Diagnostic accuracy of anti-3-[18F]-FACBC PET/MRI in gliomas.

PURPOSE: The primary aim was to evaluate whether anti-3-[18F]FACBC PET combined with conventional MRI correlated better with histomolecular diagnosis (reference standard) than MRI alone in glioma diagnostics. The ability of anti-3-[18F]FACBC to differentiate between molecular and histopathological entities in gliomas was also evaluated. METHODS: In this prospective study, patients with suspected primary or recurrent gliomas were recruited from two sites in Norway and examined with PET/MRI prior to surgery. Anti-3-[18F]FACBC uptake (TBRpeak) was compared to histomolecular features in 36 patients. PET results were then added to clinical MRI readings (performed by two neuroradiologists, blinded for histomolecular results and PET data) to assess the predicted tumor characteristics with and without PET. RESULTS: Histomolecular analyses revealed two CNS WHO grade 1, nine grade 2, eight grade 3, and 17 grade 4 gliomas. All tumors were visible on MRI FLAIR. The sensitivity of contrast-enhanced MRI and anti-3-[18F]FACBC PET was 61% (95%CI [45, 77]) and 72% (95%CI [58, 87]), respectively, in the detection of gliomas. Median TBRpeak was 7.1 (range: 1.4-19.2) for PET positive tumors. All CNS WHO grade 1 pilocytic astrocytomas/gangliogliomas, grade 3 oligodendrogliomas, and grade 4 glioblastomas/astrocytomas were PET positive, while 25% of grade 2-3 astrocytomas and 56% of grade 2-3 oligodendrogliomas were PET positive. Generally, TBRpeak increased with malignancy grade for diffuse gliomas. A significant difference in PET uptake between CNS WHO grade 2 and 4 gliomas (p < 0.001) and between grade 3 and 4 gliomas (p = 0.002) was observed. Diffuse IDH wildtype gliomas had significantly higher TBRpeak compared to IDH1/2 mutated gliomas (p < 0.001). Adding anti-3-[18F]FACBC PET to MRI improved the accuracy of predicted glioma grades, types, and IDH status, and yielded 13.9 and 16.7 percentage point improvement in the overall diagnoses for both readers, respectively. CONCLUSION: Anti-3-[18F]FACBC PET demonstrated high uptake in the majority of gliomas, especially in IDH wildtype gliomas, and improved the accuracy of preoperatively predicted glioma diagnoses. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04111588, URL: https://clinicaltrials.gov/study/NCT04111588.

AI-driven attenuation correction for brain PET/MRI: Clinical evaluation of a dementia cohort and importance of the training group size.

INTRODUCTION: Robust and reliable attenuation correction (AC) is a prerequisite for accurate quantification of activity concentration. In combined PET/MRI, AC is challenged by the lack of bone signal in the MRI from which the AC maps has to be derived. Deep learning-based image-to-image translation networks present itself as an optimal solution for MRI-derived AC (MR-AC). High robustness and generalizability of these networks are expected to be achieved through large training cohorts. In this study, we implemented an MR-AC method based on deep learning, and investigated how training cohort size, transfer learning, and MR input affected robustness, and subsequently evaluated the method in a clinical setup, with the overall aim to explore if this method could be implemented in clinical routine for PET/MRI examinations. METHODS: A total cohort of 1037 adult subjects from the Siemens Biograph mMR with two different software versions (VB20P and VE11P) was used. The software upgrade included updates to all MRI sequences. The impact of training group size was investigated by training a convolutional neural network (CNN) on an increasing training group size from 10 to 403. The ability to adapt to changes in the input images between software versions were evaluated using transfer learning from a large cohort to a smaller cohort, by varying training group size from 5 to 91 subjects. The impact of MRI sequence was evaluated by training three networks based on the Dixon VIBE sequence (DeepDixon), T1-weighted MPRAGE (DeepT1), and ultra-short echo time (UTE) sequence (DeepUTE). Blinded clinical evaluation relative to the reference low-dose CT (CT-AC) was performed for DeepDixon in 104 independent 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG) PET patient studies performed for suspected neurodegenerative disorder using statistical surface projections. RESULTS: Robustness increased with group size in the training data set: 100 subjects were required to reduce the number of outliers compared to a state-of-the-art segmentation-based method, and a cohort >400 subjects further increased robustness in terms of reduced variation and number of outliers. When using transfer learning to adapt to changes in the MRI input, as few as five subjects were sufficient to minimize outliers. Full robustness was achieved at 20 subjects. Comparable robust and accurate results were obtained using all three types of MRI input with a bias below 1% relative to CT-AC in any brain region. The clinical PET evaluation using DeepDixon showed no clinically relevant differences compared to CT-AC. CONCLUSION: Deep learning based AC requires a large training cohort to achieve accurate and robust performance. Using transfer learning, only five subjects were needed to fine-tune the method to large changes to the input images. No clinically relevant differences were found compared to CT-AC, indicating that clinical implementation of our deep learning-based MR-AC method will be feasible across MRI system types using transfer learning and a limited number of subjects.

