MITF functions as a tumor suppressor in non-small cell lung cancer beyond the canonically oncogenic role.

Microphthalamia-associated transcription factor (MITF) is a critical mediator in melanocyte differentiation and exerts oncogenic functions in melanoma progression. However, the role of MITF in non-small cell lung cancer (NSCLC) is still unknown. We found that MITF is dominantly expressed in the low-invasive CL1-0 lung adenocarcinoma cells and paired adjacent normal lung tissues. MITF expression is significantly associated with better overall survival and disease-free survival in NSCLC and serves as an independent prognostic marker. Silencing MITF promotes tumor cell migration, invasion and colony formation in lung adenocarcinoma cells. In xenograft mouse model, MITF knockdown enhances metastasis and tumorigenesis, but decreases angiogenesis in the Matrigel plug assay. Whole transcriptome profiling of the landscape of MITF regulation in lung adenocarcinoma indicates that MITF is involved in cell development, cell cycle, inflammation and WNT signaling pathways. Chromatin immunoprecipitation assays revealed that MITF targets the promoters of FZD7, PTGR1 and ANXA1. Moreover, silencing FZD7 reduces the invasiveness that is promoted by silencing MITF. Strikingly, MITF has significantly inverse correlations with the expression of its downstream genes in lung adenocarcinoma. In summary, we demonstrate the suppressive role of MITF in lung cancer progression, which is opposite to the canonical oncogenic function of MITF in melanoma.

Effects of RF pulse profile and intra-voxel phase dispersion on MR fingerprinting with balanced SSFP readout.

PURPOSE: To investigate possible errors in T1 and T2 quantification via MR fingerprinting with balanced steady-state free precession readout in the presence of intra-voxel phase dispersion and RF pulse profile imperfections, using computer simulations based on Bloch equations. MATERIALS AND METHODS: A pulse sequence with TR changing in a Perlin noise pattern and a nearly sinusoidal pattern of flip angle following an initial 180-degree inversion pulse was employed. Gaussian distributions of off-resonance frequency were assumed for intra-voxel phase dispersion effects. Slice profiles of sinc-shaped RF pulses were computed to investigate flip angle profile influences. Following identification of the best fit between the acquisition signals and those established in the dictionary based on known parameters, estimation errors were reported. In vivo experiments were performed at 3T to examine the results. RESULTS: Slight intra-voxel phase dispersion with standard deviations from 1 to 3Hz resulted in prominent T2 under-estimations, particularly at large T2 values. T1 and off-resonance frequencies were relatively unaffected. Slice profile imperfections led to under-estimations of T1, which became greater as regional off-resonance frequencies increased, but could be corrected by including slice profile effects in the dictionary. Results from brain imaging experiments in vivo agreed with the simulation results qualitatively. CONCLUSION: MR fingerprinting using balanced SSFP readout in the presence of intra-voxel phase dispersion and imperfect slice profile leads to inaccuracies in quantitative estimations of the relaxation times.

De-aliasing for signal restoration in Propeller MR imaging.

PURPOSE: Objects falling outside of the true elliptical field-of-view (FOV) in Propeller imaging show unique aliasing artifacts. This study proposes a de-aliasing approach to restore the signal intensities in Propeller images without extra data acquisition. MATERIALS AND METHODS: Computer simulation was performed on the Shepp-Logan head phantom deliberately placed obliquely to examine the signal aliasing. In addition, phantom and human imaging experiments were performed using Propeller imaging with various readouts on a 3.0 Tesla MR scanner. De-aliasing using the proposed method was then performed, with the first low-resolution single-blade image used to find out the aliasing patterns in all the single-blade images, followed by standard Propeller reconstruction. The Propeller images without and with de-aliasing were compared. RESULTS: Computer simulations showed signal loss at the image corners along with aliasing artifacts distributed along directions corresponding to the rotational blades, consistent with clinical observations. The proposed de-aliasing operation successfully restored the correct images in both phantom and human experiments. CONCLUSION: The de-aliasing operation is an effective adjunct to Propeller MR image reconstruction for retrospective restoration of aliased signals.

