Artificial intelligence-based, volumetric assessment of the bone marrow metabolic activity in [18F]FDG PET/CT predicts survival in multiple myeloma.

PURPOSE: Multiple myeloma (MM) is a highly heterogeneous disease with wide variations in patient outcome. [18F]FDG PET/CT can provide prognostic information in MM, but it is hampered by issues regarding standardization of scan interpretation. Our group has recently demonstrated the feasibility of automated, volumetric assessment of bone marrow (BM) metabolic activity on PET/CT using a novel artificial intelligence (AI)-based tool. Accordingly, the aim of the current study is to investigate the prognostic role of whole-body calculations of BM metabolism in patients with newly diagnosed MM using this AI tool. MATERIALS AND METHODS: Forty-four, previously untreated MM patients underwent whole-body [18F]FDG PET/CT. Automated PET/CT image segmentation and volumetric quantification of BM metabolism were based on an initial CT-based segmentation of the skeleton, its transfer to the standardized uptake value (SUV) PET images, subsequent application of different SUV thresholds, and refinement of the resulting regions using postprocessing. In the present analysis, ten different uptake thresholds (AI approaches), based on reference organs or absolute SUV values, were applied for definition of pathological tracer uptake and subsequent calculation of the whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Correlation analysis was performed between the automated PET values and histopathological results of the BM as well as patients' progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curve analysis was used to investigate the discrimination performance of MTV and TLG for prediction of 2-year PFS. The prognostic performance of the new Italian Myeloma criteria for PET Use (IMPeTUs) was also investigated. RESULTS: Median follow-up [95% CI] of the patient cohort was 110 months [105-123 months]. AI-based BM segmentation and calculation of MTV and TLG were feasible in all patients. A significant, positive, moderate correlation was observed between the automated quantitative whole-body PET/CT parameters, MTV and TLG, and BM plasma cell infiltration for all ten [18F]FDG uptake thresholds. With regard to PFS, univariable analysis for both MTV and TLG predicted patient outcome reasonably well for all AI approaches. Adjusting for cytogenetic abnormalities and BM plasma cell infiltration rate, multivariable analysis also showed prognostic significance for high MTV, which defined pathological [18F]FDG uptake in the BM via the liver. In terms of OS, univariable and multivariable analysis showed that whole-body MTV, again mainly using liver uptake as reference, was significantly associated with shorter survival. In line with these findings, ROC curve analysis showed that MTV and TLG, assessed using liver-based cut-offs, could predict 2-year PFS rates. The application of IMPeTUs showed that the number of focal hypermetabolic BM lesions and extramedullary disease had an adverse effect on PFS. CONCLUSIONS: The AI-based, whole-body calculations of BM metabolism via the parameters MTV and TLG not only correlate with the degree of BM plasma cell infiltration, but also predict patient survival in MM. In particular, the parameter MTV, using the liver uptake as reference for BM segmentation, provides solid prognostic information for disease progression. In addition to highlighting the prognostic significance of automated, global volumetric estimation of metabolic tumor burden, these data open up new perspectives towards solving the complex problem of interpreting PET scans in MM with a simple, fast, and robust method that is not affected by operator-dependent interventions.

Combined whole-body dynamic and static PET/CT with low-dose [18F]PSMA-1007 in prostate cancer patients.

