How [18F]FDG-PET/CT Affects the Management of Patients with Differentiated Thyroid Carcinoma in Clinical Routines.

PURPOSE: To investigate the impact of [18F]FDG-PET/CT on the management of differentiated thyroid carcinoma (DTC) in routine clinical settings. MATERIAL AND METHODS: In total, 98 patients (55 females, age 56 ± 18 years) with histologically confirmed thyroid cancer, including all types of DTC and poorly differentiated thyroid cancer (PDTC, n = 7), underwent [18F]FDG-PET/CT for staging or recurrence diagnostics performed using a state-of-the art clinical scanner (Biograph mCT, Siemens Healthineers) with a standardized examination protocol. The impact of PET/CT on clinical decision making was prospectively evaluated using standardized questionnaires completed by the referring physicians before and after PET/CT. Patient outcome was analyzed for OS drawn from patient records. RESULTS: Referring physicians were unable to establish a treatment plan for 81% of patients with thyroid cancer in the absence of PET/CT. The use of PET/CT had a notable influence on patient management, leading to the development of a well-defined treatment plan for 92% of patients. Moreover, after PET/CT a change in pre-PET/CT-intended treatments occurred in 32% of cases, and further invasive diagnostic could be waived in 7% of cases. [18F]FDG-PET/CT revealed a tumor detection rate of 68% (local tumor: 19%, lymph node metastases: 40%, distant metastases: 42%). HTg levels, when stimulated via TSH, were considerably higher in patients with metastases detected on PET/CT, compared to those without metastatic findings (p = 0.02). OS was significantly worse in patients with PDTC (p = 0.002) compared to follicular thyroid cancer (FTC) and PTC or even in patients with distant metastases at first diagnosis (p = 0.03). CONCLUSIONS: This prospective registry study confirms that [18F]FDG-PET/CT used in a routine clinical setting has a very important impact on the management of patients with thyroid cancer by initiating treatments and reducing the uses of additional imaging and invasive tests.

Impact of Tracer Dose Reduction in [18 F]-Labelled Fluorodeoxyglucose-Positron Emission Tomography ([18 F]-FDG)-PET) on Texture Features and Histogram Indices: A Study in Homogeneous Tissues of Phantom and Patient.

BACKGROUND: Histogram indices (HIs) and texture features (TFs) are considered to play an important role in future oncologic PET-imaging and it is unknown how these indices are affected by changes of tracer doses. A randomized undersampling of PET list mode data enables a simulation of tracer dose reduction. We performed a phantom study to compare HIs/TFs of simulated and measured tracer dose reductions and evaluated changes of HIs/TFs in the liver of patients with PETs from simulated reduced tracer doses. Overall, 42 HIs/TFs were evaluated in a NEMA phantom at measured and simulated doses (stepwise reduction of [18 F] from 100% to 25% of the measured dose). [18 F]-FDG-PET datasets of 15 patients were simulated from 3.0 down to 0.5 MBq/kgBW in intervals of 0.25 MBq/kgBW. HIs/TFs were calculated from two VOIs placed in physiological tissue of the right and left liver lobe and linear correlations and coefficients of variation analysis were performed. RESULTS: All 42 TFs did not differ significantly in measured and simulated doses (p > 0.05). Also, 40 TFs showed the same behaviour over dose reduction regarding differences in the same group (measured or simulated), and for 26 TFs a linear behaviour over dose reduction for measured and simulated doses could be validated. Out of these, 13 TFs could be identified, which showed a linear change in TF value in both the NEMA phantom and patient data and therefore should maintain the same informative value when transferred in a dose reduction setting. Out of this Homogeneity 2, Entropy and Zone size non-uniformity are of special interest because they have been described as preferentially considerable for tumour heterogeneity characterization. CONCLUSIONS: We could show that there was no significant difference of measured and simulated HIs/TFs in the phantom study and most TFs reveal a linear behaviour over dose reduction, when tested in homogeneous tissue. This indicates that texture analysis in PET might be robust to dose modulations.

Non-invasive estimation of split renal function from routine 68Ga-SSR-PET/CT scans.

