Remodeling of tumor stroma combined with photothermal therapy in the treatment of triple-negative breast cancer / 中华肿瘤杂志

Objective: Polyethylene glycol-modified gold nanostar particles (GNS-PEG) were constructed to investigate whether the degradation of extracellular matrix in triple-negative breast cancer could improve the tumor delivery of GNS-PEG and enhance the efficacy of photothermal therapy. Methods: GNS-PEG were constructed and characterized for physicochemical properties as well as photothermal properties. At the cellular level, the cytotoxicity of halofuginone (HF) and the effect of photothermal therapy were detected. Mouse model of triple negative breast cancer was established by subcutaneous inoculation of 4T1 cells in BALB/c nude mice. Five injections of HF were given via tail vein (HF group), and tumor sections were stained with Masson stain and immunohistochemical staining for transforming growth factor β1 (TGFβ1), α-smooth muscle actin (α-SMA) and CD31 to observe the effect of tumor stromal degradation. Five injections of HF via tail vein followed by GNS-PEG (HF+ GNS-PEG group) were applied to determine the content of gold in tumor tissues by inductively coupled plasma mass spectrometry. The tumor sites of the mice in the GNS-PEG and HF+ GNS-PEG groups were irradiated with NIR laser and the temperature changes were recorded with an IR camera. The tumour growth and weight changes of mice in each group were observed. Ki-67 immunohistochemical staining, TdT-mediated dUTP nick-end labeling and HE staining were performed on tumor tissue sections from each group to observe tumor proliferation, apoptosis and necrosis. HE staining was performed on heart, liver, spleen, lung and kidney tissues from each group to observe the morphological changes of cells. Results: GNS-PEG nanoparticles showed a multi-branched structure with a particle size of 73.5±1.4 nm. The absorption peak of GNS was 810 nm, which is in the near infrared region. The photothermal conversion rate of GNS-PEG was up to 79.3%, and the photothermal effect could be controlled by the laser energy. HF has a concentration-dependent cytotoxicity, with a cell survival rate being as low as (22.8±2.6)% at HF concentration of up to 1 000 nmol/L. The photothermal effect of GNS-PEG was significant in killing tumor cells, with a cell survival rate of (32.7±5.2)% at the concentration of 25 pmol/L. The collagen area fraction, TGFβ1 integrated optical density and α-SMA integrated optical density in the tumor tissues of mice in the HF group were (2.1±0.2)%, 3.1±0.4 and 5.2±1.9, respectively, which were lower than those of the control group (all P<0.01), and the vessel diameter was 8.6±2.9 μm, which was higher than that of the control group (P<0.05). In the HF+ GNS-PEG group, the concentration of gold in tissues was 52.4 μg/g, higher than that in the GNS-PEG group (15.9 μg/g, P<0.05). After laser irradiation, the temperature of the tumor site in the HF+ GNS-PEG group was significantly higher than that in the GNS-PEG group. At the 4th minute, the temperatures of the tumor site in the GNS-PEG and HF+ GNS-PEG groups were 51.5 ℃ and 57.7 ℃ respectively; the tumor volume in the HF+ GNS-PEG group was effectively suppressed. The body weights of the mice in each group did not change significantly during the monitoring period. No significant abnormalities were observed in the main organs of the mice in the GNS-PEG group, but some hepatocytes in the HF and HF+ GNS-PEG groups showed edema and degeneration. Conclusion: The remodeling of extracellular matrix in triple-negative breast cancer could significantly improve the intratumoral delivery of GNS-PEG and thus achieve better photothermal therapy effect.

