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PURPOSE: In this systematic review and individual patient data (IPD) meta-analysis, we analysed the diagnostic performance of [18F]FDG PET/CT in detecting primary tumours in patients with CUP and evaluated whether the location of the predominant metastatic site influences the diagnostic performance. METHODS: A systematic literature search from January 2005 to February 2024 was performed to identify articles describing the diagnostic performance of [18F]FDG PET/CT for primary tumour detection in CUP. Individual patient data retrieved from original articles or obtained from corresponding authors were grouped by the predominant metastatic site. The diagnostic performance of [18F]FDG PET/CT in detecting the underlying primary tumour was compared between predominant metastatic sites. RESULTS: A total of 1865 patients from 32 studies were included. The largest subgroup included patients with predominant bone metastases (n = 622), followed by liver (n = 369), lymph node (n = 358), brain (n = 316), peritoneal (n = 70), lung (n = 67), and soft tissue (n = 23) metastases, leaving a small group of other/undefined metastases (n = 40). [18F]FDG PET/CT resulted in pooled detection rates to identify the primary tumour of 0.74 (for patients with predominant brain metastases), 0.54 (liver-predominant), 0.49 (bone-predominant), 0.46 (lung-predominant), 0.38 (peritoneal-predominant), 0.37 (lymph node-predominant), and 0.35 (soft-tissue-predominant). CONCLUSION: This individual patient data meta-analysis suggests that the ability of [18F]FDG PET/CT to identify the primary tumour in CUP depends on the distribution of metastatic sites. This finding emphasises the need for more tailored diagnostic approaches in different patient populations. In addition, alternative diagnostic tools, such as new PET tracers or whole-body (PET/)MRI, should be investigated.
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AIM: The aim was to explore how findings of whole-body MRI including diffusion-weighted imaging (DW-MRI) compared to the routine diagnostic workup with CT and/or 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in patients with suspected recurrent colorectal cancer (CRC). METHOD: This was an exploratory retrospective analysis of 55 patients with a clinical suspicion of recurrent CRC who underwent DW-MRI following CT and/or FDG-PET/CT. Two readers in consensus interpreted all clinical imaging reports and converted each described lesion into a confidence score (1 = definitely benign to 5 = definitely malignant). DW-MRI findings were compared to the most recent previous CT or PET/CT. Any discrepant or additional DW-MRI findings were documented and compared with histology and/or clinical follow-up (if available). RESULTS: Whole-body MRI including diffusion-weighted imaging (DW-MRI) resulted in discrepant/additional findings in 26/55 (47%) cases; 23/37 (62%) compared to previous CT and 3/18 (17%) compared to previous PET/CT. These included 10 cases where DW-MRI converted previously inconclusive CT (n = 8) or PET/CT (n = 2) findings into a conclusive diagnosis, one where it contradicted a previous CT diagnosis of recurrence, five where DW-MRI diagnosed recurrent disease not previously reported on CT and 10 cases where DW-MRI detected additional lesions compared to CT (n = 9) or PET/CT (n = 1). Eighty-eight per cent of cases with discrepant/additional findings concerned patients with recurrent/metachronous peritoneal metastases. In total, DW-MRI resulted in 42 discrepant/additional lesions; the DW-MRI diagnosis was correct in 76% of these lesions and incorrect (false positive) in 7%. In the remaining 17%, no standard of reference was available. CONCLUSIONS: This explorative study suggests that DW-MRI may be of added value to patients with a clinical suspicion for recurrent CRC, in particular to identify patients with peritoneal metastases. DW-MRI mainly has potential as a 'problem-solver' in patients with inconclusive or negative findings on previous imaging (in particular CT) and to detect additional disease sites in patients already diagnosed with recurrent disease.
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Neoplasias Colorretais , Neoplasias Peritoneais , Humanos , Imagem de Difusão por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Fluordesoxiglucose F18 , Estudos Retrospectivos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons/métodos , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Compostos RadiofarmacêuticosRESUMO
PURPOSE: To compare cerebral blood flow (CBF) values measured using magnetic resonance imaging (MRI) arterial spin labeling (ASL) with those obtained with [(15)O]H2O positron emission tomography (PET), the gold standard for measuring CBF in vivo. MATERIALS AND METHODS: Data were collected in 11 healthy men and in 20 age- and body mass index (BMI)-matched type 1 diabetic men. Pseudo-continuous ASL (PCASL) data were acquired at 3 T and [(15)O]H2O PET scans were acquired using a high-resolution PET scanner. Input functions were obtained using on-line arterial blood sampling. Whole brain and regional CBF values were compared. RESULTS: For both modalities, whole brain CBF was similar in both subject groups. In groups combined, average whole brain CBF was 0.30 ± 0.05 mL · cm(-3) · min(-1) for [(15)O]H2O PET and 0.34 ± 0.05 mL · cm(-3) · min(-1) for ASL MRI (P < 0.01). A significant correlation between methods was observed for whole brain, gray and white matter. In 12 out of 33 brain regions a significant difference between methods was observed. CONCLUSION: PCASL provides CBF values that correlate with [(15)O]H2O PET-derived values, but is less accurate. PCASL may be an attractive alternative when absolute quantification is not needed.