Shoulder MRI features with clinical correlations in subacromial pain syndrome: a cross-sectional and prognostic study.

BACKGROUND: Previous studies on shoulder patients have suggested that the prevalence of rotator cuff or bursa abnormalities are weakly related to symptoms and that similar findings are often found in asymptomatic persons. In addition, it is largely unknown whether structural changes identified by magnetic resonance imaging (MRI) affect outcome after treatment for shoulder pain. The purpose of this study was therefore to evaluate the presence of structural changes on MRI in patients with subacromial pain syndrome and to determine to what extent these changes are associated with symptoms and predict outcome after treatment (evaluated by the Shoulder Pain and Disability Index (SPADI)). METHODS: A prospective, observational assessment of a subset of shoulder patients who were included in a randomized study was performed. All participants had an MRI of the shoulder. An MRI total score for findings at the AC joint, subacromial bursa and rotator cuff was calculated. Multiple linear regression analysis was applied to examine the relationship between the MRI total score and the outcome measure at baseline and to examine to what extent the MRI total score was associated with the change in the SPADI score from baseline to the one year follow-up. RESULTS: There was a weak, inverse association between the SPADI score at baseline and the MRI total score (ß = -3.1, with 95% CI -5.9 to -0.34; p = 0.03), i.e. the SPADI score was higher for patients with a lower MRI total score. There was an association between the change in the SPADI score from baseline to the one year follow-up and the MRI total score (ß = 8.1, 95% CI -12.3 to -3.8; p < 0.001), with a poorer outcome for patients with a higher MRI total score. Both tendinosis (p = 0.01) and bursitis (p = 0.04) were associated with a poorer outcome after one year. CONCLUSIONS: In this study, MRI findings were significantly associated with the change in the SPADI score from baseline and to one year follow-up, with a poorer outcome after treatment for the patients with higher MRI total score, tendinosis and bursitis on MRI. TRIAL REGISTRATION: Clinicaltrials.gov no NCT01441830 . September 28, 2011.

PET/MR brain imaging: evaluation of clinical UTE-based attenuation correction.

UNLABELLED: One of the greatest challenges in PET/MR imaging is that of accurate MR-based attenuation correction (AC) of the acquired PET data, which must be solved if the PET/MR modality is to reach its full potential. The aim of this study was to investigate the performance of Siemens' most recent version (VB20P) of MR-based AC of head PET data, by comparing it to CT-based AC. METHODS: (18)F-FDG PET data from seven lymphoma and twelve lung cancer patients examined with a Biograph mMR PET/MR system were reconstructed with both CT-based and MR-based AC, avoiding sources of error arising when comparing PET data from different systems. The resulting images were compared quantitatively by measuring changes in mean SUV in ten different brain regions in both hemispheres, as well as the brainstem. In addition, the attenuation maps (µ maps) were compared regarding volume and localization of cranial bone. RESULTS: The UTE µ maps clearly overestimate the amount of bone in the neck, while slightly underestimating the amount of bone in the cranium, and the localization of bone in the cranial region also differ from the CT µ maps. In air/tissue interfaces in the sinuses and ears, the MRAC method struggles to correctly classify the different tissues. The misclassification of tissue is most likely caused by a combination of artefacts and the insufficiency of the UTE method to accurately separate bone. Quantitatively, this results in a combination of overestimation (0.5-3.6 %) and underestimation (2.7-5.2 %) of PET activity throughout the brain, depending on the proximity to the inaccurate regions. CONCLUSIONS: Our results indicate that the performance of the UTE method as implemented in VB20P is close to the theoretical maximum of such an MRAC method in the brain, while it does not perform satisfactorily in the neck or face/nasal area. Further improvement of the UTE MRAC or other available methods for more accurate segmentation of bone should be incorporated.

Short day-mediated cessation of growth requires the downregulation of AINTEGUMENTALIKE1 transcription factor in hybrid aspen.

