The influence of metastatic patterns and tumor load on therapeutic efficacy of immunotherapy in patients with metastatic melanoma as determined by quantitative PET-parameters using [ 18 F]-fluorodeoxyglucose PET/computed tomography.

The introduction of immunotherapy was a revolution in the treatment of metastatic melanoma. Nevertheless, there are only few clinical parameters to predict response to immunotherapy. The purpose of this study was to identify metastatic patterns that can predict response by using noninvasive 18 F-FDG PET/CT imaging. In 93 immunotherapy-treated patients, total metabolic tumor volume (MTV) was measured before and after treatment. The differences were compared to quantify therapy response. Patients were divided into seven subgroups regarding the affected organ systems. The results as well as clinical factors were evaluated in multivariate analyses. No subgroup of metastatic patterns had a significant difference in response rates, but with a trend towards poorer response regarding osseous and hepatic metastases. Osseous metastases presented with significant lower disease-specific survival (DSS) ( P = 0.001). Sole lymph node metastases were the only subgroup with MTV reduction and with significant higher DSS (57.6 months; P = 0.033). Patients, who ever developed brain metastases, showed a high progression of MTV of 201 ml ( P = 0.583) and poor DSS of 49.7 months ( P = 0.077). Lower numbers of affected organs indicated significantly higher DSS (hazard ratio, 1.346; P = 0.006). Osseous metastases represented a negative predictive factor for response to immunotherapy and survival. Cerebral metastases, especially when nonresponsive to immunotherapy, predicted poor survival and high increase of MTV. A high number of affected organ systems was identified as a negative factor for response and survival. Patients with only lymph node metastases showed a better response and survival.

Optimized Whole-Body PET MRI Sequence Workflow in Pediatric Hodgkin Lymphoma Patients.

18F-FDG PET/MRI might be the diagnostic method of choice for Hodgkin lymphoma patients, as it combines significant metabolic information from PET with excellent soft-tissue contrast from MRI and avoids radiation exposure from CT. However, a major issue is longer examination times than for PET/CT, especially for younger children needing anesthesia. Thus, a targeted selection of suitable whole-body MRI sequences is important to optimize the PET/MRI workflow. Methods: The initial PET/MRI scans of 84 EuroNet-PHL-C2 study patients from 13 international PET centers were evaluated. In each available MRI sequence, 5 PET-positive lymph nodes were assessed. If extranodal involvement occurred, 2 splenic lesions, 2 skeletal lesions, and 2 lung lesions were also assessed. A detection rate was calculated dividing the number of visible, anatomically assignable, and measurable lesions in the respective MRI sequence by the total number of lesions. Results: Relaxation time-weighted (T2w) transverse sequences with fat saturation (fs) yielded the best result, with detection rates of 95% for nodal lesions, 62% for splenic lesions, 94% for skeletal lesions, and 83% for lung lesions, followed by T2w transverse sequences without fs (86%, 49%, 16%, and 59%, respectively) and longitudinal relaxation time-weighted contrast-enhanced transverse sequences with fs (74%, 35%, 57%, and 55%, respectively). Conclusion: T2w transverse sequences with fs yielded the highest detection rates and are well suited for accurate whole-body PET/MRI in lymphoma patients. There is no evidence to recommend the use of contrast agents.

The added value of PSMA PET/MR radiomics for prostate cancer staging.

