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BACKGROUND. PET/CT with 18F-fluoroestradiol (FES) (FDA-approved in 2020) depicts tissues expressing estrogen receptor (ER). Invasive lobular carcinoma (ILC) is commonly ER positive. OBJECTIVE. The primary aim of this study was to assess the frequency with which sites of histologically proven ILC have abnormal uptake on FES PET/CT. METHODS. This prospective single-center pilot study, conducted from December 2020 to August 2021, enrolled patients with histologically confirmed ILC to undergo FES PET/CT; patients optionally underwent FDG PET/CT. Two nuclear radiologists assessed FES PET/CT and FDG PET/CT studies for abnormal uptake corresponding to known ILC sites at enrollment and for additional sites of abnormal uptake, resolving differences by consensus. The primary endpoint was percentage of known ILC sites showing abnormal FES uptake. The alternative to the null hypothesis was that more than 60% of sites would have abnormal FES uptake, exceeding the percentage of ILC with abnormal FDG uptake described in prior literature. A sample size of 24 biopsied lesions was preselected to provide 81% power for the alternative hypothesis (one-sided α = .10). Findings on FES PET/CT and FDG PET/CT were summarized for additional secondary endpoints. RESULTS. The final analysis included 17 patients (mean age, 59.1 ± 13.2 years) with 25 sites of histologically confirmed ILC at enrollment (22 breast lesions, two axillary lymph nodes, one distant metastasis). FES PET/CT showed abnormal uptake in 22 of 25 (88%) lesions, sufficient to reject the null hypothesis (p = .002). Thirteen patients underwent FDG PET/CT. Four of 23 (17%) sites of histologically confirmed ILC, including additional sites detected and confirmed after enrollment, were identified with FES PET/CT only, and 1 of 23 (4%) was identified only with FDG PET/CT (p = .18). FES PET/CT depicted additional lesions not detected with standard-of-care evaluation in 4 of 17 (24%) patients (two contralateral breast cancers and two metastatic axillary lymph nodes, all with subsequent histologic confirmation). Use of FES PET/CT resulted in changes in clinical stage with respect to standard-of-care evaluation in 3 of 17 (18%) patients. CONCLUSION. The primary endpoint of the trial was met. The frequency of abnormal FES uptake among sites of histologically known ILC was found to be to be significantly greater than 60%. CLINICAL IMPACT. This pilot study shows a potential role of FES PET/CT in evaluation of patients with ILC. TRIAL REGISTRATION. ClinicalTrials.gov NCT04252859.
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Neoplasias da Mama , Carcinoma Lobular , Humanos , Pessoa de Meia-Idade , Idoso , Feminino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Carcinoma Lobular/diagnóstico por imagem , Carcinoma Lobular/patologia , Projetos Piloto , Fluordesoxiglucose F18 , Estudos Prospectivos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Tomografia por Emissão de Pósitrons/métodos , EstradiolRESUMO
Pharmacological inhibition of KRAS>RAF>MEK1/2>ERK1/2 signaling has provided no clinical benefit to patients with pancreatic ductal adenocarcinoma (PDAC). Interestingly, combined inhibition of MEK1/2 (with trametinib [T]) plus autophagy (with chloroquine [CQ] or hydroxychloroquine [HCQ]) demonstrated striking anti-tumor effects in preclinical models and in a patient (Patient 1). However, not all patients respond to the T/HCQ regimen, and Patient 1 eventually developed resistant disease. Here we report that primary or acquired resistance is associated with focal DNA copy number gains encompassing c-MYC. Furthermore, ectopic expression of c-MYC in PDAC cell lines rendered them T/HCQ resistant. Interestingly, a CDK4/6 inhibitor, palbociclib (P), also induced autophagy and overrode c-MYC-mediated T/HCQ resistance, such that P/HCQ promoted regression of T/HCQ-resistant PDAC tumors with elevated c-MYC expression. Finally, P/HCQ treatment of Patient 1 resulted in a biochemical disease response. These data suggest that elevated c-MYC expression is both a marker and a mediator of T/HCQ resistance, which may be overcome by the use of P/HCQ.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Quinase 4 Dependente de Ciclina/uso terapêutico , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Lisossomos/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Neoplasias PancreáticasRESUMO
The rapid growth of municipal solid waste put pressure on the end treatment facilities, and the site selection of MSW treatment facilities needs to be carefully conducted. This study aims to develop a Standard Operational Procedures (SOP) for municipal solid waste (MSW) treatment station site selection based on GIS and system dynamics combination. System dynamics was used to establish a forecasting model for MSW simulation followed by the spatial analysis method to generate a geographic information system. The MSW simulation in Xiamen city using the system dynamics model proved that the model was with high prediction accuracy. An SOP for GIS-based MSW treatment station site selection was developed. The site selection for MSW comprehensive treatment in Xiamen using GIS and system dynamics screened the locations of the comprehensive solid waste treatment stations in Xiamen and eliminated unsuitable lands using the mapping function of the geographic information system, thus validating the SOP.
