Towards detection of early response in neoadjuvant chemotherapy of breast cancer using Bayesian intravoxel incoherent motion.

Introduction: The early identification of good responders to neoadjuvant chemotherapy (NACT) holds a significant potential in the optimal treatment of breast cancer. A recent Bayesian approach has been postulated to improve the accuracy of the intravoxel incoherent motion (IVIM) model for clinical translation. This study examined the prediction and early sensitivity of Bayesian IVIM to NACT response. Materials and methods: Seventeen female patients with breast cancer were scanned at baseline and 16 patients were scanned after Cycle 1. Tissue diffusion and perfusion from Bayesian IVIM were calculated at baseline with percentage change at Cycle 1 computed with reference to baseline. Cellular proliferative activity marker Ki-67 was obtained semi-quantitatively with percentage change at excision computed with reference to core biopsy. Results: The perfusion fraction showed a significant difference (p = 0.042) in percentage change between responder groups at Cycle 1, with a decrease in good responders [-7.98% (-19.47-1.73), n = 7] and an increase in poor responders [10.04% (5.09-28.93), n = 9]. There was a significant correlation between percentage change in perfusion fraction and percentage change in Ki-67 (p = 0.042). Tissue diffusion and pseudodiffusion showed no significant difference in percentage change between groups at Cycle 1, nor was there a significant correlation against percentage change in Ki-67. Perfusion fraction, tissue diffusion, and pseudodiffusion showed no significant difference between groups at baseline, nor was there a significant correlation against Ki-67 from core biopsy. Conclusion: The alteration in tumour perfusion fraction from the Bayesian IVIM model, in association with cellular proliferation, showed early sensitivity to good responders in NACT. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03501394, identifier NCT03501394.

Peri-tumoural spatial distribution of lipid composition and tubule formation in breast cancer.

BACKGROUND: Response guided treatment in breast cancer is highly desirable, but the effectiveness is only established based on residual cellularity from histopathological analysis after surgery. Tubule formation, a key component of grading score, is directly associated with cellularity, with significant implications on prognosis. Peri-tumoural lipid composition, a potential marker, can be rapidly mapped across the entire breast using novel method of chemical shift-encoded imaging, enabling the quantification of spatial distribution. We hypothesise that peri-tumoural spatial distribution of lipid composition is sensitive to tumour cellular differentiation and proliferative activity. METHODS: Twenty whole tumour specimens freshly excised from patients with invasive ductal carcinoma (9 Score 2 and 11 Score 3 in tubule formation) were scanned on a 3 T clinical scanner (Achieva TX, Philips Healthcare). Quantitative lipid composition maps were acquired for polyunsaturated, monounsaturated, and saturated fatty acids (PUFA, MUFA, SFA). The peri-tumoural spatial distribution (mean, skewness, entropy and kurtosis) of each lipid constituent were then computed. The proliferative activity marker Ki-67 and tumour-infiltrating lymphocytes (TILs) were assessed histologically. RESULTS: For MUFA, there were significant differences between groups in mean (p = 0.0119), skewness (p = 0.0116), entropy (p = 0.0223), kurtosis (p = 0.0381), and correlations against Ki-67 in mean (ρ = -0.5414), skewness (ρ = 0.6045) and entropy (ρ = 0.6677), and TILs in mean (ρ = -0.4621). For SFA, there were significant differences between groups in mean (p = 0.0329) and skewness (p = 0.0111), and correlation against Ki-67 in mean (ρ = 0.5910). For PUFA, there was no significant difference in mean, skewness, entropy or kurtosis between the groups. CONCLUSIONS: There was an association between peri-tumoural spatial distribution of lipid composition with tumour cellular differentiation and proliferation. Peri-tumoural lipid composition imaging might have potential in non-invasive quantitative assessment of patients with breast cancer for treatment planning and monitoring.

Monitoring tissue implants by field-cycling 1H-MRI via the detection of changes in the 14N-quadrupolar-peak from imidazole moieties incorporated in a "smart" scaffold material.

