de Somatostatina/análise
18.
J Thorac Oncol ; 10(1): 156-63, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25247337

RESUMO

INTRODUCTION: Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis. Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program. METHODS: Patients with NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment received afatinib. Medical history, patient demographics, EGFR mutational status, and adverse events including tumor progression were documented. RESULTS: From 2010 to 2013, 573 patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented EGFR mutation. Median time to treatment failure for patients with CNS metastasis was 3.6 months, and did not differ from a matched group of 100 patients without CNS metastasis. Thirty-five percent (11 of 31) of evaluable patients had a cerebral response, five (16%) responded exclusively in brain. Response duration (range) was 120 (21-395) days. Sixty-six percent (21 of 32) of patients had cerebral disease control on afatinib. Data from one patient with an impressive response showed an afatinib concentration in the cerebrospinal fluid of nearly 1 nMol. CONCLUSION: Afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases. Afatinib may therefore be an effective treatment for heavily pretreated patients with EGFR-mutated or EGFR-TKI-sensitive NSCLC and CNS metastasis.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Adulto , Afatinib , Idoso , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Masculino , Neoplasias Meníngeas/secundário , Pessoa de Meia-Idade , Mutação , Resultado do Tratamento
20.
PLoS One ; 8(8): e68275, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23990872

RESUMO

BACKGROUND: Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies. METHODS: Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition. RESULTS: Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week (267.5±10.6 vs. 317.0±11.3 g, n<0.05) and 8 weeks (317.0±21.1 vs. 358.7±22.4 g, n<0.05) after the intervention. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31±0.36/1.21±0.31 vs. 1.14±0.20/1.07±0.17 µl left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in sham operated rats compared to controls in absolute measures (782.2±57.2/260.2±33.2 vs. 805.9±84.8/310.4±48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed only minor inflammatory but prolonged metabolic changes after surgery not related to cardiac disease. CONCLUSION: Cardio-thoracic surgical procedures in experimental myocardial infarction cause distinct alterations upon the global integrity of the organism, which in the long term also induce circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective animal studies and transferring these findings to conditions in patients.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiopatias/cirurgia , Coração/fisiopatologia , Imageamento por Ressonância Magnética , Animais , Peso Corporal , Modelos Animais de Doenças , Eletrocardiografia , Feminino , Ventrículos do Coração/fisiopatologia , Inflamação , Imagem Cinética por Ressonância Magnética/métodos , Infarto do Miocárdio/fisiopatologia , Ratos , Ratos Wistar
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...