AIM: In addition to significant improvements in sensitivity and image quality, the recent introduction of long axial field-of-view (LAFOV) PET/CT scanners has enabled dynamic whole-body imaging for the first time. We aim herein to determine an appropriate acquisition time range for static low-dose [18F]PSMA-1007 PET imaging and to investigate the whole-body pharmacokinetics of [18F]PSMA-1007 by dynamic PET with the LAFOV Biograph Vision Quadra PET/CT in a group of prostate cancer patients. METHODOLOGY: In total, 38 prostate cancer patients were enrolled in the analysis for staging or re-staging purposes. Thirty-four patients underwent dynamic whole-body PET/CT (60 min) followed by static whole-body PET/CT and four patients underwent static whole-body PET/CT only. The activity applied was 2 MBq/kg [18F]PSMA-1007. The static PET images of 10-min duration (PET-10) were reconstructed and further split into 8-min (PET-8), 6-min (PET-6), 5-min (PET-5), 4-min (PET-4), and 2-min (PET-2) duration groups. Comparisons were made between the different reconstructed scan times in terms of lesion detection rate and image quality based on SUV calculations of tumor lesions and the spleen, which served as background. Analysis of the dynamic PET/CT data was based on a two-tissue compartment model using an image-derived input function obtained from the descending aorta. RESULTS: Analysis of lesion detection rate showed no significant differences when reducing PET acquisitions from 10 up to 5 min. In particular, a total of 169 lesions were counted with PET-10, and the corresponding lesion detection rates (95% CI for the 90% quantile of the differences in tumor lesions) for shorter acquisitions were 100% (169/169) for PET-8 (95% CI: 0-0), 98.8% (167/169) for PET-6 (95% CI: 0-1), 95.9% (162/169) for PET-5 (95% CI: 0-3), 91.7% (155/169) for PET-4 (95% CI: 1-2), and 85.2% (144/169) for PET-2 (95% CI: 1-6). With the exception of PET-2, the differences observed between PET-10 and the other shorter acquisition protocols would have no impact on any patient in terms of clinical management. Objective evaluation of PET/CT image quality showed no significant decrease in tumor-to-background ratio (TBR) with shorter acquisition times, despite a gradual decrease in signal-to-noise ratio (SNR) in the spleen. Whole-body quantitative [18F]PSMA-1007 pharmacokinetic analysis acquired with full dynamic PET scanning was feasible in all patients. Two-tissue compartment modeling revealed significantly higher values for the parameter k3 in tumor lesions and parotid gland compared to liver and spleen, reflecting a higher specific tracer binding to the PSMA molecule and internalization rate in these tissues, a finding also supported by the respective time-activity curves. Furthermore, correlation analysis demonstrated a significantly strong positive correlation (r = 0.72) between SUV and k3 in tumor lesions. CONCLUSIONS: In prostate cancer, low-dose (2 MBq/kg) [18F]PSMA-1007 LAFOV PET/CT can reduce static scan time by 50% without significantly compromising lesion detection rate and objective image quality. In addition, dynamic PET can elucidate molecular pathways related to the physiology of [18F]PSMA-1007 in both tumor lesions and normal organs at the whole-body level. These findings unfold many of the potentials of the new LAFOV PET/CT technology in the field of PSMA-based diagnosis and theranostics of prostate cancer.

Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level.

In multiple myeloma spatial differences in the subclonal architecture, molecular signatures and composition of the microenvironment remain poorly characterized. To address this shortcoming, we perform multi-region sequencing on paired random bone marrow and focal lesion samples from 17 newly diagnosed patients. Using single-cell RNA- and ATAC-seq we find a median of 6 tumor subclones per patient and unique subclones in focal lesions. Genetically identical subclones display different levels of spatial transcriptional plasticity, including nearly identical profiles and pronounced heterogeneity at different sites, which can include differential expression of immunotherapy targets, such as CD20 and CD38. Macrophages are significantly depleted in the microenvironment of focal lesions. We observe proportional changes in the T-cell repertoire but no site-specific expansion of T-cell clones in intramedullary lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity in multiple myeloma with potential implications for models of cell-cell interactions and disease progression.

Application of an artificial intelligence-based tool in [18F]FDG PET/CT for the assessment of bone marrow involvement in multiple myeloma.

PURPOSE: [18F]FDG PET/CT is an imaging modality of high performance in multiple myeloma (MM). Nevertheless, the inter-observer reproducibility in PET/CT scan interpretation may be hampered by the different patterns of bone marrow (BM) infiltration in the disease. Although many approaches have been recently developed to address the issue of standardization, none can yet be considered a standard method in the interpretation of PET/CT. We herein aim to validate a novel three-dimensional deep learning-based tool on PET/CT images for automated assessment of the intensity of BM metabolism in MM patients. MATERIALS AND METHODS: Whole-body [18F]FDG PET/CT scans of 35 consecutive, previously untreated MM patients were studied. All patients were investigated in the context of an open-label, multicenter, randomized, active-controlled, phase 3 trial (GMMG-HD7). Qualitative (visual) analysis classified the PET/CT scans into three groups based on the presence and number of focal [18F]FDG-avid lesions as well as the degree of diffuse [18F]FDG uptake in the BM. The proposed automated method for BM metabolism assessment is based on an initial CT-based segmentation of the skeleton, its transfer to the SUV PET images, the subsequent application of different SUV thresholds, and refinement of the resulting regions using postprocessing. In the present analysis, six different SUV thresholds (Approaches 1-6) were applied for the definition of pathological tracer uptake in the skeleton [Approach 1: liver SUVmedian × 1.1 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 2: liver SUVmedian × 1.5 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 3: liver SUVmedian × 2 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 4: ≥ 2.5. Approach 5: ≥ 2.5 (axial skeleton), ≥ 2.0 (extremities). Approach 6: SUVmax liver]. Using the resulting masks, subsequent calculations of the whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in each patient were performed. A correlation analysis was performed between the automated PET values and the results of the visual PET/CT analysis as well as the histopathological, cytogenetical, and clinical data of the patients. RESULTS: BM segmentation and calculation of MTV and TLG after the application of the deep learning tool were feasible in all patients. A significant positive correlation (p < 0.05) was observed between the results of the visual analysis of the PET/CT scans for the three patient groups and the MTV and TLG values after the employment of all six [18F]FDG uptake thresholds. In addition, there were significant differences between the three patient groups with regard to their MTV and TLG values for all applied thresholds of pathological tracer uptake. Furthermore, we could demonstrate a significant, moderate, positive correlation of BM plasma cell infiltration and plasma levels of ß2-microglobulin with the automated quantitative PET/CT parameters MTV and TLG after utilization of Approaches 1, 2, 4, and 5. CONCLUSIONS: The automated, volumetric, whole-body PET/CT assessment of the BM metabolic activity in MM is feasible with the herein applied method and correlates with clinically relevant parameters in the disease. This methodology offers a potentially reliable tool in the direction of optimization and standardization of PET/CT interpretation in MM. Based on the present promising findings, the deep learning-based approach will be further evaluated in future prospective studies with larger patient cohorts.

