Search

Increased plasma levels of glucagon (hyperglucagonemia) promote diabetes development but are also observed in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This may reflect hepatic glucagon resistance toward amino acid catabolism. A clinical test for measuring glucagon resistance has not been validated. We evaluated our glucagon sensitivity (GLUSENTIC) test, which consists of 2 study days: a glucagon injection and measurements of plasma amino acids and an infusion of mixed amino acids and subsequent calculation of the GLUSENTIC index (primary outcome measure) from measurements of glucagon and amino acids. To distinguish glucagon-dependent from insulin-dependent actions on amino acid metabolism, we also studied patients with type 1 diabetes (T1D). The δ-decline in total amino acids was 49% lower in MASLD following exogenous glucagon (P = 0.01), and the calculated GLUSENTIC index was 34% lower in MASLD (P < 0.0001) but not T1D (P > 0.99). In contrast, glucagon-induced glucose increments were similar in control participants and participants with MASLD (P = 0.41). The GLUSENTIC test and index may be used to measure glucagon resistance in individuals with obesity and MASLD., (© 2024 by the American Diabetes Association.)

Tattoo pigment is expected to migrate beyond the skin to regional lymph nodes and the liver. Modern tattoo ink commonly contains metals that may pose a clinical problem during MRI examinations. This study aimed to investigate the biodistribution of iron oxide pigment to internal organs in mice. Moreover, when exposed to a static magnetic field, we studied whether any reactions followed in the tattooed skin. Twenty-seven hairless C3.Cg-Hrhr/TifBomTac mice were included; 20 were tattooed with iron oxide ink in a rectangular 3 cm 2 pattern; seven were controls. Ten of the tattooed mice were exposed to a 3 T MRI scanner's static magnetic field. Following euthanasia, evaluations of dissected organs involved MRI T2*-mapping, light microscopy (LM) and metal analysis. T2*-mapping measures the relaxation times of hydrogen nuclei in water and fat, which may be affected by neighbouring ferrimagnetic particles, thus enabling the detection of iron oxide particles in organs. Elemental analysis detected a significant level of metals in the tattooed skin compared to controls, but no skin reactions occurred when exposed to a 3 T static magnetic field. No disparity was observed in the liver samples with metal analysis. T2* mapping found no significant difference between the two groups. Only minute clusters of pigment particles were observed in the liver by LM. Our results demonstrate a minimal systemic distribution of the iron oxide pigments to the liver, whereas the kidney and brain were unaffected. The static magnetic field did not trigger skin reactions in magnetic tattoos but may induce image artefacts during MRI., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Meta-[ 123 I]iodobenzylguanidine ([ 123 I]MIBG) scintigraphy with SPECT/CT is the standard of care for diagnosing and monitoring neuroblastoma. Replacing [ 123 I]MIBG with the new PET tracer meta-[ 18 F]fluorobenzylguanidine ([ 18 F]MFBG) and further improving sensitivity and reducing noise in a new long-axial-field-of-view (LAFOV) PET/CT scanner enable increased image quality and a faster acquisition time, allowing examinations to be performed without sedation or general anesthesia (GA). Focusing on feasibility, we present our first experience with [ 18 F]MFBG LAFOV PET/CT and compare it with [ 123 I]MIBG scintigraphy plus SPECT/CT for imaging in neuroblastoma in children. Methods: A pilot of our prospective, single-center study recruited children with neuroblastoma who were referred for [ 123 I]MIBG scintigraphy with SPECT/CT. Within 1 wk of [ 123 I]MIBG scintigraphy and SPECT/low-dose CT, [ 18 F]MFBG LAFOV PET/ultra-low-dose CT was performed 1 h after injection (1.5-3 MBq/kg) without sedation or GA, in contrast to the 24-h postinjection interval needed for scanning with [ 123 I]MIBG, the 2- to 2.5-h acquisition time, and the GA often needed in children less than 6 y old. Based on the spirocyclic iodonium-ylide precursor, [ 18 F]MFBG was produced in a fully automated good manufacturing practice-compliant procedure. We present the feasibility of the study. Results: In the first paired scans of the first 10 children included (5 at diagnosis, 2 during treatment, 2 during surveillance, and 1 at relapse), [ 18 F]MFBG PET/CT scan showed a higher number of radiotracer-avid lesions in 80% of the cases and an equal number of lesions in 20% of the cases. The SIOPEN score was higher in 50% of the cases, and the Curie score was higher in 70% of the cases. In particular, intraspinal, retroperitoneal lymph node, and bone marrow involvement was diagnosed with much higher precision. None of the children (median age, 1.6 y; range, 0.1-7.9 y) had sedation or GA during the PET procedure, whereas 80% had GA during [ 123 I]MIBG scintigraphy with SPECT/CT. A PET acquisition time of only 2 min without motion artifacts was the data requirement of the 10-min acquisition time for reconstruction to provide a clinically useful image. Conclusion: This pilot study demonstrates the feasibility of performing [ 18 F]MFBG LAFOV PET/CT for imaging of neuroblastoma. Further, an increased number of radiotracer-avid lesions, an increased SIOPEN score, and an increased Curie score were seen on [ 18 F]MFBG LAFOV PET/CT compared with [ 123 I]MIBG scintigraphy with SPECT/CT, and GA and sedation was avoided in all patients. Thus, with a 1-d protocol, a significantly shorter scan time, a higher sensitivity, and the avoidance of GA and sedation, [ 18 F]MFBG LAFOV PET/CT shows promise for future staging and response assessment and may also have a clinical impact on therapeutic decision-making for children with neuroblastoma., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

BACKGROUND Over the past 30 years, painful reactions during magnetic resonance imaging (MRI) in tattooed individuals have been sporadically reported. These complications manifest as burning pain in tattooed skin areas, occasionally with swelling and redness, often leading to termination of the scanning. The exact cause is unclear, but iron oxide pigments in permanent make-up or elements in carbon black tattoos may play a role. Additionally, factors like tattoo age, design, and color may influence reactions. The existing literature lacks comprehensive evidence, leaving many questions unanswered. CASE REPORT We present the unique case of a young man who experienced recurring painful reactions in a recently applied black tattoo during multiple MRI scans. Despite the absence of ferrimagnetic ingredients in the tattoo ink, the patient reported intense burning sensations along with transient erythema and edema. Interestingly, the severity of these reactions gradually decreased over time, suggesting a time-dependent factor contributing to the problem. This finding highlights the potential influence of pigment particle density in the skin on the severity and risk of MRI interactions. We hypothesize that the painful sensations could be triggered by excitation of dermal C-fibers by conductive elements in the tattoo ink, likely carbon particles. CONCLUSIONS Our case study highlights that MRI-induced tattoo reactions may gradually decrease over time. While MRI scans occasionally can cause transient reactions in tattoos, they do not result in permanent skin damage and remain a safe and essential diagnostic tool. Further research is needed to understand the mechanisms behind these reactions and explore preventive measures.

Guidelines for multiple endocrine neoplasia type 1 (MEN1) recommend intensive imaging surveillance without specifying a superior regimen, including the role of somatostatin receptor imaging (SRI) with positron emission tomography (PET). The primary outcomes were to: (1) Assess change in treatment of duodenal-pancreatic neuroendocrine neoplasms (DP-NENs), bronchopulmonary NENs, and thymic tumors attributed to use of SRI PET/computed tomography (CT) and (2) estimate radiation from imaging and risk of cancer death attributed to imaging radiation. This was a retrospective single center study, including all MEN1 patients, who had had at least one SRI PET/CT. A total of 60 patients, median age 42 (range 21-54) years, median follow-up 6 (range 1-10) years were included. Of 470 cross sectional scans (MRI, CT, SRI PET/CT), 209 were SRI PET/CT. The additional information from SRI PET had implications in 1/14 surgical interventions and 2/12 medical interventions. The estimated median radiation dose per patient was 104 (range 51-468) mSv of which PET contributed with 13 (range 5-55) mSv and CT with 91 mSv (range 46-413 mSv), corresponding to an estimated increased median risk of cancer death of 0.5% during 6 years follow-up. SRI PET had a significant impact on 3/26 decisions to intervene in 60 MEN1 patients followed for a median of 6 years with SRI PET/CT as the most frequently used modality. The surveillance program showed a high radiation dose. Multi-modality imaging strategies designed to minimize radiation exposure should be considered. Based on our findings, SRI-PET combined with CT cannot be recommended for routine surveillance in MEN1 patients., (© 2023 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Background and Purpose: In cancer treatment precise definition of the tumor volume is essential, but despite development in imaging modalities, this remains a challenge. Here, pathological tumor volumes from the surgical specimens were obtained and compared to tumor volumes defined from modern PET/MRI hybrid imaging. The purpose is to evaluate mismatch between the volumes defined from imaging and pathology was estimated and potential clinical impact., Methods and Materials: Twenty-five patients with head and neck squamous cell carcinoma were scanned on an integrated PET/MRI system prior to surgery. Three gross tumor volumes (GTVs) from the primary tumor site were delineated defined from MRI (GTV MRI ), PET (GTV PET ) and one by utilizing both anatomical images and clinical information (GTV ONCO ). Twenty-five primary tumor specimens were extracted en bloc, scanned with PET/MRI and co-registered to the patient images. Each specimen was sectioned in blocks, sliced and stained with haematoxylin and eosin. All slices were digitalized and tumor delineated by a head and neck pathologist. The pathological tumor areas in all slices were interpolated yielding a pathological 3D tumor volume (GTV PATO ). GTV PATO was compared with the imaging GTV's and potential mismatch was estimated., Results: Thirteen patients were included. The mean volume of GTV ONCO was larger than the GTV's defined from PET or MRI. The mean mismatch of the GTV PATO compared to the GTV PET , GTV MRI and GTV ONCO was 31.9 %, 54.5 % and 27.9 % respectively, and the entire GTV PATO was only fully encompassed in GTV ONCO in 1 of 13 patients. However, after the addition of a clinical 5 mm margin the GTV PATO was fully encompassed in GTV ONCO in 11 out of 13 patients., Conclusions: Despite modern hybrid imaging modalities, a mismatch between imaging and pathological defined tumor volumes was observed in all patients.A 5 mm clinical margin was sufficient to ensure inclusion of the entire pathological volume in 11 out of 13 patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

