Quantitative magnetic resonance imaging biomarkers in oncological clinical trials: Current techniques and standardization challenges

Radiological imaging plays an important role in oncological trials to provide imaging biomarkers for disease staging, stratifying patients, defining dose setting, and evaluating the safety and efficacy of new candidate drugs and innovative treatment. This paper reviews the techniques of most commonly used quantitative magnetic resonance imaging (qMRI) biomarkers (dynamic contrast enhanced, dynamic susceptibility contrast, and diffusion weighted imaging) and their applications in oncological trials. Challenges of incorporating qMRI biomarkers in oncological trials are discussed including understanding biological mechanisms revealed by MRI biomarkers, consideration of rigorous trial design and standardized implementation of qMRI protocols.

Investigation on Positive Correlation of Increased Brain Iron Deposition with Cognitive Impairment in Alzheimer Disease by Using Quantitative MR R2' Mapping

Brain iron deposition has been proposed to play an important role in the pathophysiology of Alzheimer disease（AD）.The aim of this study was to investigate the correlation of brain iron accumulation with the severity of cognitive impairment in patients with AD by using quantitative MR relaxation rate R2＇ measurements.Fifteen patients with AD,15 age-and sex-matched healthy controls,and 30 healthy volunteers underwent 1.5T MR multi-echo T2 mapping and T2＊ mapping for the measurement of transverse relaxation rate R2＇（R2＇=R2＊-R2）.We statistically analyzed the R2＇ and iron concentrations of bilateral hippocampus（HP）,parietal cortex（PC）,frontal white matter（FWM）,putamen（PU）,caudate nucleus（CN）,thalamus（TH）,red nucleus（RN）,substantia nigra（SN）,and dentate nucleus（DN） of the cerebellum for the correlation with the severity of dementia.Two-tailed t-test,Student-Newman-Keuls test（ANOVA） and linear correlation test were used for statistical analysis.In 30 healthy volunteers,the R2＇ values of bilateral SN,RN,PU,CN,globus pallidus（GP）,TH,and FWM were measured.The correlation with the postmortem iron concentration in normal adults was analyzed in order to establish a formula on the relationship between regional R2＇ and brain iron concentration.The iron concentration of regions of interest（ROI） in AD patients and controls was calculated by this formula and its correlation with the severity of AD was analyzed.Regional R2＇ was positively correlated with regional brain iron concentration in normal adults（r=0.977,P0.01）.Iron concentrations in bilateral HP,PC,PU,CN,and DN of patients with AD were significantly higher than those of the controls（P0.05）;Moreover,the brain iron concentrations,especially in parietal cortex and hippocampus at the early stage of AD,were positively correlated with the severity of patients＇ cognitive impairment（P0.05）.The higher the R2＇ and iron concentrations were,the more severe the cognitive impairment was.Regional R2＇ and iron concentration in parietal cortex and hippocampus were positively correlated with the severity of AD patients＇ cognitive impairment,indicating that it may be used as a biomarker to evaluate the progression of AD.

Comparison Thigh Skeletal Muscles between Snowboarding Halfpipe Athletes and Healthy Volunteers Using Quantitative Multi-Parameter Magnetic Resonance Imaging at Rest

Background：Magnetic resonance （MR） imaging provides a unique,noninvasive diagnostic platform to quantify the physiological and biochemical variables of skeletal muscle at rest.This study was to investigate the difference in thigh skeletal muscles between snowboarding halfpipe athletes and healthy volunteers via multiparametric MR imaging.Methods：A comparative study was conducted between 12 healthy volunteers and 14 snowboarding halfpipe athletes.MR scanning targeted the left leg at the level of the proximal thigh on a 3.0T MR system.The measured parameters compared between the two groups included T1,T2,T2＊ relaxation times,fat fraction （FF）,and cross-sectional area （CSA） of the quadriceps femoris and the hamstring muscles.Statistical analysis was carried out using independent sample t-test.Interrater reliability was also assessed with intraclass correlation coefficients （ICCs）.Results：It was statistically equivalent between two groups in age,body mass index,thigh circumference,calf circumference,systolic blood pressure,and resting heart rate （all P ＞ 0.05）.However,the T1 and T2 values of the hamstring muscles in the athlete group were found to be significantly shorter than those in control group （T1：1063.3 ± 24.1 ms vs.1112.0 ± 38.2 ms in biceps femoris,1050.4 ± 31.2 ms vs.1095.0 ± 39.5 ms in semitendinosus,1053.1 ± 31.7 ms vs.1118.4 ± 40.0 ms in semimembranosus,respectively;T2：33.4 ± 0.7 ms vs.36.1 ± 1.9 ms in biceps femoris,34.6 ± 2.0 ms vs.37.0 ± 1.9 ms in semitendinosus,36.9 ± 1.5 ms vs.38.9 ± 2.4 ms in semimembranosus,respectively;all P ＜ 0.05） although T2＊ relaxation time was detected with no significant difference.The FF of the hamstring muscles was obviously less than the control group （5.5 ± 1.9％ vs.10.7 ± 4.7％,P ＜ 0.001）.In addition,the quadriceps＇ CSA in the athlete group was substantially larger than the control group （8039.0 ± 1072.3 vs.6258.2 ± 852.0 mm2,P ＜ 0.001）.Interrater reliability was excellent （ICC：0.758-0.994）.Conclusion：Multiple MR imaging parameters indicated significant differences between snowboarding halfpipe athletes and healthy volunteers in the thigh skeletal muscles.