PURPOSE: To evaluate the performance of combined PET and multiparametric MRI (mpMRI) radiomics for the group-wise prediction of postsurgical Gleason scores (psGSs) in primary prostate cancer (PCa) patients. METHODS: Patients with PCa, who underwent [68 Ga]Ga-PSMA-11 PET/MRI followed by radical prostatectomy, were included in this retrospective analysis (n = 101). Patients were grouped by psGS in three categories: ISUP grades 1-3, ISUP grade 4, and ISUP grade 5. mpMRI images included T1-weighted, T2-weighted, and apparent diffusion coefficient (ADC) map. Whole-prostate segmentations were performed on each modality, and image biomarker standardization initiative (IBSI)-compliant radiomic features were extracted. Nine support vector machine (SVM) models were trained: four single-modality radiomic models (PET, T1w, T2w, ADC); three PET + MRI double-modality models (PET + T1w, PET + T2w, PET + ADC), and two baseline models (one with patient data, one image-based) for comparison. A sixfold stratified cross-validation was performed, and balanced accuracies (bAcc) of the predictions of the best-performing models were reported and compared through Student's t-tests. The predictions of the best-performing model were compared against biopsy GS (bGS). RESULTS: All radiomic models outperformed the baseline models. The best-performing (mean ± stdv [%]) single-modality model was the ADC model (76 ± 6%), although not significantly better (p > 0.05) than other single-modality models (T1w: 72 ± 3%, T2w: 73 ± 2%; PET: 75 ± 5%). The overall best-performing model combined PET + ADC radiomics (82 ± 5%). It significantly outperformed most other double-modality (PET + T1w: 74 ± 5%, p = 0.026; PET + T2w: 71 ± 4%, p = 0.003) and single-modality models (PET: p = 0.042; T1w: p = 0.002; T2w: p = 0.003), except the ADC-only model (p = 0.138). In this initial cohort, the PET + ADC model outperformed bGS overall (82.5% vs 72.4%) in the prediction of psGS. CONCLUSION: All single- and double-modality models outperformed the baseline models, showing their potential in the prediction of GS, even with an unbalanced cohort. The best-performing model included PET + ADC radiomics, suggesting a complementary value of PSMA-PET and ADC radiomics.

[18F]FET PET Uptake Indicates High Tumor and Low Necrosis Content in Brain Metastasis.

Amino acid positron emission tomography (PET) has been employed in the management of brain metastases. Yet, histopathological correlates of PET findings remain poorly understood. We investigated the relationship of O-(2-[18F]Fluoroethyl)-L-tyrosine ([18F]FET) PET, magnetic resonance imaging (MRI), and histology in brain metastases. Fifteen patients undergoing brain metastasis resection were included prospectively. Using intraoperative navigation, 39 targeted biopsies were obtained from parts of the metastases that were either PET-positive or negative and MRI-positive or negative. Tumor and necrosis content, proliferation index, lymphocyte infiltration, and vascularization were determined histopathologically. [18F]FET PET had higher specificity than MRI (66% vs. 56%) and increased sensitivity for tumor from 73% to 93% when combined with MRI. Tumor content per sample increased with PET uptake (rs = 0.3, p = 0.045), whereas necrosis content decreased (rs = -0.4, p = 0.014). PET-positive samples had more tumor (median: 75%; interquartile range: 10-97%; p = 0.016) than PET-negative samples. The other investigated histological properties were not correlated with [18F]FET PET intensity. Tumors were heterogeneous at the levels of imaging and histology. [18F]FET PET can be a valuable tool in the management of brain metastases. In biopsies, one should aim for PET hotspots to increase the chance for retrieval of samples with high tumor cell concentrations. Multiple biopsies should be performed to account for intra-tumor heterogeneity. PET could be useful for differentiating treatment-related changes (e.g., radiation necrosis) from tumor recurrence.

Diagnostic performance of quantitative and qualitative parameters for the diagnosis of aortic graft infection using [18F]-FDG PET/CT.

PURPOSE: The aim of this study was the evaluation of quantitative and qualitative parameters for the diagnosis of aortic graft infection (AGI) using [18F]-FDG PET/CT. METHODS: PET/CT was performed in 50 patients with clinically suspected AGI. 12 oncological patients with aortic repair but without suspicion of AGI were included in the analysis to serve as control cohort. The [18F]-FDG uptake pattern around the graft was assessed using (a) a five-point visual grading scale (VGS), (b) SUVmax and (c) different graft-to-background ratios (GBRs). The diagnostic performance of VGS, SUVmax and GBRs was assessed and compared by ROC analysis. RESULTS: 28 infected and 34 uninfected grafts were identified by standard of reference. SUVmax and VGS were the most powerful predictors for the diagnosis of AGI according to the area under the curve (AUC 0.988 and 0.983, respectively) without a significant difference compared to GBRs. SUVmax and VGS showed congruent and accurate findings in 54 patients (i.e. either both positive or negative), yielding sensitivity and specificity (100%) in this subgroup of patients. CONCLUSION: Quantitative analysis by SUVmax and qualitative analysis by VGS are highly effective in the diagnosis of AGI and should be tested as an outcome measure in prospective trials.

A Five-Year report on the conception and establishment of the MSc Radiation Biology at the Technical University of Munich.