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Velocidade do Fluxo Sanguíneo , Circulação Cerebrovascular , Transtornos Cerebrovasculares/fisiopatologia , Diabetes Mellitus Tipo 1/fisiopatologia , Angiografia por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Adolescente , Adulto , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/patologia , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria/métodos , Radioisótopos de Oxigênio , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Marcadores de Spin , Água , Adulto JovemRESUMO
Lutetium-177 coupled with a ligand for Prostate Specific Membrane Antigen ([177Lu]Lu-PSMA) is a new treatment in The Netherlands. Patients with metastasized castration resistant prostate carcinoma and progressive disease after hormonal therapy and chemotherapy, and no other regular therapeutic options, can be referred. A good clinical performance state, adequate bone marrow function and a PSMA PET/CT showing adequate targeting in all metastases are essential. The therapy consists of four to six intravenous administrations of 7.4 GBq [177Lu]Lu-PSMA, six weeks apart. Side effects are mild and consist of xerostomia, fatigue and bone marrow depression. This therapy is currently administered only in a few hospitals in The Netherlands, mainly in research setting. An EMA registered product is expected at the end of 2022, which can contribute to better availability for reimbursed treatment.
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Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Próstata/patologia , Antígeno Prostático Específico , Dipeptídeos/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do Tratamento , Compostos Radiofarmacêuticos/efeitos adversosRESUMO
Lutetium-177 coupled with a ligand for Prostate Specific Membrane Antigen ([177Lu]Lu-PSMA) is a new treatment in The Netherlands. Patients with metastasized castration resistant prostate carcinoma and progressive disease after hormonal therapy and chemotherapy, and no other regular therapeutic options, can be referred. A good clinical performance state, adequate bone marrow function and a PSMA PET/CT showing adequate targeting in all metastases are essential. The therapy consists of four to six intravenous administrations of 7.4 GBq [177Lu]Lu-PSMA, six weeks apart. Side effects are mild and consist of xerostomia, fatigue and bone marrow depression. This therapy is currently administered only in a few hospitals in The Netherlands, mainly in research setting. An EMA registered product is expected at the end of 2022, which can contribute to better availability for reimbursed treatment.
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Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Próstata/patologia , Antígeno Prostático Específico , Dipeptídeos/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Resultado do Tratamento , Compostos Radiofarmacêuticos/efeitos adversosRESUMO
ABSTRACT: A 71-year-old man was referred for 177 Lu-PSMA therapy. He had metastatic castration-resistant prostate cancer, progressive on several treatment lines, with current PSA 260 µg/L and deteriorating condition. CT showed ascites with omental and peritoneal metastases, all positive on PSMA PET/CT. He was treated with 4 cycles of 7.4 GBq (0.2 Ci) 177 Lu-PSMA-I&T. Posttherapy scans showed good targeting of all metastases. After 4 cycles, PSA had dropped to 44 µ/L. Four months after the fourth cycle, the patients' general condition had significantly improved, and PSA had decreased to 7.0 µg/L.
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Carcinoma , Neoplasias Peritoneais , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Idoso , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Antígeno Prostático Específico , Resultado do Tratamento , Neoplasias Peritoneais/diagnóstico por imagem , Próstata/patologia , Compostos Radiofarmacêuticos , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Lutécio/uso terapêutico , Compostos Heterocíclicos com 1 Anel , Estudos RetrospectivosRESUMO
A defect in neo-vascularization process involving circulating angiogenic mononuclear cells (CACs) dysfunction is associated with diabetes. We showed that oxidative stress was elevated in CACs cultured from blood of individuals with metabolic syndrome (MetS) and diabetes. We then assessed the action of palmitic acid (PA), a deregulated and increased NEFA in metabolic disorders, focusing on its oxidant potential. We observed that the phyto-polyphenol resveratrol normalized oxidative stress both in CACs isolated from MetS patients or treated with PA. Resveratrol further decreased the deleterious action of PA on gene expression of vascularization factors (TNFα, VEGF-A, SDF1α, PECAM-1, VEGFR2, Tie2 and CXCR4) and improved CAC motility. Particularly, resveratrol abolished the PA-induced over-expression of the pro-oxidant protein p66Shc. Neither KLF2 nor SIRT1, previously shown in resveratrol and p66Shc action, was directly involved. Silencing p66Shc normalized PA action on VEGF-A and TNFα specifically, without abolishing the PA-induced oxidative stress, which suggests a deleterious role of p66Shc independently of any major modulation of the cellular oxidative status in a high NEFA levels context. Besides showing that resveratrol reverses PA-induced harmful effects on human CAC function, certainly through profound cellular modifications, we establish p66Shc as a major therapeutic target in metabolic disorders, independent from glycemic control.
