Brown fat does not cause cachexia in cancer patients: A large retrospective longitudinal FDG-PET/CT cohort study.

BACKGROUND: Brown adipose tissue (BAT) is a specialized form of adipose tissue, able to increase energy expenditure by heat generation in response to various stimuli. Recently, its pathological activation has been implicated in the pathogenesis of cancer cachexia. To establish a causal relationship, we retrospectively investigated the longitudinal changes in BAT and cancer in a large FDG-PET/CT cohort. METHODS: We retrospectively analyzed 13 461 FDG-PET/CT examinations of n = 8 409 patients at our institution from the winter months of 2007-2015. We graded the activation strength of BAT based on the anatomical location of the most caudally activated BAT depot into three tiers, and the stage of the cancer into five general grades. We validated the cancer grading by an interreader analysis and correlation with histopathological stage. Ambient temperature data (seven-day average before the examination) was obtained from a meteorological station close to the hospital. Changes of BAT, cancer, body mass index (BMI) and temperature between the different examinations were examined with Spearman's test and a mixed linear model for correlation, and with a causal inference algorithm for causality. RESULTS: We found n = 283 patients with at least two examinations and active BAT in at least one of them. There was no significant interaction between the changes in BAT activation, cancer burden or BMI. Temperature changes exhibited a strong negative correlation with BAT activity (ϱ = -0.57, p<0.00001). These results were confirmed with the mixed linear model. Causal inference revealed a link of Temperature ➜ BAT in all subjects and also of BMI ➜ BAT in subjects who had lost weight and increased cancer burden, but no role of cancer and no causal links of BAT ➜ BMI. CONCLUSIONS: Our data did not confirm the hypothesis that BAT plays a major role in cancer-mediated weight loss. Temperature changes are the main driver of incidental BAT activity on FDG-PET scans.

68Ga-PSMA-11 dose reduction for dedicated pelvic imaging with simultaneous PET/MR using TOF BSREM reconstructions.

OBJECTIVES: When increasing the PET acquisition time to match the longer MRI protocol in simultaneous PET/MR, the injected PET tracer dose can possibly be lowered to reduce radiation exposure. Moreover, applying new commercially available time-of-flight (TOF) block sequential regularized expectation maximization (BSREM)-based reconstruction algorithms could allow for further dose reductions. The purpose of this study was to find the minimal dose of the tracer targeting the prostate specific membrane antigen (68Ga-PSMA-11) for a dedicated 15-min pelvic PET/MR scan that still matches the image quality of a reference 3-min scan at 100% (150 MBq) dose. METHODS: In this retrospective analysis, 25 patients were included. PET emission datasets were edited to simulate stepwise reductions of injected tracer dose. Reference TOF ordered subset expectation maximum (OSEM) and new TOF BSREM reconstructions were performed and differences in the resulting PET images were visually and quantitatively assessed. RESULTS: Visually, TOF BSREM reconstructions with relatively high regularization parameter (ß) values are preferred. Quantitatively, however, high ß-values result in lower lesion maximum standardized uptake values (SUVmax) compared to the reference. A ß-value of 550 was considered the optimal compromise for the lowest possible 10% dose reconstructions, resulting in comparable visual assessment and lesion SUVmax. CONCLUSIONS: This study indicates that the injected 68Ga-PSMA-11 tracer dose for a standard 3-min PET scan can be reduced to approximately 10% (15 MBq) when the PET acquisition time is matched to the 15-min pelvic MRI protocol, and when reconstructed with TOF BSREM using ß = 550. This decreases the effective dose from 3.54 to 0.35 mSv. KEY POINTS: • Low-dose dedicated pelvic68Ga-PSMA-11 PET/MR reduces radiation exposure for patients. • Retrospective study investigating the minimal dose needed for adequate image quality for 15-min PET frames over the pelvis showed using quantitative and qualitative analysis that a substantial dose reduction is possible without significant loss of image quality when using the TOF BSREM reconstruction algorithm. • With the introduction of low-dose pelvic68Ga-PSMA-11 PET/MR, new potential applications of68Ga-PSMA-11 PET for local staging or investigation of equivocal MRI findings could become applicable, even for patients without confirmed prostate cancer.

Quantitative performance and optimal regularization parameter in block sequential regularized expectation maximization reconstructions in clinical 68Ga-PSMA PET/MR.