We investigated the effect of pharmacologically induced weight loss on markers of glucagon resistance in individuals with overweight during treatment with the glucagon-like peptide-1 receptor agonist liraglutide. We performed an open-label study in 14 men with overweight (age 38 ± 11 years, BMI 32 ± 4 kg/m 2 ) without simultaneously diabetes. Subjects were treated with liraglutide, initiated and titrated with 0.6 mg/day/week to reach the final dose of 3.0 mg/day. Subjects were examined at baseline, during titration (Week 4), after 2 weeks of steady state (Week 6) of final dosing of liraglutide and 3 weeks after discontinuation of liraglutide (follow-up). Study participants lost 3.3 ± 1.9 kg (3%) total body weight during the first 4 weeks of treatment with liraglutide. Simultaneously, liver fat content decreased from 12.4 ± 11.6% to 10.2 ± 11.1%, p = 0.025, whereas fat content in the spleen and subcutaneous tissue was unaltered. Markers of glucagon resistance, including plasma glucagon and the glucagon-alanine-index, also decreased significantly during treatment, but total and individual plasma amino acid concentrations did not. Insulin resistance (HOMA-IR) was unchanged during treatment, whereas insulin clearance increased. Treatment with the GLP-1 receptor analogue liraglutide decreased liver fat content, and simultaneously attenuated glucagon concentrations and the glucagon-alanine index in individuals with overweight without diabetes., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Bilateral carpal tunnel syndrome (CTS) is a common extracardiac manifestation of amyloidosis and usually predates overt cardiac amyloidosis (CA) by several years. Screening studies on patients undergoing CTS surgery have shown a low yield of CA (2.0%), but high prevalence of amyloid in the carpal ligament. The proportion of patients with amyloid in the carpal ligament who later develop CA is unknown., Objectives: The authors sought to investigate the prevalence of undiagnosed CA 5 to 15 years after surgery for bilateral CTS., Methods: Using national registries, the authors identified subjects aged 60 to 85 years with prior CTS surgery, where the first procedure on the second wrist was performed 5 to 15 years earlier. Invitations to participate in the study were sent by mail. Per international recommendations, the initial cardiac evaluation included echocardiography, 99m technetium-pyrophosphate scintigraphy, and assessment of monoclonal proteins in serum and urine., Results: A total of 250 subjects (35.7% of those invited) participated in the study. The median age was 70.4 years, and 50% were female. CA was diagnosed in 12 patients (4.8%; 95% CI: 2.5%-8.2%), and all cases were wild-type transthyretin amyloidosis (ATTRwt). The prevalence of ATTRwt in men was 8.8% (95% CI: 4.5%-15.2%; n = 11), and 21.2% (95% CI: 11.1%-34.7%) in male subjects ≥70 years with a BMI <30 kg/m 2 . All but 2 patients diagnosed with ATTRwt were in the lowest disease severity score (Mayo score)., Conclusions: Screening for CA in patients with prior surgery for bilateral CTS finds approximately 5% with early-stage transthyretin CA. The clinical yield was higher (>1 in 5) when focusing on nonobese men ≥70 years, showing potential for systematic screening., Competing Interests: Funding Support and Author Disclosures The study was funded by independent research grants from Erik og Susanna Olesens Almenvelgørende Fond, Pfizer, Arvid Nilssons Fond, Højmosegård-legatet, Frimodt-Heineke Fonden, and Hjertecentrets forskningsudvalg, Rigshospitalet (Dr Westin). Dr Fosbøl has received an independent research grant from Novo Nordisk Foundation, outside the submitted work. Dr Maurer has received grant support from NIH grants R01HL139671, R21AG058348, and K24AG036778; has been a consultant for Intellia, Novo-Nordisk, Pfizer, Eidos, Prothena, Akcea, and Alnylam; and his institution has received clinical trial funding from Pfizer, Prothena, Eidos, and Alnylam. Dr Gustafsson has received personal fees from Abbott, AstraZeneca, Pfizer, Boehringer Ingelheim, Novartis, and Orion Pharma outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The Scandinavian winter-swimming culture combines brief dips in cold water with hot sauna sessions, with conceivable effects on body temperature. We study thermogenic brown adipose tissue (BAT) in experienced winter-swimming men performing this activity 2-3 times per week. Our data suggest a lower thermal comfort state in the winter swimmers compared with controls, with a lower core temperature and absence of BAT activity. In response to cold, we observe greater increases in cold-induced thermogenesis and supraclavicular skin temperature in the winter swimmers, whereas BAT glucose uptake and muscle activity increase similarly to those of the controls. All subjects demonstrate nocturnal reduction in supraclavicular skin temperature, whereas a distinct peak occurs at 4:30-5:30 a.m. in the winter swimmers. Our data leverage understanding of BAT in adult human thermoregulation, suggest both heat and cold acclimation in winter swimmers, and propose winter swimming as a potential strategy for increasing energy expenditure., Competing Interests: C. Scheele is a consultant for Novo Nordisk A/S on human brown adipose tissue biology. Z.G.-H. works, in some capacity, for Embark Biotech ApS, a company developing therapeutics for the treatment of diabetes and obesity. All other authors declare no competing interests associated with this manuscript., (© 2021 The Authors.)

Angiogenesis is crucial in tissue repair and prevents scar tissue formation following an ischemic event such as myocardial infarction. The ischemia induces formation of new capillaries, which have high expression of integrin α v β 3 . [ 68 Ga]Ga-NODAGA-E[(cRGDyK)] 2 ([ 68 Ga]Ga-RGD) is a promising PET-radiotracer reflecting angiogenesis by binding to integrin α v β 3 . A Göttingen mini-pig underwent transient catheter-induced left anterior descending artery (LAD) occlusion for 120 min, and after 8 weeks was imaged on a Siemens mMR 3T PET/MR system. A large antero-septal infarction was evident by late gadolinium enhancement (LGE) on the short axis and 2-4 chamber views. The infarcted area corresponded to the area with high [ 68 Ga]Ga-RGD uptake on the fused PET/MR images, with no uptake in the healthy myocardium. To support the hypothesis that [ 68 Ga]Ga-RGD uptake reflects angiogenesis, biopsies were sampled from the infarct border and healthy myocardium. Expression of α v β 3 was evaluated using immunohistochemistry. The staining showed higher α v β 3 expression in the capillaries of the infarct border compared to those in the healthy myocardium. These initial data confirm in vivo detection of angiogenesis using [ 68 Ga]Ga-RGD PET in a translational model, which overall support the method applicability when evaluating novel cardio-protective therapies.

