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1.
Med Phys ; 46(10): 4553-4562, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31381174

RESUMO

PURPOSE: We have developed a clinically viable method for measurement of direct, patient-specific intravertebral displacements using a novel digital tomosynthesis based digital volume correlation technique. These displacements may be used to calculate vertebral stiffness under loads induced by a patient's body weight; this is particularly significant because, among biomechanical variables, stiffness is the strongest correlate of bone strength. In this proof of concept study, we assessed the feasibility of the method through a preliminary evaluation of the accuracy and precision of the method, identification of a range of physiological load levels for which displacements are measurable, assessment of the relationship of measured displacements with microcomputed tomography based standards, and demonstration of the in vivo application of the technique. METHODS: Five cadaveric T11 vertebrae were allocated to three groups in order to study (a) the optimization of digital volume correlation algorithm input parameters, (b) accuracy and precision of the method and the ability to measure displacements at a range of physiological load levels, and (c) the correlation between displacements measured using tomosynthesis based digital volume correlation vs. high resolution microcomputed tomography based digital volume correlation and large scale finite element models. Tomosynthesis images of one patient (Female, 60 yr old) were used to calculate displacement maps, and in turn stiffness, using images acquired in both standing and standing-with-weight (8 kg) configurations. RESULTS: We found that displacements were accurate (2.28 µm total error) and measurable at physiological load levels (above 267 N) with a linear response to applied load. Calculated stiffness among three tested vertebral bodies was within an acceptable range relative to reported values for vertebral stiffness (5651-13260 N/mm). Displacements were in good qualitative and quantitative agreement with both microcomputed tomography based finite element (r2  = 0.762, P < 0.001) and digital volume correlation (r2  = 0.799, P < 0.001) solutions. For one patient tested twice, once standing and once holding weights, results demonstrated excellent qualitative reproducibility of displacement distributions with superior endplate displacements increasing by 22% with added weight. CONCLUSIONS: The results of this work collectively suggest the feasibility of the method for in vivo measurement of intravertebral displacements and stiffness in humans. These findings suggest that digital volume correlation using digital tomosynthesis imaging may be useful in understanding the mechanical response of bone to disease and may further enhance our ability to assess fracture risk and treatment efficacy for the spine.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Deslocamento do Disco Intervertebral/fisiopatologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiopatologia , Microtomografia por Raio-X , Fenômenos Biomecânicos , Feminino , Humanos , Pessoa de Meia-Idade , Suporte de Carga
2.
AJR Am J Roentgenol ; : W1-W7, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30973772

RESUMO

OBJECTIVE: The objective of this study was to investigate the association of fractal-derived bone microstructural parameters with vertebral fracture status using in vivo digital tomosynthesis images of the spine. MATERIALS AND METHODS: Digital tomosynthesis images of the thoracic and lumbar spine from T1 to L5 were acquired from 36 patients with newly diagnosed multiple myeloma or monoclonal gammopathy of uncertain significance (age range, 39-85 years old). Scans were performed with patients in the supine position with reconstructed planes formed in the coronal direction. Bone mineral density (BMD) was recorded for 10 patients who had recently undergone dual x-ray absorptiometry. Vertebral fracture and lytic lesion status was determined by a radiologist from digital radiographs. Radiologist interpretation was reviewed to identify levels with a minimum number of fractures or lesions. For fractal analysis, the largest possible cuboid volume of interest within the cancellous bone was cropped from T7 and T11 images. Mean and SD of fractal variables between slices of fractal dimension (FD, a measure of self-similarity in the texture), mean lacunarity (λ, a measure of heterogeneity) and the slope of lacunarity versus box size relationship (Sλ, a measure of sensitivity of heterogeneity to size scale) were calculated using a box-counting method. A generalized estimating equation (GEE) platform was used to examine fractal variables as predictors of fracture status. RESULTS: Fracture status was not significantly associated with sex, race, age, stage of myeloma, presence of lesion in the spine, or BMD. In light of these results, no correction was made for these variables in further analyses of fractal variables. No interaction was found between vertebral level and any of the fractal variables (p = 0.12-0.77). Therefore, vertebral level was not considered further as an independent variable. Logistic regression analysis within GEE indicated that probability of fracture decreased with increasing mean FD (p = 0.02). In contrast, probability of fracture increased with increasing mean λ (p = 0.03). Although not to a statistically significant degree, probability of fracture increased with increasing mean Sλ (p = 0.08), SD of FD (p = 0.07), SD of λ (p = 0.07), and SD of Sλ (p = 0.06). CONCLUSION: We found FD and lacunarity calculated within the cancellous centrum of T7 and T11 vertebrae to be significantly associated with the presence of a vertebral fracture in this cohort. The decreased probability of fracture with increasing fractal dimension and increased probability of fracture with increasing lacunarity are consistent with the idea that cancellous bone with a better organized trabecular architecture is mechanically more competent. To our knowledge, this is the first in vivo evidence that fractal analysis of vertebral bone from tomosynthesis images may be useful in assessing vertebral fracture risk in patients with multiple myeloma.