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Eliminação de Resíduos , Gerenciamento de Resíduos , Cidades , Monitoramento Ambiental , Sistemas de Informação Geográfica , Eliminação de Resíduos/métodos , Resíduos Sólidos/análise , Instalações de Eliminação de Resíduos , Gerenciamento de Resíduos/métodosRESUMO
This study is aimed to rationalise and demonstrate the efficacy of utilising laser cutting technique in the fabrication of glulam mortise & tenon joints in timber frame. Trial-and-error experiments aided by laser cutter were conducted to produce 3D timber mortise & tenon joints models. The two main instruments used were 3D modelling software and the laser cutter TH 1390/6090. Plywood was chosen because it could produce smooth and accurate cut edges whereby the surface could remain crack-free, and it could increase stability due to its laminated nature. Google SketchUp was used for modelling and Laser CAD v7.52 was used to transfer the 3D models to the laser cutter because it is compatible with AI, BMP, PLT, DXF and DST templates. Four models were designed and fabricated in which the trial-and-error experiments proved laser cutting could speed up the manufacturing process with superb quality and high uniformity. Precision laser cutting supports easy automation, produces small heat-affected zone, minimises deformity, relatively quiet and produces low amount of waste. The LaserCAD could not process 3D images directly but needed 2D images to be transferred, so layering and unfolding works were therefore needed. This study revealed a significant potential of rapid manufacturability of mortise & tenon joints with high-quality and high-uniformity through computer-aided laser cutting technique for wide applications in the built environment.
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OBJECTIVE: To determine if heparin labeled with 99mTechnetium (99mTc) could be an imaging probe to detect eosinophil-related inflammation in eosinophilic esophagitis and to determine the biodistribution and radiation dosimetry of 99mTc-heparin oral administration using image-based dosimetry models with esophageal modeling. METHODS: Freshly prepared 99mTc-heparin was administered orally to 5 research subjects. Radioactivity was measured by whole-body scintigraphy and single-photon emission computed tomography during the 24 hours postadministration. Following imaging, endoscopic examination was performed. The biodistribution of esophageal radioactivity was compared with endoscopic findings, eosinophil counts in biopsy tissues, and immunostaining for eosinophil granule major basic protein-1 (eMBP1). These studies were conducted from July 1, 2013, until April 22, 2017. RESULTS: Oral administration of 99mTc-heparin was well tolerated in all 5 subjects. The entire esophagus could be visualized dynamically during oral administration. Bound esophageal radioactivity marked areas of inflammation as judged by endoscopy scores, by eosinophils per high power field and by localization of eMBP1 using immunostaining. Ninety percent of the radioactivity did not bind to the esophagus and passed through the gastrointestinal tract. CONCLUSION: The biodistribution of ingested 99mTc-heparin is almost exclusively localized to the gastrointestinal tract. Radiation exposure was highest in the lower gastrointestinal tract and was comparable with other orally administered diagnostic radiopharmaceuticals. The use of swallowed 99mTc-heparin may aid in assessing eosinophil-related inflammation in the esophagus.