Rationale: Tumor biopsy cannot detect heterogeneity and an association between heterogeneity in functional imaging and molecular biology will have an impact on both diagnostics and treatment possibilities., Purpose: Multiparametric imaging can provide 3D information on functional aspects of a tumor and may be suitable for predicting intratumor heterogeneity. Here, we investigate the correlation between intratumor heterogeneity assessed with multiparametric imaging and multiple-biopsy immunohistochemistry., Methods: In this prospective study, patients with primary or recurrent head and neck squamous cell carcinoma (HNSCC) underwent PET/MRI scanning prior to surgery. Tumors were removed en bloc and six core biopsies were used for immunohistochemical (IHC) staining with a predefined list of biomarkers: p40, p53, EGFR, Ki-67, GLUT1, VEGF, Bcl-2, CAIX, PD-L1. Intratumor heterogeneity of each IHC biomarker was quantified by calculating the coefficient of variation (CV) in tumor proportion score among the six core biopsies within each tumor lesion. The heterogeneity in the imaging biomarkers was assessed by calculating CV in 18 F-fluorodeoxyglucose (FDG)-uptake, diffusion and perfusion. Concordance of the two variance measures was quantified using Spearman's rank correlation RESULTS: Twenty-eight patients with a total of 33 lesions were included. There was considerable heterogeneity in most of the IHC biomarkers especially in GLUT1, PD-L1, Ki-67, CAIX and p53, however we only observed a correlation between the heterogeneity in GLUT1 and p53 and between Ki-67 and EGFR. Heterogeneity in FDG uptake and diffusion correlated with heterogeneity in cell density., Conclusion: Considerable heterogeneity of IHC biomarkers was found, however, only few and weak correlations between the studied IHC markers were observed. The studied functional imaging biomarkers showed weak associations with heterogeneity in some of the IHC biomarkers. Thus, biological heterogeneity is not a general tumor characteristic but depends on the specific biomarker or imaging modality., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Metastatic colorectal cancer (mCRC) is treated with cetuximab 250 mg/m 2 administered weekly over 1 hour or biweekly (q2w) over 3.5 hours when combined with irinotecan. This prospective study investigated cetuximab 500 mg/m 2 plus irinotecan 180 mg/m 2 administered q2w over 1.5 hours independent of RAS or BRAF mutation status in mCRC patients in a third-line setting. The intention-to-treat population included 181 patients. No patients had complete response, 18% had partial responses (PR) and 48% stable disease (SD). For cetuximab, a relative dose intensity of ≥90% was reached in 78% and for irinotecan in 67% of the patients. Grade 3 to 4 toxicities were pain (17%), fatigue (9%), neutropenia (8%), diarrhea (8%), rash (8%), infection (7%) and hypersensitivity (3%). No deaths occurred. Next-generation sequencing in 96.7% of the patients revealed that 50.3% had RAS and BRAF V600E wild type (WT), with a mutation type (MT) in 45.1% of the RAS and 4.4% of the BRAF V600E genes. In patients with RAS-WT and RAS-MT tumors, a PR was obtained in 32% and 4% (P = .000003) and an SD in 43% and 53%, respectively, with a superior PFS (6.2 vs 3.7 months; hazard ratio [HR] 2.12, P = .00001) and OS (12.9 vs 8.8 months; HR 1.71, P = .0008). Treatment efficacy was poor in 7.4% of patients with an RAS mutation outside KRAS exon 2 and in 38% of patients with KRAS exon 2 mutations. Administration of cetuximab and irinotecan q2w, shortening treatment time from 3.5 to 1.5 hours, is recommended as standard therapy., (© 2020 UICC.)

Diagnosing relapse after radiotherapy for lung cancer is challenging. The specificity of both CT and 18 F-FDG PET/CT is low because of radiation-induced changes. 3'-deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT) PET has previously demonstrated higher specificity for malignancy than 18 F-FDG PET. We investigated the value of 18 F-FLT PET/CT for diagnosing relapse in irradiated lung cancer. Methods: Patients suspected of relapse of lung cancer after definitive radiotherapy (conventional fractionated radiotherapy [cRT] or stereotactic body radiotherapy [SBRT]) were included. Sensitivity and specificity were analyzed both within the irradiated high-dose volume (HDV) and on a patient basis. Marginal differences and interobserver agreement were assessed. Results: Sixty-three patients who had received radiotherapy in 70 HDVs (34 cRT; 36 SBRT) were included. The specificity of 18 F-FLT PET/CT was higher than that of 18 F-FDG PET/CT (HDV, 96% [95% CI, 87-100] vs. 71% [95% CI, 57-83] [ P = 0.0039]; patient-based, 90% [95% CI, 73-98] vs. 55% [95% CI, 36-74] [ P = 0.0020]). The difference in specificity between 18 F-FLT PET/CT and 18 F-FDG PET/CT was higher after cRT than after SBRT. The sensitivity of 18 F-FLT PET/CT was lower than that of 18 F-FDG PET/CT (HDV, 69% [95% CI, 41-89] vs. 94% [95% CI, 70-100] [ P = 0.1250]; patient-based, 70% [95% CI, 51-84] vs. 94% [95% CI, 80-99] [ P = 0.0078]). Adding 18 F-FLT PET/CT when 18 F-FDG PET/CT was positive or inconclusive improved the diagnostic value compared with 18 F-FDG PET/CT alone. In cRT HDVs, the probability of malignancy increased from 67% for 18 F-FDG PET/CT alone to 100% when both tracers were positive. Conclusion: 18 F-FLT PET/CT adds diagnostic value to 18 F-FDG PET/CT in patients with suspected relapse. The diagnostic impact of 18 F-FLT PET/CT was highest after cRT. We suggest adding 18 F-FLT PET/CT when 18 F-FDG PET/CT is inconclusive or positive within the previously irradiated volume to improve diagnostic value in patients for whom histologic confirmation is not easily obtained., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Eosinophilic cystitis (EC) is a relatively rare, but benign inflammatory bladder disease compared to that of the malignant pediatric rhabdomyosarcoma (RMS), in which it can be mimicking on initial suspicion. The origin, symptoms and findings of both EC and RMS are still discussed and hence, lead to the challenge in distinguishing them by cystoscopy and several image modalities. We present a case in which cross-sectional imaging modalities including fluorine-18-fluro-2-deoxy-D-glucose ( 18 F-FDG)-positron emission tomography (PET) / computed tomography (CT) / magnetic resonance imaging (MRI) ( 18 F-FDG-PET/CT/MRI (The imaging modality 18 F-FDG-PET/CT/MRI referring to two continuous scans scanned on the same 18 F-FDG-tracer dose for both the whole-body 18 F-FDG-PET/CT and the regional 18 F-FDG-PET/MRI of the pelvis.)) raised suspicion of RMS. Hence, the final diagnosis of EC was established by repeated histopathology. It is important to have EC in mind when seeking differential diagnosis of malignant diseases like RMS in order to provide the correct treatment for the patient and highly homogenously increased 18 F-FDG-uptake should raise the suspicion of EC as a differential diagnosis. Furthermore, 18 F-FDG-uptake rate is suggested as a future potential biomarker for monitoring of therapeutic response in eosinophilic inflammatory diseases, thus more research on this topic is needed.

The aim of this study was to evaluate the correlation between uptake of the PET ligand 68 Ga-NOTA-AE105, targeting the urokinase-type plasminogen activator receptor (uPAR), and Gleason score in patients undergoing prostate biopsy. Methods: Patients with clinical suspicion of prostate cancer (PCa) or previously diagnosed with PCa were prospectively enrolled in this phase 2 trial. A combination of uPAR PET and multiparametric MRI (mpMRI) was performed, and the SUV in the primary tumor, as delineated by mpMRI, was measured by 2 independent readers. The correlation between the SUV and the Gleason score obtained by biopsy was assessed. Results: A total of 27 patients had histologically verified PCa visible on mpMRI and constituted the study population. There was a positive correlation between the SUV max and the Gleason score (Spearman ρ = 0.55; P = 0.003). Receiver operating characteristic analysis showed an area under the curve of 0.88 (95% CI, 0.67-1.00) for discriminating a Gleason score of greater than or equal to 3 + 4 from a Gleason score of less than or equal to 3 + 3. A cutoff for the tumor SUV max could be established with a sensitivity of 96% (79%-99%) and a specificity of 75% (30%-95%) for detecting a Gleason score of greater than or equal to 3 + 4. For discriminating a Gleason score of greater than or equal to 4 + 3 from a Gleason score of less than or equal to 3 + 4, a cutoff could be established for detecting a Gleason score of greater than or equal to 4 + 3 with a sensitivity of 93% (69%-99%) and a specificity of 62% (36%-82%). Conclusion: SUV measurements from uPAR PET in primary tumors, as delineated by mpMRI, showed a significant correlation with the Gleason score, and the tumor SUV max was able to discriminate between low-risk Gleason score profiles and intermediate risk Gleason score profiles with a high diagnostic accuracy. Consequently, uPAR PET/MRI could be a promising method for the noninvasive evaluation of PCa and might reduce the need for repeated biopsies (e.g., in active surveillance)., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

The recent introduction of solid-state detectors in clinical positron emission tomography (PET) scanners has significantly improved image quality and spatial resolution and shortened acquisition time compared to conventional analog PET scanners. In an initial evaluation of the performance of our newly acquired Siemens Biograph Vision 600 PET/CT (digital PET/CT) scanner for 64 Cu-DOTATATE imaging, we compared PET/CT acquisitions from patients with neuroendocrine neoplasms (NENs) grades 1 and 2 and stable disease on CT who were scanned on both our Siemens Biograph 128 mCT PET/CT (analog PET/CT) and digital PET/CT within 6 months as part of their routine clinical management. Five patients fulfilled the criteria and were included in the analysis. The digital PET acquisition time was less than 1/3 of the analog PET acquisition time (digital PET, mean (min:s): 08:20 (range, 07:59-09:45); analog PET, 25:28 (24:39-28:44), p < 0.001). All 44 lesions detected on the analog PET with corresponding structural correlates on the CT were also found on the digital PET performed 137 (107-176) days later. Our initial findings suggest that digital 64 Cu-DOTATATE PET can successfully be performed in patients with NENs using an image acquisition time of only 1/3 of what is used for an analog 64 Cu-DOTATATE PET.