3.
Cancer Epidemiol Biomarkers Prev ; 28(4): 724-730, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30642838

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition with respect to onset, progression, and response to therapy. Incorporating clinical- and imaging-based features to refine COPD phenotypes provides valuable information beyond that obtained from traditional clinical evaluations. We characterized the spectrum of COPD-related phenotypes in a sample of former and current smokers and evaluated how these subgroups differ with respect to sociodemographic characteristics, COPD-related comorbidities, and subsequent risk of lung cancer. METHODS: White (N = 659) and African American (N = 520) male and female participants without lung cancer (controls) in the INHALE study who completed a chest CT scan, interview, and spirometry test were used to define distinct COPD-related subgroups based on hierarchical clustering. Seven variables were used to define clusters: pack years, quit years, FEV1/FVC, % predicted FEV1, and from quantitative CT (qCT) imaging, % emphysema, % air trapping, and mean lung density ratio. Cluster definitions were then applied to INHALE lung cancer cases (N = 576) to evaluate lung cancer risk. RESULTS: Five clusters were identified that differed significantly with respect to sociodemographic (e.g., race, age) and clinical (e.g., BMI, limitations due to breathing difficulties) characteristics. Increased risk of lung cancer was associated with increasingly detrimental lung function clusters (when ordered from most detrimental to least detrimental). CONCLUSIONS: Measures of lung function vary considerably among smokers and are not fully explained by smoking intensity. IMPACT: Combining clinical (spirometry) and radiologic (qCT) measures of COPD defines a spectrum of lung disease that predicts lung cancer risk differentially among patient clusters.

4.
Hepatology ; 69(5): 2258-2270, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30382576

RESUMO

After a decade of stagnation in drug development, therapeutic reversal of immune-exhaustion with immune checkpoint inhibitors (ICPIs) has been shown to be effective in advanced hepatocellular carcinoma (HCC). The clinical development of novel ICPIs continues at a rapid pace, with more than 50 clinical trials of immunotherapeutic agents registered as of May 2018 for this indication. The development of ICPI is particularly challenging in patients with HCC, a population with unique features which impact on safety and efficacy of immune-modulating therapies. In this review, we discuss the biological foundations supporting the development of ICPIs across the advancing stages of HCC, focusing on the rational positioning of ICPIs across the various Barcelona-Clinic Liver Cancer (BCLC) stages of the disease. Translational studies should guide adequate prioritization of those therapeutic agents and combination strategies which are most likely to achieve patient benefit based on solid mechanistic and clinical justifications.

5.
J Biomech ; 79: 191-197, 2018 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-30173933

RESUMO

The purpose of this study was to examine the potential of digital tomosynthesis (DTS) derived cancellous bone textural measures to predict vertebral strength under conditions simulating a wedge fracture. 40 vertebral bodies (T6, T8, T11, and L3 levels) from 5 male and 5 female cadaveric donors were utilized. The specimens were scanned using dual energy X-ray absorptiometry (DXA) and high resolution computed tomography (HRCT) to obtain measures of bone mineral density (BMD) and content (BMC), and DTS to obtain measures of bone texture. Using a custom loading apparatus designed to deliver a nonuniform displacement resulting in a wedge deformity similar to those observed clinically, the specimens were loaded to fracture and their fracture strength was recorded. Mixed model regressions were used to determine the associations between wedge strength and DTS derived textural variables, alone and in the presence of BMD or BMC information. DTS derived fractal, lacunarity and mean intercept length variables correlated with wedge strength, and individually explained up to 53% variability. DTS derived textural variables, notably fractal dimension and lacunarity, contributed to multiple regression models of wedge strength independently from BMC and BMD. The model from a scan orientation transverse to the spine axis and in the anterior-posterior view resulted in highest explanatory capability (R2adj = 0.91), with a scan orientation parallel to the spine axis and in the lateral view offering an alternative (R2adj = 0.88). In conclusion, DTS can be used to examine cancellous texture relevant to vertebral wedge strength, and potentially complement BMD in assessment of vertebral fracture risk.


