Optimal transformations leading to normal distributions of positron emission tomography standardized uptake values

Scarpelli, M; Eickhoff, Jens; Cuña, Enrique Gustavo; Perlman, Scott; Jeraj, Robert

doi:10.1088/1361-6560/aaa175

Cited by 11 publications

(10 citation statements)

References 22 publications

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“…The tumor gadolinium enhancement status (binary variable derived from T1W MRI) and tumor volume were also included as independent variables in the multivariate regression. Before inclusion in the multivariate regression, measurements were log transformed (to better approximate normal distributions) ( 24 ) and scaled to have a mean of zero and standard deviation of 1 (to enable comparison of regression coefficients). The multivariate regression was performed using R version 4.0.2 using the Fitting Linear Models function.…”

Section: Methodsmentioning

confidence: 99%

Imaging Glioblastoma With 18F-Fluciclovine Amino Acid Positron Emission Tomography

et al. 2022

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IntroductionConventional methods of imaging brain tumors fail to assess metabolically active tumor regions, which limits their capabilities for tumor detection, localization, and response assessment. Positron emission tomography (PET) with 18F-fluciclovine (fluciclovine) provides regional assessment of amino acid uptake in tumors that could overcome some of the limitations of conventional imaging. However, the biological basis of enhanced fluciclovine uptake is insufficiently characterized in brain tumors, which confounds clinical interpretation and application. This study sought to address this gap by correlating multiple biologic quantities with fluciclovine PET uptake across a range of human glioblastoma xenograft models.MethodsThirty-one rats underwent orthotopic implantations with one of five different human glioblastoma cell lines. After tumors were established, fluciclovine PET and magnetic resonance imaging (MRI) scans were performed. The fluciclovine tumor-to-normal-brain (TN) uptake ratio was used to quantify fluciclovine uptake. MRI scans were used to assess tumor volume and gadolinium enhancement status. Histologic assessments quantified tumor cell proliferation, tumor cell density, and tumor cell amino acid transporters (LAT1 and ASCT2). Multivariate linear regression models related fluciclovine uptake with the other measured quantities.ResultsWithin the multivariate regression, the fluciclovine TN uptake ratio (measured 15 to 35 minutes after fluciclovine injection) was most strongly associated with tumor ASCT2 levels (β=0.64; P=0.001). The fluciclovine TN uptake ratio was also significantly associated with tumor volume (β=0.45; P=0.001) and tumor enhancement status (β=0.40; P=0.01). Tumor cell proliferation, tumor cell density, and LAT1 levels were not significantly associated with fluciclovine uptake in any of the multivariate models. In general, both enhancing and non-enhancing tumors could be visualized on fluciclovine PET images, with the median TN uptake ratio across the five tumor lines being 2.4 (range 1.1 to 8.9).ConclusionsIncreased fluciclovine PET uptake was associated with increased levels of the amino acid transporter ASCT2, suggesting fluciclovine PET may be useful for assessing brain tumor amino acid metabolism. Fluciclovine PET uptake was elevated in both enhancing and non-enhancing tumors but the degree of uptake was greater in larger tumors and tumors with enhancement, indicating these variables could confound fluciclovine metabolic measurements if not accounted for.

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Section: Methodsmentioning

confidence: 99%

Imaging Glioblastoma With 18F-Fluciclovine Amino Acid Positron Emission Tomography

et al. 2022

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“…Due to the skewed nature of PET SUV distributions [43], non-parametric statistics were used to analyze the data. Wilcoxon signed-rank tests were used to assess whether there were significant changes in PET uptake from baseline to 12 weeks.…”

Section: Methodsmentioning

confidence: 99%

FLT PET/CT imaging of metastatic prostate cancer patients treated with pTVG-HP DNA vaccine and pembrolizumab

Scarpelli

Zahm

Perlman

et al. 2019

j. immunotherapy cancer

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BackgroundImmunotherapy has demonstrated remarkable success in treating different cancers. Nonetheless, a large number of patients do not respond, many respond without immediate changes detectable with conventional imaging, and many have unusual immune-related adverse events that cannot be predicted in advance. In this exploratory study, we investigate how 3′-Deoxy-3’-18F-fluorothymidine (FLT) positron emission tomography (PET) measurements of tumor and immune cell proliferation might be utilized as biomarkers in immunotherapy.MethodsSeventeen patients with metastatic castrate resistant prostate cancer were treated with combination pTVG-HP DNA vaccine and pembrolizumab. Patients underwent baseline and 12-week FLT PET/CT scans. FLT PET standardized uptake values (SUVs) were extracted from tumors, non-metastatic lymph nodes, spleen, bone marrow, pancreas, and thyroid to quantify cell proliferation in these tissues. Regional immune cell responses to pTVG-HP DNA vaccine were assessed by comparing FLT uptake changes in vaccine draining and non-draining lymph nodes. Cox proportional hazards regression was utilized to relate FLT uptake and other clinical markers (PSA and tumor size) to progression-free survival. Area under receiver operating characteristic (AUC) curves and concordance indices were used to assess the predictive capabilities of FLT uptake.ResultsChanges in FLT uptake in vaccine draining lymph nodes were significantly greater than changes in non-draining lymph nodes (P = 0.02), suggesting a regional immune response to vaccination. However, the changes in FLT uptake in lymph nodes were not significantly predictive of progression-free survival. Increases in tumor FLT uptake were significantly predictive of shorter progression-free survival (concordance index = 0.83, P < 0.01). Baseline FLT uptake in the thyroid was significantly predictive of whether or not a patient would subsequently experience a thyroid-related adverse event (AUC = 0.97, P < 0.01).ConclusionsFLT PET uptake was significantly predictive of progression-free survival and the occurrence of adverse events relating to thyroid function. The results suggest FLT PET imaging has potential as a biomarker in immunotherapy, providing a marker of tumor and immune responses, and as a possible means of anticipating specific immune-related adverse events.Trial registrationNCT02499835.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0516-1) contains supplementary material, which is available to authorized users.