Day length is a key environmental cue regulating the timing of major developmental transitions in plants. For example, in perennial plants such as the long-lived trees of the boreal forest, exposure to short days (SD) leads to the termination of meristem activity and bud set (referred to as growth cessation). The mechanism underlying SD-mediated induction of growth cessation is poorly understood. Here we show that the AIL1-AIL4 (AINTEGUMENTALIKE) transcription factors of the AP2 family are the downstream targets of the SD signal in the regulation of growth cessation response in hybrid aspen trees. AIL1 is expressed in the shoot apical meristem and leaf primordia, and exposure to SD signal downregulates AIL1 expression. Downregulation of AIL gene expression by SDs is altered in transgenic hybrid aspen plants that are defective in SD perception and/or response, e.g. PHYA or FT overexpressors. Importantly, SD-mediated regulation of growth cessation response is also affected by overexpression or downregulation of AIL gene expression. AIL1 protein can interact with the promoter of the key cell cycle genes, e.g. CYCD3.2, and downregulation of the expression of D-type cyclins after SD treatment is prevented by AIL1 overexpression. These data reveal that execution of SD-mediated growth cessation response requires the downregulation of AIL gene expression. Thus, while early acting components like PHYA and the CO/FT regulon are conserved in day-length regulation of flowering time and growth cessation between annual and perennial plants, signaling pathways downstream of SD perception diverge, with AIL transcription factors being novel targets of the CO/FT regulon connecting the perception of SD signal to the regulation of meristem activity.

Activity-dormancy transition in the cambial meristem involves stage-specific modulation of auxin response in hybrid aspen.

The molecular basis of short-day-induced growth cessation and dormancy in the meristems of perennial plants (e.g., forest trees growing in temperate and high-latitude regions) is poorly understood. Using global transcript profiling, we show distinct stage-specific alterations in auxin responsiveness of the transcriptome in the stem tissues during short-day-induced growth cessation and both the transition to and establishment of dormancy in the cambial meristem of hybrid aspen trees. This stage-specific modulation of auxin signaling appears to be controlled via distinct mechanisms. Whereas the induction of growth cessation in the cambium could involve induction of repressor auxin response factors (ARFs) and down-regulation of activator ARFs, dormancy is associated with perturbation of the activity of the SKP-Cullin-F-box(TIR) (SCF(TIR)) complex, leading to potential stabilization of repressor auxin (AUX)/indole-3-acetic acid (IAA) proteins. Although the role of hormones, such as abscisic acid (ABA) and gibberellic acid (GA), in growth cessation and dormancy is well established, our data now implicate auxin in this process. Importantly, in contrast to most developmental processes in which regulation by auxin involves changes in cellular auxin contents, day-length-regulated induction of cambial growth cessation and dormancy involves changes in auxin responses rather than auxin content.

18F-FACBC and 18F-FDG PET/MRI in the evaluation of 3 patients with primary central nervous system lymphoma: a pilot study.

BACKGROUND: This PET/MRI study compared contrast-enhanced MRI, 18F-FACBC-, and 18F-FDG-PET in the detection of primary central nervous system lymphomas (PCNSL) in patients before and after high-dose methotrexate chemotherapy. Three immunocompetent PCNSL patients with diffuse large B-cell lymphoma received dynamic 18F-FACBC- and 18F-FDG-PET/MRI at baseline and response assessment. Lesion detection was defined by clinical evaluation of contrast enhanced T1 MRI (ce-MRI) and visual PET tracer uptake. SUVs and tumor-to-background ratios (TBRs) (for 18F-FACBC and 18F-FDG) and time-activity curves (for 18F-FACBC) were assessed. RESULTS: At baseline, seven ce-MRI detected lesions were also detected with 18F-FACBC with high SUVs and TBRs (SUVmax:mean, 4.73, TBRmax: mean, 9.32, SUVpeak: mean, 3.21, TBRpeak:mean: 6.30). High TBR values of 18F-FACBC detected lesions were attributed to low SUVbackground. Baseline 18F-FDG detected six lesions with high SUVs (SUVmax: mean, 13.88). In response scans, two lesions were detected with ce-MRI, while only one was detected with 18F-FACBC. The lesion not detected with 18F-FACBC was a small atypical MRI detected lesion, which may indicate no residual disease, as this patient was still in complete remission 12 months after initial diagnosis. No lesions were detected with 18F-FDG in the response scans. CONCLUSIONS: 18F-FACBC provided high tumor contrast, outperforming 18F-FDG in lesion detection at both baseline and in response assessment. 18F-FACBC may be a useful supplement to ce-MRI in PCNSL detection and response assessment, but further studies are required to validate these findings. Trial registration ClinicalTrials.gov. Registered 15th of June 2017 (Identifier: NCT03188354, https://clinicaltrials.gov/study/NCT03188354 ).

Histomolecular Validation of [18F]-FACBC in Gliomas Using Image-Localized Biopsies.