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Esofagite Eosinofílica/diagnóstico por imagem , Heparina/administração & dosagem , Compostos de Organotecnécio/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Tomografia Computadorizada de Emissão de Fóton Único , Administração Oral , Adulto , Esofagoscopia , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Tecidual , Imagem Corporal TotalRESUMO
OBJECTIVE: This study aimed to test the hypothesis that young adults with obesity and cold-activated brown adipose tissue (BAT) are less likely to have metabolic dysfunction (dyslipidemia, insulin resistance, and hypertension) than those without cold-activated BAT. Previous studies have noted a potentially protective effect of BAT and higher adiponectin/leptin ratios, but they have acknowledged that the clinical implications of these findings remain uncertain. METHODS: Twenty-one females and twenty-three males with obesity (BMI ≥ 30 kg/m2 ) underwent a 2-hour cooling protocol before 18 F-fluorodeoxyglucose (18 F-FDG)-positron emission tomography/x-ray computed tomography scan to determine the prevalence, volume, and 18 F-FDG uptake of cold-activated BAT. RESULTS: Cold-activated BAT was identified in 43% of participants (11 female, 8 male); females had greater 18 F-FDG uptake. Those with cold-activated BAT had a lesser degree of metabolic dysfunction. Cold-activated BAT volume correlated with triglycerides (inversely) and adiponectin (concordantly). Body-mass-adjusted cold-activated BAT activity correlated with high-density lipoprotein cholesterol (concordantly). Males with cold-activated BAT had lower leptin and higher adiponectin/leptin ratio. CONCLUSIONS: A high prevalence of cold-activated BAT was found in the study participants. BAT could be important in decreasing metabolic dysfunction among young adults with obesity, making it a potential target for treating metabolically unhealthy obesity.
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Tecido Adiposo Marrom/metabolismo , Doenças Cardiovasculares/fisiopatologia , Fluordesoxiglucose F18/uso terapêutico , Obesidade/fisiopatologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto JovemRESUMO
PURPOSE: Most gastrointestinal stromal tumors (GIST) have activating mutations of KIT, PDGFRA, or uncommonly BRAF. Fifteen percent of adult and 85% of pediatric GISTs are wild type (WT), commonly having high expression of IGF-1R and loss of succinate dehydrogenase (SDH) complex function. We tested the efficacy of linsitinib, an oral TKI IGF-1R inhibitor, in patients with WT GIST. PATIENTS AND METHODS: A multicenter phase II trial of linsitinib was conducted. The primary endpoint was objective response rate. Secondary endpoints were clinical benefit rate: complete response, partial response, and stable disease (SD) ≥ 9 months, and quantitative 2[18F]fluoro-2-deoxy-D-glucose (FDG) metabolic response (MR) at week 8. Serum levels for glucose, insulin, IGF-1R ligand IGF1, and binding proteins were obtained to explore correlations to patient outcomes and FDG-PET results. RESULTS: Twenty patients were accrued in a 6-month period. Grade 3-4 toxicities possibly related to linsitinib were uncommon (8.5%). No objective responses were seen. Clinical benefit rate (CBR) at 9 months was 40%. Intense FDG uptake was observed at baseline, with partial MR of 12% and stable metabolic disease of 65% at week 8; these patients had RECIST 1.1 SD as their best response. Progression-free survival (PFS) and overall survival Kaplan-Meier estimates at 9 months were 52% and 80%, respectively. SDHA/B loss determined by IHC was seen in 35% and 88% of cases, respectively. CONCLUSIONS: Linsitinib is well tolerated in patients with WT GIST. Although the 9-month CBR was 40%, and PFS at 9 months was 52%, no objective responses were observed. Rapid accrual to this study demonstrates that clinical trials of experimental agents in selected subtypes of GIST are feasible.
