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.

Intra-tumoural lipid composition and lymphovascular invasion in breast cancer via non-invasive magnetic resonance spectroscopy.

OBJECTIVES: Despite improved survival due to new treatments, the 10-year survival rate in patients with breast cancer is approximately 75%. Lymphovascular invasion (LVI), a prognostic marker independent from histological grade and stage, can only be fully determined at final histological examination. Lipid composition is deregulated in tumour via de novo lipogenesis, with alteration in lipogenic genes in LVI. We hypothesise alteration in lipid composition derived from novel non-invasive spectroscopy method is associated with LVI positivity. METHODS: Thirty female patients (age 39-78) with invasive ductal carcinoma were enrolled, with 13 LVI negative and 17 LVI positive. Saturated, monounsaturated, polyunsaturated fatty acids and triglycerides (SFA, MUFA, PUFA and TRG) were quantified from ex vivo breast tumours freshly excised from patients on a 3 T clinical MRI scanner, and proliferative activity marker Ki-67 and serotonin derived histologically. RESULTS: There were significantly lower MUFA (p = 0.0189) in LVI positive (median: 0.37, interquartile range (IQR): 0.25-0.64) than negative (0.63, 0.49-0.96). There were significantly lower TRG (p = 0.0226) in LVI positive (1.32, 0.95-2.43) than negative (2.5, 1.92-4.15). There was no significant difference in SFA (p = 0.6009) or PUFA (p = 0.1641). There was no significant correlation between lipid composition against Ki-67 or serotonin, apart from a borderline negative correlation between PUFA and serotonin (r = - 0.3616, p = 0.0496). CONCLUSION: Lipid composition might provide a biomarker to study lymphovascular invasion in breast cancer. KEY POINTS: • Monounsaturated fatty acids in lymphovascular invasion (LVI) positive invasive breast carcinoma were significantly lower than that in LVI negative. • Triglycerides in LVI positive invasive breast carcinoma were significantly lower than that in LVI negative. • Lipid composition from MR spectroscopy reflects the rate of de novo lipogenesis and provides a potential biomarker independent from histological grade and stage.

Lactate concentration in breast cancer using advanced magnetic resonance spectroscopy.

BACKGROUND: Precision medicine in breast cancer demands markers sensitive to early treatment response. Aerobic glycolysis (AG) upregulates lactate dehydrogenase A (LDH-A) with elevated lactate production; however, existing approaches for lactate quantification are either invasive or impractical clinically. METHODS: Thirty female patients (age 39-78 years, 15 grade II and 15 grade III) with invasive ductal carcinoma were enrolled. Lactate concentration was quantified from freshly excised whole tumours with double quantum filtered (DQF) magnetic resonance spectroscopy (MRS), and Nottingham Prognostic Index (NPI), LDH-A and proliferative marker Ki-67 were assessed histologically. RESULTS: There was a significantly higher lactate concentration (t = 2.2224, p = 0.0349) in grade III (7.7 ± 2.9 mM) than in grade II (5.5 ± 2.4 mM). Lactate concentration was correlated with NPI (ρ = 0.3618, p = 0.0495), but not with Ki-67 (ρ = 0.3041, p = 0.1023) or tumour size (r = 0.1716, p = 0.3645). Lactate concentration was negatively correlated with LDH-A (ρ = -0.3734, p = 0.0421). CONCLUSION: Our results showed that lactate concentration in whole breast tumour from DQF MRS is sensitive to tumour grades and patient prognosis.

Spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive breast cancer.

Deregulation of lipid composition in adipose tissue adjacent to breast tumour is observed in ex vivo and animal models. Novel non-invasive magnetic resonance imaging (MRI) allows rapid lipid mapping of the human whole breast. We set out to elucidate the spatial heterogeneity of peri-tumoural lipid composition in postmenopausal patients with oestrogen receptor positive (ER +) breast cancer. Thirteen participants (mean age, 62 ± [SD] 6 years) with ER + breast cancer and 13 age-matched postmenopausal healthy controls were scanned on MRI. The number of double bonds in triglycerides was computed from MRI images to derive lipid composition maps of monounsaturated, polyunsaturated, and saturated fatty acids (MUFA, PUFA, SFA). The spatial heterogeneity measures (mean, median, skewness, entropy and kurtosis) of lipid composition in the peri-tumoural region and the whole breast of participants and in the whole breast of controls were computed. The Ki-67 proliferative activity marker and CD163 antibody on tumour-associated macrophages were assessed histologically. Mann Whitney U or Wilcoxon tests and Spearman's coefficients were used to assess group differences and correlations, respectively. For comparison against the whole breast in participants, peri-tumoural MUFA had a lower mean (median (IQR), 0.40 (0.02), p < .001), lower median (0.42 (0.02), p < .001), a negative skewness with lower magnitude (- 1.65 (0.77), p = .001), higher entropy (4.35 (0.64), p = .007) and lower kurtosis (5.13 (3.99), p = .001). Peri-tumoural PUFA had a lower mean (p < .001), lower median (p < .001), a positive skewness with higher magnitude (p = .005) and lower entropy (p = .002). Peri-tumoural SFA had a higher mean (p < .001), higher median (p < .001), a positive skewness with lower magnitude (p < .001) and lower entropy (p = .012). For comparison against the whole breast in controls, peri-tumoural MUFA had a negative skewness with lower magnitude (p = .01) and lower kurtosis (p = .009), however there was no difference in PUFA or SFA. CD163 moderately correlated with peri-tumoural MUFA skewness (rs = - .64), PUFA entropy (rs = .63) and SFA skewness (rs = .59). There was a lower MUFA and PUFA while a higher SFA, and a higher heterogeneity of MUFA while a lower heterogeneity of PUFA and SFA, in the peri-tumoural region in comparison with the whole breast tissue. The degree of lipid deregulation was associated with inflammation as indicated by CD163 antibody on macrophages, serving as potential marker for early diagnosis and response to therapy.

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.

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.

Optimal Phased-Array Signal Combination For Polyunsaturated Fatty Acids Measurement In Breast Cancer Using Multiple Quantum Coherence MR Spectroscopy At 3T.

Polyunsaturated fatty acid (PUFA), a key marker in breast cancer, is non-invasively quantifiable using multiple quantum coherence (MQC) magnetic resonance spectroscopy (MRS) at the expense of losing half of the signal. Signal combination for phased array coils provides potential pathways to enhance the signal to noise ratio (SNR), with current algorithms developed for conventional brain MRS. Since PUFA spectra and the biochemical environment in the breast deviate significantly from those in the brain, we set out to identify the optimal algorithm for PUFA in breast cancer. Combination algorithms were compared using PUFA spectra from 17 human breast tumour specimens, 15 healthy female volunteers, and 5 patients with breast cancer on a clinical 3 T MRI scanner. Adaptively Optimised Combination (AOC) yielded the maximum SNR improvement in specimens (median, 39.5%; interquartile range: 35.5-53.2%, p < 0.05), volunteers (82.4 ± 37.4%, p < 0.001), and patients (median, 61%; range: 34-105%, p < 0.05), while independent from voxel volume (rho = 0.125, p = 0.632), PUFA content (rho = 0.256, p = 0.320) or water/fat ratio (rho = 0.353, p = 0.165). Using AOC, acquisition in patients is 1.5 times faster compared to non-noise decorrelated algorithms. Therefore, AOC is the most suitable current algorithm to improve SNR or accelerate the acquisition of PUFA MRS from breast in a clinical setting.

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.