BACKGROUND: Gliomas have a heterogeneous nature, and identifying the most aggressive parts of the tumor and defining tumor borders are important for histomolecular diagnosis, surgical resection, and radiation therapy planning. This study evaluated [18F]-FACBC PET for glioma tissue classification. METHODS: Pre-surgical [18F]-FACBC PET/MR images were used during surgery and image-localized biopsy sampling in patients with high- and low-grade glioma. TBR was compared to histomolecular results to determine optimal threshold values, sensitivity, specificity, and AUC values for the classification of tumor tissue. Additionally, PET volumes were determined in patients with glioblastoma based on the optimal threshold. [18F]-FACBC PET volumes and diagnostic accuracy were compared to ce-T1 MRI. In total, 48 biopsies from 17 patients were analyzed. RESULTS: [18F]-FACBC had low uptake in non-glioblastoma tumors, but overall higher sensitivity and specificity for the classification of tumor tissue (0.63 and 0.57) than ce-T1 MRI (0.24 and 0.43). Additionally, [18F]-FACBC TBR was an excellent classifier for IDH1-wildtype tumor tissue (AUC: 0.83, 95% CI: 0.71-0.96). In glioblastoma patients, PET tumor volumes were on average eight times larger than ce-T1 MRI volumes and included 87.5% of tumor-positive biopsies compared to 31.5% for ce-T1 MRI. CONCLUSION: The addition of [18F]-FACBC PET to conventional MRI could improve tumor classification and volume delineation.

The AINTEGUMENTA LIKE1 homeotic transcription factor PtAIL1 controls the formation of adventitious root primordia in poplar.

Adventitious rooting is an essential but sometimes rate-limiting step in the clonal multiplication of elite tree germplasm, because the ability to form roots declines rapidly with age in mature adult plant tissues. In spite of the importance of adventitious rooting, the mechanism behind this developmental process remains poorly understood. We have described the transcriptional profiles that are associated with the developmental stages of adventitious root formation in the model tree poplar (Populus trichocarpa). Transcriptome analyses indicate a highly specific temporal induction of the AINTEGUMENTA LIKE1 (PtAIL1) transcription factor of the AP2 family during adventitious root formation. Transgenic poplar samples that overexpressed PtAIL1 were able to grow an increased number of adventitious roots, whereas RNA interference mediated the down-expression of PtAIL1 expression, which led to a delay in adventitious root formation. Microarray analysis showed that the expression of 15 genes, including the transcription factors AGAMOUS-Like6 and MYB36, was overexpressed in the stem tissues that generated root primordia in PtAIL1-overexpressing plants, whereas their expression was reduced in the RNA interference lines. These results demonstrate that PtAIL1 is a positive regulator of poplar rooting that acts early in the development of adventitious roots.

Predicting Regions of Local Recurrence in Glioblastomas Using Voxel-Based Radiomic Features of Multiparametric Postoperative MRI.

The globally accepted surgical strategy in glioblastomas is removing the enhancing tumor. However, the peritumoral region harbors infiltration areas responsible for future tumor recurrence. This study aimed to evaluate a predictive model that identifies areas of future recurrence using a voxel-based radiomics analysis of magnetic resonance imaging (MRI) data. This multi-institutional study included a retrospective analysis of patients diagnosed with glioblastoma who underwent surgery with complete resection of the enhancing tumor. Fifty-five patients met the selection criteria. The study sample was split into training (N = 40) and testing (N = 15) datasets. Follow-up MRI was used for ground truth definition, and postoperative structural multiparametric MRI was used to extract voxel-based radiomic features. Deformable coregistration was used to register the MRI sequences for each patient, followed by segmentation of the peritumoral region in the postoperative scan and the enhancing tumor in the follow-up scan. Peritumoral voxels overlapping with enhancing tumor voxels were labeled as recurrence, while non-overlapping voxels were labeled as nonrecurrence. Voxel-based radiomic features were extracted from the peritumoral region. Four machine learning-based classifiers were trained for recurrence prediction. A region-based evaluation approach was used for model evaluation. The Categorical Boosting (CatBoost) classifier obtained the best performance on the testing dataset with an average area under the curve (AUC) of 0.81 ± 0.09 and an accuracy of 0.84 ± 0.06, using region-based evaluation. There was a clear visual correspondence between predicted and actual recurrence regions. We have developed a method that accurately predicts the region of future tumor recurrence in MRI scans of glioblastoma patients. This could enable the adaptation of surgical and radiotherapy treatment to these areas to potentially prolong the survival of these patients.

Innovative forest products in the circular bioeconomy.