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Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Imidazóis/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Receptor IGF Tipo 1/antagonistas & inibidores , Adolescente , Adulto , Complexo II de Transporte de Elétrons/genética , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Proteínas Proto-Oncogênicas c-kit/genética , Receptor IGF Tipo 1/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: There are few reports of the association of other cancers with Ewing sarcoma in patients and their relatives. We use a resource combining statewide genealogy and cancer reporting to provide unbiased risks. METHODS: Using a combined genealogy of 2.3 million Utah individuals and the Utah Cancer Registry (UCR), relative risks (RRs) for cancers of other sites were estimated in 143 Ewing sarcoma patients using a Cox proportional hazards model with matched controls; however, risks in relatives were estimated using internal cohort-specific cancer rates in first-, second-, and third-degree relatives. RESULTS: Cancers of three sites (breast, brain, complex genotype/karyotype sarcoma) were observed in excess in Ewing sarcoma patients. No Ewing sarcoma patients were identified among first-, second-, or third-degree relatives of Ewing sarcoma patients. Significantly increased risk for brain, lung/bronchus, female genital, and prostate cancer was observed in first-degree relatives. Significantly increased risks were observed in second-degree relatives for breast cancer, nonmelanoma eye cancer, malignant peripheral nerve sheath cancer, non-Hodgkin lymphoma, and translocation sarcomas. Significantly increased risks for stomach cancer, prostate cancer, and acute lymphocytic leukemia were observed in third-degree relatives. CONCLUSIONS: This analysis of risk for cancer among Ewing sarcoma patients and their relatives indicates evidence for some increased cancer predisposition in this population which can be used to individualize consideration of potential treatment of patients and screening of patients and relatives.
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Família , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Sarcoma de Ewing/epidemiologia , Humanos , Masculino , Vigilância da População , Modelos de Riscos Proporcionais , Sistema de Registros , Medição de Risco , Fatores de Risco , Utah/epidemiologiaRESUMO
In the version of this article initially published, the label over the bottom schematic in Fig. 1a was "pH > 5.0"; it should have been "pH < 5.0". Further, the original article misspelt the surname of Katrin P. Guillen as "Gullien". These errors have been corrected in the print, PDF and HTML versions of the article.
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Pancreatic ductal adenocarcinoma (PDA) was responsible for ~ 44,000 deaths in the United States in 2018 and is the epitome of a recalcitrant cancer driven by a pharmacologically intractable oncoprotein, KRAS1-4. Downstream of KRAS, the RAFâMEKâERK signaling pathway plays a central role in pancreatic carcinogenesis5. However, paradoxically, inhibition of this pathway has provided no clinical benefit to patients with PDA6. Here we show that inhibition of KRASâRAFâMEKâERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition. Mechanistically, inhibition of MEK1/2 leads to activation of the LKB1âAMPKâULK1 signaling axis, a key regulator of autophagy. Furthermore, combined inhibition of MEK1/2 plus autophagy displays synergistic anti-proliferative effects against PDA cell lines in vitro and promotes regression of xenografted patient-derived PDA tumors in mice. The observed effect of combination trametinib plus chloroquine was not restricted to PDA as other tumors, including patient-derived xenografts (PDX) of NRAS-mutated melanoma and BRAF-mutated colorectal cancer displayed similar responses. Finally, treatment of a patient with PDA with the combination of trametinib plus hydroxychloroquine resulted in a partial, but nonetheless striking disease response. These data suggest that this combination therapy may represent a novel strategy to target RAS-driven cancers.