Assuntos
Densidade Óssea , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/fisiologia , Fenômenos Mecânicos , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/fisiologia , Tomografia Computadorizada por Raios X , Absorciometria de Fóton , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino
6.
Sci Rep ; 8(1): 10479, 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29992976

RESUMO

Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs.


Assuntos
Antineoplásicos/química , Benzodiazepinas/farmacocinética , Imunotoxinas/química , Pirróis/farmacocinética , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Benzodiazepinas/uso terapêutico , Linhagem Celular Tumoral , Reagentes para Ligações Cruzadas , DNA/metabolismo , Reparo do DNA , Dimerização , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Pirróis/uso terapêutico , Ratos
7.
J Biomech ; 73: 92-98, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29599039

RESUMO

Creep, the time dependent deformation of a structure under load, is an important viscoelastic property of bone and may play a role in the development of permanent deformity of the vertebrae in vivo leading to clinically observable spinal fractures. To date, creep properties and their relationship to geometric, microstructural, and material properties have not been described in isolated human vertebral bodies. In this study, a range of image-based measures of vertebral bone geometry, bone mass, microarchitecture and mineralization were examined in multiple regression models in an effort to understand their contribution to creep behavior. Several variables, such as measures of mineralization heterogeneity, average bone density, and connectivity density persistently appeared as significant effects in multiple regression models (adjusted r2: 0.17-0.56). Although further work is needed to identify additional tissue properties to fully describe the portion of variability not explained by these models, these data are expected to help understand mechanisms underlying creep and improve prediction of vertebral deformities that eventually progress to a clinically observable fracture.


Assuntos
Coluna Vertebral/anatomia & histologia , Coluna Vertebral/fisiologia , Idoso , Animais , Densidade Óssea , Feminino , Humanos , Masculino , Tamanho do Órgão , Coluna Vertebral/citologia , Suporte de Carga
8.
Med Phys ; 45(2): e32-e39, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29220101

RESUMO

PURPOSE: The AAPM Task Group 162 aimed to provide a standardized approach for the assessment of image quality in planar imaging systems. This report offers a description of the approach as well as the details of the resultant software bundle to measure detective quantum efficiency (DQE) as well as its basis components and derivatives. METHODS: The methodology and the associated software include the characterization of the noise power spectrum (NPS) from planar images acquired under specific acquisition conditions, modulation transfer function (MTF) using an edge test object, the DQE, and effective DQE (eDQE). First, a methodological framework is provided to highlight the theoretical basis of the work. Then, a step-by-step guide is included to assist in proper execution of each component of the code. Lastly, an evaluation of the method is included to validate its accuracy against model-based and experimental data. RESULTS: The code was built using a Macintosh OSX operating system. The software package contains all the source codes to permit an experienced user to build the suite on a Linux or other *nix type system. The package further includes manuals and sample images and scripts to demonstrate use of the software for new users. The results of the code are in close alignment with theoretical expectations and published results of experimental data. CONCLUSIONS: The methodology and the software package offered in AAPM TG162 can be used as baseline for characterization of inherent image quality attributes of planar imaging systems.


Assuntos
Intensificação de Imagem Radiográfica , Software , Processamento de Imagem Assistida por Computador , Controle de Qualidade
9.
Expert Opin Pharmacother ; 18(14): 1477-1490, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28820000

RESUMO

INTRODUCTION: Immune-checkpoint inhibitor (ICPI) drugs, which include antibodies against CTLA-4, PD-1 and PD-L1, have been shown to induce durable complete responses in a proportion of patients with particular efficacy demonstrated in both the first line and refractory setting in advanced NSCLC and melanoma. However, these drugs remain effective only in a minority of unselected patients. Areas covered: This review will focus on mechanisms of resistance to ICPI and underline the importance of identification of novel predictive markers of responsiveness. The rationale for the combination of ICPI with specific chemotherapies, targeted therapies and other immuno-oncology drugs in order to improve efficacy will be provided. Expert opinion: There are near-endless permutations of combination strategies of these agents with ICPI that have become feasible treatment strategies. Development of an understanding of resistance mechanisms to ICPI by a shift towards translational approaches to comprehensive genomic profiling and interrogation of the tumor microenvironment will encourage recruitment of patients into biomarker-driven combination trials. More than ever, industry professionals, clinicians and scientists will need to collaborate to increase the investment in clinical trials of those therapeutic agents and combination strategies which are most likely to be transformative for patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Melanoma/tratamento farmacológico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Biomarcadores/análise , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Melanoma/imunologia , Melanoma/patologia , Terapia de Alvo Molecular , Metástase Neoplásica , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
10.
Br J Haematol ; 179(1): 20-35, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28556984

