Sinonasal mucosal melanoma treatment response assessment to immune checkpoint inhibitors using hybrid positron emission tomography imaging.

The purpose of this retrospective study was to investigate response of sinonasal mucosal melanoma (SMM) patients to treatment with immune checkpoint inhibitors (ICI), using hybrid PET imaging. Fifteen SMM patients underwent hybrid PET imaging before and three months after initiation of ICI. The disease-specific survival (DSS) was calculated. Quantitative PET parameters of the primary tumor and their association with DSS and therapy response were investigated. Nine of the fifteen (60%) patients responded to ICI therapy. Patients with therapy response depicted on hybrid PET imaging had better DSS than those without (p = 0.0058). Quantitative PET parameters of the initial PET harbored no association with DSS or therapy response. However, these findings lack of sufficient statistical power and must be interpreted with caution. The first restaging PET-imaging after ICI initiation can help stratify patients with regard to DSS.

Outcome analysis in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy with Lu-177-DOTATATE.

Background: Patients with neuroendocrine tumors (NET) of the gastroenteropancreatic tract (GEP-NET) were effectively treated with peptide receptor radionuclide therapy (PRRT) with Lu-177-DOTATATE in the NETTER-1 trial. The aim of this study was to assess the outcome of metastatic GEP-NET patients within a European Neuroendocrine Tumor Society (ENETS) certified center of excellence after this treatment. Methods: A total of 41 GEP-NET patients who received PRRT with Lu-177-DOTATATE between 2012 and 2017 at a single center were included in this analysis. Data on pre- and post-PRRT treatments [selective internal radiation therapy (SIRT), somatostatin analogue therapy (SSA), blood parameters, patient symptomatic burden and overall survival] was extracted from patient records. Results: Overall, PRRT was well tolerated and did not increase patient symptomatic burden. Blood parameters were not significantly affected by PRRT (means before and after therapy: hemoglobin: 125.4 vs. 122.3 mg/L, P=0.201; creatinine: 73.8 vs. 77.7 µmol/L, P=0.146), while leukocytes (6.6 vs. 5.6 G/L, P<0.01) and platelets (269.9 vs. 216.7 G/L, P<0.001) were significantly decreased yet without clinical significance in our study. Seven of 9 patients with SIRT treatment prior to PRRT were deceased (mortality odds ratio =4.083). The mortality odds ratio of patients with a pancreatic tumor and SIRT was 1.33 compared to patients with a different tumor origin. 6 of 15 patients (40%) with post-PRRT SSA were deceased (mortality odds ratio =0.429 without SSA after PRRT). Conclusions: Patients with advanced GEP-NET might benefit from PRRT with Lu-177-DOTATATE as it can provide a valuable treatment modality in advanced disease stages. Safety profiles of PRRT were manageable without increasing the symptomatic burden. SIRT before PRRT or lack of SSA after PRRT seem to impair the response and reduce survival.

A descriptive analysis of the characteristics, treatment response and prognosis of hepatic dominant solid tumors undergoing selective internal radiation therapy (SIRT).

Background: Selective internal radiotherapy is widely used for liver dominant diseases of solid tumors. However, data about sequential treatment and prognostic factors are lacking. Methods: We consecutively included all 209 patients who received a selective internal radiotherapy intervention between January 2015 and May 2019. A retrospective analysis of their electronic patient records was performed regarding diagnosis of cancer, previous therapies and applied radioactive activity. A multicenter follow-up at least 6 weeks after intervention to assess radiological response and irregular subsequent follow-ups to asses disease progression were conducted. In addition, subgroup analyses were carried out. Results: The most frequently treated indications were hepatocellular carcinoma (37%), colorectal cancers (14%), neuroendocrine tumors (9%), and breast cancer (8%). In hepatocellular carcinoma, selective internal radiotherapy was most performed without prior systemic therapy (40%), and for the remaining indications, most often after surgery with systemic therapy in sequence. Local radiological response, defined as either regression or stable disease, was assessed at least 6 weeks after intervention and showed 52% across all indications. Hepatocellular carcinoma (59%) and breast cancer (67%) showed an excellent, colorectal cancers (29%) a particularly poor response rate. Neuroendocrine tumors showed the third longest median post-selective internal radiation therapy (SIRT) survival with 12.4 months and the second longest median progression-free time with 5.2 months. Hepatocellular carcinoma showed even better results with a post-SIRT survival of 15.7 months and a median progression-free time of 5.3 months. Pancreatic neuroendocrine tumors showed significantly worse outcomes than other neuroendocrine tumors, regarding median post-SIRT survival and median progression-free time. No relevant SIRT related differences among sexes were detected. Conclusions: Patients with neuroendocrine tumors, breast cancer in late therapy lines and early-stage hepatocellular carcinoma seem to show better responses to SIRT than other entities. Colorectal cancers were mainly treated with SIRT in a second or third therapy line but with considerably weaker results than other entities.