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Autofagia/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas ras/metabolismo , Animais , Antígeno CA-19-9/metabolismo , Linhagem Celular Tumoral , Cloroquina/farmacologia , Humanos , Camundongos SCID , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Piridonas/farmacologia , Pirimidinonas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias PancreáticasRESUMO
Amyloid beta (Aß) plaques are not specific to Alzheimer's disease and occur with aging and neurodegenerative disorders. Soluble brain Aß may be neuroprotective and increases in response to neuroinflammation. Sepsis is associated with neurocognitive compromise. The objective was to determine, in a rat endotoxemia model of sepsis, whether neuroinflammation and soluble Aß production are associated with Aß plaque and hyperphosphorylated tau deposition in the brain. Male Sprague Dawley rats received a single intraperitoneal injection of 10 mg/kg of lipopolysaccharide endotoxin (LPS). Brain and blood levels of IL-1ß, IL-6, and TNFα and cortical microglial density were measured in LPS-injected and control animals. Soluble brain Aß and p-tau were compared and Aß plaques were quantified and characterized. Brain uptake of [18F]flutemetamol was measured by phosphor imaging. LPS endotoxemia resulted in elevations of cytokines in blood and brain. Microglial density was increased in LPS-treated rats relative to controls. LPS resulted in increased soluble Aß and in p-tau levels in whole brain. Progressive increases in morphologically-diffuse Aß plaques occurred throughout the interval of observation (to 7-9 days post LPS). LPS endotoxemia resulted in increased [18F]flutemetamol in the cortex and increased cortex: white matter ratios of activity. In conclusion, LPS endotoxemia causes neuroinflammation, increased soluble Aß and Aß diffuse plaques in the brain. Aß PET tracers may inform this neuropathology. Increased p-tau in the brain of LPS treated animals suggests that downstream consequences of Aß plaque formation may occur. Further mechanistic and neurocognitive studies to understand the causes and consequences of LPS-induced neuropathology are warranted.
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Synovial sarcomas are deadly soft tissue malignancies associated with t(X;18) balanced chromosomal translocations. Expression of the apoptotic regulator BCL2 is prominent in synovial sarcomas and has prompted the hypothesis that synovial sarcomagenesis may depend on it. Herein, it is demonstrated that Bcl2 overexpression enhances synovial sarcomagenesis in an animal model. Furthermore, we determined increased familial clustering of human synovial sarcoma patients with victims of other BCL2-associated malignancies in the Utah Population Database. Conditional genetic disruption of Bcl2 in mice also led to reduced sarcomagenesis. Pharmacologic inhibition specific to BCL2 had no demonstrable efficacy against human synovial sarcoma cell lines or mouse tumors. However, targeting BCLxL in human and mouse synovial sarcoma with the small molecule BH3 domain inhibitor, BXI-72, achieved significant cytoreduction and increased apoptotic signaling. Thus, the contributory role of BCL2 in synovial sarcomagenesis does not appear to render it as a therapeutic target, but mitochondrial antiapoptotic BCL2 family members may be.Implications: The association of BCL2 expression with synovial sarcoma is found to fit with a subtle, but significant, impact of its enhanced presence or absence during early tumorigenesis. However, specific pharmacologic inhibition of BCL2 does not demonstrate a persistent dependence in fully developed tumors. Conversely, inhibition of the BCL2 family member BCLxL resulted in nanomolar potency against human synovial sarcoma cell lines and 50% tumor reduction in a genetically engineered mouse model. Mol Cancer Res; 15(12); 1733-40. ©2017 AACR.