PURPOSE: The MSc Radiation Biology course is a highly interdisciplinary degree program placing radiation biology at the interface between biology, medicine, and physics, as well as their associated technologies. The goal was to establish an internationally acknowledged program with diverse and heterogeneous student cohorts, who benefit from each other academically as well as culturally. We have completed a Five-Year evaluation of the program to assess our qualification profile and the further direction we want to take. MATERIALS AND METHODS: We evaluated the student cohort's data from the last 5 years regarding gender, age, and nationality as well as the highest degree before applying and career path after graduation. RESULTS: Data shows a great diversity regarding nationalty as well as undergraduate background. Cohort sizes could be increased and future prospects mainly aimed to a PhD. Measures after regular quality meetings and students' feedback led to improving the curriculum and workload, teacher's training, and changes to examination regulations. CONCLUSIONS: After 5 years, statistics show that our expectations have been met exceedingly. All graduates had excellent career opportunities reflecting the necessity of this MSc and its topics. We are continuously working on improving the program and adapting the curriculum to the requirements in radiation sciences. The future vision includes an expansion of the program as well as undergraduate education opportunities in this field.

Aberrant striatal dopamine links topographically with cortico-thalamic dysconnectivity in schizophrenia.

Aberrant dopamine function in the dorsal striatum and aberrant intrinsic functional connectivity (iFC) between distinct cortical networks and thalamic nuclei are among the most consistent large-scale brain imaging findings in schizophrenia. A pathophysiological link between these two alterations is suggested by theoretical models based on striatal dopamine's topographic modulation of cortico-thalamic connectivity within cortico-basal-ganglia-thalamic circuits. We hypothesized that aberrant striatal dopamine links topographically with aberrant cortico-thalamic iFC, i.e. aberrant associative striatum dopamine is associated with aberrant iFC between the salience network and thalamus, and aberrant sensorimotor striatum dopamine with aberrant iFC between the auditory-sensorimotor network and thalamus. Nineteen patients with schizophrenia during remission of psychotic symptoms and 19 age- and sex-comparable control subjects underwent simultaneous fluorodihydroxyphenyl-l-alanine PET (18F-DOPA-PET) and resting state functional MRI (rs-fMRI). The influx constant kicer based on 18F-DOPA-PET was used to measure striatal dopamine synthesis capacity; correlation coefficients between rs-fMRI time series of cortical networks and thalamic regions of interest were used to measure iFC. In the salience network-centred system, patients had reduced associative striatum dopamine synthesis capacity, which correlated positively with decreased salience network-mediodorsal-thalamus iFC. This correlation was present in both patients and healthy controls. In the auditory-sensorimotor network-centred system, patients had reduced sensorimotor striatum dopamine synthesis capacity, which correlated positively with increased auditory-sensorimotor network-ventrolateral-thalamus iFC. This correlation was present in patients only. Results demonstrate that reduced striatal dopamine synthesis capacity links topographically with cortico-thalamic intrinsic dysconnectivity in schizophrenia. Data suggest that aberrant striatal dopamine and cortico-thalamic dysconnectivity are pathophysiologically related within dopamine-modulated cortico-basal ganglia-thalamic circuits in schizophrenia.

Prognostic factors in hepatocellular carcinoma patients undergoing transarterial chemoembolization and radioembolization: a retrospective study.

OBJECTIVE: Most patients with hepatocellular carcinoma are diagnosed at intermediate or advanced stages (BCLC B or C) and undergo palliative local treatments such as transarterial chemoembolization or selective internal radiation therapy, also called radioembolization. In terms of liver function and tumor extent, stages BCLC B and C comprise a wide spectrum of tumor manifestations. Predictors of survival in these patients undergoing transarterial chemoembolization and selective internal radiation therapy might help stratification into different prognostic groups and help to select the optimal treatment modality. METHODS: In this retrospective study, all patients with hepatocellular carcinoma who underwent transarterial chemoembolization between January 2010 and December 2014 and all hepatocellular carcinoma patients who underwent selective internal radiation therapy between August 2012 and December 2016 were recruited. The prognostic value of pretherapeutic clinical and laboratory parameters for the prediction of overall survival was analyzed using uni- and multi-variable Cox regression models. RESULTS: We enrolled 129 patients in the transarterial chemoembolization group and 34 patients in the selective internal radiation therapy group. The predictive value of the albumin-bilirubin grade was validated for both the transarterial chemoembolization and the selective internal radiation therapy group. Multivariable analysis identified albumin-bilirubin grade and tumor size as independent predictors for the transarterial chemoembolization group and tumor size, serum albumin and serum sodium as independent predictors for the selective internal radiation therapy group. CONCLUSION: While measures of liver dysfunction predicted survival similarly in both cohorts, we found tumor size to predict survival differently in transarterial chemoembolization- and selective internal radiation therapy-treated patients. Tumor size might help to select the most appropriate treatment in hepatocellular carcinoma patients, although this finding has to be validated in further studies.