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Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico/metabolismo , Proteínas Adaptadoras da Sinalização Shc/genética , Estilbenos/farmacologia , Antioxidantes/farmacologia , Estudos de Casos e Controles , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Tipo 2/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Neovascularização Fisiológica/efeitos dos fármacos , Resveratrol , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de SrcRESUMO
UNLABELLED: Studies in rodents have demonstrated that insulin in the central nervous system induces satiety. In humans, these effects are less well established. Insulin detemir is a basal insulin analog that causes less weight gain than other basal insulin formulations, including the current standard intermediate-long acting Neutral Protamine Hagedorn (NPH) insulin. Due to its structural modifications, which render the molecule more lipophilic, it was proposed that insulin detemir enters the brain more readily than other insulins. The aim of this study was to investigate whether insulin detemir treatment differentially modifies brain activation in response to food stimuli as compared to NPH insulin. In addition, cerebral spinal fluid (CSF) insulin levels were measured after both treatments. Brain responses to viewing food and non-food pictures were measured using functional Magnetic Resonance Imaging in 32 type 1 diabetic patients, after each of two 12-week treatment periods with insulin detemir and NPH insulin, respectively, both combined with prandial insulin aspart. CSF insulin levels were determined in a subgroup. Insulin detemir decreased body weight by 0.8 kg and NPH insulin increased weight by 0.5 kg (pâ=â0.02 for difference), while both treatments resulted in similar glycemic control. After treatment with insulin detemir, as compared to NPH insulin, brain activation was significantly lower in bilateral insula in response to visual food stimuli, compared to NPH (pâ=â0.02 for right and pâ=â0.05 for left insula). Also, CSF insulin levels were higher compared to those with NPH insulin treatment (pâ=â0.003). Our findings support the hypothesis that in type 1 diabetic patients, the weight sparing effect of insulin detemir may be mediated by its enhanced action on the central nervous system, resulting in blunted activation in bilateral insula, an appetite-regulating brain region, in response to food stimuli. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626080.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina Isófana/uso terapêutico , Insulina de Ação Prolongada/uso terapêutico , Regulação do Apetite/efeitos dos fármacos , Barreira Hematoencefálica , Peso Corporal/efeitos dos fármacos , Mapeamento Encefálico , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/líquido cefalorraquidiano , Insulina Detemir , Insulina Isófana/efeitos adversos , Insulina de Ação Prolongada/efeitos adversos , Imageamento por Ressonância Magnética , Estimulação LuminosaRESUMO
Subclinical systemic microvascular dysfunction exists in asymptomatic patients with type 1 diabetes. We hypothesized that microangiopathy, resulting from long-standing systemic hyperglycemia and hyperinsulinemia, may be generalized to the brain, resulting in changes in cerebral blood flow (CBF) and metabolism in these patients. We performed dynamic [(15)O]H2O and [(18)F]-fluoro-2-deoxy-d-glucose brain positron emission tomography scans to measure CBF and cerebral glucose metabolism (CMRglu), respectively, in 30 type 1 diabetic patients and 12 age-matched healthy controls after an overnight fast. Regions of interest were automatically delineated on coregistered magnetic resonance images and full kinetic analysis was performed. Plasma glucose and insulin levels were higher in patients versus controls. Total gray matter CBF was 9%, whereas CMRglu was 21% lower in type 1 diabetic subjects versus control subjects. We conclude that at real-life fasting glucose and insulin levels, type 1 diabetes is associated with decreased resting cerebral glucose metabolism, which is only partially explained by the decreased CBF. These findings suggest that mechanisms other than generalized microangiopathy account for the altered CMRglu observed in well-controlled type 1 diabetes.
