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Total metabolic tumor volume (TMTV) is prognostic in lymphoma. However, cutoff values for risk stratification vary markedly, according to the tumor delineation method used. We aimed to create a standardized TMTV benchmark dataset allowing TMTV to be tested and applied as a reproducible biomarker. Methods: Sixty baseline 18F-FDG PET/CT scans were identified with a range of disease distributions (20 follicular, 20 Hodgkin, and 20 diffuse large B-cell lymphoma). TMTV was measured by 12 nuclear medicine experts, each analyzing 20 cases split across subtypes, with each case processed by 3-4 readers. LIFEx or ACCURATE software was chosen according to reader preference. Analysis was performed stepwise: TMTV1 with automated preselection of lesions using an SUV of at least 4 and a volume of at least 3 cm3 with single-click removal of physiologic uptake; TMTV2 with additional removal of reactive bone marrow and spleen with single clicks; TMTV3 with manual editing to remove other physiologic uptake, if required; and TMTV4 with optional addition of lesions using mouse clicks with an SUV of at least 4 (no volume threshold). Results: The final TMTV (TMTV4) ranged from 8 to 2,288 cm3, showing excellent agreement among all readers in 87% of cases (52/60) with a difference of less than 10% or less than 10 cm3 In 70% of the cases, TMTV4 equaled TMTV1, requiring no additional reader interaction. Differences in the TMTV4 were exclusively related to reader interpretation of lesion inclusion or physiologic high-uptake region removal, not to the choice of software. For 5 cases, large TMTV differences (>25%) were due to disagreement about inclusion of diffuse splenic uptake. Conclusion: The proposed segmentation method enabled highly reproducible TMTV measurements, with minimal reader interaction in 70% of the patients. The inclusion or exclusion of diffuse splenic uptake requires definition of specific criteria according to lymphoma subtype. The publicly available proposed benchmark allows comparison of study results and could serve as a reference to test improvements using other segmentation approaches.
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BACKGROUND: Addition of neoadjuvant immune checkpoint inhibition to standard-of-care interventions for locally advanced oral cancer could improve clinical outcome. METHODS: In this study, 16 evaluable patients with stage III/IV oral cancer were treated with one dose of 480 mg nivolumab 3 weeks prior to surgery. Primary objectives were safety, feasibility, and suitability of programmed death receptor ligand-1 positron emission tomography (PD-L1 PET) as a biomarker for response. Imaging included 18F-BMS-986192 (PD-L1) PET and 18F-fluorodeoxyglucose (FDG) PET before and after nivolumab treatment. Secondary objectives included clinical and pathological response, and immune profiling of peripheral blood mononuclear cells (PBMCs) for response prediction. Baseline tumor biopsies and postnivolumab resection specimens were evaluated by histopathology. RESULTS: Grade III or higher adverse events were not observed and treatment was not delayed in relation to nivolumab administration and other study procedures. Six patients (38%) had a pathological response, of whom three (19%) had a major (≥90%) pathological response (MPR). Tumor PD-L1 PET uptake (quantified using standard uptake value) was not statistically different in patients with or without MPR (median 5.3 vs 3.4). All major responders showed a significantly postnivolumab decreased signal on FDG PET. PBMC immune phenotyping showed higher levels of CD8+ T cell activation in MPR patients, evidenced by higher baseline expression levels of PD-1, TIGIT, IFNγ and lower levels of PD-L1. CONCLUSION: Together these data support that neoadjuvant treatment of advanced-stage oral cancers with nivolumab was safe and induced an MPR in a promising 19% of patients. Response was associated with decreased FDG PET uptake as well as activation status of peripheral T cell populations.