Purpose: Cancer has a multitude of phenotypic expressions and identifying these are important for correct diagnosis and treatment selection. Clinical molecular imaging such as positron emission tomography can access several of these hallmarks of cancer non-invasively. Recently, hyperpolarized magnetic resonance spectroscopy with [1- 13 C] pyruvate has shown great potential to probe metabolic pathways. Here, we investigate simultaneous dual modality clinical molecular imaging of angiogenesis and deregulated energy metabolism in canine cancer patients., Methods: Canine cancer patients (n = 11) underwent simultaneous [ 68 Ga]Ga-NODAGA-E[(cRGDyK)] 2 (RGD) PET and hyperpolarized [1- 13 C]pyruvate-MRSI (hyperPET). Standardized uptake values and [1- 13 C]lactate to total 13 C ratio were quantified and compared generally and voxel-wise., Results: Ten out of 11 patients showed clear tumor uptake of [ 68 Ga]Ga-NODAGA-RGD at both 20 and 60 min after injection, with an average SUV mean of 1.36 ± 0.23 g/mL and 1.13 ± 0.21 g/mL, respectively. A similar pattern was seen for SUV max values, which were 2.74 ± 0.41 g/mL and 2.37 ± 0.45 g/mL. The [1- 13 C]lactate generation followed patterns previously reported. We found no obvious pattern or consistent correlation between the two modalities. Voxel-wise tumor values of RGD uptake and lactate generation analysis revealed a tendency for each canine cancer patient to cluster in separated groups., Conclusion: We demonstrated combined imaging of [ 68 Ga]Ga-NODAGA-RGD-PET for angiogenesis and hyperpolarized [1- 13 C]pyruvate-MRSI for probing energy metabolism. The results suggest that [ 68 Ga]Ga-NODAGA-RGD-PET and [1- 13 C]pyruvate-MRSI may provide complementary information, indicating that hyperPET imaging of angiogenesis and energy metabolism is able to aid in cancer phenotyping, leading to improved therapy planning.

64 Cu-DOTATATE PET/CT imaging 1 h after injection is excellent for lesion detection in patients with neuroendocrine neoplasms (NENs). We hypothesized that the imaging time window can be extended up to 3 h after injection without significant differences in the number of lesions detected. Methods: From a prospective study, we compared, on a head-to-head basis, sets of 64 Cu-DOTATATE PET/CT images from 35 patients with NENs scanned 1 and 3 h after injection of 200 MBq of 64 Cu-DOTATATE. The number of lesions on both PET scans was counted and grouped according to organs or regions and compared with negative binomial regression. Discordant lesions (visible on only the 1-h images or only the 3-h 64 Cu-DOTATATE PET images) were considered true if found on simultaneous CT or later MR, CT, or somatostatin receptor imaging. We measured lesion SUV max , reference normal-organ or -tissue SUV mean , and tumor-to-normal-tissue ratios calculated from SUV max and SUV mean Results: We found 822 concordant lesions (visible on both 1-h and 3-h 64 Cu-DOTATATE PET) and 5 discordant lesions, of which 4 were considered true. One discordant case in 1 patient involved a discordant organ system (lymph node) detected on 3-h but not 1-h 64 Cu-DOTATATE PET that did not alter the patient's disease stage (stage IV) because the patient had 11 additional concordant liver lesions. We found no significant differences between the number of lesions detected on 1-h and 3-h 64 Cu-DOTATATE PET. Throughout the 1- to 3-h imaging window, the mean tumor-to-normal-tissue ratio remained high in all key organs: liver (1 h: 12.6 [95% confidence interval (CI), 10.2-14.9]; 3 h: 11.0 [95%CI, 8.7-13.4]), intestines (1 h: 24.2 [95%CI, 14.9-33.4]; 3 h: 28.2 [95%CI, 16.5-40.0]), pancreas (1 h: 42.4 [95%CI, 12.3-72.5]; 3 h: 41.1 [95%CI, 8.7-73.4]), and bone (1 h: 103.0 [95%CI, 38.6-167.4]; 3 h: 124.2 [95%CI, 57.1-191.2]). Conclusion: The imaging time window of 64 Cu-DOTATATE PET/CT for patients with NENs can be expanded from 1 h to 1-3 h without significant differences in the number of lesions detected., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Tattooed patients undergoing magnetic resonance imaging (MRI) can develop cutaneous complications during the procedure. Our aim was to review all published case reports on MRI-induced tattoo complications to identify a possible pattern. So far, 17 cases have been reported. Five (29%) of the cases were in cosmetic tattoos. Symptoms are abrupt and painful with fast onset during MRI, sometimes requiring termination of the procedure. Clinical signs are absent or manifested as inflammation sensed as burning. No thermal skin burns have been recognized. Full recovery is fast, with no sequelae. MRI-induced tattoo complications are uncommon. Patients with cosmetic and traditional tattoos can undergo routine MRI.

Aim: To investigate the effect of a glucagon-like peptide-1 receptor agonist (GLP-1RA), liraglutide, on pancreatic volume, oedema, cellularity and DNA synthesis in humans., Materials and Methods: We performed an open-label study in 14 obese men (age 38 ± 11 years, body mass index 32 ± 4 kg/m 2 ) without diabetes. Subjects were examined at baseline, during titration (week 4) of liraglutide towards 3.0 mg/day, and 2 weeks after steady-state treatment (week 6) of a final dose of liraglutide. The primary endpoint was pancreatic volume determined by magnetic resonance imaging. Secondary endpoints included pancreatic oedema and cellularity, positron emission tomography-based [ 18 F]fluorothymidine (FLT) uptake (DNA synthesis) and plasma pancreatic enzymes., Results: Plasma amylase (+7 U/L [95% confidence intervals 3-11], P < .01) and lipase (+19 U/L [7-30], P < .01) increased during liraglutide treatment. Pancreatic volume did not change from baseline to steady state of treatment (+0.2 cm 3 [-8-8], P = .96) and no change in pancreatic cellular infiltration was found (P = .22). During titration of liraglutide, FLT uptake in pancreatic tissue increased numerically (+0.08 [0.00-0.17], P = .0507)., Conclusions: Six weeks of treatment with liraglutide did not affect pancreatic volume, oedema or cellularity in obese men without diabetes., (© 2020 John Wiley & Sons Ltd.)

Background: Patient head motion is a major concern in clinical brain MRI, as it reduces the diagnostic image quality and may increase examination time and cost., Purpose: To investigate the prevalence of MR images with significant motion artifacts on a given clinical scanner and to estimate the potential financial cost savings of applying motion correction to clinical brain MRI examinations., Study Type: Retrospective., Subjects: In all, 173 patients undergoing a PET/MRI dementia protocol and 55 pediatric patients undergoing a PET/MRI brain tumor protocol. The total scan time of the two protocols were 17 and 40 minutes, respectively., Field Strength/sequences: 3 T, Siemens mMR Biograph, MPRAGE, DWI, T 1 and T 2 -weighted FLAIR, T 2 -weighted 2D-FLASH, T 2 -weighted TSE., Assessment: A retrospective review of image sequences from a given clinical MRI scanner was conducted to investigate the prevalence of motion-corrupted images. The review was performed by three radiologists with different levels of experience using a three-step semiquantitative scale to classify the quality of the images. A total of 1013 sequences distributed on 228 MRI examinations were reviewed. The potential cost savings of motion correction were estimated by a cost estimation for our country with assumptions., Statistical Test: The cost estimation was conducted with a 20% lower and upper bound on the model assumptions to include the uncertainty of the assumptions., Results: 7.9% of the sequences had motion artifacts that decreased the interpretability, while 2.0% of the sequences had motion artifacts causing the images to be nondiagnostic. The estimated annual cost to the clinic/hospital due to patient head motion per scanner was $45,066 without pediatric examinations and $364,242 with pediatric examinations., Data Conclusion: The prevalence of a motion-corrupted image was found in 2.0% of the reviewed sequences. Based on the model, repayment periods are presented as a function of the price for applying motion correction and its performance., Evidence Level: 4 TECHNICAL EFFICACY: Stage 6 J. Magn. Reson. Imaging 2020;52:731-738., (© 2020 International Society for Magnetic Resonance in Medicine.)

Background: The purpose of this study is to test if functional multiparametric imaging with 18 F-FDG-PET/MRI correlates spatially with immunohistochemical biomarker status within a lesion of head and neck squamous cell carcinoma (HNSCC), and also whether a biopsy with the highest FDG uptake was more likely to have the highest PD-L1 expression or the highest percentage of vital tumour cells (VTC) compared with a random biopsy., Methods: Thirty-one patients with HNSCC were scanned on an integrated PET/MRI scanner with FDG prior to surgery in this prospective study. Imaging was quantified with SUV, ADC and K trans . A 3D-morphometric MRI scan of the specimen was used to co-register the patient and the specimen scans. All specimens were sectioned in consecutive slices, and slices from six different locations were selected randomly from each tumour. Core biopsies were performed to construct TMA blocks for IHC staining with the ten predefined biomarkers. The spatial correlation was assessed with a partial correlation analysis., Results: Twenty-eight patients with a total of 33 lesions were eligible for further analysis. There were significant correlations between the three imaging biomarkers and some of the IHC biomarkers. Moreover, a biopsy taken from the most FDG-avid part of the tumour did not have a statistically significantly higher probability of higher PD-L1 expression or VTC, compared with a random biopsy., Conclusion: We found statistically significant correlations between functional imaging parameters and key molecular cancer markers.

