miRNA circuit modules for precise, tunable control of gene expression.

The ability to express transgenes at specified levels is critical for understanding cellular behaviors, and for applications in gene and cell therapy. Transfection, viral vectors, and other gene delivery methods produce varying protein expression levels, with limited quantitative control, while targeted knock-in and stable selection are inefficient and slow. Active compensation mechanisms can improve precision, but the need for additional proteins or lack of tunability have prevented their widespread use. Here, we introduce a toolkit of compact, synthetic miRNA-based circuit modules that provide precise, tunable control of transgenes across diverse cell types. These circuits, termed DIMMERs (Dosage-Invariant miRNA-Mediated Expression Regulators) use multivalent miRNA regulatory interactions within an incoherent feed-forward loop architecture to achieve nearly uniform protein expression over more than two orders of magnitude variation in underlying gene dosages or transcription rates. They also allow coarse and fine control of expression, and are portable, functioning across diverse cell types. In addition, a heuristic miRNA design algorithm enables the creation of orthogonal circuit variants that independently control multiple genes in the same cell. These circuits allowed dramatically improved CRISPR imaging, and super-resolution imaging of EGFR receptors with transient transfections. The toolbox provided here should allow precise, tunable, dosage-invariant expression for research, gene therapy, and other biotechnology applications.

Synthetic dosage-compensating miRNA circuits allow precision gene therapy for Rett syndrome.

A longstanding challenge in gene therapy is expressing a dosage-sensitive gene within a tight therapeutic window. For example, loss of MECP2 function causes Rett syndrome, while its duplication causes MECP2 duplication syndrome. Viral gene delivery methods generate variable numbers of gene copies in individual cells, creating a need for gene dosage-invariant expression systems. Here, we introduce a compact miRNA-based, incoherent feed-forward loop circuit that achieves precise control of Mecp2 expression in cells and brains, and improves outcomes in an AAV-based mouse model of Rett syndrome gene therapy. Single molecule analysis of endogenous and ectopic Mecp2 mRNA revealed precise, sustained expression across a broad range of gene dosages. Delivered systemically in a brain-targeting AAV capsid, the circuit strongly suppressed Rett behavioral symptoms for over 24 weeks, outperforming an unregulated gene therapy. These results demonstrate that synthetic miRNA-based regulatory circuits can enable precise in vivo expression to improve the safety and efficacy of gene therapy.

Stiffness and Strain Properties Derived From Digital Tomosynthesis-Based Digital Volume Correlation Predict Vertebral Strength Independently From Bone Mineral Density.

Vertebral fractures are the most common osteoporotic fractures, but their prediction using standard bone mineral density (BMD) measurements from dual energy X-ray absorptiometry (DXA) is limited in accuracy. Stiffness, displacement, and strain distribution properties derived from digital tomosynthesis-based digital volume correlation (DTS-DVC) have been suggested as clinically measurable metrics of vertebral bone quality. However, the extent to which these properties correlate to vertebral strength is unknown. To establish this relationship, two independent experiments, one examining isolated T11 and the other examining L3 vertebrae within the L2-L4 segments from cadaveric donors were utilized. Following DXA and DTS imaging, the specimens were uniaxially compressed to fracture. BMD, bone mineral content (BMC), and bone area were recorded for the anteroposterior and lateromedial views from DXA, stiffness, endplate to endplate displacement and distribution statistics of intravertebral strains were calculated from DTS-DVC and vertebral strength was measured from mechanical tests. Regression models were used to examine the relationships of strength with the other variables. Correlations of BMD with vertebral strength varied between experimental groups (R2adj = 0.19-0.78). DTS-DVC derived properties contributed to vertebral strength independently from BMD measures (increasing R2adj to 0.64-0.95). DTS-DVC derived stiffness was the best single predictor (R2adj = 0.66, p < 0.0001) and added the most to BMD in models of vertebral strength for pooled T11 and L3 specimens (R2adj = 0.95, p < 0.0001). These findings provide biomechanical relevance to DTS-DVC calculated properties of vertebral bone and encourage further efforts in the development of the DTS-DVC approach as a clinical tool.

Ovarian cancer recurrence: is the definition of platinum resistance modified by PARPi and other intervening treatments? The evolving landscape in the management of platinum-resistant ovarian cancer.

Definitions of platinum resistance have been questioned and changed over the last five years, even though no predictive biomarker of resistance exists. These have sculpted how we approach platinum retreatment and, consequently, how we devise new treatment strategies for those patients with tumour progression on platinum therapy. Platinum-non-eligible ovarian cancer is treated with single-agent non-platinum drugs. When bevacizumab can be added to chemotherapy, progression-free survival improves significantly. For patients with a BRCA mutation, PARP inhibitor monotherapy is an option compared to chemotherapy. There is currently no clearly identified role for immune-checkpoint inhibition in this patient population. This review describes some of the challenges in treating patients with platinum resistance and suggests refinements in the selection of patients most likely to benefit from targeting a DNA damage response, angiogenesis or immune modulation. It also describes novel agents of interest and possible mechanisms of the synergy of therapeutic combinations.