Can physiologic colonic [18F]FDG uptake in PET/CT imaging predict response to immunotherapy in metastatic melanoma?

AIM: The development of biomarkers that can reliably and early predict response to immune checkpoint inhibitors (ICIs) is crucial in melanoma. In recent years, the gut microbiome has emerged as an important regulator of immunotherapy response, which may, moreover, serve as a surrogate marker and prognosticator in oncological patients under immunotherapy. Aim of the present study is to investigate if physiologic colonic [18F]FDG uptake in PET/CT before start of ICIs correlates with clinical outcome of metastatic melanoma patients. The relation between [18F]FDG uptake in lymphoid cell-rich organs and long-term patient outcome is also assessed. METHODOLOGY: One hundred nineteen stage IV melanoma patients scheduled for immunotherapy with ipilimumab, applied either as monotherapy or in combination with nivolumab, underwent baseline [18F]FDG PET/CT. PET/CT data analysis consisted of standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) calculations in the colon as well as measurements of the colon-to-liver SUV ratios (CLRmean, CLRmax). Visual grading of colon uptake based on a four-point scale was also performed. Moreover, the spleen-to-liver SUV ratios (SLRmean, SLRmax) and the bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were calculated. We also measured serum lipopolysaccharide (LPS) levels as a marker for bacterial translocation and surrogate for mucosal defense homeostasis. The results were correlated with patients' best clinical response, progression-free survival (PFS), and overall survival (OS) as well as clinical signs of colitis. RESULTS: Median follow-up [95%CI] from the beginning of immunotherapy was 64.6 months [61.0-68.6 months]. Best response to treatment was progressive disease (PD) for 60 patients, stable disease (SD) for 37 patients, partial response (PR) for 18 patients, and complete response (CR) for 4 patients. Kaplan-Meier curves demonstrated a trend for longer PFS and OS in patients with lower colonic SUV and CLR values; however, no statistical significance for these parameters as prognostic factors was demonstrated. On the other hand, patients showing disease control as best response to treatment (SD, PR, CR) had significantly lower colonic MTV and TLG than those showing PD. With regard to lymphoid cell-rich organs, significantly lower baseline SLRmax and BLRmax were observed in patients responding with disease control than progression to treatment. Furthermore, patients with lower SLRmax and BLRmax values had a significantly longer OS when dichotomized at their median. In multivariate analysis, PET parameters that were found to significantly adversely correlate with patient survival were colonic MTV for PFS, colonic TLG for PFS, and BLRmax for PFS and OS. CONCLUSIONS: Physiologic colonic [18F]FDG uptake in PET/CT, as assessed by means of SUV, before start of ipilimumab-based treatment does not seem to independently predict patient survival of metastatic melanoma. On the other hand, volumetric PET parameters, such as MTV and TLG, derived from the normal gut may identify patients showing disease control to immunotherapy and significantly correlate with PFS. Moreover, the investigation of glucose metabolism in the spleen and the bone marrow may offer prognostic information.

Long axial field of view (LAFOV) PET-CT: implementation in static and dynamic oncological studies.