Background: Small cell lung cancer (SCLC) is an aggressive cancer often presenting in an advanced stage and prognosis is poor. Early response evaluation may have impact on the treatment strategy., Aim: We evaluated 18 F-fluorothymidine-(FLT)-PET/diffusion-weighted-(DW)-MRI early after treatment start to describe biological changes during therapy, the potential of early response evaluation, and the added value of FLT-PET/DW-MRI., Methods: Patients with SCLC referred for standard chemotherapy were eligible. FLT-PET/DW-MRI of the chest and brain was acquired within 14 days after treatment start. FLT-PET/DW-MRI was compared with pretreatment FDG-PET/CT. Standardized uptake value (SUV), apparent diffusion coefficient (ADC), and functional tumor volumes were measured. FDG-SUV peak , FLT-SUV peak , and ADC median ; spatial distribution of aggressive areas; and voxel-by-voxel analyses were evaluated to compare the biological information derived from the three functional imaging modalities. FDG-SUV peak , FLT-SUV peak , and ADC median were also analyzed for ability to predict final treatment response., Results: Twelve patients with SCLC completed FLT-PET/MRI 1-9 days after treatment start. In nine patients, pretreatment FDG-PET/CT was available for comparison. A total of 16 T-sites and 12 N-sites were identified. No brain metastases were detected. FDG-SUV peak was 2.0-22.7 in T-sites and 5.5-17.3 in N-sites. FLT-SUV peak was 0.6-11.5 in T-sites and 1.2-2.4 in N-sites. ADC median was 0.76-1.74 × 10 - 3  mm 2 /s in T-sites and 0.88-2.09 × 10 -3  mm 2 /s in N-sites. FLT-SUV peak correlated with FDG-SUV peak , and voxel-by-voxel correlation was positive, though the hottest regions were dissimilarly distributed in FLT-PET compared to FDG-PET. FLT-SUV peak was not correlated with ADC median , and voxel-by-voxel analyses and spatial distribution of aggressive areas varied with no systematic relation. LT-SUV peak was significantly lower in responding lesions than non-responding lesions (mean FLT-SUV peak in T-sites: 1.5 vs. 5.7; p = 0.007, mean FLT-SUV peak in N-sites: 1.6 vs. 2.2; p = 0.013)., Conclusions: FLT-PET and DW-MRI performed early after treatment start may add biological information in patients with SCLC. Proliferation early after treatment start measured by FLT-PET is a promising predictor for final treatment response that warrants further investigation., Trial Registration: Clinicaltrials.gov, NCT02995902. Registered 11 December 2014 - Retrospectively registered.

Phase-contrast mapping (PCM) magnetic resonance imaging (MRI) provides easy-access non-invasive quantification of global cerebral blood flow (gCBF) but its accuracy in altered perfusion states is not established. We aimed to compare paired PCM MRI and 15 O-H 2 O positron emission tomography (PET) measurements of gCBF in different perfusion states in a single scanning session. Duplicate combined gCBF PCM-MRI and 15 O-H 2 O PET measurements were performed in the resting condition, during hyperventilation and after acetazolamide administration (post-ACZ) using a 3T hybrid PET/MR system. A total of 62 paired gCBF measurements were acquired in 14 healthy young male volunteers. Average gCBF in resting state measured by PCM-MRI and 15 O-H 2 O PET were 58.5 ± 10.7 and 38.6 ± 5.7 mL/100 g/min, respectively, during hyperventilation 33 ± 8.6 and 24.7 ± 5.8 mL/100 g/min, respectively, and post-ACZ 89.6 ± 27.1 and 57.3 ± 9.6 mL/100 g/min, respectively. On average, gCBF measured by PCM-MRI was 49% higher compared to 15 O-H 2 O PET. A strong correlation between the two methods across all states was observed (R 2  = 0.72, p  < 0.001). Bland-Altman analysis suggested a perfusion dependent relative bias resulting in higher relative difference at higher CBF values. In conclusion, measurements of gCBF by PCM-MRI in healthy volunteers show a strong correlation with 15 O-H 2 O PET, but are associated with a large and non-linear perfusion-dependent difference.

Background and Aims: The advantage of combining molecular and morphological imaging, e.g. positron emission tomography and magnetic resonance imaging (PET/MRI), is reflected in the increased use of these modalities as surrogate end-points in clinical trials. This study aimed at evaluating plaque inflammation using 18 F-fluorodeoxyglucose ( 18 F-FDG)-PET/MRI, and gene expression in a minipig model of atherosclerosis., Methods: Göttingen Minipigs were fed for 60 weeks with fat/fructose/cholesterol-rich diet (FFC), chow (Control) or FFC-diet changed to chow midway (diet normalization group; DNO). In all groups, 18 F-FDG-PET/MRI of the abdominal aorta was assessed midway and at study-end. The aorta was analyzed using histology and gene expression., Results: At study-end, FFC had significantly higher FDG-uptake compared to Control (target-to-background maximal uptake, TBR Max (95% confidence interval) CI TBRMax : 0.092; 7.32) and DNO showed significantly decreased uptake compared to FFC (CI TBRMax : -5.94;-0.07). No difference was observed between DNO and Control (CI TBRMax : -2.71; 4.11). FFC displayed increased atherosclerosis and gene expression of inflammatory markers, including vascular cell adhesion molecule 1 (VCAM-1), cluster of differentiation 68 (CD68), matrix metalloproteinase 9 (MMP9), cathepsin K (CTSK) and secreted phosphoprotein 1 (SPP1) compared to Control and DNO (all, p < 0.05). FDG-uptake correlated with gene expression of inflammatory markers, including CD68, ρ s  = 0.58; MMP9, ρ s  = 0.46; SPP1, ρ s  = 0.44 and CTSK, ρ s  = 0.49; (p ≤ 0.01 for all)., Conclusions: In a model of atherosclerosis, 18 F-FDG-PET/MRI technology allows for detection of inflammation in atherosclerotic plaques, consistent with increased inflammatory gene expression. Our findings corroborate clinical data and are important in pre-clinical drug development targeting plaque inflammation., (Copyright © 2019. Published by Elsevier B.V.)

Intratumor heterogeneity may contribute to the ambiguous clinical results on PD-L1 status as a predictor for immunotherapy response in patients with HNSCC. This decreases the utility of PD-L1 expression from single tumour biopsies as a predictive biomarker. In this prospective study, intratumor heterogeneity of PD-L1 expression in HNSCC was investigated with both Tumour Proportion Score (TPS) and Combined Positive Score (CPS). Thirty-three whole surgical specimens from 28 patients with HNSCC were included. PD-L1 expression in six random core biopsies from each surgical specimen was used to assess the concordance between multiple biopsies and the negative predictive value of a single negative core biopsy. With 1% cut off, 36% of the specimens were concordant with TPS and 52% with CPS. With a 50% cut-off value the concordance was 70% with TPS and 55% with CPS. Defining a tumour as positive if just a single-one of the biopsies was positive, the negative predictive value (NPV) of a single negative core biopsy was 38.9 and 0% (1% cut off), and 79.9% and 62.8% (50% cut off) for TPS and CPS, respectively. In conclusion, PD-L1 positivity varies markedly within the tumour, both with TPS and CPS, challenging the utility of this biomarker.

Purpose: With the increasing number of therapy options available for patients with lung cancer, early response evaluation is needed. We performed this pilot study to assess the feasibility of early, repeated Positron emission tomography-magnetic resonance (PET/MR), the impact of timing and the capability for response prediction in lung tumors during chemotherapy. Methods: Patients with stage IV non-small cell lung cancer referred for chemotherapy were prospectively recruited. Fluorine-18-Fluorodeoxyglucose( 18 F-FDG)-PET/MR scans were performed prior to, during and after the first or second cycle of chemotherapy. Primary tumors were defined on all scans and size, FDG-uptake and apparent diffusion coefficient (ADC) were measured. Early response was described over time and a Standard Linear Mixed Model was applied to analyze changes over time. Results: 45 FDG-PET/MR scans were performed in 11 patients. Whereas the overall changes measured by ADC did not change significantly, there was an overall significant decrease in FDG-uptake from pre to post treatment scans. There was no difference in the FDG-uptake measured 1 or 3 weeks after therapy, but uptake measured 2 weeks after therapy differed from measurements at week 3. Changes measured in patients scanned during the first treatment cycle appeared more pronounced than during the second cycle. Conclusions: This pilot study indicates that response evaluation shortly after initiation of chemotherapy appears concordant with later evaluation and probably more reliable than evaluation midway between cycles. Responses during or after the first cycle of chemotherapy rather than during subsequent cycles are likely to be more readily measured.