Radiation dose reduction with deep-learning image reconstruction for coronary computed tomography angiography.

OBJECTIVES: Deep-learning image reconstruction (DLIR) offers unique opportunities for reducing image noise without degrading image quality or diagnostic accuracy in coronary CT angiography (CCTA). The present study aimed at exploiting the capabilities of DLIR to reduce radiation dose and assess its impact on stenosis severity, plaque composition analysis, and plaque volume quantification. METHODS: This prospective study includes 50 patients who underwent two sequential CCTA scans at normal-dose (ND) and lower-dose (LD). ND scans were reconstructed with Adaptive Statistical Iterative Reconstruction-Veo (ASiR-V) 100%, and LD scans with DLIR. Image noise (in Hounsfield units, HU) and quantitative plaque volumes (in mm3) were assessed quantitatively. Stenosis severity was visually categorized into no stenosis (0%), stenosis (< 20%, 20-50%, 51-70%, 71-90%, 91-99%), and occlusion (100%). Plaque composition was classified as calcified, non-calcified, or mixed. RESULTS: Reduction of radiation dose from ND scans with ASiR-V 100% to LD scans with DLIR at the highest level (DLIR-H; 1.4 mSv vs. 0.8 mSv, p < 0.001) had no impact on image noise (28 vs. 27 HU, p = 0.598). Reliability of stenosis severity and plaque composition was excellent between ND scans with ASiR-V 100% and LD scans with DLIR-H (intraclass correlation coefficients of 0.995 and 0.974, respectively). Comparison of plaque volumes using Bland-Altman analysis revealed a mean difference of - 0.8 mm3 (± 2.5 mm3) and limits of agreement between - 5.8 and + 4.1 mm3. CONCLUSION: DLIR enables a reduction in radiation dose from CCTA by 43% without significant impact on image noise, stenosis severity, plaque composition, and quantitative plaque volume. KEY POINTS: •Deep-learning image reconstruction (DLIR) enables radiation dose reduction by over 40% for coronary computed tomography angiography (CCTA). •Image noise remains unchanged between a normal-dose CCTA reconstructed by ASiR-V and a lower-dose CCTA reconstructed by DLIR. •There is no impact on the assessment of stenosis severity, plaque composition, and quantitative plaque volume between the two scans.

Comparison of MR Ultrashort Echo Time and Optimized 3D-Multiecho In-Phase Sequence to Computed Tomography for Assessment of the Osseous Craniocervical Junction.

BACKGROUND: To assess changes of the craniocervical junction (CCJ), computed tomography (CT) is considered the reference standard. Recent advances in bone depiction on magnetic resonance imaging (MRI) enable high-quality visualization of osseous structures. Consequently, MRI may serve as an alternative to CT, without the use of ionizing radiation. PURPOSE: To compare two MRI sequences optimized for bone visualization to the CT reference standard in the assessment of the osseous CCJ. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Twenty-seven decedents and five healthy volunteers. FIELD STRENGTH/SEQUENCE: 3T/ultrashort-echo time gradient echo (UTE) and optimized 3D-multiecho in-phase gradient echo sequences (FRACTURE). ASSESSMENT: All decedents were scanned with both MRI sequences and CT. Three observers rated degeneration to obtain a score for the upper (atlanto-dental and left/right atlanto-occipital joint) and for the lower part of the CCJ (left and right atlanto-axial joint). Two reader rated the following quantitative parameters: basion-axial-interval, atlanto-dental-interval, atlanto-occipital-interval, Powers-ratio, and signal/contrast-to-noise-ratio. As a proof of concept, five healthy volunteers were scanned with both MRI sequences. STATISTICAL TESTS: Degeneration was assessed on a Likert scale by three independent observers. Interrater and intermodality reliability were calculated using an intraclass correlation coefficient. To compare distance measurements between examination methods, a Friedman test, between-degenerative ratings, and a Kruskal-Wallis test were performed. RESULTS: Degenerative ratings of the CCJ between MRI sequences and CT showed a good interrater and intermodality agreement. MRI sequences tended to underestimate the degree of degeneration compared to CT, and this became more marked with increasing degeneration severity. There were no significant relationships between distance measurements and the degree of degeneration (PCT = 0.62, PUTE = 0.64, PFRACTURE = 0.67). The in vivo examination proved the feasibility of both MRI methods in a clinical setting. DATA CONCLUSION: Quantitative and qualitative ratings on MR images were comparable to CT images; thus, MRI may be a valid alternative to CT assessing the CCJ. LEVEL OF EVIDENCE: 1. TECHNICAL EFFICACY STAGE: 3.