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Neoplasias Bucais , Terapia Neoadjuvante , Humanos , Masculino , Feminino , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/diagnóstico por imagem , Neoplasias Bucais/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Imagem Molecular/métodos , Nivolumabe/uso terapêutico , Nivolumabe/farmacologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Tomografia por Emissão de Pósitrons/métodos , AdultoRESUMO
INTRODUCTION: Immune checkpoint inhibitors (ICIs) can elicit anticancer immune responses, but predictive biomarkers are needed. We measured programmed death ligand 1 (PD-L1) expression in organs and lymph nodes using 18F-BMS-986192 positron emission tomography (PET)-imaging and looked for correlations with response and immune-related adverse events. METHODS: Four 18F-BMS-986192 PET studies in patients with melanoma, lung, pancreatic and oral cancer, receiving ICI treatment, were combined. Imaging data (organ standardized uptake value (SUV)mean, lymph node SUVmax) and clinical data (response to treatment and incidence of immune-related adverse events) were extracted. RESULTS: Baseline PD-L1 uptake in the spleen was on average higher in non-responding patients than in responders (spleen SUVmean 16.1±4.4 vs 12.5±3.4, p=0.02). This effect was strongest in lung cancer, and not observed in oral cancer. In the oral cancer cohort, benign tumor-draining lymph nodes (TDLNs) had higher PD-L1 uptake (SUVmax 3.3 IQR 2.5-3.9) compared with non-TDLNs (SUVmax 1.8, IQR 1.4-2.8 p=0.04). Furthermore, in the same cohort non-responders showed an increase in PD-L1 uptake in benign TDLNs on-treatment with ICIs (+15%), while for responders the PD-L1 uptake decreased (-11%). PD-L1 uptake did not predict immune-related adverse events, though elevated thyroid uptake on-treatment correlated with pre-existing thyroid disease or toxicity. CONCLUSION: PD-L1 PET uptake in the spleen is a potential negative predictor of response to ICIs. On-treatment with ICIs, PD-L1 uptake in benign TDLNs increases in non-responders, while it decreases in responders, potentially indicating a mechanism for resistance to ICIs in patients with oral cancer.
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Antígeno B7-H1 , Linfonodos , Tomografia por Emissão de Pósitrons , Humanos , Antígeno B7-H1/metabolismo , Linfonodos/metabolismo , Linfonodos/patologia , Linfonodos/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Masculino , Feminino , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/diagnóstico por imagem , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Pessoa de Meia-Idade , IdosoRESUMO
PURPOSE: Long axial field-of-view (LAFOV) PET/CT systems enable PET/CT scans with reduced injected activities because of improved sensitivity. With this study, we aimed to examine the foetal radiation dose from an 18F-FDG PET/CT scan on a LAFOV PET/CT system with reduced injected activity. METHODS: Two pregnant women were retrospectively included and received an 18F-FDG PET/CT scan on a LAFOV PET/CT system with an intravenous bolus injection of 0.30 MBq/kg. Foetal radiation exposure from the PET was estimated using dose conversion factors from three published papers. Radiation exposure from the CT scans was estimated using CT-Expo. RESULTS: Foetal radiation dose from the PET scan ranged between 0.11 and 0.44 mGy. Foetal radiation exposure from the CT scan ranged between < 0.10 - 0.90 mGy depending if the foetus was included in the field-of-view. CONCLUSION: Foetal radiation dose could be reduced to < 1.5 mGy when scanning pregnant patients on a LAFOV PET/CT system. The radiation dose to the foetus was reduced significantly in our study due to the increased sensitivity of the LAFOV PET/CT system.