Accurate Quantification of Pure Thiacloprid with Mass Balance and Quantitative H-NMR

Thiacloprid is the first-generation neonicotinoid insecticide,which is widely used in modern agriculture.Reference materials are essential for sound measurement and traceability of results in chemical analysis.Pure thiacloprid was comprehensively assessed by two orthonormal methods:mass balance(MB) and quantitative nuclear magnetic resonance spectroscopy(qNMR).From MB,its mass fraction value was 998.4 mg/g with the subtraction of structurally related impurities(99.87%),inorganic impurities(0.006 mg/g),water(0.33 mg/g),and volatile organic solvent(0 mg/g).To guarantee sufficient separation of structurally related purity,peak purity of thiacloprid was evaluated by five points of UV spectra.From the qNMR of hydrogen,its mass fraction value was 995.7 mg/g which was traced to the internal standard(methyl sulfone).Finally,the certified value was assigned to 997 mg/g,together with an expanded uncertainty of 3 mg/g(k=2).This high-purity thiacloprid can be applied to routine monitoring in agriculture and the food fields.

Determination of chlorogenic acid in traditional Chinese prescription Shuanghuanglian capsule using quantitative nuclear magnetic resonance spectroscopy in combination with solid phase extraction

The determination method of chlorogenic acid in traditional Chinese prescription Shuanghuanglian capsule was established by using quantitative nuclear magnetic resonance spectroscopy(q NMR) in combination with solid phase extraction(SPE). As the capsule’s main active component, chlorogenic acid comes from the extraction of Chinese herb medicine Flos Lonicerae. The chlorogenic acid in capsule was ultrasonically extracted at room temperature using pure water as solvent. The extracting solution was enriched and cleaned using HC-C18 SPE cartridge. The effect of ultrasonic extraction, sample pretreatment conditions via SPE and q NMR experimental conditions were investigated. The q NMR experiment conditions were selected using deuterated DMSO as solvent, calibrated 1,4-phthalaldehyde as internal standard, and P1(pulse width) = 14.4 μs, d1(pulse delay time) = 1 s, NS(number of scan) = 512. The 1 H NMR peaks of δ 6.138–6.182(H-8’, d, 1 H) of chlorogenic acid was chosen as the quantitative peaks. Method validation was performed, including precision(the intra-day RSD = 1.2% and the inter-day RSD = 1.5%), linearity(correlation coefficient r>0.9999), LOD(0.0017 mg/g) and LOQ(0.079 mg/g). The recovery of the SPE-q NMR was within the range of 100.2%–103.2%. The result showed that the method was stable, accurate and reliabile. Determined by the method, the chlorogenic acid in a real Shuanghuanglian capsule was within the range of 9.68–10.35 mg/g.

Pancreatic imaging:Current status of clinical practices and small animal studies

Different causative factors acting on the pancreas can result in diseases such as pancreatitis, diabetes and pancreatic tumors. The high incidence and mortality of pancreatic diseases have placed diagnostic imaging in a crucial position in daily clinical practice. In this minireview article different pancreatic imaging techniques are discussed, from the standard clinical imaging modalities and state of the art clinical magnetic resonance imaging techniques to current situations in pre-clinical pancreatic imaging studies. In particular, the challenges of pre-clinical rodent pancreatic imaging are addressed, with both the image acquisition techniques and the post-processing methods for rodent pancreatic imaging elaborated.