Influence of amplitude-related perfusion parameters in the parotid glands by non-fat-saturated dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: To verify whether quantification of parotid perfusion is affected by fat signals on non-fat-saturated (NFS) dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and whether the influence of fat is reduced with fat saturation (FS). METHODS: This study consisted of three parts. First, a retrospective study analyzed DCE-MRI data previously acquired on different patients using NFS (n = 18) or FS (n = 18) scans. Second, a phantom study simulated the signal enhancements in the presence of gadolinium contrast agent at six concentrations and three fat contents. Finally, a prospective study recruited nine healthy volunteers to investigate the influence of fat suppression on perfusion quantification on the same subjects. Parotid perfusion parameters were derived from NFS and FS DCE-MRI data using both pharmacokinetic model analysis and semiquantitative parametric analysis. T tests and linear regression analysis were used for statistical analysis with correction for multiple comparisons. RESULTS: NFS scans showed lower amplitude-related parameters, including parameter A, peak enhancement (PE), and slope than FS scans in the patients (all with P < 0.0167). The relative signal enhancement in the phantoms was proportional to the dose of contrast agent and was lower in NFS scans than in FS scans. The volunteer study showed lower parameter A (6.75 ± 2.38 a.u.), PE (42.12% ± 14.87%), and slope (1.43% ± 0.54% s(-1)) in NFS scans as compared to 17.63 ± 8.56 a.u., 104.22% ± 25.15%, and 9.68% ± 1.67% s(-1), respectively, in FS scans (all with P < 0.005). These amplitude-related parameters were negatively associated with the fat content in NFS scans only (all with P < 0.05). CONCLUSIONS: On NFS DCE-MRI, quantification of parotid perfusion is adversely affected by the presence of fat signals for all amplitude-related parameters. The influence could be reduced on FS scans.

Temporal Evolution of Parotid Volume and Parotid Apparent Diffusion Coefficient in Nasopharyngeal Carcinoma Patients Treated by Intensity-Modulated Radiotherapy Investigated by Magnetic Resonance Imaging: A Pilot Study.

PURPOSE: To concurrently quantify the radiation-induced changes and temporal evolutions of parotid volume and parotid apparent diffusion coefficient (ADC) in nasopharyngeal carcinoma (NPC) patients treated by intensity-modulated radiotherapy by using magnetic resonance imaging (MRI). MATERIALS AND METHODS: A total of 11 NPC patients (9 men and 2 women; 48.7 ± 11.7 years, 22 parotid glands) were enrolled. Radiation dose, parotid sparing volume, severity of xerostomia, and radiation-to-MR interval (RMI) was recorded. MRI studies were acquired four times, including one before and three after radiotherapy. The parotid volume and the parotid ADC were measured. Statistical analysis was performed using SPSS and MedCalc. Bonferroni correction was applied for multiple comparisons. A P value less than 0.05 was considered as statistically significant. RESULTS: The parotid volume was 26.2 ± 8.0 cm(3) before radiotherapy. The parotid ADC was 0.8 ± 0.15 × 10(-3) mm(2)/sec before radiotherapy. The parotid glands received a radiation dose of 28.7 ± 4.1 Gy and a PSV of 44.1 ± 12.6%. The parotid volume was significantly smaller at MR stage 1 and stage 2 as compared to pre-RT stage (P < .005). The volume reduction ratio was 31.2 ± 13.0%, 26.1 ± 13.5%, and 17.1 ± 16.6% at stage 1, 2, and 3, respectively. The parotid ADC was significantly higher at all post-RT stages as compared to pre-RT stage reciprocally (P < .005 at stage 1 and 2, P < .05 at stage 3). The ADC increase ratio was 35.7 ± 17.4%, 27.0 ± 12.8%, and 20.2 ± 16.6% at stage 1, 2, and 3, respectively. The parotid ADC was negatively correlated to the parotid volume (R = -0.509; P < .001). The parotid ADC was positively associated with the radiation dose significantly (R(2) = 0.212; P = .0001) and was negatively associated with RMI significantly (R(2) = 0.203; P = .00096) significantly. Multiple regression analysis further showed that the post-RT parotid ADC was related to the radiation dose and RMI significantly (R(2) = 0.3580; P < .0001). At MR stage 3, the parotid volume was negatively associated with the dry mouth grade significantly (R(2) = 0.473; P < .0001), while the parotid ADC was positively associated with the dry mouth grade significantly (R(2) = 0.288; P = .015). CONCLUSION: Our pilot study successfully demonstrates the concurrent changes and temporal evolution of parotid volume and parotid ADC quantitatively in NPC patients treated by IMRT. Our results suggest that the reduction of parotid volume and increase of parotid ADC are dominated by the effect of acinar loss rather than edema at early to intermediate phases and the following recovery of parotid volume and ADC toward the baseline values might reflect the acinar regeneration of parotid glands.

Effects of gender, age, and body mass index on fat contents and apparent diffusion coefficients in healthy parotid glands: an MRI evaluation.