Prognostic value of O-(2-[18F]-fluoroethyl)-L-tyrosine PET in relapsing oligodendroglioma.

PURPOSE: To assess the relationship between F-18-fluoro-ethyl-tyrosine positron emission tomography (FET-PET) parameters of relapsing oligodendroglioma and progression-free survival. MATERIAL AND METHODS: The relationship of clinical parameters, FET-PET parameters (SUVmax, TBRmax, BTV, time-activity curves) and progression-free survival was analyzed using univariate and multivariate analysis in 42 adult patients with relapsing oligodendroglioma. Kaplan-Meier analysis was used to assess survival. RESULTS: Patients who did not undergo surgical resection of their relapsing tumor had significantly lower PFS if the tumor exhibited an SUVmax above 3.40 than those with an SUVmax below 3.40 (13.1 ± 2.3 months vs. 47.3 ± 6.0 months, respectively, p < .001). Patients who underwent surgery had similar PFS as the aforementioned non-operated patients with low SUVmax (53.6 ± 6.7 months, p = .948). The same was true for TBRmax using a threshold of 3.03 (PFS 12.5 ± 2.4 months vs. 44.0 ± 6.3 months / 53.6 ± 6.7 months, respectively; p < .001 / p = .825). Also, subjects with BTV below 10 cm3 that did not undergo surgery had a similar PFS as subjects who underwent surgery (40.2 ± 6.0 months vs. 52.4 ± 8.9 months, respectively, p = .587). Subjects with BTV above 10 cm3 and without surgery had a significantly worse PFS (13.8 ± 3.3 months, p < .001). Multivariate analysis showed that the prognostication by clinical parameters is improved by adding TBRmax to the model (AUC 0.945 (95% CI: 0.881-1.000), true classification rate 88.1%). CONCLUSION: FET-PET may provide added value for the prognostication of relapsing oligodendroglioma in addition to clinical parameters.

Outpatient Yttrium-90 microsphere radioembolization: assessment of radiation safety and quantification of post-treatment adverse events causing hospitalization.

PURPOSE: Quantification of post-interventional adverse events of outpatient SIRT leading to hospitalization and quantification of radiation exposure. MATERIALS AND METHODS: In this single-center, retrospective cohort study, we reviewed 212 patients treated with SIRT (90Y-microspheres) for primary and secondary liver malignancies. We searched for adverse events (AEs) and serious adverse events (SAEs), defined as AE's causing hospitalization. Additionally, radiation exposure was measured in 36 patients. RESULTS: Seven patients had an SAE (3.3%), four patients had AE without readmission/hospitalization (1.9%) and 201 patients had no complications (94.8%). The mean ambient dose rate at 1 m distance from the source after administration of 90Y-microspheres was 1.88 µSv/h ± 0.74 (± SD) with a range from 4.3 to 0.2 µSv/h. CONCLUSION: Outpatient radioembolization with 90Y-microspheres is safe and requires hospitalization only in a very small number of patients. The mean dose rate was low and met the national conditions for outpatient treatment (< 5 µSv/h).

Impact of different image reconstructions on PET quantification in non-small cell lung cancer: a comparison of adenocarcinoma and squamous cell carcinoma.