Long axial field of view (LAFOV) PET-CT scanners have been recently developed and are already in clinical use in few centers worldwide. Although still limited, the hitherto acquired experience with these novel systems highlights an increased sensitivity as their main advantage, which results in an increased lesion detectability. This attribute, alternatively, allows a reduction in PET acquisition time and/or administered radiotracer dose, while it renders delayed scanning of satisfying diagnostic accuracy possible. Another potential advantage of the new generation scanners is CT-less approaches for attenuation correction with the impact of marked reduction of radiation exposure, which may in turn lead to greater acceptance of longitudinal PET studies in the oncological setting. Further, the possibility for the first time of whole-body dynamic imaging, improved compartment modeling, and whole-body parametric imaging represent unique characteristics of the LAFOV PET-CT scanners. On the other hand, the advent of the novel LAFOV scanners is linked to specific challenges, such as the high purchase price and issues related to logistics and their optimal operation in a nuclear medicine department. Moreover, with regard to its research applications in oncology, the full potential of the new scanners can only be reached if different radiopharmaceuticals, both short and long-lived ones, as well as novel tracers, are available for use, which would, in turn, require the appropriate infrastructure in the area of radiochemistry. Although the novel LAFOV scanners are not yet widely used, this development represents an important step in the evolution of molecular imaging. This review presents the advantages and challenges of LAFOV PET-CT imaging for oncological applications with respect to static and dynamic acquisition protocols as well as to new tracers, while it provides an overview of the literature in the field.

The prognostic value of [18F]FDG PET/CT based response monitoring in metastatic melanoma patients undergoing immunotherapy: comparison of different metabolic criteria.

PURPOSE: To investigate the prognostic value of [18F]FDG PET/CT as part of response monitoring in metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs). METHODS: Sixty-seven patients underwent [18F]FDG PET/CT before start of treatment (baseline PET/CT), after two cycles (interim PET/CT) and after four cycles of ICIs administration (late PET/CT). Metabolic response evaluation was based on the conventional EORTC and PERCIST criteria, as well as the newly introduced, immunotherapy-modified PERCIMT, imPERCIST5 and iPERCIST criteria. Metabolic response to immunotherapy was classified according to four response groups (complete metabolic response [CMR], partial metabolic response [PMR], stable metabolic disease [SMD], progressive metabolic disease [PMD]), and further dichotomized by response rate (responders = [CMR] + [PMR] vs. non-responders = [PMD] + [SMD]), and disease control rate (disease control = [CMR] + [PMR] + [SMD] vs. [PMD]). The spleen-to-liver SUV ratios (SLRmean, SLRmax) and bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were also calculated. The results of PET/CT were correlated with patients' overall survival (OS). RESULTS: Median patient follow up [95% CI] was 61.5 months [45.3 - 66.7 months]. On interim PET/CT, the application of the novel PERCIMT demonstrated significantly longer survival for metabolic responders, while the rest criteria revealed no significant survival differences between the different response groups. Respectively on late PET/CT, both a trend for longer OS and significantly longer OS were observed in patients responding to ICIs with metabolic response and disease control after application of various criteria, both conventional and immunotherapy-modified. Moreover, patients with lower SLRmean values demonstrated significantly longer OS. CONCLUSION: In patients with metastatic melanoma PET/CT-based response assessment after four ICIs cycles is significantly associated with OS after application of different metabolic criteria. The prognostic performance of the modality is also high after the first two ICIs cycles, especially with employment of novel criteria. In addition, investigation of spleen glucose metabolism may provide further prognostic information.

Positron Emission Tomography-Based Immunoimaging for Cancer Patient Stratification: Toward a More Holistic Approach.

Immunotherapy with immune checkpoint inhibitors (ICIs) changed the treatment management in several solid metastatic tumors with very poor prognosis, in particular in melanoma stage IV since its introduction in 2011. However, it is not yet fully understood why some patients respond to ICIs and others not, and it is also unclear why melanomas are the most sensitive tumors to ICI treatment. Selection criteria for patient stratification are needed and several approaches are under evaluation. These include the PD-L1 expression in the tumor samples, assessment of the tumor mutational burden as well as radiological and molecular imaging techniques, such as positron emission tomography (PET)-CT and PET-MRI with 18F-fluorodeoxyglucose (FDG) or novel radiopharmaceuticals. In the near future, a more holistic approach based on the combination of imaging data and sequencing data and the development of radiogenomic signatures will be needed for a better characterization of immunotherapy response and selection of patients who will benefit from ICI therapy alone or in combination with chemotherapy.

Unusual Extramedullary Manifestation in Multiple Myeloma: Bilateral Synchronous Testicular Infiltration.