Impact of non-uniform attenuation correction in a dynamic [18F]-FDOPA brain PET/MRI study.

BACKGROUND: PET (positron emission tomography) biokinetic modelling relies on accurate quantitative data. One of the main corrections required in PET imaging to obtain high quantitative accuracy is tissue attenuation correction (AC). Incorrect non-uniform PET-AC may result in local bias in the emission images, and thus in relative activity distributions and time activity curves for different regions. MRI (magnetic resonance imaging)-based AC is an active area of research in PET/MRI neuroimaging, where several groups developed in the last few years different methods to calculate accurate attenuation (µ-)maps. Some AC methods have been evaluated for different PET radioisotopes and pathologies. However, AC in PET/MRI has scantly been investigated in dynamic PET studies where the aim is to get quantitative kinetic parameters, rather than semi-quantitative parameters from static PET studies. In this work, we investigated the impact of AC accuracy in PET image absolute quantification and, more importantly, in the slope of the Patlak analysis based on the simplified reference tissue model, from a dynamic [18F]-fluorodopa (FDOPA) PET/MRI study. In the study, we considered the two AC methods provided by the vendor and an in-house AC method based on the dual ultrashort time echo MRI sequence, using as reference a multi-atlas-based AC method based on a T1-weighted MRI sequence. RESULTS: Non-uniform bias in absolute PET quantification across the brain, from - 20% near the skull to - 10% in the central region, was observed using the two vendor's µ-maps. The AC method developed in-house showed a - 5% and 1% bias, respectively. Our study resulted in a 5-9% overestimation of the PET kinetic parameters with the vendor-provided µ-maps, while our in-house-developed AC method showed < 2% overestimation compared to the atlas-based AC method, using the cerebellar cortex as reference region. The overestimation obtained using the occipital pole as reference region resulted in a 7-10% with the vendor-provided µ-maps, while our in-house-developed AC method showed < 6% overestimation. CONCLUSIONS: PET kinetic analyses based on a reference region are especially sensitive to the non-uniform bias in PET quantification from AC inaccuracies in brain PET/MRI. Depending on the position of the reference region and the bias with respect to the analysed region, kinetic analyses suffer different levels of bias. Considering bone in the µ-map can potentially result in larger errors, compared to the absence of bone, when non-uniformities in PET quantification are introduced.

Classification of Polar Maps from Cardiac Perfusion Imaging with Graph-Convolutional Neural Networks.

Myocardial perfusion imaging is a non-invasive imaging technique commonly used for the diagnosis of Coronary Artery Disease and is based on the injection of radiopharmaceutical tracers into the blood stream. The patient's heart is imaged while at rest and under stress in order to determine its capacity to react to the imposed challenge. Assessment of imaging data is commonly performed by visual inspection of polar maps showing the tracer uptake in a compact, two-dimensional representation of the left ventricle. This article presents a method for automatic classification of polar maps based on graph convolutional neural networks. Furthermore, it evaluates how well localization techniques developed for standard convolutional neural networks can be used for the localization of pathological segments with respect to clinically relevant areas. The method is evaluated using 946 labeled datasets and compared quantitatively to three other neural-network-based methods. The proposed model achieves an agreement with the human observer on 89.3% of rest test polar maps and on 91.1% of stress test polar maps. Localization performed on a fine 17-segment division of the polar maps achieves an agreement of 83.1% with the human observer, while localization on a coarse 3-segment division based on the vessel beds of the left ventricle has an agreement of 78.8% with the human observer. Our method could thus assist the decision-making process of physicians when analyzing polar map data obtained from myocardial perfusion images.

Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms.