RESUMO

CD25 (also termed IL2RA) forms one component of the high-affinity heterotrimeric interleukin 2 (IL2) receptor on activated T cells. Its affinity for IL2 and cellular function are tightly regulated and vary in different cell types. The high frequency of CD25 on the surface of many different haematological tumour cells is now well established and, apart from its prognostic significance, CD25 may be present on leukaemic stem cells and enable oncogenic signalling pathways in leukaemic cells. Additionally, high CD25 expression in activated circulating immune cells and Tregs is a factor that has already been exploited by IL2 immunotherapies for treatment of tumours and autoimmune disease. The relative clinical safety and efficacy of administering anti-CD25 radioimmunoconjugates and immunotoxins in various haematological tumour indications has been established and clinical trials of a novel CD25-directed antibody drug conjugate are underway.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunomodulação/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Anticorpos Monoclonais/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/farmacologia , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Receptores de Interleucina-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
11.
J Comp Psychol ; 131(2): 128-138, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28277720

RESUMO

The human ability to detect regularities in sound sequences is a fundamental substrate of our language faculty. However, is this an ability exclusive to human language processing, or have we usurped a more general learning mechanism for this purpose, one shared with other species? The current study is an attempt to replicate and extend Hauser, Weiss, and Marcus's (2002) retracted study (2010) of artificial grammar learning in tamarins to determine if tamarins can detect an underlying grammatical structure in a pattern of sounds. Human language consonant-vowel (CV) combinations from Hauser et al.'s original study, newly created tone sequences, and newly created monkey vocalizations made into sequences were used to familiarize tamarins to an AAB or ABB pattern. Tests of novel sounds in each condition were presented that either were consistent with the familiarized pattern or were different from it. Longer looking times toward the sound source (an audio speaker with a specific location in the auditory field) indicated recognition of novelty. Tamarins looked toward the speaker significantly longer with inconsistent human language CV sequences and with inconsistent tone sequences but not when an inconsistent monkey vocalization was presented. Moreover, tamarins showed differential rates of habituation to the different types of sound patterns, with more robust habituation to CV sequences and tone sequences than to monkey call sequences. The implications of these findings for the generality of learning mechanisms for linguistic and nonlinguistic input across species and the importance of testing across various stimuli are discussed. (PsycINFO Database Record


Assuntos
Idioma , Aprendizagem , Animais , Percepção Auditiva , Humanos , Saguinus
12.
AJR Am J Roentgenol ; 208(5): 1082-1088, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28267354

RESUMO

OBJECTIVE: We calculated body size-specific organ and effective doses for 23,734 participants in the National Lung Screening Trial (NLST) using a CT dose calculator. MATERIALS AND METHODS: We collected participant-specific technical parameters of 23,734 participants who underwent CT in the clinical trial. For each participant, we calculated two sets of organ doses using two methods. First, we computed body size-specific organ and effective doses using the National Cancer Institute CT (NCICT) dosimetry program, which is based on dose coefficients derived from a library of body size-dependent adult male and female computational phantoms. We then recalculated organ and effective doses using dose coefficients from reference size phantoms for all examinations to investigate potential errors caused by the lack of body size consideration in the dose calculations. RESULTS: The underweight participants (body mass index [BMI; weight in kilograms divided by the square of height in meters] < 18.5) received 1.3-fold greater lung dose (median, 4.93 mGy) than the obese participants (BMI > 30) (3.90 mGy). Thyroid doses were approximately 1.3- to 1.6-fold greater than the lung doses (6.3-6.5 mGy). The reference phantom-based dose calculation underestimates the body size-specific lung dose by up to 50% for the underweight participants and overestimates that value by up to 200% for the overweight participants. The median effective dose ranges from 2.01 mSv in obese participants to 2.80 mSv in underweight participants. CONCLUSION: Body size-specific organ and effective doses were computed for 23,734 NLST participants who underwent low-dose CT screening. The use of reference size phantoms can lead to significant errors in organ dose estimates when body size is not considered in the dose assessment.