Study Design and Purpose: Positron emission tomography (PET)/magnetic resonance imaging (MRI) is a new modality that has showed promising results for various clinical indications. Currently, evaluation of neoadjuvant therapy (NT) among patients with adenocarcinoma of the esophagogastric junction has primarily been reserved for PET/computed tomography. Our aim was to evaluate if early response evaluation by PET/MRI is a feasible method to predict resectability., Methods and Materials: Patients with untreated adenocarcinoma of the esophagogastric junction (Siewert types I/II) and fit for NT with no contraindications for PET/MRI were considered eligible. A baseline scan was performed prior to NT induction and an evaluation scan 3 weeks later. For histopathological response evaluation, the Mandard tumor regression grade score was applied. Response on PET/MRI was evaluated with Response Evaluation Criteria in Solid Tumors (RECIST 1.1), and change in ADC and SUV max values., Results: Twenty-eight patients were enrolled, and 22 completed both scans and proceeded to final analyses. Seventeen patients were found resectable versus five who were found unresectable. PET/MRI response evaluation had a sensitivity 94%, specificity 80%, and AUC = 0.95 when predicting resectability in patients with adenocarcinoma of the esophagogastric junction. No association with histopathological response (tumor regression grade) was found nor was RECIST correlated with resectability., Conclusion: Response evaluation using PET/MRI was a feasible method to predict resectability in patients with adenocarcinoma of the esophagogastric junction in this pilot study. However, larger studies are warranted to justify the use of the modality for this indication.

This feasibility study set out to investigate the use of FDG-PET/DW-MRI in chronic hepatitis C patients to examine changes in local liver inflammation after treatment with direct-acting antivirals (DAA). Twelve patients with chronic hepatitis C were prospectively enrolled, performing FDG-PET/DW-MRI prior to and after DAA treatment. PET/DW-MRI included PET acquisition 60 and 90 min after FDG-injection, DIXON, for attenuation correction, T2- and DW-MRI with 10 b-values between 0-700 s/mm 2 . The following parameters were measured from fusion of 3 volumes of interest (VOIs) placed in the liver parenchyma: Mean standard uptake value after 60 and 90 minutes (SUV mean60 and SUV mean90 ), total Apparent Diffusion Coefficient (ADC), perfusion fraction (PF), pseudo-diffusion (D*) and perfusion-free diffusion (D). We found PET/DW-MRI of chronic hepatitis C patients to be feasible. Patients were cooperative, tolerated the scans well and the image quality was acceptable. A total of 10 patients were available for final analysis. All patients achieved sustained virologic response and normalized alanine -aminotransferase (ALAT) levels after treatment with DAA. Perfusion fraction measured by DW-MRI changed significantly after treatment, from mean 0.21 (± 0.04) to 0.26 (± 0.06), P=0.005 and D* from 0.50 (± 0.13) × 10 -3 s/mm 2 to 0.62 (± 0.15) × 10 -3 s/mm 2 , P=0.028. All other parameters, including FDG-uptake, was unchanged. These results suggest that liver perfusion is changed shortly after DAA treatment, with no significant change in inflammation. The study concludes that PET/DW-MR is feasible in quantifying perfusion and possibly inflammation in chronic hepatitis C patients and may be used to follow treatment., Competing Interests: None.

Background: Electrochemotherapy is an established treatment for cutaneous tumors. This study aimed at determining efficacy of electrochemotherapy in recurrent head and neck cancer., Methods: Phase II clinical trial in patients with recurrent head and neck carcinomas with no curative treatment options. Electrochemotherapy was performed under general anesthesia. Primary endpoint was tumor response (CT scanning) evaluated at week 8. Secondary endpoints included biopsy results, MRI and fluorodeoxyglucose-positron emission tomography scanning, safety, toxicity, pain score, and quality-of-life questionnaires., Results: Of 26 patients treated, 5 (19%) achieved complete response, 10 (39%) partial response, resulting in an objective response of 58%. Two responders remain without recurrence. No serious adverse events occurred during treatment. Four events occurred posttreatment: one bleeding episode, two episodes with mucosal swelling, and one patient died due to disease progression., Conclusion: Electrochemotherapy is efficient against local recurrence of head and neck cancer with an overall response rate of 58%., (© 2018 Wiley Periodicals, Inc.)

Background: Calcium electroporation is a novel cancer treatment, which combines temporary cell permeability from electroporation with a high influx of calcium intracellularly resulting in cancer cell necrosis., Methods: A phase I trial performing calcium electroporation on 6 patients suffering from recurrent head and neck cancer. In general anesthesia, intratumoral calcium injections were followed by electroporation. Safety was monitored by adverse events registration, serum Ca 2+ , ECG, and pain scores. Tumor response was measured on PET/MRI scans., Results: Procedures were performed without complications. No serious adverse events, signs of hypercalcemia, or cardiac arrhythmias were observed. Two months post-treatment tumor responses on MRI: three partial responses, one stable disease, and two progression. Responses on PET: one partial metabolic disease, four with stable metabolic disease, and one not evaluable. One patient was without clinical evidence of disease after 12 months of observation., Conclusion: Calcium electroporation is feasible and safe in head and neck tumors. Clinical responses were observed in three of six patients, warranting further studies., Level of Evidence: Level 4.

Background: Nasal irrigations with antibiotics are used to eradicate Pseudomonas aeruginosa from the upper airways in patients with cystic fibrosis (CF) and thereby avoid lung colonisations; nevertheless, the efficacy is uncertain., Methodology: The aim of this study was to investigate the accessibility and durability of solutions in the sinuses before and after sinus surgery. The participants irrigated their noses with radioactively marked saline and were evaluated using a dynamic SPECT/CT scan. The preoperative and postoperative (after 30 days) examinations were compared., Results: Twelve CF patients were included. In 10 out of the 24 scanned maxillary sinuses an improvement was seen postoperatively compared with the preoperative fluid volume. Notably, in 7 out of the 24 sinuses the mucosa was so swollen postoperatively that no fluid was detected. Ten patients had developed their frontal sinuses. We observed no fluid in the frontal or sphenoid sinuses, neither before nor after surgery. At best, a mean of 23% of the maxillary sinuses were filled with fluid; thus, all sinuses had postoperatively areas of the mucosa that did not have contact with the fluid. A mean of 76% of the initial volume was present after 30 min in the maxillary sinuses., Conclusion: Fluid-depositing using nasal irrigation will not sufficiently or not at all get in contact with all the sinus mucosa despite of sinus surgery. Thus, the efficacy of topical deposition of antibiotics is presumably reduced.

Here, we developed a symmetric echo-planar spectroscopic imaging (EPSI) sequence for hyperpolarized 13 C imaging on a clinical hybrid positron emission tomography/magnetic resonance imaging system. The pulse sequence uses parallel reconstruction pipelines to separately reconstruct data from odd-and-even gradient echoes to reduce artifacts from gradient imbalances. The ramp-sampled data in the spatiotemporal frequency space are regridded to compensate for the chemical-shift displacements. Unaliasing of nonoverlapping peaks outside of the sampled spectral width was performed to double the effective spectral width. The sequence was compared with conventional phase-encoded chemical-shift imaging (CSI) in phantoms, and it was evaluated in a canine cancer patient with ameloblastoma after injection of hyperpolarized [1- 13 C]pyruvate. The relative signal-to-noise ratio of EPSI with respect to CSI was 0.88, which is consistent with the decrease in sampling efficiency due to ramp sampling. Data regridding in the spatiotemporal frequency space significantly reduced spatial blurring compared with direct fast Fourier transform. EPSI captured the spatial distributions of both metabolites and their temporal dynamics in vivo with an in-plane spatial resolution of 5 × 9 mm 2 and a temporal resolution of 3 seconds. Significantly higher spatial and temporal resolution for delineating anatomical structures in vivo was achieved for EPSI metabolic maps than for CSI maps, which suffered spatiotemporal blurring. The EPSI sequence showed promising results in terms of short acquisition time and sufficient spectral bandwidth of 500 Hz, allowing to adjust the trade-off between signal-to-noise ratio and encoding speed., Competing Interests: Conflict of Interest: The authors have no conflict of interest to declare.

Background: Alterations in the gut microbiome have been associated with inflammation and increased cardiovascular risk in HIV-infected individuals. The aim of this study was to investigate the effects of the probiotic strain Lactobacillus rhamnosus GG (LGG) on intestinal inflammation, gut microbiota composition, and systemic markers of microbial translocation and inflammation in HIV-infected individuals., Methods: This prospective, clinical interventional trial included 45 individuals [15 combination antiretroviral treatment (cART) naive and 30 cART treated] who ingested LGG twice daily at a dosage of 6 × 109 colony-forming units per capsule for a period of 8 weeks. Intestinal inflammation was assessed using F-2-fluoro-2-deoxy-D-glucose positron emission tomography/magnetic resonance imaging (F-FDG PET/MRI) scans in 15 individuals. Gut microbiota composition (V3-V4 region of the 16s rRNA gene) and markers of microbial translocation and inflammation (lipopolysaccharide, sCD14, sCD163, sCD25, high-sensitive CRP, IL-6, and tumor necrosis factor-alpha) were analyzed at baseline and after intervention., Results: At baseline, evidence of intestinal inflammation was found in 75% of the participants, with no significant differences between cART-naive and cART-treated individuals. After LGG supplementation, a decrease in intestinal inflammation was detected on PET/MRI (-0.3 mean difference in the combined activity grade score from 6 regions, P = 0.006), along with a reduction of Enterobacteriaceae (P = 0.018) and Erysipelotrichaceae (P = 0.037) in the gut microbiome, with reduced Enterobacteriaceae among individuals with decreased F-FDG uptake on PET/MRI (P = 0.048). No changes were observed for soluble markers of microbial translocation and inflammation., Conclusions: A decrease in intestinal inflammation was found in HIV-infected individuals after ingestion of LGG along with a reduced abundance of Enterobacteriaceae, which may explain the local anti-inflammatory effect in the gut.