BACKGROUND: In contrast to ordered subset expectation maximization (OSEM), block sequential regularized expectation maximization (BSREM) positron emission tomography (PET) reconstruction algorithms can run until full convergence while controlling image quality and noise. Recent studies with BSREM and 18F-FDG PET reported higher signal-to-noise ratios and higher standardized uptake values (SUV). In this study, we investigate the optimal regularization parameter (ß) for clinical 68Ga-PSMA PET/MR reconstructions in the pelvic region applying time-of-flight (TOF) BSREM in comparison to TOF OSEM. Two-minute emission data from the pelvic region of 25 patients who underwent 68Ga-PSMA PET/MR were retrospectively reconstructed. Reference OSEM reconstructions had 28 subsets and 2 iterations. BSREM reconstructions were performed with 15 ß values between 150 and 1200. Regions of interest (ROIs) were drawn around lesions and in uniform background. Background SUVmean (average) and SUVstd (standard deviation), and lesion SUVmax (average of 5 hottest voxels) were calculated. Differences were analyzed using the Wilcoxon matched pairs signed-rank test. RESULTS: A total of 40 lesions were identified in the pelvic region. Background noise (SUVstd) and lesions SUVmax decreased with increasing ß. Image reconstructions with ß values lower than 400 have higher (p < 0.01) background noise, compared to the reference OSEM reconstructions, and are therefore less useful. Lesions with low activity on images reconstructed with ß values higher than 600 have a lower (p < 0.05) SUVmax compared to the reference. These reconstructions are likely visually appealing due to the lower background noise, but the lower SUVmax could possibly render small low-uptake lesions invisible. CONCLUSIONS: In our study, we showed that PET images reconstructed with TOF BSREM in combination with the 68Ga-PSMA tracer result in lower background noise and higher SUVmax values in lesions compared to TOF OSEM. Our study indicates that a ß value between 400 and 550 might be the optimal compromise between high SUVmax and low background noise.

Correction to: impact of time-of-flight PET on quantification accuracy and lesion detection in simultaneous 18F-choline PET/MRI for prostate cancer.

Unfortunately, after publication of this article [1], it was noticed that the name of Urs J. Muehlematter was incorrectly displayed as Urs J. Mühlematter. The corrected author list can be seen above and the original article has been corrected to reflect this.

Impact of time-of-flight PET on quantification accuracy and lesion detection in simultaneous 18F-choline PET/MRI for prostate cancer.

BACKGROUND: Accurate attenuation correction (AC) is an inherent problem of positron emission tomography magnetic resonance imaging (PET/MRI) systems. Simulation studies showed that time-of-flight (TOF) detectors can reduce PET quantification errors in MRI-based AC. However, its impact on lesion detection in a clinical setting with 18F-choline has not yet been evaluated. Therefore, we compared TOF and non-TOF 18F-choline PET for absolute and relative difference in standard uptake values (SUV) and investigated the detection rate of metastases in prostate cancer patients. RESULTS: Non-TOF SUV was significantly lower compared to TOF in all osseous structures, except the skull, in primary lesions of the prostate, and in pelvic nodal and osseous metastasis. Concerning lymph node metastases, both experienced readers detected 16/19 (84%) on TOF PET, whereas on non-TOF PET readers 1 and 2 detected 11 (58%), and 14 (73%), respectively. With TOF PET readers 1 and 2 detected 14/15 (93%) and 11/15 (73%) bone metastases, respectively, whereas detection rate with non-TOF PET was 73% (11/15) for reader 1 and 53% (8/15) for reader 2. The interreader agreement was good for osseous metastasis detection on TOF (kappa 0.636, 95% confidence interval [CI] 0.453-0.810) and moderate on non-TOF (kappa = 0.600, CI 0.438-0.780). CONCLUSION: TOF reconstruction for 18F-choline PET/MRI shows higher SUV measurements compared to non-TOF reconstructions in physiological osseous structures as well as pelvic malignancies. Our results suggest that addition of TOF information has a positive impact on lesion detection rate for lymph node and bone metastasis in prostate cancer patients.

Case Report: Encephalitis, with Brainstem Involvement, Following Checkpoint Inhibitor Therapy in Metastatic Melanoma.