While there is consistent evidence for increased presynaptic dopamine synthesis capacity in the striatum of patients with schizophrenia during psychosis, it is unclear whether this also holds for patients during psychotic remission. This study investigates whether striatal dopamine synthesis capacity is altered in patients with schizophrenia during symptomatic remission of positive symptoms, and whether potential alterations relate to symptoms other than positive, such as cognitive difficulties. Twenty-three patients with schizophrenia in symptomatic remission of positive symptoms according to Andreasen, and 24 healthy controls underwent 18F-DOPA-PET and behavioural-cognitive assessment. Imaging data were analysed with voxel-wise Patlak modelling with cerebellum as reference region, resulting in the influx constant kicer reflecting dopamine synthesis capacity. For the whole striatum and its subdivisions (i.e. limbic, associative, and sensorimotor), averaged regional kicer values were calculated, compared across groups, and correlated with behavioural-cognitive scores, including a mediation analysis. Patients had negative symptoms (Positive and Negative Syndrome Scale-negative 14.13 ± 5.91) and cognitive difficulties, i.e. they performed worse than controls in Trail-Making-Test-B (TMT-B; P = 0.01). Furthermore, kicer was reduced in patients for whole striatum (P = 0.004) and associative (P = 0.002) and sensorimotor subdivisions (P = 0.007). In patients, whole striatum kicer was negatively correlated with TMT-B (rho = -0.42, P = 0.04; i.e. the lower striatal kicer, the worse the cognitive performance). Mediation analysis showed that striatal kicer mediated the group difference in TMT-B. Results demonstrate that patients with schizophrenia in symptomatic remission of positive symptoms have decreased striatal dopamine synthesis capacity, which mediates the disorder's impact on cognitive difficulties. Data suggest that striatal dopamine dysfunction contributes to cognitive difficulties in schizophrenia.

TRIMAGE: A dedicated trimodality (PET/MR/EEG) imaging tool for schizophrenia.

Simultaneous PET/MR/EEG (Positron Emission Tomography - Magnetic Resonance - Electroencephalography), a new tool for the investigation of neuronal networks in the human brain, is presented here within the framework of the European Union Project TRIMAGE. The trimodal, cost-effective PET/MR/EEG imaging tool makes use of cutting edge technology both in PET and in MR fields. A novel type of magnet (1.5T, non-cryogenic) has been built together with a PET scanner that makes use of the most advanced photodetectors (i.e., SiPM matrices), scintillators matrices (LYSO) and digital electronics. The combined PET/MR/EEG system is dedicated to brain imaging and has an inner diameter of 260 mm and an axial Field-of-View of 160 mm. It enables the acquisition and assessment of molecular metabolic information with high spatial and temporal resolution in a given brain simultaneously. The dopaminergic system and the glutamatergic system in schizophrenic patients are investigated via PET, the same physiological/pathophysiological conditions with regard to functional connectivity, via fMRI, and its electrophysiological signature via EEG. In addition to basic neuroscience questions addressing neurovascular-metabolic coupling, this new methodology lays the foundation for individual physiological and pathological fingerprints for a wide research field addressing healthy aging, gender effects, plasticity and different psychiatric and neurological diseases. The preliminary performances of two components of the imaging tool (PET and MR) are discussed. Initial results of the search of possible candidates for suitable schizophrenia biomarkers are also presented as obtained with PET/MR systems available to the collaboration.

Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma.

Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with increased morbidity and mortality compared with hypertensive controls. The central diagnostic challenge is the differentiation between bilateral and unilateral disease, which determines treatment options. Bilateral adrenal venous sampling, currently recommended for differential diagnosis, is an invasive procedure with several drawbacks, making it desirable to develop novel noninvasive diagnostic tools. When investigating the expression pattern of chemokine receptors by quantitative real-time polymerase chain reaction and immunohistochemistry, we observed high expression of CXCR4 (CXC chemokine receptor type 4) in aldosterone-producing tissue in normal adrenals, adjacent adrenal cortex from adrenocortical adenomas, and in aldosterone-producing adenomas (APA), correlating strongly with the expression of CYP11B2 (aldosterone synthase). In contrast, CXCR4 was not detected in the majority of nonfunctioning adenomas that are frequently found coincidently. The specific CXCR4 ligand 68Ga-pentixafor has recently been established as radiotracer for molecular imaging of CXCR4 expression and showed strong and specific binding to cryosections of APAs in our study. We further investigated 9 patients with primary aldosteronism because of APA by 68Ga-pentixafor-positron emission tomography. The tracer uptake was significantly higher on the side of increased adrenocortical aldosterone secretion in patients with APAs compared with patients investigated by 68Ga-pentixafor-positron emission tomography for other causes. Molecular imaging of aldosterone-producing tissue by a CXCR4-specific ligand may, therefore, be a highly promising tool for noninvasive characterization of patients with APAs.