The relationship of whole human vertebral body creep to bone density and texture via clinically available imaging modalities.

Creep deformation of human vertebrae accumulates under physiological levels of load and is understood to contribute to the progression toward clinically observable vertebral fracture. However, little information is available in terms of clinically measurable predictors of creep behavior in human vertebrae. In this study, creep tests were performed on 22 human cadaveric T12 vertebrae (13 male, 9 female; age 41-90). Areal and volumetric bone density parameters were measured from the same specimens using dual x-ray absorptiometry and high resolution computed tomography. Image textural analyses (which probe the organization of image intensities within the cancellous bone in low resolution clinical imaging) were performed using digital tomosynthesis (DTS) images. Multiple regression models were constructed to examine the relationship between creep properties and bone density and DTS image textural parameters. For the standard clinical imaging configuration, models including DTS derived image textural parameters alone were generally more explanatory (adjusted R2: 0.14-0.68) than those with bone density parameters forced in the models (adjusted R2: 0.17-0.61). Metrics of textural heterogeneity and anisotropy presented as the most explanatory imaging markers for creep deformation and recovery from creep. These metrics of image texture may help provide, independent from bone mass, important clinically measurable indicators of the time dependent deformation of human vertebrae.

Measuring the thickness of vertebral endplate and shell using digital tomosynthesis.

The vertebral endplate and cortical shell play an important structural role and contribute to the overall strength of the vertebral body, are at highest risk of initial failure, and are involved in degenerative disease of the spine. The ability to accurately measure the thickness of these structures is therefore important, even if difficult due to relatively low resolution clinical imaging. We posit that digital tomosynthesis (DTS) may be a suitable imaging modality for measurement of endplate and cortical shell thickness owing to the ability to reconstruct multiplanar images with good spatial resolution at low radiation dose. In this study, for 25 cadaveric L1 vertebrae, average and standard deviation of endplate and cortical shell thickness were measured using images from DTS and microcomputed tomography (µCT). For endplate thickness measurements, significant correlations between DTS and µCT were found for all variables when comparing thicknesses measured in both the overall endplate volume (R2 = 0.25-0.54) and when measurements were limited to a central range of coronal or sagittal slices (R2 = 0.24-0.62). When compared to reference values from the overall shell volume, DTS thickness measurements were generally nonsignificant. However, when measurement of cortical shell thickness was limited to a range of central slices, DTS outcomes were significantly correlated with reference values for both sagittal and coronal central regions (R2 = 0.21-0.49). DTS may therefore offer a means for measurement of endplate thickness and, within a limited sagittal or coronal measurement volume, for measurement of cortical shell thickness.

An In-Depth Review of Niraparib in Ovarian Cancer: Mechanism of Action, Clinical Efficacy and Future Directions.

Niraparib is an oral, potent, highly selective poly-ADP ribose polymerase 1 (PARP1) and PARP2 inhibitor. In most developed countries, it is approved as a maintenance treatment for epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients with complete or partial response to platinum-based therapy. These approvals are based on results of randomised, double-blind, placebo-controlled trials, particularly the NOVA trial and more recently the PRIMA trial. In this comprehensive review, we delve into the scientific basis of PARP inhibition, discussing both preclinical and clinical data which have led to the current approval status of niraparib. We also discuss ongoing trials and biological rationale of combination treatments involving niraparib, with particular focus on antiangiogenic drugs, immune checkpoint inhibitors and cyclic GMP-AMP synthase stimulator of interferon genes (cGAS/STING) pathway. In addition, we reflect on potential strategies and challenges of utilising current biomarkers for treatment selection of patients to ensure maximal benefit.

Assessment of Intravertebral Mechanical Strains and Cancellous Bone Texture Under Load Using a Clinically Available Digital Tomosynthesis Modality.

Vertebral fractures are the most common osteoporotic fractures, but clinical means for assessment of vertebral bone integrity are limited in accuracy, as they typically use surrogate measures that are indirectly related to mechanics. The objective of this study was to examine the extent to which intravertebral strain distributions and changes in cancellous bone texture generated by a load of physiological magnitude can be characterized using a clinically available imaging modality. We hypothesized that digital tomosynthesis-based digital volume correlation (DTS-DVC) and image texture-based metrics of cancellous bone microstructure can detect development of mechanical strains under load. Isolated cadaveric T11 vertebrae and L2-L4 vertebral segments were DTS imaged in a nonloaded state and under physiological load levels. Axial strain, maximum principal strain, maximum compressive and tensile principal strains, and von Mises equivalent strain were calculated using the DVC technique. The change in textural parameters (line fraction deviation, anisotropy, and fractal parameters) under load was calculated within the cancellous centrum. The effect of load on measured strains and texture variables was tested using mixed model analysis of variance, and relationships of strain and texture variables with donor age, bone density parameters, and bone size were examined using regression models. Magnitudes and heterogeneity of intravertebral strain measures correlated with applied loading and were significantly different from background noise. Image texture parameters were found to change with applied loading, but these changes were not observed in the second experiment testing L2-L4 segments. DTS-DVC-derived strains correlated with age more strongly than did bone mineral density (BMD) for T11.