OBJECTIVES: To establish standard apparent diffusion coefficient (ADC) and the fat content as a function of age, gender and body mass index (BMI) in healthy parotid glands, and to address the influences of fat suppression on ADC measurements. METHODS: A total of 100 healthy adults (gender and age evenly distributed) were prospectively recruited, with parotid fat content measured from gradient-echo images with fat-water separated using iterative decomposition with echo asymmetry and least squares (IDEAL). The ADCs were estimated using both fat-saturated and non-fat-saturated diffusion-weighted imaging via a periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) technique. RESULTS: Parotid fat content was larger in men than in women by about 10 percentage points (P < 0.005), and positively associated with BMI and age for both genders (mostly with P < 0.001). ADCs estimated with non-fat-saturated PROPELLER were significantly lower in men than in women (P < 0.005), but showed no gender difference if measured using fat-saturated PROPELLER (P = 0.840). The negative association between parotid ADC and age/BMI/fat (P < 0.001) showed greater regression slopes in non-fat-saturated PROPELLER than in fat-saturated data. CONCLUSIONS: Parotid fat content in healthy adults correlates positively with both age and BMI; the correlation with age is gender-dependent. Parotid ADC measurements are strongly influenced by fat saturation. KEY POINTS: Parotid fat content in healthy adults correlates positively with age and BMI. The rate of aging-related increase in fat contents is gender-dependent. Parotid ADC measurements are strongly influenced by fat saturation.

Parotid perfusion in nasopharyngeal carcinoma patients in early-to-intermediate stage after low-dose intensity-modulated radiotherapy: evaluated by fat-saturated dynamic contrast-enhanced magnetic resonance imaging.

PURPOSE: To investigate parotid perfusion in early-to-intermediate stage after parotid-sparing radiation dose using fat-saturated DCE-MRI, and to verify whether the perfusion alteration was related to radiation dose and the PSV. METHODS AND MATERIALS: Thirty-two parotid glands from 16 consecutive patients with pathologically proven nasopharyngeal carcinoma treated by IMRT were examined. The parotid glands received a radiation dose of 28.9±3.9Gy with a PSV of 43.1%±13.9%. Perfusion parameters were calculated using time-shifted Brix model from fat-saturated DCE-MRI data before (pre-RT) and in early-to-intermediate stage after (post-RT) IMRT. Paired t-test was used to evaluate perfusion changes, while Pearson's correlation test was used to examine perfusion dependency on radiation dose and PSV. For multiple comparisons Bonferroni correction was applied. RESULTS: Successful fat saturation was achieved in 29 of 32 parotid glands. Compared with pre-RT, the post-RT parotid glands showed significantly higher A, peak enhancement, and wash-in slope, plus a lower Kel, suggesting a mixed effect of increased vascular permeability and acinar loss. Linear regression showed that peak enhancement was positively associated with radiation dose in post-RT parotid glands. Kel and slope were negatively associated with PSV, while time-to-peak was positively associated with PSV significantly. CONCLUSIONS: Our results suggest that time-shifted Brix model is feasible for quantifying parotid perfusion using DCE-MRI. The perfusion alterations in early-to-intermediate stage after IMRT might be related to a mixed effect of increased vascular permeability and acinar loss with dose and PSV dependencies.

Parotid fat contents in healthy subjects evaluated with iterative decomposition with echo asymmetry and least squares fat-water separation.

PURPOSE: To evaluate the effectiveness of three fat measurement methods for parotid glands in healthy subjects, with or without metallic dental implants. MATERIALS AND METHODS: The institutional review board approved this study, with informed consent obtained from 114 volunteers undergoing magnetic resonance (MR) imaging at 1.5 T. Fat-saturated (FS) and non-fat-saturated (NFS) fast spin-echo T1-weighted imaging (T1 method), FS and NFS T2-weighted periodically rotated overlapping parallel lines with enhanced reconstruction fast spin-echo imaging (T2 method), and gradient-echo imaging with fat-water separation using iterative decomposition with echo asymmetry and least squares (IDEAL) method were used to derive parotid fat contents. Two raters examined the homogeneity of fat saturation to determine whether parotid fat quantification was successful, with the success rate in the 114 subjects recorded for each protocol. In subjects whose fat quantification was successful with all three imaging methods, linear regression was used to analyze the correlation between any pair of the three parotid fat content measurement methods. RESULTS: Success rates in parotid fat measurements by using T1, T2, and IDEAL methods were 87.7% (100 of 114), 87.7% (100 of 114), and 100% (114 of 114), respectively. The means of measured parotid fat contents revealed significant differences (P < .001) between any pair of the three measurement methods. The parotid fat contents measured with the three methods were significantly correlated with each other between any pair of combinations. CONCLUSION: The IDEAL method provided a high success rate for parotid fat measurements, even in subjects with metallic dental implants.