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BACKGROUND: PET scans using zirconium-89 labelled monoclonal antibodies (89Zr-mAbs), known as 89Zr-immuno-PET, are made to measure uptake in tumour and organ tissue. Uptake is related to the supply of 89Zr-mAbs in the blood. Measuring activity concentrations in blood, however, requires invasive blood sampling. This study aims to identify the best delineation strategy to obtain the image-derived blood concentration (IDBC) from 89Zr-immuno-PET scans. METHODS: PET imaging and blood sampling of two 89Zr-mAbs were included, 89Zr-cetuximab and 89Zr-durvalumab. For seven patients receiving 89Zr-cetuximab, PET scans on 1-2 h, 2 and 6 days post-injection (p.i.) were analysed. Five patients received three injections of 89Zr-durvalumab. The scanning protocol for the first two injections consisted of PET scanning on 2, 5 and 7 days p.i. and for the third injection only on 7 days p.i. Blood samples were drawn with every PET scan and the sample-derived blood concentration (SDBC) was used as gold standard for the IDBC. According to an in-house developed standard operating procedure, the aortic arch, ascending aorta, descending aorta and left ventricle were delineated. Bland-Altman analyses were performed to assess the bias (mean difference) and variability (1.96 times the standard deviation of the differences) between IDBC and SDBC. RESULTS: Overall, the activity concentration obtained from the IDBC was lower than from the SDBC. When comparing IDBC with SDBC, variability was smallest for the ascending aorta (20.3% and 17.0% for 89Zr-cetuximab and 89Zr-durvalumab, respectively). Variability for the other regions ranged between 17.9 and 30.8%. Bias for the ascending aorta was - 10.9% and - 11.4% for 89Zr-cetuximab and 89Zr-durvalumab, respectively. CONCLUSIONS: Image-derived blood concentrations should be obtained from delineating the ascending aorta in 89Zr-immuno-PET scans, as this results in the lowest variability with respect to sample-derived blood concentrations.
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BACKGROUND: Distribution of mAbs into tumour tissue may occur via different processes contributing differently to the 89Zr-mAb uptake on PET. Target-specific binding in tumours is of main interest; however, non-specific irreversible uptake may also be present, which influences quantification. The aim was to investigate the presence of non-specific irreversible uptake in tumour tissue using Patlak linearization on 89Zr-immuno-PET data of biopsy-proven target-negative tumours. Data of two studies, including target status obtained from biopsies, were retrospectively analysed, and Patlak linearization provided the net rate of irreversible uptake (Ki). RESULTS: Two tumours were classified as CD20-negative and two as CD20-positive. Four tumours were classified as CEA-negative and nine as CEA-positive. Ki values of CD20-negative (0.43 µL/g/h and 0.92 µL/g/h) and CEA-negative tumours (mdn = 1.97 µL/g/h, interquartile range (IQR) = 1.50-2.39) were higher than zero. Median Ki values of target-negative tumours were lower than CD20-positive (1.87 µL/g/h and 1.90 µL/g/h) and CEA-positive tumours (mdn = 2.77 µL/g/h, IQR = 2.11-3.65). CONCLUSION: Biopsy-proven target-negative tumours showed irreversible uptake of 89Zr-mAbs measured in vivo using 89Zr-immuno-PET data, which suggests the presence of non-specific irreversible uptake in tumours. Consequently, for 89Zr-immuno-PET, even if the target is absent, a tumour-to-plasma ratio always increases over time.
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BACKGROUND: In patients with locally advanced unresectable non-small cell lung cancer (NSCLC), durvalumab, an anti-programmed cell death ligand-1 (PD-L1) antibody, has shown improved overall survival when used as consolidation therapy following concurrent chemoradiotherapy (CRT). However, it is unclear whether CRT itself upregulates PD-L1 expression. Therefore, this study aimed to explore the changes in the uptake of the anti PD-L1 antibody [89Zr]Zr-durvalumab in tumors and healthy organs during CRT in patients with NSCLC. METHODS: Patients with NSCLC scheduled to undergo CRT were scanned 7±1 days after administration of 37±1 MBq [89Zr]Zr-durvalumab at baseline, 1-week on-treatment and 1 week after finishing 6 weeks of CRT. First, [89Zr]Zr-durvalumab uptake was visually assessed in a low dose cohort with a mass dose of 2 mg durvalumab (0.13% of therapeutic dose) and subsequently, quantification was done in a high dose cohort with a mass dose of 22.5 mg durvalumab (1.5% of