Tumor volume definitions in head and neck squamous cell carcinoma - Comparing PET/MRI and histopathology.

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 (GTVMRI), PET (GTVPET) and one by utilizing both anatomical images and clinical information (GTVONCO). 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 (GTVPATO). GTVPATOwas compared with the imaging GTV's and potential mismatch was estimated. RESULTS: Thirteen patients were included. The mean volume of GTVONCOwas larger than the GTV's defined from PET or MRI. The mean mismatch of the GTVPATOcompared to the GTVPET, GTVMRIand GTVONCOwas 31.9 %, 54.5 % and 27.9 % respectively, and the entire GTVPATO was only fully encompassed in GTVONCO in 1 of 13 patients. However, after the addition of a clinical 5 mm margin the GTVPATO was fully encompassed in GTVONCO 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.

Four weeks treatment with the GLP-1 receptor analogue liraglutide lowers liver fat and concomitantly circulating glucagon in individuals with overweight.

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/m2) 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.

Altered brown fat thermoregulation and enhanced cold-induced thermogenesis in young, healthy, winter-swimming men.

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.

Intratumor heterogeneity is biomarker specific and challenges the association with heterogeneity in multimodal functional imaging in head and neck squamous cell carcinoma.

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 18F-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.

Initial Experience with 64Cu-DOTATATE Digital PET of Patients with Neuroendocrine Neoplasms: Comparison with Analog PET.

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 64Cu-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 64Cu-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 64Cu-DOTATATE PET.

[68Ga]Ga-NODAGA-E[(cRGDyK)]2 PET and hyperpolarized [1-13C] pyruvate MRSI (hyperPET) in canine cancer patients: simultaneous imaging of angiogenesis and the Warburg effect.

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 [1-13C] 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 [68Ga]Ga-NODAGA-E[(cRGDyK)]2 (RGD) PET and hyperpolarized [1-13C]pyruvate-MRSI (hyperPET). Standardized uptake values and [1-13C]lactate to total 13C ratio were quantified and compared generally and voxel-wise. RESULTS: Ten out of 11 patients showed clear tumor uptake of [68Ga]Ga-NODAGA-RGD at both 20 and 60 min after injection, with an average SUVmean of 1.36 ± 0.23 g/mL and 1.13 ± 0.21 g/mL, respectively. A similar pattern was seen for SUVmax values, which were 2.74 ± 0.41 g/mL and 2.37 ± 0.45 g/mL. The [1-13C]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 [68Ga]Ga-NODAGA-RGD-PET for angiogenesis and hyperpolarized [1-13C]pyruvate-MRSI for probing energy metabolism. The results suggest that [68Ga]Ga-NODAGA-RGD-PET and [1-13C]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.

64Cu-DOTATATE PET in Patients with Neuroendocrine Neoplasms: Prospective, Head-to-Head Comparison of Imaging at 1 Hour and 3 Hours After Injection.

64Cu-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 64Cu-DOTATATE PET/CT images from 35 patients with NENs scanned 1 and 3 h after injection of 200 MBq of 64Cu-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 64Cu-DOTATATE PET images) were considered true if found on simultaneous CT or later MR, CT, or somatostatin receptor imaging. We measured lesion SUVmax, reference normal-organ or -tissue SUVmean, and tumor-to-normal-tissue ratios calculated from SUVmax and SUVmeanResults: We found 822 concordant lesions (visible on both 1-h and 3-h 64Cu-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 64Cu-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 64Cu-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 64Cu-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.

Cetuximab plus irinotecan administered biweekly with reduced infusion time to heavily pretreated patients with metastatic colorectal cancer and related RAS and BRAF mutation status.

Metastatic colorectal cancer (mCRC) is treated with cetuximab 250 mg/m2 administered weekly over 1 hour or biweekly (q2w) over 3.5 hours when combined with irinotecan. This prospective study investigated cetuximab 500 mg/m2 plus irinotecan 180 mg/m2 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 BRAFV600E wild type (WT), with a mutation type (MT) in 45.1% of the RAS and 4.4% of the BRAFV600E 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.