Objective: Patients with impaired kidney function are at elevated risk for nephrotoxicity and hematotoxicity from peptide receptor radionuclide therapy (PPRT) for advanced neuroendocrine tumors. Somatostatin receptor (SSR)-PET/CT imaging is the method of choice to identify sufficient SSR expression as a prerequisite for PRRT. Therefore, our study aimed to explore whether split renal function could be evaluated using imaging data from routine SSR-PET/CT prior to PRRT. Methods: In total, 25 consecutive patients who underwent SSR-PET/CT (Siemens Biograph mCT®) before PRRT between June 2019 and December 2020 were enrolled in this retrospective study. PET acquisition in the caudocranial direction started at 20 ± 0.5 min after an i.v. injection of 173 ± 20 MBq [68Ga]Ga-ha DOTATATE, and the kidneys were scanned at 32 ± 0.5 min p.i. The renal parenchyma was segmented semi-automatically using an SUV-based isocontour (SUV between 5 and 15). Multiple parameters including SUVmean of renal parenchyma and blood pool, as well as parenchyma volume, were extracted, and accumulation index (ACI: renal parenchyma volume/SUVmean) and total kidney accumulation (TKA: SUVmean x renal parenchyma volume) were calculated. All data were correlated with the reference standard tubular extraction rate (TER-MAG) from [99mTc]Tc-MAG3 scintigraphy and glomerular filtration rate (GFRCDK - EPI). Results: SUVmean of the parenchymal tracer retention showed a negative correlation with TERMAG (r: -0.519, p < 0.001) and GFRCDK - EPI (r: -0.555, p < 0.001) at 32 min p.i. The herein-introduced ACI revealed a significant correlation (p < 0.05) with the total tubular function (r: 0.482), glomerular renal function (r: 0.461), split renal function (r: 0.916), and absolute single-sided renal function (r: 0.549). The mean difference between the split renal function determined by renal scintigraphy and ACI was 1.8 ± 4.2 % points. Conclusion: This pilot study indicates that static [68Ga]Ga-ha DOTATATE PET-scans at 32 min p.i. may be used to estimate both split renal function and absolute renal function using the herein proposed "Accumulation Index" (ACI).

Whole-Body Magnetic Resonance Imaging (MRI) for Staging Melanoma Patients in Direct Comparison to Computed Tomography (CT): Results from a Prospective Positron Emission Tomography (PET)/CT and PET/MRI Study.

PURPOSE: The consideration of radiation exposure is becoming more important in metastatic melanoma due to improved prognoses. The aim of this prospective study was to investigate the diagnostic performance of whole-body (WB) magnetic resonance imaging (MRI) in comparison to computed tomography (CT) with 18F-FDG positron emission tomography (PET)/CT and 18F-PET/MRI together with a follow-up as the reference standard. METHODS: Between April 2014 and April 2018, a total of 57 patients (25 females, mean age of 64 ± 12 years) underwent WB-PET/CT and WB-PET/MRI on the same day. The CT and MRI scans were independently evaluated by two radiologists who were blinded to the patients' information. The reference standard was evaluated by two nuclear medicine specialists. The findings were categorized into different regions: lymph nodes/soft tissue (I), lungs (II), abdomen/pelvis (III), and bone (IV). A comparative analysis was conducted for all the documented findings. Inter-reader reliability was assessed using Bland-Altman procedures, and McNemar's test was utilized to determine the differences between the readers and the methods. RESULTS: Out of the 57 patients, 50 were diagnosed with metastases in two or more regions, with the majority being found in region I. The accuracies of CT and MRI did not show significant differences, except in region II where CT detected more metastases compared to MRI (0.90 vs. 0.68, p = 0.008). On the other hand, MRI had a higher detection rate in region IV compared to CT (0.89 vs. 0.61, p > 0.05). The level of agreement between the readers varied depending on the number of metastases and the specific region, with the highest agreement observed in region III and the lowest observed in region I. CONCLUSIONS: In patients with advanced melanoma, WB-MRI has the potential to serve as an alternative to CT with comparable diagnostic accuracy and confidence across most regions. The observed limited sensitivity for the detection of pulmonary lesions might be improved through dedicated lung imaging sequences.

4D-Printed Soft and Stretchable Self-Folding Cuff Electrodes for Small-Nerve Interfacing.

Peripheral nerve interfacing (PNI) has a high clinical potential for treating various diseases, such as obesity or diabetes. However, currently existing electrodes present challenges to the interfacing procedure, which limit their clinical application, in particular, when targeting small peripheral nerves (<200 µm). To improve the electrode handling and implantation, a nerve interface that can fold itself to a cuff around a small nerve, triggered by the body moisture during insertion, is fabricated. This folding is achieved by printing a bilayer of a flexible polyurethane printing resin and a highly swelling sodium acrylate hydrogel using photopolymerization. When immersed in an aqueous liquid, the hydrogel swells and folds the electrode softly around the nerve. Furthermore, the electrodes are robust, can be stretched (>20%), and bent to facilitate the implantation due to the use of soft and stretchable printing resins as substrates and a microcracked gold film as conductive layer. The straightforward implantation and extraction of the electrode as well as stimulation and recording capabilities on a small peripheral nerve in vivo are demonstrated. It is believed that such simple and robust to use self-folding electrodes will pave the way for bringing PNI to a broader clinical application.