Assuntos
Tamanho Corporal , Neoplasias Pulmonares/diagnóstico por imagem , Programas de Rastreamento , Radiografia Torácica/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso , Feminino , Humanos , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Imagens de Fantasmas , Doses de Radiação , Fumar/epidemiologia , Estados Unidos/epidemiologia
13.
Ann Biomed Eng ; 45(5): 1236-1246, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28083858

RESUMO

Digital tomosynthesis (DTS) derived textural parameters of human vertebral cancellous bone have been previously correlated to the finite element (FE) stiffness and 3D microstructure. The objective of this study was to optimize scanning configuration and use of multiple image slices in the analysis, so that FE stiffness prediction using DTS could be maximized. Forty vertebrae (T6, T8, T11, and L3) from ten cadavers (63-90 years) were scanned using microCT to obtain trabecular bone volume fraction (BV/TV) and FE stiffness. The vertebrae were then scanned using DTS anteroposteriorly (AP) and laterally (LM) while aligned axially (0°), transversely (90°) or obliquely (23°) to the superior-inferior axis of the vertebrae. From the serial DTS images, fractal dimension (FD), mean intercept length (MIL) and line fraction deviation (LFD) parameters were obtained from a 2D-single mid-stack location and 3D-multi-image stack. The DTS derived textural parameters were then correlated with FE stiffness using linear regression models within each scanning orientation. 3D-multi-image stack models obtained from Transverse-LM scanning orientation (90°) were most explanatory regardless of accounting for the effects of BV/TV. Therefore, DTS scanning perpendicular to the axis of the spine in an LM view is the preferred configuration for prediction of vertebral cancellous bone stiffness.


Assuntos
Osso Esponjoso , Coluna Vertebral , Microtomografia por Raio-X/métodos , Idoso , Idoso de 80 Anos ou mais , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/metabolismo , Análise de Elementos Finitos , Humanos , Masculino , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/metabolismo
14.
Mol Cancer Ther ; 15(11): 2709-2721, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27535974

RESUMO

Despite the many advances in the treatment of hematologic malignancies over the past decade, outcomes in refractory lymphomas remain poor. One potential strategy in this patient population is the specific targeting of IL2R-α (CD25), which is overexpressed on many lymphoma and leukemic cells, using antibody-drug conjugates (ADC). ADCT-301 is an ADC composed of human IgG1 HuMax-TAC against CD25, stochastically conjugated through a dipeptide cleavable linker to a pyrrolobenzodiazepine (PBD) dimer warhead with a drug-antibody ratio (DAR) of 2.3. ADCT-301 binds human CD25 with picomolar affinity. ADCT-301 has highly potent and selective cytotoxicity against a panel of CD25-expressing human lymphoma cell lines. Once internalized, the released warhead binds in the DNA minor groove and exerts its potent cytotoxic action via the formation of DNA interstrand cross-links. A strong correlation between loss of viability and DNA cross-link formation is demonstrated. DNA damage persists, resulting in phosphorylation of histone H2AX, cell-cycle arrest in G2-M, and apoptosis. Bystander killing of CD25-negative cells by ADCT-301 is also observed. In vivo, a single dose of ADCT-301 results in dose-dependent and targeted antitumor activity against both subcutaneous and disseminated CD25-positive lymphoma models. In xenografts of Karpas 299, which expressed both CD25 and CD30, marked superiority over brentuximab vedotin (Adcetris) is observed. Dose-dependent increases in DNA cross-linking, γ-H2AX, and PBD payload staining were observed in tumors in vivo indicating a role as relevant pharmacodynamic assays. Together, these data support the clinical testing of this novel ADC in patients with CD25-expressing tumors. Mol Cancer Ther; 15(11); 2709-21. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas , Neoplasias Hematológicas/metabolismo , Imunoconjugados/farmacologia , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Pirróis , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Apoptose/genética , Benzodiazepinas/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histonas/metabolismo , Humanos , Imunoconjugados/química , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos , Pirróis/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Med Phys ; 43(7): 4017, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27370120