In-depth Characterization of a TCR-specific Tracer for Sensitive Detection of Tumor-directed Transgenic T Cells by Immuno-PET.

A number of different technologies have been developed to monitor in vivo the distribution of gene-modified T cells used in immunotherapy. Nevertheless, in-depth characterization of novel approaches with respect to sensitivity and clinical applicability are so far missing. We have previously described a novel method to track engineered human T cells in tumors using 89Zr-Df-aTCRmu-F(ab')2 targeting the murinized part of the TCR beta domain (TCRmu) of a transgenic TCR. Here, we performed an in-depth in vitro characterization of the tracer in terms of antigen affinity, immunoreactivity, influence on T-cell functionality and stability in vitro and in vivo. Of particular interest, we have developed diverse experimental settings to quantify TCR-transgenic T cells in vivo. Local application of 89Zr-Df-aTCRmu-F(ab')2-labeled T cells in a spot-assay revealed signal detection down to approximately 1.8x104 cells. In a more clinically relevant model, NSG mice were intravenously injected with different numbers of transgenic T cells, followed by injection of the 89Zr-Df-aTCRmu-F(ab')2 tracer, PET/CT imaging and subsequent ex vivo T-cell quantification in the tumor. Using this setting, we defined a comparable detection limit of 1.0x104 T cells. PET signals correlated well to total numbers of transgenic T cells detected ex vivo independently of the engraftment rates observed in different individual experiments. Thus, these findings confirm the high sensitivity of our novel PET/CT T-cell tracking method and provide critical information about the quantity of transgenic T cells in the tumor environment suggesting our technology being highly suitable for further clinical translation.

Intra-lesional spatial correlation of static and dynamic FET-PET parameters with MRI-based cerebral blood volume in patients with untreated glioma.

PURPOSE: 18F-fluorethyltyrosine-(FET)-PET and MRI-based relative cerebral blood volume (rCBV) have both been used to characterize gliomas. Recently, inter-individual correlations between peak static FET-uptake and rCBV have been reported. Herein, we assess the local intra-lesional relation between FET-PET parameters and rCBV. METHODS: Thirty untreated glioma patients (27 high-grade) underwent simultaneous PET/MRI on a 3 T hybrid scanner obtaining structural and dynamic susceptibility contrast sequences. Static FET-uptake and dynamic FET-slope were correlated with rCBV within tumour hotspots across patients and intra-lesionally using a mixed-effects model to account for inter-individual variation. Furthermore, maximal congruency of tumour volumes defined by FET-uptake and rCBV was determined. RESULTS: While the inter-individual relationship between peak static FET-uptake and rCBV could be confirmed, our intra-lesional, voxel-wise analysis revealed significant positive correlations (median r = 0.374, p < 0.0001). Similarly, significant inter- and intra-individual correlations were observed between FET-slope and rCBV. However, rCBV explained only 12% of the static and 5% of the dynamic FET-PET variance and maximal overlap of respective tumour volumes was 37% on average. CONCLUSIONS: Our results show that the relation between peak values of MR-based rCBV and static FET-uptake can also be observed intra-individually on a voxel basis and also applies to a dynamic FET parameter, possibly determining hotspots of higher biological malignancy. However, just a small part of the FET-PET signal variance is explained by rCBV and tumour volumes determined by the two modalities showed only moderate overlap. These findings indicate that FET-PET and MR-based rCBV provide both congruent and complimentary information on glioma biology.

Rate of elimination of radioiodine-avid lymph node metastases of differentiated thyroid carcinoma by postsurgical radioiodine ablation. A bicentric study.