ABSTRACT: A 73-year-old man with multiple myeloma (initial diagnosis 21 months earlier) was referred to our center for a whole-body 18 F-FDG PET/CT. We detected a bilateral synchronous testicular manifestation, which was confirmed by histopathology after orchiectomy. Besides hypermetabolic lesions in the spine and ribs (most likely old fractures), known osteolysis showed no uptake. Extramedullary manifestation occurs in 13% to 20% of cases, among these 4% demonstrate testicular manifestation, which is associated with poor survival rates. Optimal therapy management is still unclear, due to limited data. To the authors' knowledge, so far only 3 comparable cases have been described.

Application of the long axial field-of-view PET/CT with low-dose [18F]FDG in melanoma.

AIM: The recent introduction of long axial field-of-view (LAFOV) PET/CT scanners has yielded very promising results regarding image quality and sensitivity in oncological patients. We, herein, aim to determine an appropriate acquisition time range for the new long axial field of view Biograph Vision Quadra PET/CT (Siemens Healthcare) using low dose [18F]FDG activity in a group of melanoma patients. METHODOLOGY: Forty-nine melanoma patients were enrolled in the study. All patients underwent total body PET/CT from the top of the head through the feet in two bed positions (field-of-view 106 cm) after i.v. injection of 2.0 MBq/kg [18F]FDG. The PET images of the first bed position (head to upper thigh; PET-10) were reconstructed and further split into 8-min (PET-8), 6-min (PET-6), 5-min (PET-5), 4-min (PET-4), and 2-min (PET-2) duration groups. Comparisons were performed between the different reconstructed scan times with regard to the visual evaluation of the PET/CT scans using the PET-10 images as reference and by calculating the 95%-CI for the differences between different time acquisitions. Moreover, objective evaluation of PET/CT image quality was performed based on SUV calculations of tumor lesions and background, leading to calculation of liver signal-to-noise ratio (SNR), and tumor-to-background ratio (TBR). RESULTS: A total of 60 scans were evaluated. Concerning visual analysis, 49/60 (81.7%) PET-10 scans were pathological, while the respective frequencies were 49/60 (81.7%) for PET-8 (95%-CI: - 0.0602-0.0602), 49/60 (81.7%) for PET-6 (95%-CI: - 0.0602-0.0602), 48/60 (80%) for PET-5 (95%-CI: - 0.0445-0.0886), 46/60 (76.7%) for PET-4 (95%-CI: - 0.0132-0.1370), and 45/60 (75%) for PET-2 (95%-CI: 0.0025-0.1593). In 18 PET-10 scans, the extent of metastatic involvement was very large, rendering the accurate calculation of [18F]FDG-avid tumor lesions very complicated. In the remaining 42 PET-10 scans, for which the exact calculation of tumor lesions was feasible, a total of 119 tumor lesions were counted, and the respective lesion detection rates for shorter acquisitions were as follows: 97.5% (116/119) for PET-8 (95%-CI: 0-1), 95.0% (113/119) for PET-6 (95%-CI: 0-1), 89.9% (107/119) for PET-5 (95%-CI: 0-2), 83.2% (99/119) for PET-4 (95%-CI: 1-2), and 73.9% (88/119) for PET-2 (95%-CI: 2-4). With regard to objective image quality evaluations, as a general trend, the reduction of acquisition time was associated with a decrease of liver SNR and a decrease of TBR, although in lesion-based analysis the change in TBR and tumor SUVmean values was non-significant up to 6 and 5 min acquisitions, respectively. CONCLUSIONS: In melanoma, low-dose LAFOV PET/CT imaging is feasible and can reduce the total scan time from head to upper thigh up to 5 min providing comparable diagnostic data to standard lengths of acquisition. This may have significant implications for the diagnostic work-up of patients with melanoma, given the need for true whole-body imaging in this type of cancer.

A comparative assessment of intra- and inter- observer repeatability of three widely used software packages for the quantification of defect size in stress myocardial perfusion scintigraphy.