Remodeling of tumor stroma combined with photothermal therapy in the treatment of triple-negative breast cancer / 中华肿瘤杂志

Objective: Polyethylene glycol-modified gold nanostar particles (GNS-PEG) were constructed to investigate whether the degradation of extracellular matrix in triple-negative breast cancer could improve the tumor delivery of GNS-PEG and enhance the efficacy of photothermal therapy. Methods: GNS-PEG were constructed and characterized for physicochemical properties as well as photothermal properties. At the cellular level, the cytotoxicity of halofuginone (HF) and the effect of photothermal therapy were detected. Mouse model of triple negative breast cancer was established by subcutaneous inoculation of 4T1 cells in BALB/c nude mice. Five injections of HF were given via tail vein (HF group), and tumor sections were stained with Masson stain and immunohistochemical staining for transforming growth factor β1 (TGFβ1), α-smooth muscle actin (α-SMA) and CD31 to observe the effect of tumor stromal degradation. Five injections of HF via tail vein followed by GNS-PEG (HF+ GNS-PEG group) were applied to determine the content of gold in tumor tissues by inductively coupled plasma mass spectrometry. The tumor sites of the mice in the GNS-PEG and HF+ GNS-PEG groups were irradiated with NIR laser and the temperature changes were recorded with an IR camera. The tumour growth and weight changes of mice in each group were observed. Ki-67 immunohistochemical staining, TdT-mediated dUTP nick-end labeling and HE staining were performed on tumor tissue sections from each group to observe tumor proliferation, apoptosis and necrosis. HE staining was performed on heart, liver, spleen, lung and kidney tissues from each group to observe the morphological changes of cells. Results: GNS-PEG nanoparticles showed a multi-branched structure with a particle size of 73.5±1.4 nm. The absorption peak of GNS was 810 nm, which is in the near infrared region. The photothermal conversion rate of GNS-PEG was up to 79.3%, and the photothermal effect could be controlled by the laser energy. HF has a concentration-dependent cytotoxicity, with a cell survival rate being as low as (22.8±2.6)% at HF concentration of up to 1 000 nmol/L. The photothermal effect of GNS-PEG was significant in killing tumor cells, with a cell survival rate of (32.7±5.2)% at the concentration of 25 pmol/L. The collagen area fraction, TGFβ1 integrated optical density and α-SMA integrated optical density in the tumor tissues of mice in the HF group were (2.1±0.2)%, 3.1±0.4 and 5.2±1.9, respectively, which were lower than those of the control group (all P<0.01), and the vessel diameter was 8.6±2.9 μm, which was higher than that of the control group (P<0.05). In the HF+ GNS-PEG group, the concentration of gold in tissues was 52.4 μg/g, higher than that in the GNS-PEG group (15.9 μg/g, P<0.05). After laser irradiation, the temperature of the tumor site in the HF+ GNS-PEG group was significantly higher than that in the GNS-PEG group. At the 4th minute, the temperatures of the tumor site in the GNS-PEG and HF+ GNS-PEG groups were 51.5 ℃ and 57.7 ℃ respectively; the tumor volume in the HF+ GNS-PEG group was effectively suppressed. The body weights of the mice in each group did not change significantly during the monitoring period. No significant abnormalities were observed in the main organs of the mice in the GNS-PEG group, but some hepatocytes in the HF and HF+ GNS-PEG groups showed edema and degeneration. Conclusion: The remodeling of extracellular matrix in triple-negative breast cancer could significantly improve the intratumoral delivery of GNS-PEG and thus achieve better photothermal therapy effect.

Intravoxel Incoherent Motion Magnetic Resonance Imaging for Assessing Parotid Gland Tumors: Correlation and Comparison with Arterial Spin Labeling Imaging

Objective@#To compare and correlate the findings of intravoxel incoherent motion (IVIM) magnetic resonance (MR) imaging and arterial spin labeling (ASL) imaging in characterizing parotid gland tumors. @*Materials and Methods@#We retrospectively reviewed 56 patients with parotid gland tumors evaluated by MR imaging. The true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and fraction of perfusion (f) values of IVIM imaging and tumor-to-parotid gland signal intensity ratio (SIR) on ASL imaging were calculated. Spearman rank correlation coefficient, chi-squared, Mann-Whitney U, and Kruskal-Wallis tests with the post-hoc Dunn-Bonferroni method and receiver operating characteristic curve assessments were used for statistical analysis. @*Results@#Malignant parotid gland tumors showed significantly lower D than benign tumors (p = 0.019). Within subgroup analyses, pleomorphic adenomas (PAs) showed significantly higher D than malignant tumors (MTs) and Warthin’s tumors (WTs) (p < 0.001). The D* of WTs was significantly higher than that of PAs (p = 0.031). The f and SIR on ASL imaging of WTs were significantly higher than those of MTs and PAs (p < 0.05). Significantly positive correlation was found between SIR on ASL imaging and f (r = 0.446, p = 0.001). In comparison with f, SIR on ASL imaging showed a higher area under curve (0.853 vs. 0.891) in discriminating MTs from WTs, although the difference was not significant (p = 0.720). @*Conclusion@#IVIM and ASL imaging could help differentiate parotid gland tumors. SIR on ASL imaging showed a significantly positive correlation with f. ASL imaging might hold potential to improve the ability to discriminate MTs from WTs.