No effects of a 6-week intervention with a glucagon-like peptide-1 receptor agonist on pancreatic volume and oedema in obese men without diabetes.

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/m2 ) 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 cm3 [-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.

Does multiparametric imaging with 18F-FDG-PET/MRI capture spatial variation in immunohistochemical cancer biomarkers in head and neck squamous cell carcinoma?

BACKGROUND: The purpose of this study is to test if functional multiparametric imaging with 18F-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 Ktrans. 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.

Quantifying the Financial Savings of Motion Correction in Brain MRI: A Model-Based Estimate of the Costs Arising From Patient Head Motion and Potential Savings From Implementation of Motion Correction.

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, T1 and T2 -weighted FLAIR, T2 -weighted 2D-FLASH, T2 -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.

Intratumor heterogeneity of PD-L1 expression in head and neck squamous cell carcinoma.

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.

18F-FDG PET/MR-imaging in a Göttingen Minipig model of atherosclerosis: Correlations with histology and quantitative gene expression.

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 18F-fluorodeoxyglucose (18F-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, 18F-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, TBRMax (95% confidence interval) CITBRMax: 0.092; 7.32) and DNO showed significantly decreased uptake compared to FFC (CITBRMax: -5.94;-0.07). No difference was observed between DNO and Control (CITBRMax: -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, ρs = 0.58; MMP9, ρs = 0.46; SPP1, ρs = 0.44 and CTSK, ρs = 0.49; (p ≤ 0.01 for all). CONCLUSIONS: In a model of atherosclerosis, 18F-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.

PET/DW-MRI for evaluating treatment in chronic hepatitis C patients.

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/mm2. 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 (SUVmean60 and SUVmean90), 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/mm2 to 0.62 (± 0.15) × 10-3 s/mm2, 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.

Phase contrast mapping MRI measurements of global cerebral blood flow across different perfusion states - A direct comparison with 15O-H2O positron emission tomography using a hybrid PET/MR system.

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 15O-H2O positron emission tomography (PET) measurements of gCBF in different perfusion states in a single scanning session. Duplicate combined gCBF PCM-MRI and 15O-H2O 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 15O-H2O 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 15O-H2O PET. A strong correlation between the two methods across all states was observed (R2 = 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 15O-H2O PET, but are associated with a large and non-linear perfusion-dependent difference.

Components of day-to-day variability of cerebral perfusion measurements - Analysis of phase contrast mapping magnetic resonance imaging measurements in healthy volunteers.

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.

Effect of Lactobacillus rhamnosus GG Supplementation on Intestinal Inflammation Assessed by PET/MRI Scans and Gut Microbiota Composition in HIV-Infected Individuals.

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.

Combined hyperpolarized 13C-pyruvate MRS and 18F-FDG PET (hyperPET) estimates of glycolysis in canine cancer patients.

13C Magnetic Resonance Spectroscopy (MRS) using hyperpolarized 13C-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 [1-13C]pyruvate MRS with simultaneous 18F-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 [1-13C]pyruvate was obtained using dissolution-DNP. 18F-FDG PET, dynamic 13C MRS, 13C MRS Imaging (MRSI) and anatomical 1H MRI was acquired from 17 patients. Apparent pyruvate-to-lactate rate constants were estimated from dynamic 13C MRS. 18F-FDG Standard Uptake Values and maximum [1-13C]lactate-to-total-13C 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 18F-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 18F-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 18F-FDG uptake and higher lactate generation than carcinoma patients. However, the ratio of lactate generation to 18F-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 13C MRS and as an [1-13C]lactate to total 13C ratio from 13C MRSI. CONCLUSIONS: A comparison of hyperpolarized [1-13C]pyruvate MRS with simultaneous 18F-FDG PET indicate that lactate generation and 18F-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 13C. In addition, the differences between the two modalities may allow for better metabolic phenotyping performing hybrid imaging in the form of hyperPET.

Repeated diffusion MRI reveals earliest time point for stratification of radiotherapy response in brain metastases.

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).