Development of a Hybrid-Imaging-Based Prognostic Index for Metastasized-Melanoma Patients in Whole-Body 18F-FDG PET/CT and PET/MRI Data.

Besides tremendous treatment success in advanced melanoma patients, the rapid development of oncologic treatment options comes with increasingly high costs and can cause severe life-threatening side effects. For this purpose, predictive baseline biomarkers are becoming increasingly important for risk stratification and personalized treatment planning. Thus, the aim of this pilot study was the development of a prognostic tool for the risk stratification of the treatment response and mortality based on PET/MRI and PET/CT, including a convolutional neural network (CNN) for metastasized-melanoma patients before systemic-treatment initiation. The evaluation was based on 37 patients (19 f, 62 ± 13 y/o) with unresectable metastasized melanomas who underwent whole-body 18F-FDG PET/MRI and PET/CT scans on the same day before the initiation of therapy with checkpoint inhibitors and/or BRAF/MEK inhibitors. The overall survival (OS), therapy response, metastatically involved organs, number of lesions, total lesion glycolysis, total metabolic tumor volume (TMTV), peak standardized uptake value (SULpeak), diameter (Dmlesion) and mean apparent diffusion coefficient (ADCmean) were assessed. For each marker, a Kaplan−Meier analysis and the statistical significance (Wilcoxon test, paired t-test and Bonferroni correction) were assessed. Patients were divided into high- and low-risk groups depending on the OS and treatment response. The CNN segmentation and prediction utilized multimodality imaging data for a complementary in-depth risk analysis per patient. The following parameters correlated with longer OS: a TMTV < 50 mL; no metastases in the brain, bone, liver, spleen or pleura; ≤4 affected organ regions; no metastases; a Dmlesion > 37 mm or SULpeak < 1.3; a range of the ADCmean < 600 mm2/s. However, none of the parameters correlated significantly with the stratification of the patients into the high- or low-risk groups. For the CNN, the sensitivity, specificity, PPV and accuracy were 92%, 96%, 92% and 95%, respectively. Imaging biomarkers such as the metastatic involvement of specific organs, a high tumor burden, the presence of at least one large lesion or a high range of intermetastatic diffusivity were negative predictors for the OS, but the identification of high-risk patients was not feasible with the handcrafted parameters. In contrast, the proposed CNN supplied risk stratification with high specificity and sensitivity.

Thyroid Metastasis in Whole-Body 18F-FDG PET/CT Restaging of Small Cell Lung Cancer.

ABSTRACT: Incidental findings of thyroid lesions, some of which show increased FDG uptake, are common in whole-body FDG PET/CT imaging of oncological patients. As metastases to the thyroid are extremely rare, it is often a matter of debate, whether thyroid lesions should be considered as benign goiter or evaluated further. Here, we present the case of a 65-year-old woman with history of small cell lung cancer and multiple thyroid lesions, classified as benign nodular goiter. Because in restating using 18F-FDG PET/CT these lesions showed an increased FDG uptake and growth progression, decision was made for fine-needle aspiration, which revealed small cell lung cancer metastasis 14 months after first tumor diagnosis.

ER Stress in ERp57 Knockout Knee Joint Chondrocytes Induces Osteoarthritic Cartilage Degradation and Osteophyte Formation.

Ageing or obesity are risk factors for protein aggregation in the endoplasmic reticulum (ER) of chondrocytes. This condition is called ER stress and leads to induction of the unfolded protein response (UPR), which, depending on the stress level, restores normal cell function or initiates apoptotic cell death. Here the role of ER stress in knee osteoarthritis (OA) was evaluated. It was first tested in vitro and in vivo whether a knockout (KO) of the protein disulfide isomerase ERp57 in chondrocytes induces sufficient ER stress for such analyses. ER stress in ERp57 KO chondrocytes was confirmed by immunofluorescence, immunohistochemistry, and transmission electron microscopy. Knee joints of wildtype (WT) and cartilage-specific ERp57 KO mice (ERp57 cKO) were analyzed by indentation-type atomic force microscopy (IT-AFM), toluidine blue, and immunofluorescence/-histochemical staining. Apoptotic cell death was investigated by a TUNEL assay. Additionally, OA was induced via forced exercise on a treadmill. ER stress in chondrocytes resulted in a reduced compressive stiffness of knee cartilage. With ER stress, 18-month-old mice developed osteoarthritic cartilage degeneration with osteophyte formation in knee joints. These degenerative changes were preceded by apoptotic death in articular chondrocytes. Young mice were not susceptible to OA, even when subjected to forced exercise. This study demonstrates that ER stress induces the development of age-related knee osteoarthritis owing to a decreased protective function of the UPR in chondrocytes with increasing age, while apoptosis increases. Therefore, inhibition of ER stress appears to be an attractive therapeutic target for OA.