Thyroid-Associated Orbitopathy: Evaluating Microstructural Changes of Extraocular Muscles and Optic Nerves Using Readout-Segmented Echo-Planar Imaging-Based Diffusion Tensor Imaging

OBJECTIVE: We aimed to investigate the ability of readout-segmented echo-planar imaging (rs-EPI)-based diffusion tensor imaging (DTI) in assessing the microstructural change of extraocular muscles (EOMs) and optic nerves in patients with thyroid-associated orbitopathy (TAO) as well as in evaluating disease activity.MATERIALS AND METHODS: We enrolled 35 TAO patients and 22 healthy controls (HCs) who underwent pre-treatment rs-EPI-based DTI. Mean, axial, and radial diffusivity (MD, AD, and RD) and fractional anisotropy (FA) of the medial and lateral EOMs and optic nerve for each orbit were calculated and compared between TAO and HC groups and between active and inactive TAO groups. Factors such as age, sex, disease duration, mediation, and smoking history between groups were also compared. Logistic regression analysis was used to evaluate the predictive value of significant variables for disease activity.RESULTS: Disease duration was significantly shorter in active TAOs than in inactive ones (p < 0.001). TAO patients showed significantly lower FA and higher MD, AD, and RD than HCs for both medial and lateral EOMs (p < 0.001), but not the AD value of lateral EOMs (p = 0.619). Active patients had significantly higher FA, MD, and AD than inactive patients for medial EOMs (p < 0.005), whereas only FA differed significantly in the lateral EOMs (p = 0.018). The MD, AD, and RD of optic nerves were significantly lower in TAO patients than HCs (p < 0.05), except for FA (p = 0.129). Multivariate analysis showed that the MD of medial EOMs and disease duration were significant predictors for disease activity. The combination of these two parameters showed optimal diagnostic efficiency for disease activity (area under the curve, 0.855; sensitivity, 68.4%; specificity, 96.9%).CONCLUSION: rs-EPI-based DTI is promising in assessing microstructural changes of EOMs and optic nerves and can help to indicate the disease activity of TAO, especially through the MD of medial EOMs.

Utility of Readout-Segmented Echo-Planar Imaging-Based Diffusion Kurtosis Imaging for Differentiating Malignant from Benign Masses in Head and Neck Region

OBJECTIVE: To compare the diagnostic performance of readout-segmented echo-planar imaging (RS-EPI)-based diffusion kurtosis imaging (DKI) and that of diffusion-weighted imaging (DWI) for differentiating malignant from benign masses in head and neck region. MATERIALS AND METHODS: Between December 2014 and April 2016, we retrospectively enrolled 72 consecutive patients with head and neck masses who had undergone RS-EPI-based DKI scan (b value of 0, 500, 1000, and 1500 s/mm2) for pretreatment evaluation. Imaging data were post-processed by using monoexponential and diffusion kurtosis (DK) model for quantitation of apparent diffusion coefficient (ADC), apparent diffusion for Gaussian distribution (Dapp), and apparent kurtosis coefficient (Kapp). Unpaired t test and Mann-Whitney U test were used to compare differences of quantitative parameters between malignant and benign groups. Receiver operating characteristic curve analyses were performed to determine and compare the diagnostic ability of quantitative parameters in predicting malignancy. RESULTS: Malignant group demonstrated significantly lower ADC (0.754 ± 0.167 vs. 1.222 ± 0.420, p < 0.001) and Dapp (1.029 ± 0.226 vs. 1.640 ± 0.445, p < 0.001) while higher Kapp (1.344 ± 0.309 vs. 0.715 ± 0.249, p < 0.001) than benign group. Using a combination of Dapp and Kapp as diagnostic index, significantly better differentiating performance was achieved than using ADC alone (area under curve: 0.956 vs. 0.876, p = 0.042). CONCLUSION: Compared to DWI, DKI could provide additional data related to tumor heterogeneity with significantly better differentiating performance. Its derived quantitative metrics could serve as a promising imaging biomarker for differentiating malignant from benign masses in head and neck region.