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Encéfalo/metabolismo , Circulação Cerebrovascular/fisiologia , Diabetes Mellitus Tipo 1/metabolismo , Glucose/metabolismo , Adolescente , Adulto , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Estudos Transversais , Diabetes Mellitus Tipo 1/diagnóstico por imagem , Diabetes Mellitus Tipo 1/fisiopatologia , Hormônio do Crescimento Humano , Humanos , Masculino , Pessoa de Meia-Idade , CintilografiaRESUMO
OBJECTIVE: To test the hypothesis that insulin detemir, which is associated with less weight gain than other basal insulin formulations, exerts its weight-modulating effects by acting on brain regions involved in appetite regulation, as represented by altered cerebral blood flow (CBF) or cerebral glucose metabolism (CMRglu). RESEARCH DESIGN AND METHODS: Twenty-eight male type 1 diabetic patients (age 36.9 ± 9.7 years, BMI 24.9 ± 2.7 kg/m(2), A1C 7.5 ± 0.6%) successfully completed a randomized crossover study, consisting of two periods of 12-week treatment with either insulin detemir or NPH insulin, both in combination with prandial insulin aspart. After each treatment period, patients underwent positron emission tomography scans to measure regional CBF and CMRglu. RESULTS: After 12 weeks, A1C, daily insulin doses, fasting insulin, and blood glucose levels were similar between treatments. Insulin detemir resulted in body weight loss, whereas NPH insulin induced weight gain (between-treatment difference 1.3 kg; P = 0.02). After treatment with insulin detemir relative to NPH insulin, CBF was higher in brain regions involved in appetite regulation, whereas no significant difference in CMRglu was observed. CONCLUSIONS: Treatment with insulin detemir versus NPH insulin resulted in weight loss, paralleled by increased CBF in appetite-related brain regions in the resting state, in men with well-controlled type 1 diabetes. These findings lend support to the hypothesis that a differential effect on the brain may contribute to the consistently observed weight-sparing effect of insulin detemir.
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Encéfalo/fisiopatologia , Circulação Cerebrovascular/fisiologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucose/metabolismo , Insulina Isófana/administração & dosagem , Insulina de Ação Prolongada/administração & dosagem , Fluxo Sanguíneo Regional/fisiologia , Adolescente , Adulto , Apetite/fisiologia , Encéfalo/metabolismo , Encéfalo/patologia , Estudos Cross-Over , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/fisiopatologia , Feminino , Seguimentos , Humanos , Hipoglicemiantes/administração & dosagem , Imageamento Tridimensional , Insulina Detemir , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Positron emission tomography (PET) allows for the measurement of cerebral blood flow (CBF; based on [15O]H2O) and cerebral metabolic rate of glucose utilization (CMRglu; based on [18 F]-2-fluoro-2-deoxy-d-glucose ([18 F]FDG)). By using kinetic modeling, quantitative CBF and CMRglu values can be obtained. However, hardware limitations led to the development of semiquantitive calculation schemes which are still widely used. In this paper, the analysis of CMRglu and CBF scans, acquired on a current state-of-the-art PET brain scanner, is presented. In particular, the correspondence between nonlinear as well as linearized methods for the determination of CBF and CMRglu is investigated. As a further step towards widespread clinical applicability, the use of an image-derived input function (IDIF) is investigated. METHODS: Thirteen healthy male volunteers were included in this study. Each subject had one scanning session in the fasting state, consisting of a dynamic [15O]H2O scan and a dynamic [18 F]FDG PET scan, acquired at a high-resolution research tomograph. Time-activity curves (TACs) were generated for automatically delineated and for manually drawn gray matter (GM) and white matter regions. Input functions were derived using on-line arterial blood sampling (blood sampler derived input function (BSIF)). Additionally, the possibility of using carotid artery IDIFs was investigated. Data were analyzed using nonlinear regression (NLR) of regional TACs and parametric methods. RESULTS: After quality control, 9 CMRglu and 11 CBF scans were available for analysis. Average GM CMRglu values were 0.33 ± 0.04 µmol/cm3 per minute, and average CBF values were 0.43 ± 0.09 mL/cm3 per minute. Good correlation between NLR and parametric CMRglu measurements was obtained as well as between NLR and parametric CBF values. For CMRglu Patlak linearization, BSIF and IDIF derived results were similar. The use of an IDIF, however, did not provide reliable CBF estimates. CONCLUSION: Nonlinear regression analysis, allowing for the derivation of regional CBF and CMRglu values, can be applied to data acquired with high-spatial resolution current state-of-the-art PET brain scanners. Linearized models, applied to the voxel level, resulted in comparable values. CMRglu measurements do not require invasive arterial sampling to define the input function. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626080.