Background: The forest-based industry has been moving towards the manufacture of bio-based products in response to the increasing concern by consumers and governments regarding the use of non-renewable materials and the generation of residues. Various innovative technologies geared towards reducing the environmental footprint of products and processes are currently being developed and applied in the forest-based industry. This study presents some innovative wood-based products that are about to enter the market or that are already being commercialized but have the potential to expand in market size. Methods: We collected data from interviews and a survey with organisations working with product development and manufacturing, and from the literature. Results: Many innovative products that are already produced at an industrial scale, such as cross-laminated timber, wood-based composites, and lyocell, can still increase their market share in the coming years. Some of the up-and-coming products with high potential to substitute fossil-based materials and will likely enter the market in the near future are wood foam, lignin-based adhesives, glycols, bioplastics, and textile fibres. Our study indicates that, although biomass demand is expected to increase, stakeholders do not consider future supply a limiting factor. Conclusions: The ease of market introduction of innovative products relies heavily on the products' ability to take advantage of existing value chains. Overall, many of the reviewed products have the advantage of being 'drop-in'. This is because products that require adjustments to production lines are less likely to get into the market without strong external drivers that push for bio-based alternatives. According to stakeholders, the economic viability and the market expansion of these products could be encouraged to a certain extent by EU policies, and certain barriers could be alleviated by reducing bureaucracy, increasing the support for pilot-scale to full-scale production, and increasing subsidies for bio-based alternatives.

Pegs not superior to screws for fixation of fractures of the proximal humerus.

BACKGROUND: Angular stable plates were introduced two decades ago as a promising treatment for fixation of displaced fractures of the proximal humerus (PHF). However, high rates of adverse events and reoperations have been reported. One frequent reason is secondary penetration of screws into the glenohumeral joint, due to sinking of the fracture or avascular head necrosis. To prevent joint penetrations angular stable plates with smooth locking pegs instead of locking screws have been developed. The aim of the present study was to investigate whether blunt pegs instead of pointed screws reduced the risk of secondary penetration into the glenohumeral joint during fracture healing after operatively treated PHFs. METHODS: From two different patient cohorts with displaced PHFs (60 treated with PHILOS plate with screws and 50 with ALPS-PHP plate with pegs), two groups were matched according to fracture type AO/OTA 11-B2 and 11-C2 and age (55-85 years). They were followed up at 3, 6 and 12 months. Primary outcome was radiographic signs of peg or screw penetrations into the glenohumeral joint at 12 months. Secondary outcomes were Oxford shoulder score (OSS) and Constant Score (CS) and radiographic signs of avascular humeral head necrosis (AVN). RESULTS: Eighteen PHILOS patients with B2 and C2 fractures could be matched with a corresponding group of 18 operated with ALPS-PHP with pegs. The number of penetrations of pegs and screws were equal between the two groups and the development of avascular head necrosis did not differ either. The functional outcomes for both OSS and CS at 12 months was clearly in favor of patients without joint penetrations in both groups. CONCLUSION: We found no differences in the number of screw or peg penetrations in the PHILOS and ALPS-PHP group and the occurrence of AVN was equal. Joint penetrations led to inferior functional outcomes at 1 year. The ClinicalTrials.gov identifier 20/11/12 prospectively for the Philos Group is NCT01737060, and for the ALPS group 11/03/20 retrospectively is NCT04622852.

Diagnostic Value of 18 F-FACBC PET/MRI in Brain Metastases.

PURPOSE: The study aims to evaluate whether combined 18 F-FACBC PET/MRI could provide additional diagnostic information compared with MRI alone in brain metastases. PATIENTS AND METHODS: Eighteen patients with newly diagnosed or suspected recurrence of brain metastases received dynamic 18 F-FACBC PET/MRI. Lesion detection was evaluated on PET and MRI scans in 2 groups depending on prior stereotactic radiosurgery (SRS group) or not (no-SRS group). SUVs, time-activity curves, and volumetric analyses of the lesions were performed. RESULTS: In the no-SRS group, 29/29 brain lesions were defined as "MRI positive." With PET, 19/29 lesions were detected and had high tumor-to-background ratios (TBRs) (D max MR , ≥7 mm; SUV max , 1.2-8.4; TBR, 3.9-25.9), whereas 10/29 lesions were undetected (D max MR , ≤8 mm; SUV max , 0.3-1.2; TBR, 1.0-2.7). In the SRS group, 4/6 lesions were defined as "MRI positive," whereas 2/6 lesions were defined as "MRI negative" indicative of radiation necrosis. All 6 lesions were detected with PET (D max MR , ≥15 mm; SUV max , 1.4-4.2; TBR, 3.6-12.6). PET volumes correlated and were comparable in size with contrast-enhanced MRI volumes but were only partially congruent (mean DSC, 0.66). All time-activity curves had an early peak, followed by a plateau or a decreasing slope. CONCLUSIONS: 18 F-FACBC PET demonstrated uptake in brain metastases from cancer of different origins (lung, gastrointestinal tract, breast, thyroid, and malignant melanoma). However, 18 F-FACBC PET/MRI did not improve detection of brain metastases compared with MRI but might detect tumor tissue beyond contrast enhancement on MRI. 18 F-FACBC PET should be further evaluated in recurrent brain metastases.