OBJECTIVE: To assess the intra- and inter-observer repeatability of popular software packages for the quantitative determination of abnormality size in stress myocardial perfusion scintigraphy. SUBJECTS AND METHODS: A total of 182 tomographic stress myocardial perfusion scans were processed in duplicate by an experienced and trainee observer to assess SSSext (summed stress score multiplied by 100/68) and total defect extent (TDE), as % of the left ventricle, with 4 dimension-myocardial (4DM), emory cardiac toolbox (ECTb) and quantitative perfusion SPECT (QPS) packages. The Bland-Altman (B-A) analysis and Lin's concordance correlation coefficient (CCC) were used to assess agreement. RESULTS: In SSSext's intra-observer repeatability, CCC showed substantial agreement for 4DM and QPS, and moderate agreement for ECTb for both observers. In inter-observer repeatability, CCC revealed substantial agreement for 4DM and QPS, and poor agreement for ECTb. Regarding TDE, CCC showed substantial intra-observer repeatability for both operators using all packages, while the inter-observer repeatability was substantial for 4DM and QPS, and moderate for ECTb.In SSSext's intra-observer repeatability for 4DM, ECTb and QPS, the B-A analysis provided (mean±1.96SD of paired measurements) 0.0±4.3, 0.2±7.8, -0.6±7.6 for the experienced physician and 0.2±5.9, 0.0±7.5, -0.5±5.4 for the trainee, respectively; in inter-observer repeatability it provided 0.2±5.4, 0.1±9.6, 0.2±8.1, respectively. Regarding TDE, the B-A values for intra-observer repeatability were 0.1±5.2, 0.1±7.9, 0.1±2.8 for the experienced reader and 0.3±6.6, -0.1±6.4, -0.1±2.4 for the trainee, respectively; in inter-observer agreement the B-A provided 0.6±6.4, -0.2±10.3, -0.1±4.3, respectively. CONCLUSION: Considerable differences in intra- and inter- observer agreement were noted for the quantitative determination of defect size using widely employed software packages, suggesting limitations in the clinical use of these measurements. Quantitative perfusion SPECT appears preferable, but with no significant advantage over 4DM. There were no significant differences between the observers.

Adverse effects under immune checkpoint inhibitors on [18F]FDG PET/CT imaging.

Despite their undisputed contribution to the management of various tumors and the prolongation of patient survival, immune checkpoint inhibitors (ICIs) exert their effect at the cost of toxicity. In the context of the activation of the host immune system triggered by ICIs, collateral, inflammatory side effects, commonly addressed as immune-related adverse events (irAEs) often occur. Early detection of irAEs can be critical for adequate decisions on patient management that may subsequently improve patient outcome. Moreover, the emergence of irAEs has been linked with the antitumor effect elicited by ICIs, thus, their identification may potentially provide prognostic information. Although the diagnosis of irAEs is mainly clinical, some adverse events may be asymptomatic and only diagnosed by imaging modalities. At the same time, radiological signs of irAEs are not necessarily associated with clinical symptoms, however, clinicians should be alerted to their presence. Among imaging modalities [18F]FDG PET/CT has shown satisfying efficiency in response assessment and monitoring of ICIs' treatment, especially in patients suffering from metastatic melanoma and lung cancer. In this context, [18F]FDG PET/CT may also be a valuable method for surveillance of irAEs during immunotherapy. This article aims to review the most common adverse events observed on [18F]FDG PET/CT under immunotherapy and summarize potential results linking PET signs of irAEs with response assessment to ICIs.

Parametric Imaging With Dynamic PET for Oncological Applications: Protocols, Interpretation, Current Applications and Limitations for Clinical Use.

Nuclear medicine imaging modalities, and in particular positron emission tomography (PET), provide functional images that demonstrate the mean radioactivity distribution at a defined point in time. With the help of mathematical model's, it is possible to depict isolated parameters of the radiotracers' pharmacokinetics and to visualize them. These so called parametric images add a new dimension to the existing conventional PET images and provide more detailed information about the tracer distribution over time and space. Prerequisite for the calculation of parametric images, which reflect specific pharmacokinetic parameters, is the dynamic PET (dPET) data acquisition. Hitherto, PET parametric imaging has mainly found use for research purposes. However, it has not been yet implemented into clinical routine, since it is more time-consuming, it requires a complicated analysis and still lacks a clear benefit over conventional PET imaging. However, the recent introduction of new PET-CT scanners with an ultralong field of view, which allow a faster data acquisition and are associated with higher sensitivity, as well as the development of more sophisticated evaluation software packages will probably lead to a renaissance of dPET and parametric maps even of the whole body. The implementation of dPET imaging in daily routine with appropriate acquisition protocols, as well as the calculation, interpretation and potential clinical applications of parametric images will be discussed in this review article.

[Positron emission tomography/computed tomography (PET/CT) in multiple myeloma]. / Positronen-Emissions-Tomographie/Computertomographie (PET/CT) beim multiplen Myelom.