OBJECTIVE:: Positron emission tomography (PET) using 18F-fludeoxyglucose (18F-FDG) is an established imaging modality for tumor staging in patients with non-small cell lung cancer (NSCLC). There is a growing interest in using 18F-FDG PET for therapy response assessment in NSCLC which relies on quantitative PET parameters such as standardized uptake values (SUV). Different reconstruction algorithms in PET may affect SUV. We sought to determine the variation of SUV in patients with NSCLC when using ordered subset expectation maximization (OSEM) and block sequential regularized expectation maximization (BSREM) in latest-generation digital PET/CT, including a subanalysis for adenocarcinoma and squamous cell carcinoma. METHODS:: A total of 58 patients (34 = adenocarcinoma, 24 = squamous cell carcinoma) who underwent a clinically indicated 18F-FDG PET/CT for staging were reviewed. PET images were reconstructed with OSEM and BSREM reconstruction with noise penalty strength ß-levels of 350, 450, 600, 800 and 1200. Lung tumors maximum standardized uptake value (SUVmax) were compared. RESULTS:: Lung tumors SUVmax were significantly lower in adenocarcinomas compared to squamous cell carcinomas in all reconstructions evaluated (all p < 0.01). Comparing BSREM to OSEM, absolute SUVmax differences were highest in lower ß-levels of BSREM with + 2.9 ± 1.6 in adenocarcinoma and + 4.0 ± 2.9 in squamous cell carcinoma (difference between histology; p-values > 0.05). There was a statistically significant difference of the relative increase of SUVmax in adenocarcinoma (mean + 34.8%) and squamous cell carcinoma (mean 23.4%), when using BSREM350 instead of OSEMTOF (p < 0.05). CONCLUSION:: In NSCLC the relative change of SUV when using BSREM instead of OSEM is significantly higher in adenocarcinoma as compared to squamous cell carcinoma. ADVANCES IN KNOWLEDGE:: The impact of BSREM on SUV may vary in different histological subtypes of NSCLC. This highlights the importance for careful standardization of ß-value used for serial 18F-FDG PET scans when following-up NSCLC patients.

Magnetisation transfer as a biomarker for chronic airway fibrosis in a mouse lung transplantation model.

BACKGROUND: Chronic airway fibrosis (CAF) is the most prevalent complication in human lung transplant recipients. The aim of the study is to evaluate magnetisation transfer (MT) as a biomarker of developing CAF of lung transplants in a mouse model. METHODS: Lung transplantation was performed in 48 mice, applying major or minor histocompatibility mismatches between strains for the induction of CAF. MT measurements were performed in vivo with systematic variation of off-resonance frequencies and flip angle of the MT prepulse. MT ratios (MTRs) were compared for lungs showing CAF and without CAF. RESULTS: Seven out of 24 animals (29%) showed a pattern of CAF at histology. All mice developing CAF also showed signs of acute rejection, whereas none of the lungs showed signs of other post-transplant complications. After lung transplantation, pulmonary infiltration was a frequent finding (14 out of 24) exhibiting a higher MTR (24.8% ± 4.5%) compared to well-ventilated lungs (12.3% ± 6.9%, p = 0.001) at 8000 Hz off-resonance frequency, 3000° flip angle. In infiltrated lung tissue exhibiting CAF, lower MTR values (21.8% ± 5.7%) were found compared to infiltrated lungs showing signs of acute rejection alone (26.5% ± 2.9%, p = 0.028), at 8000 Hz, 3000° flip angle. The highest MTR values were observed at 3000° flip angle, using a 1000 Hz off-resonance frequency. CONCLUSION: MTR might serve as a tool for the detection of CAF in infiltrated lung tissue.

Chronic Airway Fibrosis in Orthotopic Mouse Lung Transplantation Models-An Experimental Reappraisal.

BACKGROUND: Several mouse lung transplantation (Tx) models have been proposed for the study of chronic airway fibrosis (CAF), the most prevalent complication seen in human lung transplant recipients, termed chronic lung allograft dysfunction. Alternatively, it has been called for to establish an experimental animal model for restrictive allograft syndrome, another phenotype of chronic lung allograft dysfunction. However, these mouse transplant models exhibit significant heterogeneity in consistency and reproducibility. We therefore aimed at reevaluating current available models. METHODS: Four different Tx combinations were used that manifest CAF: 2 minor antigen-mismatched Tx combinations (MINOR, donor: C57BL/10, recipient: C57BL/6J); or MINOR-N using recipient C57BL/6N, major histocompatibility antigen-mismatched immunosuppressed Tx (MAJOR, donor: BALB/c, recipient: C57BL/6J), and syngeneic Tx (donor and recipient: C57BL/6J) as control. The recipients were harvested and analyzed at week 8. Oxygenation, histology, reverse transcription polymerase chain reaction, and magnetic resonance imaging were performed to analyze outcome of those models. RESULTS: The most prominent manifestation of CAF, thickest subepithelial fibrotic changes, worst oxygenation, and the most severe acute rejection were detected in the MAJOR group compared with all other (P < 0.05). Gene expressions of TNF-α and TGF-ß1 were higher, and IL-10 was lower in the MAJOR group. Immunohistochemistry found pleuroparenchymal fibrotic change in both the MAJOR and MINOR-J groups. CONCLUSIONS: We propose the major mismatch model under mild immunosuppression as the most suitable model for studying posttransplant CAF, and both the major and minor mismatch models for the restrictive phenotype.