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Carcinogênese/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sarcoma Sinovial/tratamento farmacológico , Sarcoma Sinovial/genética , Proteína bcl-X/genética , Animais , Apoptose/efeitos dos fármacos , Benzimidazóis/administração & dosagem , Linhagem Celular Tumoral , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/patologia , Sarcoma Sinovial/patologia , Transdução de Sinais/efeitos dos fármacos , Translocação Genética/genéticaRESUMO
An important challenge to using fluorodeoxyglucose-positron emission tomography (FDG-PET) in clinical trials of brain tumor patients is to identify malignant regions whose metabolic activity shows significant changes between pretreatment and a posttreatment scans in the presence of high normal brain background metabolism. This paper describes a semiautomated processing and analysis pipeline that is able to detect such changes objectively with a given false detection rate. Image registration and voxelwise comparison of the pre- and posttreatment images were performed. A key step is adjustment of the observed difference by the estimated background change at each voxel, thereby overcoming the confounding effect of spatially heterogeneous metabolic activity in the brain. Components of the proposed method were validated via phantom experiments and computer simulations. It achieves a false response volume accuracy of 0.4% at a significance threshold of 3 standard deviations. It is shown that the proposed methodology can detect lesion response with 100% accuracy with a tumor-to-background-ratio as low as 1.5, and it is not affected by the background brain glucose metabolism change. We also applied the method to FDG-PET patient images from a clinical trial to assess treatment effects of lapatinib, which demonstrated significant changes in metabolism corresponding to tumor regions.
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Glioblastoma (GBM) is an incurable brain tumor characterized by the expression of pro-angiogenic cytokines. A recent phase II clinical trial studied VEGF Trap in adult patients with temozolomide-resistant GBM. We sought to explore changes in [18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) or magnetic resonance imaging (MRI) in trial participants correlating these changes with disease response. FDG-PET and MRI images obtained before and after the first dose of VEGF Trap were spatially co-registered. Regions of interest on each image slice were combined to produce a volume of interest representative of the entire tumor. Percent and absolute changes in maximum FDG-avidity, mean apparent diffusion coefficient (ADC), Ktrans, and Ve were calculated per lesion. Among the 12 participants that underwent dynamic contrast enhanced MRI (DCE-MRI), there were large, statistically significant reductions in Ktrans and Ve (median difference = -41.8 %, p < 0.02 and -42.6 %, p < 0.04, respectively). In contrast, there were no significant reductions in ADC or FDG-PET SUVmax values. DCE-MRI is a useful measure of early pharmacodynamic effects of VEGF Trap on tumor vasculature. The absence of significant changes in FDG-PET and DW-MRI suggest that the early pharmacodynamic effects are specific to tumor perfusion and/or permeability and do not directly inhibit metabolism or induce cell death. DCE-MRI in conjunction with standard imaging may be promising for the identification of anti-angiogenic effects in this patient population with this therapeutic target. Further studies are needed to evaluate the relationship between DCE-MRI response and clinical outcome.
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Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/diagnóstico por imagem , Glioblastoma/tratamento farmacológico , Imageamento por Ressonância Magnética , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Estatísticas não Paramétricas , Análise de Sobrevida , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: There is a paucity of data on quality of life issues in patients with leprosy suffering from erythema nodosum leprosum (ENL). Thus, we aim to study the effect of ENL on quality of life. MATERIALS AND METHODS: This cross-sectional study was conducted in Hansen's Clinic, Hospital Kuala Lumpur between January 2010 and December 2013 among patients with multibacillary leprosy using the Dermatology Life Quality Index (DLQI). RESULTS: A total of 153 patients participated with 31.4% suffering from ENL. The mean age at presentation was 40.5 ± 16.49 years. The mean DLQI was 7.1 ± 3.72. Patients with ENL were younger (mean age 36.5 vs. 42.4, P = 0.026), had higher mean bacteriologic index (4.3 vs. 3.8, P = 0.004), had physical deformities (47.9% vs. 31.4%, P = 0.049), and had higher mean DLQI score (9.1 vs. 6.2, P < 0.001). All the DLQI domains were higher in patients suffering from ENL except the treatment domain. Symptoms and feeling was the domain with the largest effect followed by daily activities and leisure. Personal relationship had the lowest effect. CONCLUSION: Quality of life impairment in patients with leprosy in Malaysia is moderate, with larger effect among patients with ENL. The impairment in ENL is comparable to itchy skin conditions such as urticarial and is worse than chronic skin disease such as psoriasis. Thus, it is essential that management of leprosy incorporate quality of life issues.