RESUMO

PURPOSE: The authors discuss measurement methods and instrumentation useful for the characterization of the gray tracking performance of medical color monitors for diagnostic applications. The authors define gray tracking as the variability in the chromaticity of the gray levels in a color monitor. METHODS: The authors present data regarding the capability of color measurement instruments with respect to their abilities to measure a target white point corresponding to the CIE Standard Illuminant D65 at different luminance values within the grayscale palette of a medical display. The authors then discuss evidence of significant differences in performance among color measurement instruments currently available for medical physicists to perform calibrations and image quality checks for the consistent representation of color in medical displays. In addition, the authors introduce two metrics for quantifying grayscale chromaticity consistency of gray tracking. RESULTS: The authors' findings show that there is an order of magnitude difference in the accuracy of field and reference instruments. The gray tracking metrics quantify how close the grayscale chromaticity is to the chromaticity of the full white point (equal amounts of red, green, and blue at maximum level) or to consecutive levels (equal values for red, green, and blue), with a lower value representing an improved grayscale tracking performance. An illustrative example of how to calculate and report the gray tracking performance according to the Task Group definitions is provided. CONCLUSIONS: The authors' proposed methodology for characterizing the grayscale degradation in chromaticity for color monitors that can be used to establish standards and procedures aiding in the quality control testing of color displays and color measurement instrumentation.


Assuntos
Cor , Apresentação de Dados , Diagnóstico por Imagem/instrumentação , Diagnóstico por Imagem/métodos , Algoritmos , Computadores , Diagnóstico por Imagem/economia
16.
Cancer Epidemiol Biomarkers Prev ; 25(9): 1341-7, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27383774

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk. METHODS: A total of 341 lung cancer cases and 752 volunteer controls, ages 21 to 89 years, participated in a structured interview, standardized CT scan, and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than -950 Hounsfield units on the inspiratory scan (HUI) and percent voxels less than -856 HU on expiratory scan (HUE). RESULTS: The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared with those without, regardless of assessment method; however, in multivariable modeling, only percent voxels <-856 HUE as a continuous measure of air trapping [OR = 1.04; 95% confidence interval (CI), 1.03-1.06] and FEV1/FVC < 0.70 (OR = 1.71; 95% CI, 1.21-2.41) were independent predictors of lung cancer risk. Nearly 10% of lung cancer cases were negative on all objective measures of COPD. CONCLUSION: Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplementary measures at the time of screening for lung cancer. IMPACT: Quantitative measures of air trapping based on imaging provide additional information for the identification of high-risk groups who might benefit the most from lung cancer screening. Cancer Epidemiol Biomarkers Prev; 25(9); 1341-7. ©2016 AACR.


Assuntos
Neoplasias Pulmonares/epidemiologia , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Testes de Função Respiratória , Fatores de Risco , Fumar/efeitos adversos , Fumar/epidemiologia , Espirometria , Tomografia Computadorizada por Raios X , Capacidade Vital
17.
Bone ; 81: 300-305, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26220145

RESUMO

Endplate morphology is understood to play an important role in the mechanical behavior of vertebral bone as well as degenerative processes in spinal tissues; however, the utility of clinical imaging modalities in assessment of the vertebral endplate has been limited. The objective of this study was to evaluate the ability of two clinical imaging modalities (digital tomosynthesis, DTS; high resolution computed tomography, HRCT) to assess endplate topography by correlating the measurements to a microcomputed tomography (µCT) standard. DTS, HRCT, and µCT images of 117 cadaveric thoracolumbar vertebrae (T10-L1; 23 male, 19 female; ages 36-100 years) were segmented, and inferior and superior endplate surface topographical distribution parameters were calculated. Both DTS and HRCT showed statistically significant correlations with µCT approaching a moderate level of correlation at the superior endplate for all measured parameters (R(2)Adj=0.19-0.57), including averages, variability, and higher order statistical moments. Correlation of average depths at the inferior endplate was comparable to the superior case for both DTS and HRCT (R(2)Adj=0.14-0.51), while correlations became weak or nonsignificant for higher moments of the topography distribution. DTS was able to capture variations in the endplate topography to a slightly better extent than HRCT, and taken together with the higher speed and lower radiation cost of DTS than HRCT, DTS appears preferable for endplate measurements.