A Micro CT Study in Patients with Breast Microcalcifications Using a Mathematical Algorithm to Assess 3D Structure.

PURPOSE: The aim of this study was to evaluate the relevance of the three-dimensional (3D) structure of breast microcalcifications (MC) as a predictor of malignancy using highly resolved micro-computed tomography (micro-CT) datasets of biopsy samples. MATERIAL AND METHODS: The study included 28 women with suspicious MC in their mammogram undergoing vacuum-assisted biopsy. Directly after the intervention, the specimens were scanned in a micro-CT with an isometric spatial resolution of 9 µm. Datasets were analysed regarding the number, volume and morphology of suspicious non-monomorphic MC (fl-fine linear, fp-fine pleomorphic, ch-coarse heterogeneous) and the structure model index (SMI). Histological evaluation was performed according to the B-classification: normal tissue or benign (group A: B1, B2), unclear malignant potential or suspicious of malignancy (group B: B3, B4) and malignant lesions (group C: B5). RESULTS: In all groups, suspicious non-monomorphic MC were found: group A exhibited fp MC in 38.5% of samples, no fl/ch; group B: fl 14.3%, fp 28.6%, ch 14.3%; group C always had at least one type of suspicious non-monomorphic MC (fl (57.1%) or fp (57.1%)) in each sample. The different histologic groups showed a similar mean SMI (benign: 2.97 ± 0.31, malignant: 3.02 ± 0.10, unclear: 2.90 ± 0.28). Between the three groups, no significant differences were found regarding number, volume or SMI value of MC. CONCLUSION: 3D structure based on the SMI of MC analysed with highest spatial resolution is not significantly associated with the B-classification of breast lesions. Thus, magnification views of MC may be omitted in the analysis of MC detected in mammograms.

Neer Award 2016: reduced muscle degeneration and decreased fatty infiltration after rotator cuff tear in a poly(ADP-ribose) polymerase 1 (PARP-1) knock-out mouse model.

BACKGROUND: Disturbed muscular architecture, atrophy, and fatty infiltration remain irreversible in chronic rotator cuff tears even after repair. Poly (adenosine 5'-diphosphate-ribose) polymerase 1 (PARP-1) is a key regulator of inflammation, apoptosis, muscle atrophy, muscle regeneration, and adipocyte development. We hypothesized that the absence of PARP-1 would lead to a reduction in damage to the muscle subsequent to combined tenotomy and neurectomy in a PARP-1 knockout (KO) mouse model. METHODS: PARP-1 KO and wild-type C57BL/6 (WT group) mice were analyzed at 1, 6, and 12 weeks (total n = 84). In all mice, the supraspinatus and infraspinatus muscles of the left shoulder were detached and denervated. Macroscopic analysis, magnetic resonance imaging, gene expression analysis, immunohistochemistry, and histology were used to assess the differences in PARP-1 KO and WT mice. RESULTS: The muscles in the PARP-1 KO group had significantly less retraction, atrophy, and fatty infiltration after 12 weeks than in the WT group. Gene expression of inflammatory, apoptotic, adipogenic, and muscular atrophy genes was significantly decreased in PARP-1 KO mice in the first 6 weeks. DISCUSSION: Absence of PARP-1 leads to a reduction in muscular architectural damage, early inflammation, apoptosis, atrophy, and fatty infiltration after combined tenotomy and neurectomy of the rotator cuff muscle. Although the macroscopic reaction to injury is similar in the first 6 weeks, the ability of the muscles to regenerate was much greater in the PARP-1 KO group, leading to a near-normalization of the muscle after 12 weeks.

Simultaneous Multislice Diffusion-Weighted Imaging of the Kidney: A Systematic Analysis of Image Quality.