A major forest insect pest, the pine weevil Hylobius abietis, is more susceptible to Diptera- than Coleoptera-targeted Bacillus thuringiensis strains.

BACKGROUND: The pine weevil (Hylobius abietis) is a major forest regeneration pest causing high levels of seedling mortality and economic losses. Current management relies on silviculture, stem coatings and insecticides. Here we evaluated for the first time the effects of Bacillus thuringiensis (Bt) strains on H. abietis adults: two producing the Coleoptera-targeted toxins Cry3Aa (Bt tenebrionis NB-176) and Cry8Da (Bt galleriae SDS-502), and one producing the Diptera-targeted Cry10A (Bt israelensis AM65-52). Choice and nonchoice assays using individual and mixtures of Bt formulations, containing these strains respectively, were conducted. RESULTS: We found that Bt had toxic and lethal effects on H. abietis, but effects varied with strain and formulation concentration. The Diptera-targeted Bt israelensis had the most negative effects on weevil weight, feeding and mortality (70-82% feeding reduction, 65-82% greater mortality than control), whereas the effect was lower for the Coleoptera-specific Bt tenebrionis (38-42%; 37-42%) and Bt galleriae (11-30%; 15-32%). Reduced weevil feeding was observed after 3 days, and the highest mortality occurred 7-14 days following Bt exposure. However, we found no synergistic toxic effects, and no formulation combination was better than Bt israelensis alone at reducing consumption and survival. Also, pine weevils were not deterred by Bt, feeding equally on Bt-treated and non-Bt treated food. CONCLUSION: There is potential to develop forest pest management measures against H. abietis that include Bt, but only the Diptera-targeted Bt israelensis would provide effective seedling protection. Its Diptera-specificity may need reconsideration, and evaluation of other Bt strains/toxins against H. abietis would be of interest. © 2020 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

18F-FACBC PET/MRI in the evaluation of human brain metastases: a case report.

BACKGROUND: Patients with metastatic cancer to the brain have a poor prognosis. In clinical practice, MRI is used to delineate, diagnose and plan treatment of brain metastases. However, MRI alone is limited in detecting micro-metastases, delineating lesions and discriminating progression from pseudo-progression. Combined PET/MRI utilises superior soft tissue images from MRI and metabolic data from PET to evaluate tumour structure and function. The amino acid PET tracer 18F-FACBC has shown promising results in discriminating high- and low-grade gliomas, but there are currently no reports on its use on brain metastases. This is the first study to evaluate the use of 18F-FACBC on brain metastases. CASE PRESENTATION: A middle-aged female patient with brain metastases was evaluated using hybrid PET/MRI with 18F-FACBC before and after stereotactic radiotherapy, and at suspicion of recurrence. Static/dynamic PET and contrast-enhanced T1 MRI data were acquired and analysed. This case report includes the analysis of four 18F-FACBC PET/MRI examinations, investigating their utility in evaluating functional and structural metastasis properties. CONCLUSION: Analysis showed high tumour-to-background ratios in brain metastases compared to other amino acid PET tracers, including high uptake in a very small cerebellar metastasis, suggesting that 18F-FACBC PET can provide early detection of otherwise overlooked metastases. Further studies to determine a threshold for 18F-FACBC brain tumour boundaries and explore its utility in clinical practice should be performed.

Hypoxia imaging and theranostic potential of [64Cu][Cu(ATSM)] and ionic Cu(II) salts: a review of current evidence and discussion of the retention mechanisms.

BACKGROUND: Tumor hypoxia (low tissue oxygenation) is an adverse condition of the solid tumor environment, associated with malignant progression, radiotherapy resistance, and poor prognosis. One method to detect tumor hypoxia is by positron emission tomography (PET) with the tracer [64Cu][Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)] ([64Cu][Cu(ATSM)]), as demonstrated in both preclinical and clinical studies. In addition, emerging studies suggest using [64Cu][Cu(ATSM)] for molecular radiotherapy, mainly due to the release of therapeutic Auger electrons from copper-64, making [64Cu][Cu(ATSM)] a "theranostic" agent. However, the radiocopper retention based on a metal-ligand dissociation mechanism under hypoxia has long been controversial. Recent studies using ionic Cu(II) salts as tracers have raised further questions on the original mechanism and proposed a potential role of copper itself in the tracer uptake. We have reviewed the evidence of using the copper radiopharmaceuticals [60/61/62/64Cu][Cu(ATSM)]/ionic copper salts for PET imaging of tumor hypoxia, their possible therapeutic applications, issues related to the metal-ligand dissociation mechanism, and possible explanations of copper trapping based on studies of the copper metabolism under hypoxia. RESULTS: We found that hypoxia selectivity of [64Cu][Cu(ATSM)] has been clearly demonstrated in both preclinical and clinical studies. Preclinical therapeutic studies in mice have also demonstrated promising results, recently reporting significant tumor volume reductions and improved survival in a dose-dependent manner. Cu(II)-[Cu(ATSM)] appears to be accumulated in regions with substantially higher CD133+ expression, a marker for cancer stem cells. This, combined with the reported requirement of copper for activation of the hypoxia inducible factor 1 (HIF-1), provides a possible explanation for the therapeutic effects of [64Cu][Cu(ATSM)]. Comparisons between [64Cu][Cu(ATSM)] and ionic Cu(II) salts have showed similar results in both imaging and therapeutic studies, supporting the argument for the central role of copper itself in the retention mechanism. CONCLUSIONS: We found promising evidence of using copper-64 radiopharmaceuticals for both PET imaging and treatment of hypoxic tumors. The Cu(II)-[Cu(ATSM)] retention mechanism remains controversial and future mechanistic studies should be focused on understanding the role of copper itself in the hypoxic tumor metabolism.