Assuntos
Vértebras Lombares/diagnóstico por imagem , Vértebras Torácicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X/normas , Microtomografia por Raio-X/normas , Densidade Óssea , Feminino , Humanos , Masculino , Tomografia Computadorizada por Raios X/métodos , Microtomografia por Raio-X/métodos
18.
J Digit Imaging ; 28(1): 41-52, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25005868

RESUMO

This article summarizes the consensus reached at the Summit on Color in Medical Imaging held at the Food and Drug Administration (FDA) on May 8-9, 2013, co-sponsored by the FDA and ICC (International Color Consortium). The purpose of the meeting was to gather information on how color is currently handled by medical imaging systems to identify areas where there is a need for improvement, to define objective requirements, and to facilitate consensus development of best practices. Participants were asked to identify areas of concern and unmet needs. This summary documents the topics that were discussed at the meeting and recommendations that were made by the participants. Key areas identified where improvements in color would provide immediate tangible benefits were those of digital microscopy, telemedicine, medical photography (particularly ophthalmic and dental photography), and display calibration. Work in these and other related areas has been started within several professional groups, including the creation of the ICC Medical Imaging Working Group.


Assuntos
Cor/normas , Diagnóstico por Imagem/normas , Humanos , Padrões de Referência , Estados Unidos , United States Food and Drug Administration
19.
Med Eng Phys ; 37(1): 109-20, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25498138

RESUMO

Digital tomosynthesis (DTS) provides slice images of an object using conventional radiographic methods with high in-plane resolution. The objective of this study was to explore the potential of DTS for describing microstructural, stiffness and stress distribution properties of vertebral cancellous bone. Forty vertebrae (T6, T8, T11, and L3) from 10 cadavers (63-90 years) were scanned using microCT and DTS. Anisotropy (µCT.DA), and the specimen-average and standard deviation of trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N) and separation (Tb.Sp) were obtained using stereology. Apparent modulus (EFEM), and the magnitude (VMExp/σapp) and variability (VMCV) of trabecular stresses were calculated using microCT-based finite element modeling. Mean intercept length, line fraction deviation and fractal parameters were obtained from coronal DTS slices, then correlated with stereological and finite element parameters using linear regression models. Twenty-one DTS parameters (out of 27) correlated to BV/TV, Tb.Th, Tb.N, Tb.Sp and/or µCT.DA (p<0.0001-p<0.05). DTS parameters increased the explained variability in EFEM and VMCV (by 9-11% and 13-19%, respectively; p<0.0001-p<0.04) over that explained by BV/TV. In conclusion, DTS has potential for quantitative assessment of cancellous bone and may be used as a modality complementary to those measuring bone mass for assessing spinal fracture risk.


Assuntos
Coluna Vertebral/diagnóstico por imagem , Tomografia/métodos , Idoso , Idoso de 80 Anos ou mais , Anisotropia , Elasticidade , Feminino , Análise de Elementos Finitos , Fractais , Humanos , Modelos Lineares , Masculino , Tamanho do Órgão , Radiografia , Coluna Vertebral/anatomia & histologia , Coluna Vertebral/fisiologia , Estresse Mecânico
20.
J Am Coll Radiol ; 11(12 Pt B): 1270-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25467904

RESUMO

The medical imaging display is a precision instrument with many features not found in commercial-grade displays. The more one understands what these features are and their corresponding clinical value, the better one can make a purchase decision. None of these displays maintain themselves for 5 years or more without some degree of automatic or manual performance testing. Routine calibration conformance checks are beginning to be mandated by the departments of health of many states. Most manufacturers provide mechanisms to perform these checks and keep track of their results, some more easily than others. A consistent display brightness of about 400 cd/m(2) and close conformance to the DICOM curve are the key components of a successful check. Displays are typically characterized by the number of pixels they contain, usually 2, 3, or 5 megapixels, but this is the least useful determinant of image quality. What matters most is the size of the pixels and the size of the whole display, which should be selected on the basis of the typical viewing distance. The farther one's eyes are from the display, the larger the pixels and the overall display size can be while still feeding the eye as much information as it can see. Care should be taken to use the appropriate display in a given setting for the clinical purpose at hand.


Assuntos
Terminais de Computador , Apresentação de Dados , Diagnóstico por Imagem/instrumentação , Sistemas de Informação em Radiologia/instrumentação , Avaliação da Tecnologia Biomédica/métodos , Desenho de Equipamento , Análise de Falha de Equipamento , Processamento de Sinais Assistido por Computador/instrumentação , Interface Usuário-Computador
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