OBJECTIVES: The aims of this study were to implement a protocol for simultaneous multislice (SMS) accelerated diffusion-weighted imaging (DWI) of the kidneys and to perform a systematic analysis of image quality of the data sets. MATERIALS AND METHODS: Ten healthy subjects and 5 patients with renal masses underwent DWI of the kidney in this prospective institutional review board-approved study on a 3 T magnetic resonance scanner. Simultaneous multislice DWI echo-planar sequences (acceleration factors [AFs] 2 and 3) were compared with conventional echo-planar DWI as reference standard for each acquisition scheme. The following 3 acquisition schemes were applied: comparison A, with increased number of acquisitions at constant scan time; comparison B, with reduction of acquisition time; and comparison C, with increased slice resolution (constant acquisition time, increasing number of slices). Interreader reliability was analyzed by calculating the intraclass correlation coefficient (ICC). Qualitative image quality features were evaluated by 2 independent radiologists on a 5-point Likert scale. Quantification accuracy of the apparent diffusion coefficients (ADCs) and signal-to-noise ratios (SNRs) were assessed by region of interest analysis. Furthermore, lesion conspicuity in the 5 patients was assessed using a 5-point Likert scale by 2 independent radiologists. RESULTS: Interreader agreement was substantial with an ICC of 0.68 for the overall image quality and an ICC of 0.73 for the analysis of artifacts. In comparison A, AF2 resulted in increased SNR (P < 0.05) by 21% at stable image quality scores (image quality: P = 0.76, artifacts: P = 0.21). In comparison B, applying AF2, the scan time could be reduced by 46% without significant reduction in qualitative image quality scores (P = 0.059) or SNR (P = 0.126). In comparison C, slice resolution could be improved by 28% using AF2 with stable image quality scores and SNR. In general, AF3 resulted in reduced image quality and SNR. Significantly reduced ADC values were observed for AF3 in comparison C (cortex: P = 0.003; medulla: P = 0.001) compared with the standard echo-planar imaging sequence. The conventional DWI and the SMS DWI with AF2 showed stable lesion conspicuity ([AF1/AF2]: reader 1 [1.8/1.4] and reader 2 [1.8/1.4]). The lesion conspicuity was lower using AF3 (reader 1: 2.2 and reader 2: 1.8). CONCLUSIONS: In conclusion, SMS DWI of the kidney is a potential tool to substantially reduce scan time without negative effects on SNR, ADC quantification accuracy, and image quality if an AF2 is used. Although AF3 results in even higher scan time reduction, a negative impact on image quality, SNR, ADC quantification accuracy, and lesion conspicuity must be considered.

Separation of collagen-bound and porous bone-water longitudinal relaxation in mice using a segmented inversion recovery zero-echo-time sequence.

PURPOSE: Cortical bone mechanical properties are related to the collagen-bound water (CBW) and pore water (PW) components of cortical bone. The study evaluates the feasibility of zero-echo-time imaging in mice in vivo for longitudinal relaxation time (T1) measurements in cortical bone and separation of CBW and PW components. METHODS: Zero-echo-time data were acquired at 4.7 Tesla in six mice with 14 different inversion times (0-2,600 ms). Region-of-interest analysis was performed at level of femur diaphysis. The T1 of cortical bone and of CBW (T1cbw) and PW (T1pw) as well as the CBW fraction (cbwf) was computed using a mono-exponential and a bi-exponential fitting approach, respectively. The sum of the squared residuals (Res) to the fit was provided for both approaches. RESULTS: For the mono-exponential model, mean T1 ± standard deviation (SD) was 1,057 ± 160 ms. The bi-exponential approach provided a reliable separation of two different bone-water components, with a mean T1cbw of 213 ± 95 ms, T1pw of 2,152 ± 894 ms, and cbwf of 7.4 ± 2.7 %. Lower Res was obtained with bi-exponential approach (P < 0.001), and Res mean values ± SD were 0.016 ± 0.007 (bi-exponential) and 0.033 ± 0.016 (mono-exponential). CONCLUSION: Zero-echo-time imaging allows for longitudinal relaxation measurements of cortical bone in vivo in mice models, with a reliable separation of PW and CBW components using a bi-exponential curve fitting approach. Magn Reson Med 77:1909-1915, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Simultaneous multi-slice echo planar diffusion weighted imaging of the liver and the pancreas: Optimization of signal-to-noise ratio and acquisition time and application to intravoxel incoherent motion analysis.