This study is focused on the development of innovative sensors to non-invasively monitor the tissue implant status by Fast-Field-Cycling Magnetic Resonance Imaging (FFC-MRI). These sensors are based on oligo-histidine moieties that are conjugated to PLGA polymers representing the structural matrix for cells hosting scaffolds. The presence of 14N atoms of histidine causes a quadrupolar relaxation enhancement (also called Quadrupolar Peak, QP) at 1.39 MHz. This QP falls at a frequency well distinct from the QPs generated by endogenous semisolid proteins. The relaxation enhancement is pH dependent in the range 6.5-7.5, thus it acts as a reporter of the scaffold integrity as it progressively degrades upon lowering the microenvironmental pH. The ability of this new sensors to generate contrast in an image obtained at 1.39 MHz on a FFC-MRI scanner is assessed. A good biocompatibility of the histidine-containing scaffolds is observed after its surgical implantation in healthy mice. Over time the scaffold is colonized by endogenous fibroblasts and this process is accompanied by a progressive decrease of the intensity of the relaxation peak. In respect to the clinically used contrast agents this material has the advantage of generating contrast without the use of potentially toxic paramagnetic metal ions.

A Novel Class of 1 H-MRI Contrast Agents Based on the Relaxation Enhancement Induced on Water Protons by 14 N-Containing Imidazole Moieties.

This study reports the development of a completely new class of MRI contrast agents, displaying remarkable relaxation effects in the absence of paramagnetic metal ions. Their detection requires the acquisition of images at variable magnetic field strength as provided by fast field cycling imaging scanners. They contain poly-histidine chains (poly-His), whose imidazole groups generate 14 N-quadrupolar-peaks that cause a relaxation enhancement of water protons at a frequency (1.38±0.3 MHz) that is readily detectable from the frequencies associated with endogenous proteins. The poly-His quadrupolar peaks are detectable only when the polymer is in a solid-like form, that is, at pH>6.6. Above this value, their intensity is pH dependent and can be used to report on the occurring pH changes. On this basis, the poly-His moieties were conjugated to biocompatible polymers, such as polylactic and glycolic acid, in order to form stable nanoparticles able to encapsulate structured water in their core. FFC images were acquired to assess their contrast-generating ability.

Phased-array combination of 2D MRS for lipid composition quantification in patients with breast cancer.

Lipid composition in breast cancer, a central marker of disease progression, can be non-invasively quantified using 2D MRS method of double quantum filtered correlation spectroscopy (DQF-COSY). The low signal to noise ratio (SNR), arising from signal retention of only 25% and depleted lipids within tumour, demands improvement approaches beyond signal averaging for clinically viable applications. We therefore adapted and examined combination algorithms, designed for 1D MRS, for 2D MRS with both internal and external references. Lipid composition spectra were acquired from 17 breast tumour specimens, 15 healthy female volunteers and 25 patients with breast cancer on a clinical 3 T MRI scanner. Whitened singular value decomposition (WSVD) with internal reference yielded maximal SNR with an improvement of 53.3% (40.3-106.9%) in specimens, 84.4 ± 40.6% in volunteers, 96.9 ± 54.2% in peritumoural adipose tissue and 52.4% (25.1-108.0%) in tumours in vivo. Non-uniformity, as variance of improvement across peaks, was low at 21.1% (13.7-28.1%) in specimens, 5.5% (4.2-7.2%) in volunteers, 6.1% (5.0-9.0%) in peritumoural tissue, and 20.7% (17.4-31.7%) in tumours in vivo. The bias (slope) in improvement ranged from - 1.08 to 0.21%/ppm along the diagonal directions. WSVD is therefore the optimal algorithm for lipid composition spectra with highest SNR uniformly across peaks, reducing acquisition time by up to 70% in patients, enabling clinical applications.

Metabolic and Structural Skeletal Muscle Health in Systemic Lupus Erythematosus-Related Fatigue: A Multimodal Magnetic Resonance Imaging Study.