Correlation of C-arm CT acquired parenchymal blood volume (PBV) with 99mTc-macroaggregated albumin (MAA) SPECT/CT for radioembolization work-up.

OBJECTIVE: SPECT/CT with 99mTc-macroaggregated albumin (MAA) is generally used for diagnostic work-up prior to transarterial radioembolization (TARE) to exclude shunts and to provide additional information for treatment stratification and dose calculation. C-arm CT is used for determination of lobular vascular supply and assessment of parenchymal blood volume (PBV). Aim of this study was to correlate MAA-uptake and PBV-maps in hepatocellular carcinoma (HCC) and hepatic metastases of the colorectal carcinoma (CRC). MATERIALS AND METHODS: 34 patients underwent a PBV C-arm CT immediately followed by 99mTc-MAA injection and a SPECT/CT acquisition after 1 h uptake. MAA-uptake and PBV-maps were visually assessed and semi-quantitatively analyzed (MAA-tumor/liver-parenchyma = MAA-TBR or PBV in ml/100ml). In case of a poor match, tumors were additionally correlated with post-TARE 90Y-Bremsstrahlung-SPECT/CT as a reference. RESULTS: 102 HCC or CRC metastases were analyzed. HCC presented with significantly higher MAA-TBR (7.6 vs. 3.9, p<0.05) compared to CRC. Tumors showed strong intra- and inter-individual dissimilarities between TBR and PBV with a weak correlations for capsular HCCs (r = 0.45, p<0.05) and no correlation for CRC. The demarcation of lesions was slightly better for both HCC and CRC in PBV-maps compared to MAA-SPECT/CT (exact match: 52%/50%; same intensity/homogeneity: 38%/39%; insufficient 10%/11%). MAA-SPECT/CT revealed a better visual correlation with post-therapeutic 90Y-Bremsstrahlung-SPECT/CT. CONCLUSION: The acquisition of PBV can improve the detectability of small intrahepatic tumors and correlates with the MAA-Uptake in HCC. The results indicate that 99mTc-MAA-SPECT/CT remains to be the superior method for the prediction of post-therapeutic 90Y-particle distribution, especially in CRC. However, intra-procedural PBV acquisition has the potential to become an additional factor for TARE planning, in addition to improving the determination of segment and tumor blood supply, which has been demonstrated previously.

Imbalanced cellular metabolism compromises cartilage homeostasis and joint function in a mouse model of mucolipidosis type III gamma.

Mucolipidosis type III (MLIII) gamma is a rare inherited lysosomal storage disorder caused by mutations in GNPTG encoding the γ-subunit of GlcNAc-1-phosphotransferase, the key enzyme ensuring proper intracellular location of multiple lysosomal enzymes. Patients with MLIII gamma typically present with osteoarthritis and joint stiffness, suggesting cartilage involvement. Using Gnptg knockout (Gnptgko ) mice as a model of the human disease, we showed that missorting of a number of lysosomal enzymes is associated with intracellular accumulation of chondroitin sulfate in Gnptgko chondrocytes and their impaired differentiation, as well as with altered microstructure of the cartilage extracellular matrix (ECM). We also demonstrated distinct functional and structural properties of the Achilles tendons isolated from Gnptgko and Gnptab knock-in (Gnptabki ) mice, the latter displaying a more severe phenotype resembling mucolipidosis type II (MLII) in humans. Together with comparative analyses of joint mobility in MLII and MLIII patients, these findings provide a basis for better understanding of the molecular reasons leading to joint pathology in these patients. Our data suggest that lack of GlcNAc-1-phosphotransferase activity due to defects in the γ-subunit causes structural changes within the ECM of connective and mechanosensitive tissues, such as cartilage and tendon, and eventually results in functional joint abnormalities typically observed in MLIII gamma patients. This idea was supported by a deficit of the limb motor function in Gnptgko mice challenged on a rotarod under fatigue-associated conditions, suggesting that the impaired motor performance of Gnptgko mice was caused by fatigue and/or pain at the joint.This article has an associated First Person interview with the first author of the paper.

Radial Growth of Self-Catalyzed GaAs Nanowires and the Evolution of the Liquid Ga-Droplet Studied by Time-Resolved in Situ X-ray Diffraction.

We report on a growth study of self-catalyzed GaAs nanowires based on time-resolved in situ X-ray structure characterization during molecular-beam-epitaxy in combination with ex situ scanning-electron-microscopy. We reveal the evolution of nanowire radius and polytypism and distinguish radial growth processes responsible for tapering and side-wall growth. We interpret our results using a model for diameter self-stabilization processes during growth of self-catalyzed GaAs nanowires including the shape of the liquid Ga-droplet and its evolution during growth.