PURPOSE: To optimize and test a diffusion-weighted imaging (DWI) echo-planar imaging (EPI) sequence with simultaneous multi-slice (SMS) excitation in the liver and pancreas regarding acquisition time (TA), number of slices, signal-to-noise ratio (SNR), image quality (IQ), apparent diffusion coefficient (ADC) quantitation accuracy, and feasibility of intravoxel incoherent motion (IVIM) analysis. MATERIALS AND METHODS: Ten healthy volunteers underwent DWI of the upper abdomen at 3T. A SMS DWI sequence with CAIPIRINHA unaliasing technique (acceleration factors 2/3, denoted AF2/3) was compared to standard DWI-EPI (AF1). Four schemes were evaluated: (i) reducing TA, (ii) keeping TA identical with increasing number of averages, (iii) increasing number of slices with identical TA (iv) increasing number of b-values for IVIM. Acquisition schemes i-iii were evaluated qualitatively (reader score) and quantitatively (ADC values, SNR). RESULTS: In scheme (i) no differences in SNR were observed (p=0.321-0.038) with reduced TA (AF2 increase in SNR/time 75.6%, AF3 increase SNR/time 102.4%). No SNR improvement was obtained in scheme (ii). Increased SNR/time could be invested in acquisition of more and thinner slices or higher number of b-values. Image quality scores were stable for AF2 but decreased for AF3. Only for AF3, liver ADC values were systematically lower. CONCLUSION: SMS-DWI of the liver and pancreas provides substantially higher SNR/time, which either may be used for shorter scan time, higher slice resolution or IVIM measurements.

Magnetization transfer as a potential tool for the early detection of acute graft rejection after lung transplantation in mice.

PURPOSE: To investigate the value of magnetization transfer (MT) measurements for assessment of acute rejection (AR) in a murine lung transplantation model. MATERIALS AND METHODS: Thirty mice including 15 C57BL/10 mice serving as donors and 15 C57BL/6 mice as recipients were examined in this study. MT imaging datasets were acquired on a 4.7 Tesla small animal MR scanner using a three-dimensional zero echo time sequence with a Gaussian-shaped MT prepulse with 1000° or 3000° flip angle and systematic variation of off-resonance frequencies between 1000 and 15,000 Hz. After image acquisition, the images were qualitatively assessed, magnetization transfer ratio (MTR) values were calculated and lungs were taken for histologic examination including staining with hematoxylin/eosin, Masson's trichrome (collagen), and α-smooth muscle (fibroproliferative tissue) staining. RESULTS: Lung transplantation was successfully performed in all 15 mice. All animals showed AR characterized by the presence of interstitial mononuclear cell infiltrates. There were significant differences of MTR in lungs with and without AR (P = 0.007). With a flip angle of 1000°, the largest differences between the MTR of healthy lungs and lungs with AR were observed for an off-resonance frequency of 10,000 Hz (difference MTR 1.80%) and 15,000 Hz (1.91%) and with a flip angle of 3000° at off-resonance frequencies of 6000 Hz (1.37%) and 8000 Hz (1.70%). CONCLUSION: MT measurements may provide a tool for the quantitative assessment of AR. J. Magn. Reson. Imaging 2016;44:1091-1098.

Diffusional kurtosis MRI of the lower leg: changes caused by passive muscle elongation and shortening.

Diffusional kurtosis MRI (DKI) quantifies the deviation of water diffusion from a Gaussian distribution. We investigated the influence of passive elongation and shortening of the lower leg muscles on the DKI parameters D (diffusion coefficient) and K (kurtosis). After approval by the local ethics committee, eight healthy volunteers (age, 29.1 ± 2.9 years) underwent MRI of the lower leg at 3 T. Diffusion-weighted images were acquired with 10 different b values at three ankle positions (passive dorsiflexion 10°, neutral position 0°, passive plantar flexion 40°). Parametrical maps of D and K were obtained by voxel-wise fitting of the signal intensities using a non-linear Levenberg-Marquardt algorithm. D and K were measured in the tibialis anterior, medial and lateral gastrocnemius, and soleus muscles. In the neutral position, D and K values were in the range between 1.66-1.79 × 10(-3) mm(2) /s and 0.21-0.39, respectively. D and K increased with passive shortening, and decreased with passive elongation, which could also be illustrated on the parametrical maps. In dorsiflexion, D (p < 0.01) and K (p = 0.036) were higher in the tibialis anterior than in the medial gastrocnemius. In plantar flexion, the opposite was found for K (p = 0.035). DKI parameters in the lower leg muscles are significantly influenced by the ankle joint position, indicating that the diffusion of water molecules in skeletal muscle deviates from a Gaussian distribution depending on muscle tonus. Copyright © 2016 John Wiley & Sons, Ltd.

Antagonizing the Hedgehog Pathway with Vismodegib Impairs Malignant Pleural Mesothelioma Growth In Vivo by Affecting Stroma.