Bone health assessment via digital wrist tomosynthesis in the mammography setting.

Bone fractures attributable to osteoporosis are a significant problem. Though preventative treatment options are available for individuals who are at risk of a fracture, a substantial number of these individuals are not identified due to lack of adherence to bone screening recommendations. The issue is further complicated as standard diagnosis of osteoporosis is based on bone mineral density (BMD) derived from dual energy x-ray absorptiometry (DXA), which, while helpful in identifying many at risk, is limited in fully predicting risk of fracture. It is reasonable to expect that bone screening would become more prevalent and efficacious if offered in coordination with digital breast tomosynthesis (DBT) exams, provided that osteoporosis can be assessed using a DBT modality. Therefore, the objective of the current study was to explore the feasibility of using digital tomosynthesis imaging in a mammography setting. To this end, we measured density, cortical thickness and microstructural properties of the wrist bone, correlated these to reference measurements from microcomputed tomography and DXA, demonstrated the application in vivo in a small group of participants, and determined the repeatability of the measurements. We found that measurements from digital wrist tomosynthesis (DWT) imaging with a DBT scanner were highly repeatable ex vivo (error = 0.05%-9.62%) and in vivo (error = 0.06%-10.2%). In ex vivo trials, DWT derived BMDs were strongly correlated with reference measurements (R = 0.841-0.980), as were cortical thickness measured at lateral and medial cortices (R = 0.991 and R = 0.959, respectively) and the majority of microstructural measures (R = 0.736-0.991). The measurements were quick and tolerated by human patients with no discomfort, and appeared to be different between young and old participants in a preliminary comparison. In conclusion, DWT is feasible in a mammography setting, and informative on bone mass, cortical thickness, and microstructural qualities that are known to deteriorate in osteoporosis. To our knowledge, this study represents the first application of DBT for imaging bone. Future clinical studies are needed to further establish the efficacy for diagnosing osteoporosis and predicting risk of fragility fracture using DWT.

Vertebral stiffness measured via tomosynthesis-based digital volume correlation is strongly correlated with reference values from micro-CT-based DVC.

Digital tomosynthesis (DTS) is a clinically available modality that allows imaging of a patient's spine in supine and standing positions. The purpose of this study was to establish the extent to which vertebral displacement and stiffness derived from DTS-based digital volume correlation (DTS-DVC) are correlated with those from a reference method, i.e., microcomputed tomography-based DVC (µCT-DVC). T11 vertebral bodies from 11 cadaveric donors were DTS imaged twice in a nonloaded state and once under a fixed load level approximating upper body weight. The same vertebrae were µCT imaged in nonloaded and loaded states (40 µm voxel size). Vertebral displacements were calculated at each voxel using DVC with pairs of nonloaded and loaded images, from which endplate-to-endplate axial displacement (DDVC) and vertebral stiffness (SDVC) were calculated. Both DDVC and SDVC demonstrated strong positive correlations between DTS-DVC and µCT-DVC, with correlations being stronger when vertebral displacement was calculated using the median (R2=0.80; p<0.0002 and R2=0.93; p<0.0001, respectively) rather than average displacement (R2=0.63; p<0.004 and R2=0.69; p<0.002, respectively). In conclusion, the demonstrated relationship of DTS-DVC with the µCT standard supports further development of a biomechanics-based clinical assessment of vertebral bone quality using the DTS-DVC technique.

Practical application of AAPM Report 270 in display quality assurance: A report of Task Group 270.

Published in January 2019, AAPM Report 270 provides an update to the recommendations of the AAPM's "TG18" report. Report 270 provides new definitions of display types, updated testing patterns, and revised performance standards for the modern, flat-panel displays used as part of medical image acquisition and review. The focus of the AAPM report is on consistent image quality and appearance, and how to establish a quality assurance program to achieve those two goals. This work highlights some of the key takeaways of AAPM Report 270 and makes comparisons with existing recommendations from other references. It also provides guidance for establishing a display quality assurance program for different-sized institutions. Finally, it describes future challenges for display quality assurance and what work remains.

Digital tomosynthesis based digital volume correlation: A clinically viable noninvasive method for direct measurement of intravertebral displacements using images of the human spine under physiological load.

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.

Digital Tomosynthesis and Fractal Analysis Predict Prevalent Vertebral Fractures in Patients With Multiple Myeloma: A Preliminary In Vivo Study.

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.

Quantitative Imaging Markers of Lung Function in a Smoking Population Distinguish COPD Subgroups with Differential Lung Cancer Risk.

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.

Challenges and Opportunities in the Clinical Development of Immune Checkpoint Inhibitors for Hepatocellular Carcinoma.

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.

Assessment of vertebral wedge strength using cancellous textural properties derived from digital tomosynthesis and density properties from dual energy X-ray absorptiometry and high resolution computed tomography.

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.

Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine.

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.

The relationship of whole human vertebral body creep to geometric, microstructural, and material properties.

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.

Report of AAPM Task Group 162: Software for planar image quality metrology.

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.

Novel combination strategies for enhancing efficacy of immune checkpoint inhibitors in the treatment of metastatic solid malignancies.

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.