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BACKGROUND: Metastatic renal cell carcinoma has a poor prognosis and an intrinsic resistance to standard treatment. Sunitinib is an oral receptor tyrosine kinase inhibitor that has been used as a first-line targeted therapy in metastatic renal cell carcinoma. While computed tomography (CT) is currently the gold standard for response assessment in oncological trials, numerous studies have shown that positron emission tomography (PET) imaging can provide information predictive of tumor response to treatment earlier than the typical interval for standard of care follow-up CT imaging. In this exploratory study we sought to characterize early tumor response in patients with metastatic renal cell carcinoma treated with continuous daily 37.5 mg sunitinib therapy. METHODS: Twenty patients underwent dynamic acquisition positron emission tomography (PET) imaging using (18) F-fluorodeoxyglucose (FDG) and (18) F-fluorothymidine (FLT) at baseline and early in treatment (after 1, 2, 3 or 4 weeks) with 37.5 mg continuous daily dosing of sunitinib. Semi-quantitative analyses were performed to characterize the tumor metabolic (FDG) and proliferative (FLT) responses to treatment. RESULTS: Proliferative responses were observed in 9/19 patients and occurred in 2 patients at one week (the earliest interval evaluated) after the initiation of therapy. A metabolic response was observed in 5/19 patients, however this was not observed until after two weeks of therapy were completed. Metabolic progression was observed in 2/19 patients and proliferative progression was observed in 1/19 patients. Baseline FDG-PET tumor maximum standardized uptake values correlated inversely with overall survival (p = 0.0036). Conversely, baseline (18) F-fluorothymidine PET imaging did not have prognostic value (p = 0.56) but showed a greater early response rate at 1-2 weeks after initiating therapy. CONCLUSIONS: While preliminary in nature, these results show an immediate and sustained proliferative response followed by a delayed metabolic response beginning after two weeks in metastatic renal cell carcinoma treated with a continuous daily dose of 37.5 mg sunitinib. The results provide evidence of tumor response to lower-dose sunitinib while also supporting the inclusion of PET imaging as a tool for early assessment in oncological clinical trials. TRIAL REGISTRATION: ID: NCT00694096.
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Inibidores da Angiogênese/uso terapêutico , Antineoplásicos/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/secundário , Didesoxinucleosídeos , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Indóis/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/secundário , Pirróis/administração & dosagem , Compostos Radiofarmacêuticos , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Neoplasias Renais/metabolismo , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Sunitinibe , Resultado do TratamentoRESUMO
PURPOSE: Lapatinib plus trastuzumab improves outcomes relative to lapatinib alone in heavily pretreated, human epidermal growth factor receptor 2-positive metastatic breast cancer (MBC). We tested the combination in the earlier-line setting and explored the predictive value of [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) for clinical outcomes. PATIENTS AND METHODS: Two cohorts were enrolled (cohort 1: no prior trastuzumab for MBC and ≥ 1 year from adjuvant trastuzumab, if given; cohort 2: one to two lines of chemotherapy including trastuzumab for MBC and/or recurrence < 1 year from adjuvant trastuzumab). The primary end point was objective response rate by RECIST v1.0; secondary end points included clinical benefit rate (complete response plus partial response plus stable disease ≥ 24 weeks) and progression-free survival. [(18)F]FDG-PET scans were acquired at baseline, week 1, and week 8. Associations between metabolic response and clinical outcomes were explored. RESULTS: Eighty-seven patients were registered (85 were evaluable for efficacy). The confirmed objective response rate was 50.0% (95% CI, 33.8% to 66.2%) in cohort 1 and 22.2% (95% CI, 11.3% to 37.3%) in cohort 2. Clinical benefit rate was 57.5% (95% CI, 40.9% to 