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“…PET detects, measures, and localizes gamma rays emitted from annihilation events between positrons (emitted by administered positron-emitting isotopes) and electrons, providing for a method to distinguish tissues that have differential radiotracer activities. For example, abnormal changes in tissue metabolic activity can be detected with 18 F-fluorodeoxyglucose (FDG)-PET imaging before structural changes are detectable with computed tomography (CT) or magnetic resonance imaging (MRI). As such, metabolic activity measured from FDG-PET is an important biomarker that is clinically utilized for diagnostic, staging, prognostication, and treatment response assessment purposes in patients with cancer [2][3][4][5] .…”

Section: Background and Rationalementioning

confidence: 99%

“…In yet other methods, standardization is performed at the image post-processing stage by using various methods such as digital PET phantoms, anatomical standardization with Z-scores, or various image transformation methods. For PET images by iterating the Box-Cox transformation parameter and selecting the parameter that maximized the ShapiroWilk P-value 18 . Orlhac et al proposed the use of a harmonization method (ComBat) initially described for genomic data to normalize radiomic features as measured in PET for removing the center effect while retaining pathophysiologic information 19 .…”

Section: Related Workmentioning

confidence: 99%

Post-acquisition Standardization of Positron Emission Tomography Images

Mortazi

Udupa²,

Odhner

et al. 2023

Preprint

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Purpose Tissue radiotracer activity measured from positron emission tomography (PET) images is an important biomarker that is clinically utilized for diagnosis, staging, prognostication, and treatment response assessment in patients with cancer and other clinical disorders. Using PET image values to define a normal range of metabolic activity for quantification purposes is challenging due to variations in patient-related factors and technical factors. Although the formulation of standardized uptake value (SUV) has compensated for some of these variabilities, significant non-standardness still persists. We propose an image processing method to substantially mitigate these variabilities. Methods The standardization method is similar for activity concentration (AC) PET and SUV PET images with some differences and consists of two steps. The calibration step is performed only once for each of AC PET or SUV PET, employs a set of images of normal subjects, and requires a reference object, while the transformation step is executed for each patient image to be standardized. In the calibration step, a standardized scale is determined along with 3 key image intensity landmarks defined on it including the minimum percentile intensity smin, median intensity sm, and high percentile intensity smax. smin and sm are estimated based on image intensities within the body region in the normal calibration image set. The optimal value of the maximum percentile corresponding to the intensity smax is estimated via an optimization process by using the reference object to optimally separate the highly variable high uptake values from the normal uptake intensities. In the transformation step, the first two landmarks – the minimum percentile intensity p (I), and the median intensity pm(I) – are found for the given image I for the body region, and the high percentile intensity p (I) is determined corresponding to the optimally estimated high percentile value . Subsequently, intensities of I are mapped to the standard scale piecewise linearly for different segments. We employ three strategies for evaluation and comparison with other standardization methods: (i) Comparing coefficient of variation (CVO) of mean intensity within test objects O across different normal test subjects before and after standardization; (ii) Comparing mean absolute difference (MDO) of mean intensity within test objects O across different subjects in repeat scans before and after standardization; (iii) Comparing CVO of mean intensity across different normal subjects before and after standardization where the scans came from different brands of scanners. Results Our data set consisted of 84 FDG-PET/CT scans of the body torso including 38 normal subjects and two repeat-scans of 23 patients. We utilized one of two objects – liver and spleen – as a reference object and the other for testing. The proposed standardization method reduced CVO and MDO by a factor of 3-8 in comparison to other standardization methods and no standardization. Upon standardization by our method, the image intensities (both for AC and SUV) from two different brands of scanners become statistically indistinguishable, while without standardization, they differ significantly and by a factor of 3-9. Conclusions The proposed method is automatic, outperforms current standardization methods, and effectively overcomes the residual variation left over in SUV and inter-scanner variations.

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Optimal transformations leading to normal distributions of positron emission tomography standardized uptake values

Abstract: Optimization of the Box-Cox transformation, offers a solution for identifying normal SUV transformations for when the log transformation is insufficient. The log transformation is not always the appropriate transformation for producing normally distributed PET SUVs.

Cited by 11 publications

References 22 publications

Imaging Glioblastoma With 18F-Fluciclovine Amino Acid Positron Emission Tomography

Imaging Glioblastoma With 18F-Fluciclovine Amino Acid Positron Emission Tomography

FLT PET/CT imaging of metastatic prostate cancer patients treated with pTVG-HP DNA vaccine and pembrolizumab

Post-acquisition Standardization of Positron Emission Tomography Images

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