Purpose: The aim of the study was to investigate the components of day-to-day variability of repeated phase contrast mapping (PCM) magnetic resonance imaging measurements of global cerebral blood flow (gCBF)., Materials and Methods: Two dataset were analyzed. In Dataset 1 duplicated PCM measurements of total brain flow were performed in 11 healthy young volunteers on two separate days applying a strictly standardized setup. For comparison PCM measurements obtained from a previously published study (Dataset 2) were analyzed in order to assess long-term variability in an aged population in a less strictly controlled setup. Global CBF was calculated by normalizing total brain flow to brain volume. On each day measurements of hemoglobin, caffeine and glucose were obtained. Linear mixed models were applied to estimate coefficients of variation (CV) of total (CVt), between-subject (CVb), within-subject day-to-day (CVw), and intra-session residual variability (CVr)., Results: In Dataset 1 CVt, CVb, CVw and CVr were estimated to be 11%, 9.4%, 4% and 4.2%, respectively, and to 8.8%, 7.2%, 2.7% and 4.3%, respectively, when adjusting for hemoglobin and plasma caffeine. In Dataset 2 CVt, CVb and CVw were estimated to be 25.4%, 19.2%, and 15.0%, respectively, and decreased to 16.6%, 8.2% and 12.5%, respectively, when adjusting for the same covariates., Discussion: Our results suggest that short-term day-to-day variability of gCBF is relatively low compared to between-subject variability when studied in standardized conditions, whereas long-term variability in an aged population appears to be much larger when studied in less a standardized setup. The results further showed that from 20% to 35% of the total variability in gCBF can be attributed to the effects of hemoglobin and caffeine., Competing Interests: The authors have declared that no competing interests exist.

Background and Study Aims:  Esophageal cancer is on the rise in the western world and the disease has a poor 5-year survival prognosis below 20 %. Electrochemotherapy is a treatment where a chemotherapeutic drug is combined with locally applied electrical pulses, in order to increase the drug's cytotoxicity in malignant cells. This study presents the first results with electrochemotherapy treatment in esophageal cancer., Patients and Methods:  In this first-in-human trial, six patients with advanced esophageal cancer were treated with electrochemotherapy using intravenous bleomycin. All side effects and adverse events (AEs) were registered and the patients were later evaluated with gastroscopy and 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI)., Results:  Treatment were well tolerated, main AEs being nausea, vomiting, oral thrush, pneumonia, retrosternal pain, fever, and hoarseness. No serious complications were observed. Five patients had a visual tumor response confirmed by gastroscopy. In two cases, these findings were confirmed with 18F-FDG PET/MRI as it revealed a reduction of total tumor mass., Conclusion:  Electrochemotherapy in patients with advanced esophageal cancer was conducted without major safety concerns. This study paves the way for larger studies, which may further elucidate response rates for and side effects of this new treatment.

13 C Magnetic Resonance Spectroscopy (MRS) using hyperpolarized 13 C-labeled pyruvate as a substrate offers a measure of pyruvate-lactate interconversion and is thereby a marker of the elevated aerobic glycolysis (Warburg effect) generally exhibited by cancer cells. Here, we aim to compare hyperpolarized [1- 13 C]pyruvate MRS with simultaneous 18 F-2-fluoro-2-deoxy-d-glucose (FDG) PET in a cross-sectional study of canine cancer patients., Methods: Canine cancer patients underwent integrated PET/MRI using a clinical whole-body system. Hyperpolarized [1- 13 C]pyruvate was obtained using dissolution-DNP. 18 F-FDG PET, dynamic 13 C MRS, 13 C MRS Imaging (MRSI) and anatomical 1 H MRI was acquired from 17 patients. Apparent pyruvate-to-lactate rate constants were estimated from dynamic 13 C MRS. 18 F-FDG Standard Uptake Values and maximum [1- 13 C]lactate-to-total- 13 C ratios were obtained from tumor regions of interest. Following inspection of data, patients were grouped according to main cancer type and linear regression between measures of lactate generation and 18 F-FDG uptake were tested within groups. Between groups, the same measures were tested for group differences., Results: The main cancer types of the 17 patients were sarcoma (n = 11), carcinoma (n = 5) and mastocytoma (n = 1). Significant correlations between pyruvate-to-lactate rate constants and 18 F-FDG uptake were found for sarcoma patients, whereas no significant correlations appeared for carcinoma patients. The sarcoma patients showed a non-significant trend towards lower 18 F-FDG uptake and higher lactate generation than carcinoma patients. However, the ratio of lactate generation to 18 F-FDG uptake was found to be significantly higher in sarcoma as compared to carcinoma. The results were found both when lactate generation was estimated as an apparent pyruvate-to-lactate rate constant from dynamic 13 C MRS and as an [1- 13 C]lactate to total 13 C ratio from 13 C MRSI., Conclusions: A comparison of hyperpolarized [1- 13 C]pyruvate MRS with simultaneous 18 F-FDG PET indicate that lactate generation and 18 F-FDG uptake in cancers can be related and that their relation depend on cancer type. This finding could be important for the interpretation and eventual clinical implementation of hyperpolarized 13 C. In addition, the differences between the two modalities may allow for better metabolic phenotyping performing hybrid imaging in the form of hyperPET., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Tattooed persons examined with magnetic resonance imaging (MRI) can develop burning sensation suggested in the literature to be thermal burn from the procedure. MRI-induced thermal effect and magnetic behavior of known tattoo pigments were examined ex vivo., Materials and Methods: Magnetic resonance imaging effects on 3 commonly used commercial ink stock products marketed for cosmetic tattooing was studied. A main study tested 22 formulations based on 11 pigment raw materials, for example, one line of 11 called pastes and another called dispersions. Samples were spread in petri dishes and tested with a 0.97 T neodymium solid magnet to observe visual magnetic behavior. Before MRI, the surface temperature of the ink was measured using an infrared probe. Samples were placed in a clinical 3T scanner. Two scans were performed, that is, one in the isocenter and one 30 cm away from the center. After scanning, the surface temperature was measured again. Chemical analysis of samples was performed by mass spectroscopy., Results: Mean temperature increase measured in the isocenter ranged between 0.14 and 0.26°C (P < .01) and in the off-center position from -0.16 to 0.21°C (P < .01). Such low increase of temperature is clinically irrelevant. Chemical analysis showed high concentrations of iron, but also nickel and chrome were found as contaminants. High concentration of iron was not associated with any increase of temperature or any physical draw or move of ink., Conclusion: The study could not confirm any clinically relevant temperature increase of tattoo pigments after MRI., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Gene electrotrotransfer describes the use of electric pulses to transfer DNA to cells. Particularly skeletal muscle has potential for systemic secretion of therapeutic proteins. Gene electrotransfer to muscle using the integrin inhibitor plasmid AMEP (Antiangiogenic MEtargidin Peptide) was investigated in a phase I dose escalation study. Primary objective was safety., Material and Methods: Patients with metastatic or locally advanced solid tumors, without further standard treatments available, were treated with once-only gene electrotransfer of plasmid AMEP to the femoral muscle. Safety was monitored by adverse events registration, visual analog scale (VAS) after procedure and magnetic resonance imaging (MRI) of treated muscles. Pharmacokinetics of plasmid AMEP in plasma and urine was determined by quantitative polymerase chain reaction. Response was evaluated by positron emission tomography-computed tomography (PET-CT) scans., Results: Seven patients were enrolled and treated at dose levels from 50 to 250 μg of plasmid AMEP, the study was terminated early due to cessation of plasmid production. Minimal systemic toxicity was observed and only transient mild pain was associated with the delivery of the electric pulses. MRI of the treated muscles revealed discrete intramuscular edema 24 h after treatment. The changes in the muscle tissue resolved within 2 weeks after treatment. Peak concentrations of plasmid AMEP was detected only in plasma within the first 24 hours after injection. Protein AMEP could not be detected, which could be due to the limit of detection. No objective responses were seen., Conclusions: Gene electrotransfer of plasmid AMEP was found to be safe and tolerable. No objective responses were observed but other DNA drugs may be tested in the future using this procedure.