73.0%) in cohort 1 and 40.0% (95% CI, 25.7% to 55.7%) in cohort 2. Median progression-free survival was 7.4 and 5.3 months, respectively. Lack of week-1 [(18)F]FDG-PET/computed tomography ([(18)F]FDG-PET/CT) response was associated with failure to achieve an objective response by RECIST (negative predictive value, 91% [95% CI, 74% to 100%] for cohort 1 and 91% [95% CI, 79% to 100%] for cohort 2). CONCLUSION: Early use of lapatinib and trastuzumab is active in human epidermal growth factor receptor 2-positive MBC. Week-1 [(18)F]FDG-PET/CT may allow selection of patients who can be treated with targeted regimens and spared the toxicity of chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Fluordesoxiglucose F18 , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Humanos , Lapatinib , Pessoa de Meia-Idade , Metástase Neoplásica , Tomografia por Emissão de Pósitrons/métodos , Quinazolinas/administração & dosagem , Receptor ErbB-2/biossíntese , Trastuzumab , Resultado do TratamentoRESUMO
The Uniform Protocols for Imaging in Clinical Trials (UPICT) (18)F-FDG PET/CT protocol is intended to guide the performance of whole-body FDG PET/CT studies within the context of single- and multiple-center clinical trials of oncologic therapies by providing acceptable (minimum), target, and ideal standards for all phases of imaging. The aim is to minimize variability in intra- and intersubject, intra- and interplatform, interexamination, and interinstitutional primary or derived data. The goal of this condensed version of the much larger document is to make readers aware of the general content and subject area. The document has several main subjects: context of the imaging protocol within the clinical trial; site selection, qualification, and training; subject scheduling; subject preparation; imaging-related substance preparation and administration; imaging procedure; image postprocessing; image analysis; image interpretation; archiving and distribution of data; quality control; and imaging-associated risks and risk management.
Assuntos
Fluordesoxiglucose F18 , Imagem Multimodal/métodos , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada por Raios X/métodos , Ensaios Clínicos como Assunto , Humanos , Processamento de Imagem Assistida por Computador , Oncologia/normas , Movimento (Física) , Imagem Multimodal/normas , Tomografia por Emissão de Pósitrons/normas , Controle de Qualidade , Reprodutibilidade dos Testes , Projetos de Pesquisa , Respiração , Gestão de Riscos , Tomografia Computadorizada por Raios X/normas , Resultado do TratamentoRESUMO
BACKGROUND: The PTEN tumor suppressor is frequently lost in CRPC, with activation of Akt-mTOR signaling, driving growth. We conducted a phase I trial of the mTOR inhibitor, everolimus, and docetaxel in CRPC. PATIENTS AND METHODS: Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Patients received everolimus 10 mg daily for 2 weeks and underwent a restaging FDG-PET/computed tomography scan. Patient cohorts were subsequently treated at 3 dose levels of everolimus with docetaxel: 5 mg to 60 mg/m(2), 10 mg to 60 mg/m(2), and 10 mg to 70 mg/m(2). The primary end point was the safety and tolerability of combination therapy. RESULTS: Accrual was 4 patients at level 1, 3 patients at level 2, and 8 patients at level 3. Common toxicities were hematologic and fatigue. Serum concentrations of everolimus when administered with docetaxel were 1.5 to 14.8 ng/mL in patients receiving 5 mg everolimus and 4.5 to 55.4 ng/mL in patients receiving 10 mg everolimus. Four patients had partial metabolic response (PMR) using FDG-PET, 12 had stable metabolic disease, and 2 had progressive metabolic disease after a 2-week treatment with everolimus alone. Five of 12 evaluable patients experienced a prostate-specific antigen (PSA) reduction ≥ 50% during treatment with everolimus together with docetaxel. All 4 patients with a PMR according to PET imaging experienced a PSA reduction in response to everolimus with docetaxel, and 3 of 4 had PSA declines ≥ 50%. CONCLUSION: Everolimus 10 mg daily and docetaxel 60 mg/m(2) was safe in CRPC patients and these were the recommended doses in combination. FDG-PET response might serve as a biomarker for target inhibition by mTOR inhibitors.