Checkpoint inhibitors are increasingly being used in the treatment of malignant melanoma and other cancers. With the use of such therapies, autoimmune-mediated adverse events in the central and peripheral nervous system are likely to occur more frequently. We report a unique case of brainstem encephalitis with a sudden lethal outcome following ipilimumab and pembrolizumab therapy in a patient with malignant melanoma. The autopsy showed a diffuse nodular activation of microglia in the whole encephalon with prominent intraparenchymal and perivascular lymphocytic infiltration of the brainstem. Non-infectious brainstem encephalitis is a well-recognized subset of paraneoplastic encephalitis. Brainstem involvement is usually accompanied by a wide spectrum of signs and symptoms, which were not observed in this case. The timing of the clinical symptoms as well as the histopathological findings suggest an autoimmune-adverse event of ipilimumab and pembrolizumab administration rather than a paraneoplastic disorder. In the presence of neurological symptoms, immediate cessation of the immunotherapy and immunosuppressive therapy may lead to successful therapeutic intervention, as described in previous reports. Therefore, it is crucial that physicians are aware of the possible side effects of immunotherapies on the nervous system. IMPLICATIONS FOR PRACTICE: Metastatic melanoma patients treated with the anti-CTLA-4 inhibitor ipilimumab have a high utilization of various types of health care services, such as inpatient hospital stays or doctor visits. There are differences across countries regarding patterns of health care utilization and economic burden of the disease. Health care services are used more frequently after patients experience progression of their disease. The study highlights that better therapies leading to durable response in patients with metastatic melanoma have the potential to decrease health care costs and patient burden in terms of hospitalizations and other health care services.

In-depth analysis of interreader agreement and accuracy in categorical assessment of brown adipose tissue in (18)FDG-PET/CT.

PURPOSE: To evaluate the interreader agreement of a three-tier craniocaudal grading system for brown fat activation and investigate the accuracy of the distinction between the three grades. MATERIALS AND METHODS: After IRB approval, 340 cases were retrospectively selected from patients undergoing (18)FDG-PET/CT between 2007 and 2015 at our institution, with 85 cases in each grade and 85 controls with no active brown fat. Three readers evaluated all cases independently. Furthermore standardized uptake values (SUV) measurements were performed by two readers in a subset of 53 cases. Agreement between the readers was assessed with Cohen's Kappa (k), the concordance correlation coefficient (CCC) and the intraclass correlation coefficient (ICC). Accuracy was assessed with Bland-Altman and receiver operating characteristics (ROC) analysis. A Bonferroni-corrected two-tailed p<0.016 was considered statistically significant. RESULTS: Agreement for BAT grade was excellent by all three metrics with k=0.83-0.89, CCC=0.83-0.89 and ICC=0.91-0.94. Bland-Altman analysis revealed only slight average over- or underestimation (-0.01-0.14) with the majority of disagreements within one grade. ROC analysis yielded slightly less accurate classification between higher vs. lower grades (Area under the ROC curves 0.78-0.84 vs. 0.88-0.92) but no significant differences between readers. Agreement was also excellent for the maximum SUV and the total brown fat volume (k=0.90 and 0.94, CCC=0.93 and 0.99, ICC=0.96 and 0.99), but Bland-Altman plots revealed a tendency to underestimate activity by one of the readers. CONCLUSION: Grading the activation of brown fat by assessment of the most caudally activated depots results in excellent interreader agreement, comparable to SUV measurements.

Anatomical Grading for Metabolic Activity of Brown Adipose Tissue.

BACKGROUND: Recent advances in obesity research suggest that BAT activity, or absence thereof, may be an important factor in the growing epidemic of obesity and its manifold complications. It is thus important to assess larger populations for BAT-activating and deactivating factors. 18FDG-PET/CT is the standard method to detect and quantify metabolic BAT activity, however, the manual measurement is not suitable for large studies due to its time-consuming nature and poor reproducibility across different software and devices. METHODOLOGY/MAIN FINDINGS: In a retrospective study, 1060 consecutive scans of 1031 patients receiving a diagnostic 18FDG-PET/CT were examined for the presence of active BAT. Patients were classified according to a 3-tier system (supraclavicular, mediastinal, infradiaphragmatic) depending on the anatomical location of their active BAT depots, with the most caudal location being the decisive factor. The metabolic parameters (maximum activity, total volume and total glycolysis) were measured on a standard PET/CT workstation. Mean age of the population was 60±14.6y. 41.61% of patients were female. Metabolically active BAT was found in 53 patients (5.1%). Female, younger and leaner patients tended to have more active BAT, higher metabolic activity and more caudally active BAT. In total, 15 patients showed only supraclavicular, 27 additional mediastinal, and 11 infradiaphragmal activity. Interestingly, the activation of BAT always followed a cranio-caudal gradient. This anatomical pattern correlated with age and BMI as well as with all metabolic parameters, including maximum and total glycolysis (p<0.001). CONCLUSION: Based on our data we propose a simple method to grade or quantify the degree of BAT amount/activity in patients based on the most caudally activated depot. As new modalities for BAT visualization may arise in the future, this system would allow direct comparability with other modalities, in contrary to the PET-metrics, which are restricted to 18FDG-PET/CT.