Diffusion Weighted Imaging for Differentiating Benign from Malignant Orbital Tumors: Diagnostic Performance of the Apparent Diffusion Coefficient Based on Region of Interest Selection Method

OBJECTIVE: To evaluate the differences in the apparent diffusion coefficient (ADC) measurements based on three different region of interest (ROI) selection methods, and compare their diagnostic performance in differentiating benign from malignant orbital tumors. MATERIALS AND METHODS: Diffusion-weighted imaging data of sixty-four patients with orbital tumors (33 benign and 31 malignant) were retrospectively analyzed. Two readers independently measured the ADC values using three different ROIs selection methods including whole-tumor (WT), single-slice (SS), and reader-defined small sample (RDSS). The differences of ADC values (ADC-ROI(WT), ADC-ROI(SS), and ADC-ROI(RDSS)) between benign and malignant group were compared using unpaired t test. Receiver operating characteristic curve was used to determine and compare their diagnostic ability. The ADC measurement time was compared using ANOVA analysis and the measurement reproducibility was assessed using Bland-Altman method and intra-class correlation coefficient (ICC). RESULTS: Malignant group showed significantly lower ADC-ROI(WT), ADC-ROI(SS), and ADC-ROI(RDSS) than benign group (all p 0.05). The ROI(SS) and ROI(RDSS) required comparable measurement time (p > 0.05), while significantly shorter than ROIWT (p < 0.05). The ROI(SS) showed the best reproducibility (mean difference ± limits of agreement between two readers were 0.022 [-0.080-0.123] × 10(-3) mm2/s; ICC, 0.997) among three ROI methods. CONCLUSION: Apparent diffusion coefficient values based on the three different ROI selection methods can help to differentiate benign from malignant orbital tumors. The results of measurement time, reproducibility and diagnostic ability suggest that the ROI(SS) method are potentially useful for clinical practice.

Value of dynamic ³¹P magnetic resonance spectroscopy technique in in vivo assessment of the skeletal muscle mitochondrial function in type 2 diabetes / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Phosphorous magnetic resonance spectroscopy ((31)P-MRS) has been successfully applied to study intracellular membrane compounds and high-energy phosphate metabolism. This study aimed to evaluate the capability of dynamic (31)P-MRS for assessing energy metabolism and mitochondrial function in skeletal muscle from type 2 diabetic patients.</p><p><b>METHODS</b>Dynamic (31)P-MRS was performed on 22 patients with type 2 diabetes and 26 healthy volunteers. Spectra were acquired from quadriceps muscle while subjects were in a state of rest, at exercise and during recovery. The peak areas of inorganic phosphate (Pi), phosphocreatine (PCr), and adenosine triphosphate (ATP) were measured. The concentration of adenosine diphosphate (ADP) and the intracellular pH value were calculated from the biochemistry reaction equilibrium. The time constant and recovery rates of Pi, PCr, and ADP were analyzed using exponential curve fitting.</p><p><b>RESULTS</b>As compared to healthy controls, type 2 diabetes patients had significantly lower skeletal muscle concentrations of Pi, PCr and β-ATP, and higher levels of ADP and Pi/PCr. During exercise, diabetics experienced a significant Pi peak increase and PCr peak decrease, and once the exercise was completed both Pi and PCr peaks returned to resting levels. Quantitatively, the mean recovery rates of Pi and PCr in diabetes patients were (10.74 ± 1.26) mmol/s and (4.74 ± 2.36) mmol/s, respectively, which was significantly higher than in controls.</p><p><b>CONCLUSIONS</b>Non-invasive quantitative (31)P-MRS is able to detect energy metabolism inefficiency and mitochondrial function impairment in skeletal muscle of type 2 diabetics.</p>