BACKGROUND: Imaging plays a pivotal role in the management of multiple myeloma (MM). Besides morphological imaging methods, such as whole-body X­ray, computed tomography (CT) and magnetic resonance imaging (MRI), the hybrid modality positron emission tomography/CT (PET/CT) using the glucose analogue 18F­fluorodeoxyglucose (18F­FDG) as radiotracer is increasingly used. OBJECTIVES: Aim of this review article is to outline the major applications of PET/CT in the diagnosis and management of MM, and to provide hints on the reading and interpretation. MATERIALS AND METHODS: Background knowledge and guideline recommendations on imaging of MM are outlined and complemented by recent study results. RESULTS: Although 18F­FDG PET/CT is not currently considered a standard method for the diagnosis of MM, it is a very powerful diagnostic tool for the detection of medullary and extramedullary disease, a reliable predictor of survival and the most robust modality for treatment response evaluation. Moreover, it plays a significant role in minimal residual disease (MRD) assessment. On the other hand, practical considerations on local availability and costs limit the widespread use of PET/CT. In addition, false-negative and the seldom false-positive results and the heterogeneity of MM presentation inevitably make interpretation of PET/CT images challenging. CONCLUSIONS: PET/CT has a high value in the diagnosis, prognosis, and assessment of treatment response in patients with MM. Therefore, the role of the modality in the management of the disease is expected to increase in the near future.

A decision support system for the identification of metastases of Metastatic Melanoma using whole-body FDG PET/CT images.

Metastatic Melanoma (MM) is an aggressive type of cancer which produces metastases throughout the body with very poor survival rates. Recent advances in immunotherapy have shown promising results for controlling disease's progression. Due to the often rapid progression, fast and accurate diagnosis and treatment response assessment is vital for the whole patient management. These procedures prerequisite accurate, whole-body tumor identification. This can be offered by the imaging modality Positron Emission Tomography (PET)/Computed Tomography (CT) with the radiotracer F 18-Fluorodeoxyglucose (FDG). However, manual segmentation of PET/CT images is a very time-consuming and labor intensive procedure that requires expert knowledge. Most of the previously published segmentation techniques focus on a specific type of tumor or part of the body and require a great amount of manually labeled data, which is, however, difficult for MM. Multimodal analysis of PET/CT is also crucial because FDG-PET contains only the functional information of tumors which can be complemented by the anatomical information of CT. In this paper, we propose a whole-body segmentation framework capable of efficiently identifying the highly heterogeneous tumor lesions of MM from the whole-body 3D FDG-PET/CT images. The proposed decision support system begins with an Ensemble Unsupervised Segmentation of regions of high FDG-uptake based on Fuzzy C-means and a custom region growing algorithm. Then, a region classification model based on radiomics features and Neural Networks classifies these regions as tumors or not. Experimental results showed high performance in the identification of MM lesions with Sensitivity 83.68%, Specificity 91.82%, F1-score 75.42%, AUC 94.16% and Balanced accuracy 87.75% which were also supported by the public dataset evaluation.

Adapting Imaging Protocols for PET-CT and PET-MRI for Immunotherapy Monitoring.

Hybrid imaging with positron emission tomography (PET) in combination with computer tomography (CT) is a well-established diagnostic tool in oncological staging and restaging. The combination of PET with magnetic resonance imaging (MRI) as a clinical scanner was introduced approximately 10 years ago. Although MRI provides superb soft tissue contrast and functional information without the radiation exposure of CT, PET-MRI is not as widely introduced in oncologic imaging as PET-CT. One reason for this hesitancy lies in the relatively long acquisition times for a PET-MRI scan, if the full diagnostic potential of MRI is exploited. In this review, we discuss the possible advantages of combined imaging protocols of PET-CT and PET-MRI, within the context of staging and restaging of patients under immunotherapy, in order to achieve "multi-hybrid imaging" in one single patient visit.

Fractal and Multifractal Analysis of PET-CT Images for Therapy Assessment of Metastatic Melanoma Patients under PD-1 Inhibitors: A Feasibility Study.

Longitudinal whole-body PET-CT scans with F-18-fluorodeoxyglucose (18F-FDG) in patients suffering from metastatic melanoma were analyzed and the tracer distribution in patients was compared with that of healthy controls. Nineteen patients with metastatic melanoma were scanned before, after two and after four cycles of treatment with PD-1 inhibitors (pembrolizumab, nivolumab) applied as monotherapy or as combination treatment with ipilimumab. For comparison eight healthy controls were analyzed. As quantitative measures for the comparison between controls and patients, the nonlinear fractal dimension (FD) and multifractal spectrum (MFS) were calculated from the digitized PET-CT scans. The FD and MFS measures, which capture the dispersion of the tracer in the body, decreased with disease progression, since the tracer particles tended to accumulate around metastatic sites in patients, while the measures increased when the patients' clinical condition ameliorate. The MFS measure gave better predictions and were consistent with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while FD agreed in 77% of all cases. These results agree, qualitatively, with a previous study of our group when treatment with ipilimumab monotherapy was considered.

The prognostic significance of [18F]FDG PET/CT in multiple myeloma according to novel interpretation criteria (IMPeTUs).