OBJECTIVE: To investigate the potential structural and metabolic role of skeletal muscle in systemic lupus erythematosus (SLE)-related fatigue. METHODS: A case-control, multimodal magnetic resonance imaging (MRI) study was conducted. Cases were patients with inactive SLE who reported chronic fatigue. Controls were age- and sex-matched healthy members of the general population. Patients were clinically characterized and then underwent a 3T whole-body MRI scan. Resting and dynamic 31 P MRI spectroscopy of the calf muscles was applied, from which phosphocreatine (PCr) recovery halftime, a marker of mitochondrial dysfunction, was computed. In addition, microstructural sequences (T1-weighted anatomic images, T2 mapping, and diffusion tensor imaging) were acquired. Descriptive statistics evaluated group differences and within-case physical fatigue correlations were explored. RESULTS: Of the 37 recruits (mean age 43.8 years, 89.2% female), cases (n = 19) reported higher levels of physical fatigue, pain, depression, and sleep disturbance compared to the control group (P < 0.0001). PCr was greater (P = 0.045) among cases (mean ± SD 33.0 ± 9.0 seconds) compared to controls (mean ± SD 27.1 ± 6.6 seconds). No microstructural group differences were observed. Within cases, physical fatigue did not correlate with PCr (r = -0.28, P = 0.25). CONCLUSION: We report preliminary data demonstrating greater skeletal muscle mitochondrial dysfunction among fatigued patients with SLE compared to healthy controls.

q-Space Imaging Yields a Higher Effect Gradient to Assess Cellularity than Conventional Diffusion-weighted Imaging Methods at 3.0 T: A Pilot Study with Freshly Excised Whole-Breast Tumors.

Purpose: To determine whether q-space imaging (QSI), an advanced diffusion-weighted MRI method, provides a higher effect gradient to assess tumor cellularity than existing diffusion imaging methods, and fidelity to cellularity obtained from histologic analysis. Materials and Methods: In this prospective study, diffusion-weighted images were acquired from 20 whole-breast tumors freshly excised from participants (age range, 35-78 years) by using a clinical 3.0-T MRI unit. Median and skewness values were extracted from the histogram distributions obtained from QSI, monoexponential model, diffusion kurtosis imaging (DKI), and stretched exponential model (SEM). The skewness from QSI and other diffusion models was compared by using paired t tests and relative effect gradient obtained from correlating skewness values. Results: The skewness obtained from QSI (mean, 1.34 ± 0.77 [standard deviation]) was significantly higher than the skewness from monoexponential fitting approach (mean, 1.09 ± 0.67; P = .015), SEM (mean, 1.07 ± 0.70; P = .014), and DKI (mean, 0.97 ± 0.63; P = .004). QSI yielded a higher effect gradient in skewness (percentage increase) compared with monoexponential fitting approach (0.26 of 0.74; 35.1%), SEM (0.26 of 0.74; 35.1%), and DKI (0.37 of 0.63; 58.7%). The skewness and median from QSI were significantly correlated with the skewness (ρ = -0.468; P = .038) and median (ρ = -0.513; P = .021) of cellularity from histologic analysis. Conclusion: QSI yields a higher effect gradient in assessing breast tumor cellularity than existing diffusion methods, and fidelity to underlying histologic structure.Keywords: Breast, MR-Diffusion Weighted Imaging, MR-Imaging, Pathology, Tissue Characterization, Tumor ResponseOnline supplemental material is available for this article.Published under a CC BY 4.0 license.

High levels of genetic diversity of Plasmodium falciparum populations in Papua New Guinea despite variable infection prevalence.

High levels of genetic diversity in Plasmodium falciparum populations are an obstacle to malaria control. Here, we investigate the relationship between local variation in malaria epidemiology and parasite genetic diversity in Papua New Guinea (PNG). Cross-sectional malaria surveys were performed in 14 villages spanning four distinct malaria-endemic areas on the north coast, including one area that was sampled during the dry season. High-resolution msp2 genotyping of 2,147 blood samples identified 761 P. falciparum infections containing a total of 1,392 clones whose genotypes were used to measure genetic diversity. Considerable variability in infection prevalence and mean multiplicity of infection was observed at all of the study sites, with the area sampled during the dry season showing particularly striking local variability. Genetic diversity was strongly associated with multiplicity of infection but not with infection prevalence. In highly endemic areas, differences in infection prevalence may not translate into a decrease in parasite population diversity.