SPECT/CT detects radioiodine-positive cervical lymph node metastases (LNMs) of differentiated thyroid carcinoma (DTC) at the time of postsurgical radioablation (RA). Preliminary evidence indicates that the majority of LNMs are successfully treated by RA. The aim of this study was to confirm this evidence in a bicentric setting and to evaluate whether size is a predictor for successful elimination. PATIENTS AND METHODS: Since 01/2007 and 05/2008, respectively, SPECT/spiral-CT is performed routinely in all patients with DTC at RA in two University Clinics. The outcome of iodine-positive LNMs identified by SPECT/CT until 12/2012 was analyzed by follow-up diagnostic 131I scans and serum thyreoglobulin (Tg) values. LNM volume and short-axis diameter were evaluated as prognostic factors by a receiver-operating characteristic (ROC) analysis. RESULTS: 79 patients with 97 iodine-positive LNMs were included. Surgery was carried out in 8 patients with 13 LNMs due to the presence of additional iodine-negative lesions. Of the remaining 84 LNMs, 74 (88%) were successfully treated as demonstrated by radioiodine scans at follow-up. 10 LNMs persisted. 67/70 LNMs smaller than 0.9 ml were treated successfully, whereas this was the case of only 6/14 exceeding this threshold. Using this cut-off level to predict treatment success, sensitivity, specificity, positive and negative predictive value were 92%, 73%, 96%, and 57%. Results for short-axis diameter (cut-off level < 1cm) were 90%, 69%, 94% and 56%. CONCLUSION: RA is effective in the treatment of the majority of 131I-positive LNMs identified in SPECT/CT images. In this study, 88% of iodine-positive LNM in DTC were successfully treated by radioiodine given at RA. Both LNM volume and diameter are reliable predictors of treatment success.

Immuno-PET Imaging of Engineered Human T Cells in Tumors.

Sensitive in vivo imaging technologies applicable to the clinical setting are still lacking for adoptive T-cell-based immunotherapies, an important gap to fill if mechanisms of tumor rejection or escape are to be understood. Here, we propose a highly sensitive imaging technology to track human TCR-transgenic T cells in vivo by directly targeting the murinized constant TCR beta domain (TCRmu) with a zirconium-89 ((89)Zr)-labeled anti-TCRmu-F(ab')2 fragment. Binding of the labeled or unlabeled F(ab')2 fragment did not impair functionality of transgenic T cells in vitro and in vivo Using a murine xenograft model of human myeloid sarcoma, we monitored by Immuno-PET imaging human central memory T cells (TCM), which were transgenic for a myeloid peroxidase (MPO)-specific TCR. Diverse T-cell distribution patterns were detected by PET/CT imaging, depending on the tumor size and rejection phase. Results were confirmed by IHC and semiquantitative evaluation of T-cell infiltration within the tumor corresponding to the PET/CT images. Overall, these findings offer a preclinical proof of concept for an imaging approach that is readily tractable for clinical translation. Cancer Res; 76(14); 4113-23. ©2016 AACR.

SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide.

Serum inorganic phosphorus levels predict 30-day mortality in patients with community acquired pneumonia.

BACKGROUND: Community acquired pneumonia is a major cause of morbidity and mortality. The association between serum phosphorus levels on admission and the outcome of patients with community acquired pneumonia has not been widely examined. We aimed to investigate the prognostic value of serum phosphorus levels on admission on the 30- day mortality. METHODS: The cohort included patients of 18 years old or older who were diagnosed with community acquired pneumonia between 2006 and 2012. Patients were retrospectively analyzed to identify risk factors for a primary endpoint of 30-day mortality. Binary logistic regression analysis was used for the calculation of the odds ratios (OR) and p values in bivariate and multivariate analysis to identify association between patients' characteristic and 30-day mortality. RESULTS: The cohort included 3894 patients. In multivariate regression analysis, variables associated with increased risk of 30-day mortality included: age >80 years, increased CURB-65 score, RDW >15, hypernatremia >150 mmol/l, hypoalbuminemia <2 gr/dl and abnormal levels of phosphorus. Levels of <1.5 mg/dl and >4.5 mg/dl were significantly associated with excess 30-day mortality, 38 % (OR 2.9, CI 1.8-4.9, P = 0.001) and 39 % (OR 3.4, CI 2.7-4.2, P = 0.001), respectively. Phosphorus levels within the upper normal limits (4-4.5 mg/dl) were associated with higher mortality rates compared to levels between 1.5-3.5 mg/dl, the reference group, 24 % (OR 1.9, CI 1.5-2.4, P = 0.001). CONCLUSIONS: Abnormal phosphorus levels on admission are associated with increased mortality rates among patients hospitalized with Community acquired pneumonia.