An autocrine-driven upregulation of the Hedgehog (Hh) signaling pathway has been described in malignant pleural mesothelioma (MPM), in which the ligand, desert Hh (DHH), was produced from tumor cells. However, our investigation revealed that the Hh pathway is activated in both tumor and stroma of MPM tumor specimens and an orthotopic immunocompetent rat MPM model. This was demonstrated by positive immunohistochemical staining of Glioma-associated oncogene 1 (GLI1) and Patched1 (PTCH1) in both tumor and stromal fractions. DHH was predominantly expressed in the tumor fractions. To further investigate the role of the Hh pathway in MPM stroma, we antagonized Hh signaling in the rat model of MPM using a Hh antagonist, vismodegib, (100 mg/kg orally). Daily treatment with vismodegib efficiently downregulated Hh target genes Gli1, Hedgehog Interacting Protein (Hhip), and Ptch1, and caused a significant reduction of tumor volume and tumor growth delay. Immunohistochemical analyses revealed that vismodegib treatment primarily downregulated GLI1 and HHIP in the stromal compartment along with a reduced expression of previously described fibroblast Hh-responsive genes such as Fibronectin (Fn1) and Vegfa Primary cells isolated from the rat model cultured in 3% O2 continued to express Dhh but did not respond to vismodegib in vitro However, culture supernatant from these cells stimulated Gli1, Ptch1, and Fn1 expression in mouse embryonic fibroblasts, which was suppressed by vismodegib. Our study provides new evidence regarding the role of Hh signaling in MPM stroma in the maintenance of tumor growth, emphasizing Hh signaling as a treatment target for MPM. Mol Cancer Ther; 15(5); 1095-105. ©2016 AACR.

In vivo magnetization transfer imaging of the lung using a zero echo time sequence at 4.7 Tesla in mice: Initial experience.

PURPOSE: The aim of the present study was to assess the feasibility of magnetization transfer-prepared zero echo time (ZTE) imaging of the lung in vivo at high field strength [4.7 Tesla) T] in mice. METHODS: Eighteen C57BL/10 mice underwent MRI examinations in a 4.7T MR-scanner. A three-dimensional ZTE sequence was applied for lung imaging combined with a Gaussian MT-prepulse, which was followed by a train of 100 ZTE imaging readouts. Degree of MT was assessed by calculation of the magnetization transfer ratio (MTR). Direct saturation was estimated using Bloch equation simulations based on T1 measurements. The line-width of pulmonary tissue was estimated using T2* measurements. RESULTS: Experimental MTR-values of nonpulmonary tissues obtained with ZTE exhibited the characteristics known from conventional MT-sequences (skeletal muscle and liver: high values; fatty tissue: low values). Lung tissue demonstrated MTR-values in between fatty tissue and liver tissue. Direct saturation could be estimated by the Bloch simulation; however, an adequate approximation was only possible for T2 values nearly in the range of parenchymal organs. CONCLUSION: Pulmonary MT measurements at high field strength using the proposed MT-ZTE sequence is feasible; however, estimation of direct saturation remains challenging. Magn Reson Med 76:156-162, 2016. © 2015 Wiley Periodicals, Inc.

Whole-Body Diffusion Tensor Imaging: A Feasibility Study.

OBJECTIVE: The aim of this study was to demonstrate the feasibility of whole-body diffusion tensor imaging (DTI) as a promising tool for research applications, for instance, for investigation of systemic muscle diseases. MATERIALS AND METHODS: Twelve healthy volunteers (mean age, 26.6 years; range, 20-39 years) underwent whole-body magnetic resonance imaging at 3 T using an echo planar imaging sequence (b value, 400 s/mm) with 6 different spatial encoding directions. Coronal maps of DTI parameters including mean diffusivity, fractional anisotropy, and diffusion tensor eigenvalues (λ1-3) were generated using in-house MATLAB routines. Diffusion tensor imaging parameters were evaluated by region-of-interest analysis in skeletal muscle, cerebral gray and white matter, the kidneys, and the liver. RESULTS: The acquisition time was 79 minutes 12 seconds. The different organs could be clearly depicted on the parametrical maps. Exemplary values in skeletal muscle were mean diffusivity, 1.67 ± 0.16 × 10(-3) mm2/s; fractional anisotropy, 0.26 ± 0.03; λ1, 2.17 ± 0.20 × 10(-3) mm2/s; λ2, 1.64 ± 0.17 × 10(-3) mm2/s; and λ3, 1.22 ± 0.12 × 10(-3) mm2/s. CONCLUSION: Whole-body DTI is technically feasible. Further refinements are required to achieve a higher signal-to-noise ratio and improved spatial resolution. A possible clinical application could be the assessment of systemic myopathies.