Reverse Shoulder Arthroplasty Is Superior to Plate Fixation at 2 Years for Displaced Proximal Humeral Fractures in the Elderly: A Multicenter Randomized Controlled Trial.

BACKGROUND: Almost one-third of patients with proximal humeral fractures are treated surgically, and the number is increasing. When surgical treatment is chosen, there is sparse evidence on the optimum method. The DelPhi (Delta prosthesis-PHILOS plate) trial is a clinical trial comparing 2 surgical treatments. Our hypothesis was that reverse total shoulder arthroplasty (TSA) yields better clinical results compared with open reduction and internal fixation (ORIF) using an angular stable plate. METHODS: The DelPhi trial is a randomized controlled trial comparing reverse TSA with ORIF for displaced proximal humeral fractures (OTA/AO types 11-B2 and 11-C2) in elderly patients (65 to 85 years of age). The primary outcome measure was the Constant score at a 2-year follow-up. The secondary outcome measures included the Oxford Shoulder Score and radiographic evaluation. Results were reported as the mean difference with 95% confidence interval (CI). The intention-to-treat principle was applied for crossover patients. RESULTS: There were 124 patients included in the study. At 2 years, the mean Constant score was 68.0 points (95% CI, 63.7 to 72.4 points) for the reverse TSA group compared with 54.6 points (95% CI, 48.5 to 60.7 points) for the ORIF group, resulting in a significant mean difference of 13.4 points (95% CI, 6.2 to 20.6 points; p < 0.001) in favor of reverse TSA. When stratified for fracture classification, the mean score was 69.3 points (95% CI, 63.9 to 74.7 points) for the reverse TSA group and 50.6 points (95% CI, 41.9 to 59.2 points) for the ORIF group for type-C2 fractures, which yielded a significant mean difference of 18.7 points (95% CI, 9.3 to 28.2 points; p < 0.001). In the type-B2 fracture group, the mean score was 66.2 points (95% CI, 58.6 to 73.8 points) for the reverse TSA group and 58.5 points (95% CI, 49.6 to 67.4 points) for the ORIF group, resulting in a nonsignificant mean difference of 7.6 points (95% CI, -3.8 to 19.1 points; p = 0.19). CONCLUSIONS: At a 2-year follow-up, the data suggested an advantage of reverse TSA over ORIF in the treatment of displaced OTA/AO type-B2 and C2 proximal humeral fractures in elderly patients. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Image quality and detectability in Siemens Biograph PET/MRI and PET/CT systems-a phantom study.

BACKGROUND: The technology of modern positron emission tomography (PET) systems continuously improving, and with it the possibility to detect smaller lesions. Since first introduced in 2010, the number of hybrid PET/magnetic resonance imaging (MRI) systems worldwide is constantly increasing. It is therefore important to assess and compare the image quality, in terms of detectability, between the PET/MRI and the well-established PET/computed tomography (CT) systems. For this purpose, a PET image quality phantom (Esser) with hot spheres, ranging from 4 to 20 mm in diameter, was prepared with fluorodeoxyglucose and sphere-to-background activity concentrations of 8:1 and 4:1, to mimic clinical conditions. The phantom was scanned on a PET/MRI and a PET/CT system for both concentrations to obtain contrast recovery coefficients (CRCs) and contrast-to-noise ratios (CNRs), for a range of reconstruction settings. The detectability of the spheres was scored by three human observers for both systems and concentrations and all reconstructions. Furthermore, the impact of acquisition time on CNR and observer detectability was investigated. RESULTS: Reconstructions applying point-spread-function modeling (and time-of-flight for the PET/CT) yielded the highest CRC and CNR in general, and PET/CT demonstrated slightly higher values than PET/MRI for most sphere sizes. CNR was dependent on reconstruction settings and was maximized for 2 iterations, a pixel size of less than 2 mm and a 4 mm Gaussian filter. Acquisition times of 97 s (PET/MRI) and 150 s (PET/CT) resulted in similar total net true counts. For these acquisition times, the smallest detected spheres by the human observers in the 8:1 activity concentration was the 6-mm sphere with PET/MRI (CNR = 5.6) and the 5-mm sphere with PET/CT (CNR = 5.5). With an acquisition time of 180 s, the 5-mm sphere was also detected with PET/MRI (CNR = 5.8). The 8-mm sphere was the smallest detected sphere in the 4:1 activity concentration for both systems. CONCLUSION: In this experimental study, similar detectability was found for the PET/MRI and the PET/CT, although for an increased acquisition time for the PET/MRI.

