Imaging Biomarkers for Precision Medicine in Locally Advanced Breast Cancer

Guidelines from the American National Comprehensive Cancer Network (NCCN)recommend neoadjuvant chemotherapy (NAC) to patients with locally advanced breast cancer (LABC) to downstage tumors before surgery. However, only a small fraction (15-17%) of LABC patients achieve complete pathologic response (pCR), i.e. no residual tumor in the breast, after treatment. Measuring tumor response during 53 neoadjuvant chemotherapy can potentially help physicians adapt treatment thus, potentially improving the pCR rate. Recently, imaging biomarkers that are used to measure the tumor’s functional and biological features have been studied as pre-treatment markers for pCR or as an indicator for intra-treatment tumor response. Also, imaging biomarkers have been the focus of intense research to characterize tumor heterogeneity as well as to advance our understanding of the principle mechanisms behind chemoresistance. Advances in investigational radiology are moving rapidly to high-resolution imaging, capturing metabolic data, performing tissue characterization and statistical modelling of imaging biomarkers, with an endpoint of personalized medicine in breast cancer treatment. In this commentary, we present studies within the framework of imaging biomarkers used to measure breast tumor response to chemotherapy. Current studies are showing that significant progress has been made in the accuracy of measuring tumor response either before or during chemotherapy, yet the challenges at the forefront of these works include translational gaps such as needing large-scale clinical trials for validation, and standardization of imaging methods. However, the ongoing research is showing that imaging biomarkers may play an important role in personalized treatments for LABC

Monitoring Breast Cancer Response to Neoadjuvant Chemotherapy Using Ultrasound Strain Elastography

© 2019 The Authors Strain elastography was used to monitor response to neoadjuvant chemotherapy (NAC) in 92 patients with biopsy-proven, locally advanced breast cancer. Strain elastography data were collected before, during, and after NAC. Relative changes in tumor strain ratio (SR) were calculated over time, and responder status was classified according to tumor size changes. Statistical analyses determined the significance of changes in SR over time and between response groups. Machine learning techniques, such as a naïve Bayes classifier, were used to evaluate the performance of the SR as a marker for Miller-Payne pathological endpoints. With pathological complete response (pCR) as an endpoint, a significant difference (P < .01) in the SR was observed between response groups as early as 2 weeks into NAC. Naïve Bayes classifiers predicted pCR with a sensitivity of 84%, specificity of 85%, and area under the curve of 81% at the preoperative scan. This study demonstrates that strain elastography may be predictive of NAC response in locally advanced breast cancer as early as 2 weeks into treatment, with high sensitivity and specificity, granting it the potential to be used for active monitoring of tumor response to chemotherapy

Ultrasound imaging of apoptosis: high-resolution non-invasive monitoring of programmed cell death in vitro, in situ and in vivo

A new non-invasive method for monitoring apoptosis has been developed using high frequency (40 MHz) ultrasound imaging. Conventional ultrasound backscatter imaging techniques were used to observe apoptosis occurring in response to anticancer agents in cells in vitro, in tissues ex vivo and in live animals. The mechanism behind this ultrasonic detection was identified experimentally to be the subcellular nuclear changes, condensation followed by fragmentation, that cells undergo during apoptosis. These changes dramatically increase the high frequency ultrasound scattering efficiency of apoptotic cells over normal cells (25- to 50-fold change in intensity). The result is that areas of tissue undergoing apoptosis become much brighter in comparison to surrounding viable tissues. The results provide a framework for the possibility of using high frequency ultrasound imaging in the future to non-invasively monitor the effects of chemotherapeutic agents and other anticancer treatments in experimental animal systems and in patients. © 1999 Cancer Research Campaig

Ratio of abundances of ciliates behavioral groups as an indicator of the treated wastewater impact on rivers

A method for assessing the degree of impact of wastewater treatment plant discharge on receiving rivers was proposed, based on the structural indicators of the population of ciliated protozoa. It was shown that the ratio of attached, crawling and free-swimming forms in bottom sediments changes under the influence of discharge. In the points subject to organic pollution, the share of attached filter-feeding bacteriovorous ciliates increases in the assemblage of ciliated protozoa. The proposed Attached Form Index (AFI) takes this ratio into account. The use of AFI makes it possible to assess the restructuring of the assemblage of ciliated protozoa under the influence of point sources of pollution, to establish a zone of negative influence of runoff, to assess the degree of restoration of the aquatic ecosystem, as the influence of the pollution source weakened

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

Chemical exchange saturation transfer MRI in central nervous system tumours on a 1.5 T MR-Linac

Purpose: To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system. Methods: CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTRAmide), nuclear Overhauser effect (NOE) MTR (MTRNOE) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours. Results: The gross tumour volume (GTV) exhibited lower MTRAmide and MTRNOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease. Conclusion: CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols

Zinc on the edge—isotopic and geophysical evidence that cratonic edges control world-class shale-hosted zinc-lead deposits

The North Australian Zinc Belt is the largest zinc-lead province in the world, containing three of the ten largest known individual deposits (HYC, Hilton-George Fisher, and Mount Isa). The Northern Cordillera in North America is the second largest zinc-lead province, containing a further two of the world’s top ten deposits (Red Dog and Howards Pass). Despite this world-class endowment, exploration in both mineral provinces during the past 2 decades has not been particularly successful, yielding only two significant discoveries (Teena, Australia, and Boundary, Canada). One of the most important aspects of exploration is to choose mineral provinces and districts within geological belts that have the greatest potential for discovery. Here, we present results from these two zinc belts that highlight previously unused datasets for area selection and targeting. Lead isotope mapping using analyses of mineralized material has identified gradients in μ (238U/204Pb) that coincide closely with many major deposits. Locations of these deposits also coincide with a gradient in the depth of the lithosphere-asthenosphere boundary determined from calibrated surface wave tomography models converted to temperature. Furthermore, gradients in upward-continued gravity anomalies and a step in Moho depth correspond to a pre-existing major crustal boundary in both zinc belts. A spatial association of deposits with a linear mid- to lower-crustal resistivity anomaly from magnetotelluric data is also observed in the North Australian Zinc Belt. The change from thicker to thinner lithosphere is interpreted to localize prospective basins for zinc-lead mineralization and to control the gradient in lead isotope and geophysical data. These data, when combined with data indicative of paleoenvironment and changes in plate motion at the time of mineralization, provide new exploration criteria that can be used to identify prospective mineralized basins and define the most favorable parts of these basins

Predicting Breast Cancer Response to Neoadjuvant Chemotherapy Using Pretreatment Diffuse Optical Spectroscopic-Texture Analysis

Purpose: Diffuse optical spectroscopy (DOS) has been demonstrated capable of monitoring response to neoadjuvant chemotherapy (NAC) in locally advanced breast cancer (LABC) patients. In this study, we evaluate texture features of pre-treatment DOS functional maps for predicting LABC response to NAC. Methods: LABC patients (n = 37) underwent DOS-breast imaging before starting neoadjuvant chemotherapy. Breast-tissue parametric maps were constructed and texture analyses were performed based on grey level co-occurrence matrices (GLCM) for feature extraction. Ground-truth labels as responders (R) or non-responders (NR) were assigned to patients based on Miller-Payne pathological response criteria. The capability of DOS-textural features computed on volumetric tumour data before the start of treatment (i.e. “pre-treatment”) to predict patient responses to NAC was evaluated using a leave-one-out validation scheme at subject level. Data were analysed using a logistic regression, naïve Bayes, and k-nearest neighbour (k-NN) classifiers. Results: Data indicated that textural characteristics of pre-treatment DOS parametric maps can differentiate between treatment response outcomes. The HbO2-homogeneity resulted in the highest accuracy amongst univariate parameters in predicting response to chemotherapy: sensitivity (%Sn) and specificity (%Sp) were 86.5 and 89.0%, respectively and accuracy was 87.8%. The highest predictors using multivariate (binary) combination features were the Hb-Contrast + HbO2-Homogeneity which resulted in a %Sn/%Sp = 78.0/81.0% and an accuracy of 79.5%. Conclusions: This study demonstrated that pre-treatment tumour DOS-texture features can predict breast cancer response to NAC and potentially guide treatments

High-resolution synchrotron imaging shows that root hairs influence rhizosphere soil structure formation

In this paper, we provide direct evidence of the importance of root hairs on pore structure development at the root-soil interface during the early stage of crop establishment. This was achieved by use of high resolution (~5 μm) synchrotron radiation computed tomography (SRCT) to visualise both the structure of root hairs and the soil pore structure in plant-soil microcosms. Two contrasting genotypes of barley (Hordeum vulgare L.), with and without root hairs, were grown for 8 days in microcosms packed with sandy loam soil at 1.2 g cm-3 36 dry bulk density. Root hairs were visualised within air filled pore spaces, but not in the fine-textured soil regions. - We found that the genotype with root hairs significantly altered the porosity and connectivity of the detectable pore space (&gt; 5 μm) in the rhizosphere, as compared with the no-hair mutants. Both genotypes showed decreasing pore-space between 0.8 mm and 0.1 mm from the root surface. Interestingly the root-hair-bearing genotype had a significantly greater soil pore volume-fraction at the root-soil interface. - Effects of pore structure on diffusion and permeability were estimated to be functionally insignificant under saturated conditions when simulated using image based modelling