PURPOSE: [18F]FDG PET/CT is the elective imaging modality for treatment monitoring in multiple myeloma (MM). However, MM is a heterogeneous disease from an imaging point of view, raising challenges in interpretation of PET/CT. We herein investigated the prognostic role of the novel Italian Myeloma criteria for PET Use (IMPeTUs) in MM patients undergoing high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT). METHODS: Forty-seven patients with newly diagnosed MM underwent [18F]FDG PET/CT before commencement of treatment (baseline PET/CT). Thirty-four of them (72.3%) were also examined after completion of ASCT (follow-up PET/CT). PET/CT analysis was based on the IMPeTUs criteria, which take into consideration-among others-the metabolic state of the bone marrow based on the 5-point Deauville score (DS), the number and metabolic state of focal [18F]FDG-avid lesions, as well as the presence of paramedullary disease (PMD) and extramedullary disease (EMD). We analyzed whether parameters from IMPeTUs correlate with clinically relevant parameters and patients' outcome, as assessed by progression-free survival (PFS). RESULTS: Median follow-up from baseline and follow-up PET/CT were 85.1 months and 76.7 months, respectively. The number of focal, [18F]FDG-avid lesions significantly correlated with the bone marrow infiltration rate and the R-ISS stage, while the presence of PMD was associated with LDH. After univariate survival analysis, the number of focal, [18F]FDG-avid lesions both before and after therapy as well as the presence of PMD and EMD before therapy adversely affected PFS. Multivariate survival analysis for baseline parameters confirmed that the number of focal, [18F]FDG-avid lesions and the presence of EMD are associated with adverse prognosis, irrespective of the ISS stage and/or the presence of high-risk cytogenetic abnormalities. The 5-point DS of [18F]FDG uptake in reference bone marrow and focal lesions showed a significant decrease as response to treatment, but it did not affect PFS. CONCLUSION: Several parameters utilized in IMPeTUs predict PFS in MM patients, suggesting the potentially significant role of the new criteria in patient stratification and response assessment. Additional studies are warranted for the further evaluation of IMPeTUs in the direction of establishment of robust cut-off values with a prognostic significance in the disease.

Assessment of early metabolic progression in melanoma patients under immunotherapy: an 18F-FDG PET/CT study.

BACKGROUND: The usage of immune checkpoint inhibitors (ICIs) is the standard practice for the treatment of metastatic melanoma. However, a significant amount of patients show no response to immunotherapy, while issues on its reliable response interpretation exist. Aim of this study was to investigate the phenomenon of early disease progression in 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in melanoma patients treated with ICIs. METHODS: Thirty-one patients under ICIs serially monitored with 18F-FDG PET/CT were enrolled. All patients exhibited progressive metabolic disease (PMD) after two ICIs' cycles according to the European Organization for Research and Treatment of Cancer (EORTC) criteria, and were characterized as unconfirmed PMD (uPMD). They were further followed with at least one PET/CT for either confirmation of PMD (cPMD) or demonstration of pseudoprogression remission. Patients were also evaluated with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT). Moreover, in an attempt to investigate immune activation, the spleen to liver ratios (SLRmean, SLRmax) of 18F-FDG uptake were measured. RESULTS: Median follow up was 69.7 months [64.6-NA]. According to EORTC, 26/31 patients with uPMD eventually showed cPMD (83.9%) and 5/31 patients showed pseudoprogression (16.1%). Patients with cPMD (n = 26) had a median OS of 10.9 months [8.5-NA], while those with pseudoprogression (n = 5) did not reach a median OS [40.9-NA]. Respectively, after application of PERCIMT, 2/5 patients of the pseudoprogression group were correctly classified as non-PMD, reducing the uPMD cohort to 29 patients; eventually, 26/29 patients demonstrated cPMD (89.7%) and 3/29 pseudoprogression (10.3%). One further patient with pseudoprogression exhibited transient, sarcoid-like, mediastinal/hilar lymphadenopathy, a known immune-related adverse event (irAE). Finally, patients eventually showing cPMD exhibited a significantly higher SLRmean than those showing pseudoprogression after two ICIs' cycles (p = 0.038). CONCLUSION: PET/CT, performed already after administration of two ICIs' cycles, can identify the majority of non-responders in melanoma immunotherapy. In order to tackle however, the non-negligible phenomenon of pseudoprogression, another follow-up PET/CT, the usage of novel response criteria and vigilance over emergence of radiological irAEs are recommended. Moreover, the investigation of spleen glucose metabolism may offer further prognostic information in melanoma patients under ICIs.