Quantitative and clinical impact of MRI-based attenuation correction methods in [18F]FDG evaluation of dementia.

BACKGROUND: Positron emission tomography/magnetic resonance imaging (PET/MRI) is a promising diagnostic imaging tool for the diagnosis of dementia, as PET can add complementary information to the routine imaging examination with MRI. The purpose of this study was to evaluate the influence of MRI-based attenuation correction (MRAC) on diagnostic assessment of dementia with [18F]FDG PET. Quantitative differences in both [18F]FDG uptake and z-scores were calculated for three clinically available (DixonNoBone, DixonBone, UTE) and two research MRAC methods (UCL, DeepUTE) compared to CT-based AC (CTAC). Furthermore, diagnoses based on visual evaluations were made by three nuclear medicine physicians and one neuroradiologist (PETCT, PETDeepUTE, PETDixonBone, PETUTE, PETCT + MRI, PETDixonBone + MRI). In addition, pons and cerebellum were compared as reference regions for normalization. RESULTS: The mean absolute difference in z-scores were smallest between MRAC and CTAC with cerebellum as reference region: 0.15 ± 0.11 σ (DeepUTE), 0.15 ± 0.12 σ (UCL), 0.23 ± 0.20 σ (DixonBone), 0.32 ± 0.28 σ (DixonNoBone), and 0.54 ± 0.40 σ (UTE). In the visual evaluation, the diagnoses agreed with PETCT in 74% (PETDeepUTE), 67% (PETDixonBone), and 70% (PETUTE) of the patients, while PETCT + MRI agreed with PETDixonBone + MRI in 89% of the patients. CONCLUSION: The MRAC research methods performed close to that of CTAC in the quantitative evaluation of [18F]FDG uptake and z-scores. Among the clinically implemented MRAC methods, DixonBone should be preferred for diagnostic assessment of dementia with [18F]FDG PET/MRI. However, as artifacts occur in DixonBone attenuation maps, they must be visually inspected to assure proper quantification.

18F-FACBC PET/MRI in Diagnostic Assessment and Neurosurgery of Gliomas.

PURPOSE: This pilot study aimed to evaluate the amino acid tracer F-FACBC with simultaneous PET/MRI in diagnostic assessment and neurosurgery of gliomas. MATERIALS AND METHODS: Eleven patients with suspected primary or recurrent low- or high-grade glioma received an F-FACBC PET/MRI examination before surgery. PET and MRI were used for diagnostic assessment, and for guiding tumor resection and histopathological tissue sampling. PET uptake, tumor-to-background ratios (TBRs), time-activity curves, as well as PET and MRI tumor volumes were evaluated. The sensitivities of lesion detection and to detect glioma tissue were calculated for PET, MRI, and combined PET/MRI with histopathology (biopsies for final diagnosis and additional image-localized biopsies) as reference. RESULTS: Overall sensitivity for lesion detection was 54.5% (95% confidence interval [CI], 23.4-83.3) for PET, 45.5% (95% CI, 16.7-76.6) for contrast-enhanced MRI (MRICE), and 100% (95% CI, 71.5-100.0) for combined PET/MRI, with a significant difference between MRICE and combined PET/MRI (P = 0.031). TBRs increased with tumor grade (P = 0.004) and were stable from 10 minutes post injection. PET tumor volumes enclosed most of the MRICE volumes (>98%) and were generally larger (1.5-2.8 times) than the MRICE volumes. Based on image-localized biopsies, combined PET/MRI demonstrated higher concurrence with malignant findings at histopathology (89.5%) than MRICE (26.3%). CONCLUSIONS: Low- versus high-grade glioma differentiation may be possible with F-FACBC using TBR. F-FACBC PET/MRI outperformed MRICE in lesion detection and in detection of glioma tissue. More research is required to evaluate F-FACBC properties, especially in grade II and III tumors, and for different subtypes of gliomas.