Purpose: To evaluate the effect of capecitabine and oxaliplatin before, during, and after radiotherapy for high-risk rectal cancer., Patients and Methods: Patients with rectum cancer T4 or T3 involving the mesorectal fascia was included in a prospective phase 2 trial. Liver or lung metastases were accepted if the surgeons found them resectable. The patients received 6 weeks of capecitabine and oxaliplatin before chemoradiotherapy (CRT), continued capecitabine and oxaliplatin during radiotherapy, and received 4 weeks of capecitabine and oxaliplatin after CRT. The patients received radiotherapy as intensity-modulated radiotherapy. Total mesorectal excision was planned 8 weeks after CRT. The patients were evaluated with magnetic resonance imaging (MRI) before start of treatment, after 6 weeks of chemotherapy, and again just before the operation. The European Organization for Research and Treatment of Cancer (EORTC) QLQ-CR29 scoring system was used to evaluate adverse events., Results: Fifty-two patients were enrolled between 2009 and 2012. The treatment was well tolerated, with only one death during treatment. Eighty percent of assessable patients experienced response to chemotherapy alone as evaluated by MRI, which increased to 94% after complete oncologic treatment. Forty-nine patients had a total mesorectal excision performed, all with a R0 resection and with a pathologic complete response of 20% for patients with T3 tumor and 7% for patients with T4 tumor. Five patients had metastases at study entry, while 47 patients had locally advanced rectal cancer without metastases. Of these 47 patients, overall survival and progression-free survival at 5 years was 72% and 62%, respectively, with a median follow-up of 60 months., Conclusion: This aggressive approach with capecitabine and oxaliplatin before, during, and after radiotherapy for high-risk rectal cancer is safe and feasible; it also has an impressive response rate as measured by MRI and a promising 5-year overall survival., (Copyright © 2016 Elsevier Inc. All rights reserved.)

An imaging biomarker for early prediction of treatment response potentially provides a non-invasive tool for better prognostics and individualized management of the disease. Radiotherapy (RT) response is generally related to changes in gross tumor volume manifesting months later. In this prospective study we investigated the apparent diffusion coefficient (ADC), perfusion fraction and pseudo diffusion coefficient derived from diffusion weighted MRI as potential early biomarkers for radiotherapy response of brain metastases. It was a particular aim to assess the optimal time point for acquiring the DW-MRI scan during the course of treatment, since to our knowledge this important question has not been addressed directly in previous studies. Twenty-nine metastases (N  =  29) from twenty-one patients, treated with whole-brain fractionated external beam RT were analyzed. Patients were scanned with a 1 T MRI system to acquire DW-, T2 * W-, T2W- and T1W scans, before start of RT, at each fraction and at follow up two to three months after RT. The DW-MRI parameters were derived using regions of interest based on high b-value images (b  =  800 s mm -2 ). Both volumetric and RECIST criteria were applied for response evaluation. It was found that in non-responding metastases the mean ADC decreased and in responding metastases it increased. The volume based response proved to be far more consistently predictable by the ADC change found at fraction number 7 and later, compared to the linear response (RECIST). The perfusion fraction and pseudo diffusion coefficient did not show sufficient prognostic value with either response assessment criteria. In conclusion this study shows that the ADC derived using high b-values may be a reliable biomarker for early assessment of radiotherapy response for brain metastases patients. The earliest response stratification can be achieved using two DW-MRI scans, one pre-treatment and one at treatment day 7-9 (equivalent to 21 Gy).

Purpose: Solid organ transplant (SOT) recipients are at high risk of developing infections and malignancies. 18 F-FDG PET/CT may enable timely detection of these diseases and help to ensure early intervention. We aimed to describe the clinical utility of FDG PET/CT in consecutive, diagnostic unresolved SOT recipients transplanted from January 2004 to May 2015., Methods: Recipients with a post-transplant FDG PET/CT performed as part of diagnostic work-up were included. Detailed chart reviews were done to extract relevant clinical information and determine the final diagnosis related to the FDG PET/CT. Based on á priori defined criteria and the final diagnosis, results from each scan were classified as true or false, and diagnostic values determined., Results: Among the 1,814 recipients in the cohort, 145 had an FDG PET/CT performed; 122 under the indication of diagnostically unresolved symptoms with a suspicion of malignancy or infection. The remaining (N = 23) had an FDG PET/CT to follow-up on a known disease or to stage a known malignancy. The 122 recipients underwent a total of 133 FDG PET/CT scans performed for a suspected malignancy (66 %) or an infection (34 %). Sensitivity, specificity, and positive and negative predictive values of the FDG PET/CT in diagnosing these conditions were 97, 84, 87, and 96 %, respectively., Conclusion: FDG PET/CT is an accurate diagnostic tool for the work-up of diagnostic unresolved SOT recipients suspected of malignancy or infection. The high sensitivity and NPV underlines the potential usefulness of PET/CT for excluding malignancy or focal infections in this often complex clinical situation., Competing Interests: Compliance with Ethical Standards Funding This study was supported by funding from Centre of Health and Infectious Disease Research (CHIP) at Rigshospitalet, Copenhagen, as well as the Danish National Research Foundation [grant number DNRF126]. Conflict of interest None. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required. Informed consent Approval for patient chart review was obtained from the Danish Health and Medicines Authorities according to Danish legislation on retrospective studies.

The purpose of this study was to investigate and assess the correlation and reproducibility of multiparametric imaging in head and neck cancer patients., Methods: Twenty-one patients were included in this prospective scan-rescan study. All patients were scanned twice on an integrated PET and MRI scanner. Gross tumor volumes were defined on T2-weighted MR images, and volumes of interest were defined on diffusion-weighted MRI and 18 F-FDG PET (VOI DWI , VOI PET ). Overlap between volumes was assessed as a percentwise overlap. 18 F-FDG uptake and diffusion were measured using SUV and apparent diffusion coefficient, and correlation was tested across and within patients and as a voxel-by-voxel analysis., Results: Seventeen patients were available for correlation analysis, and 12 patients were available for assessment of tumor overlap. The median tumor overlap between VOI DWI and VOI PET was 82% (VOI DWI in VOI PET ) and 62% (VOI PET in VOI DWI ) on scan 1 and scan 2, respectively. Across patients, the correlation between SUV and apparent diffusion coefficient was weak and nonsignificant. However, in individual patients a weak but significant correlation was identified on a voxel-by-voxel basis., Conclusion: In multiparametric imaging with the integrated PET/MR scanner, the VOIs from DWI and 18 F-FDG PET were both within the target volume for radiotherapy and overlapped substantially although not completely. No correlation between 18 F-FDG uptake and DWI could be found across patients, but within individual patients a statistically significant, but weak, voxel-by-voxel correlation was found. The findings suggest that information on glucose uptake and diffusion coefficient carries complementary information of interest that may be relevant for radiotherapy treatment planning., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Regular exercise reduces the risk of cancer and disease recurrence. Yet the mechanisms behind this protection remain to be elucidated. In this study, tumor-bearing mice randomized to voluntary wheel running showed over 60% reduction in tumor incidence and growth across five different tumor models. Microarray analysis revealed training-induced upregulation of pathways associated with immune function. NK cell infiltration was significantly increased in tumors from running mice, whereas depletion of NK cells enhanced tumor growth and blunted the beneficial effects of exercise. Mechanistic analyses showed that NK cells were mobilized by epinephrine, and blockade of β-adrenergic signaling blunted training-dependent tumor inhibition. Moreover, epinephrine induced a selective mobilization of IL-6-sensitive NK cells, and IL-6-blocking antibodies blunted training-induced tumor suppression, intratumoral NK cell infiltration, and NK cell activation. Together, these results link exercise, epinephrine, and IL-6 to NK cell mobilization and redistribution, and ultimately to control of tumor growth., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: With the introduction of combined PET/MR spectroscopic (MRS) imaging, it is now possible to directly and indirectly image the Warburg effect with hyperpolarized (13)C-pyruvate and (18)F-FDG PET imaging, respectively, via a technique we have named hyperPET. The main purpose of this present study was to establish a practical workflow for performing (18)F-FDG PET and hyperpolarized (13)C-pyruvate MRS imaging simultaneously for tumor tissue characterization and on a larger scale test its feasibility. In addition, we evaluated the correlation between (18)F-FDG uptake and (13)C-lactate production., Methods: Ten dogs with biopsy-verified spontaneous malignant tumors were included for imaging. All dogs underwent a protocol of simultaneous (18)F-FDG PET, anatomic MR, and hyperpolarized dynamic nuclear polarization with (13)C-pyruvate imaging. The data were acquired using a combined clinical PET/MR imaging scanner., Results: We found that combined (18)F-FDG PET and (13)C-pyruvate MRS imaging was possible in a single session of approximately 2 h. A continuous workflow was obtained with the injection of (18)F-FDG when the dogs was placed in the PET/MR scanner. (13)C-MRS dynamic acquisition demonstrated in an axial slab increased (13)C-lactate production in 9 of 10 dogs. For the 9 dogs, the (13)C-lactate was detected after a mean of 25 s (range, 17-33 s), with a mean to peak of (13)C-lactate at 49 s (range, 40-62 s). (13)C-pyruvate could be detected on average after 13 s (range, 5-26 s) and peaked on average after 25 s (range, 13-42 s). We noticed concordance of (18)F-FDG uptake and production of (13)C-lactate in most, but not all, axial slices., Conclusion: In this study, we have shown in a series of dogs with cancer that hyperPET can easily be performed within 2 h. We showed mostly correspondence between (13)C-lactate production and (18)F-FDG uptake and expect the combined modalities to reveal additional metabolic information to improve prognostic value and improve response monitoring., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)