therapeutic dose). Tracer pharmacokinetics between injections were compared using venous blood samples drawn in the 22.5 mg cohort. Visual assessment included suspected lesion detectability. Positron emission tomography (PET) uptake in tumoral and healthy tissues was quantified using tumor to plasma ratio (TPR) and organ to plasma ratio, respectively. RESULTS: In the 2 mg dose cohort, 88% of the 17 identified tumor lesions were positive at baseline, compared with 69% (9/13) for the 22.5 mg cohort. Although the absolute plasma concentrations between patients varied, the intrapatient variability was low. The ten quantitatively assessed lesions in the 22.5 mg cohort had a median TPR at baseline of 1.3 (IQR 0.7-1.5), on-treatment of 1.0 (IQR 0.7-1.4) and at the end of treatment of 0.7 (IQR 0.6-0.7). On-treatment, an increased uptake in bone marrow was seen in three out of five patients together with a decreased uptake in the spleen in four out of five patients. CONCLUSIONS: This study successfully imaged patients with NSCLC with [89Zr]Zr-durvalumab PET before and during CRT. Our data did not show any increase in [89Zr]Zr-durvalumab uptake in the tumor 1-week on-treatment and at the end of treatment. The changes observed in bone marrow and spleen may be due to an CRT-induced effect on immune cells. TRIAL REGISTRATION NUMBER: EudraCT number: 2019-004284-51.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Antígeno B7-H1/metabolismo , Tomografia por Emissão de Pósitrons/métodos , QuimiorradioterapiaRESUMO
PURPOSE: Standardised uptake values (SUV) are commonly used to quantify 18F-FDG lesion uptake. However, SUVs may suffer from several uncertainties and errors. Long-axial field-of-view (LAFOV) PET/CT systems might enable image-based quality control (QC) by deriving 18F-FDG activity and weight from total body (TB) 18F-FDG PET images. In this study, we aimed to develop these image-based QC to reduce errors and mitigate SUV uncertainties. METHODS: Twenty-five out of 81 patient scans from a LAFOV PET/CT system were used to determine regression fits for deriving of image-derived activity and weight. Thereafter, the regression fits were applied to 56 independent 18F-FDG PET scans from the same scanner to determine if injected activity and weight could be obtained accurately from TB and half-body (HB) scans. Additionally, we studied the impact of image-based values on the precision of liver SUVmean and lesion SUVpeak. Finally, 20 scans were acquired from a short-axial field-of-view (SAFOV) PET/CT system to determine if the regression fits also applied to HB scans from a SAFOV system. RESULTS: Both TB and HB 18F-FDG activity and weight significantly predicted reported injected activity (r = 0.999; r = 0.984) and weight (r = 0.999; r = 0.987), respectively. After applying the regression fits, 18F-FDG activity and weight were accurately derived within 4.8% and 3.2% from TB scans and within 4.9% and 3.1% from HB, respectively. Image-derived values also mitigated liver and lesion SUV variability compared with reported values. Moreover, 18F-FDG activity and weight obtained from a SAFOV scanner were derived within 6.7% and 4.5%, respectively. CONCLUSION: 18F-FDG activity and weight can be derived accurately from TB and HB scans, and image-derived values improved SUV precision and corrected for lesion SUV errors. Therefore, image-derived values should be included as QC to generate a more reliable and reproducible quantitative uptake measurement.
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Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos , Tomografia por Emissão de Pósitrons/métodos , Imagem Corporal TotalRESUMO
INTRODUCTION: 89Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([89Zr]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune system. The measured uptake consists of target-specific and non-specific components, and it can be influenced by plasma availability of the tracer. To find evidence for target-specific uptake, i.e., target engagement, we studied five immune-checkpoint-targeting [89Zr]Zr-mAbs to (1) compare the uptake with previously reported baseline values for non-specific organ uptake (ns-baseline) and (2) look for saturation effects of increasing mass doses. METHOD: 89Zr-immuno-PET data from five [89Zr]Zr-mAbs, i.e., nivolumab and pembrolizumab (anti-PD-1), durvalumab (anti-PD-L1), BI 754,111 (anti-LAG-3), and ipilimumab (anti-CTLA-4), were analysed. For each mAb, 2-3 different mass doses were evaluated. PET scans and blood samples from at least two time points 24 h post injection were available. In 35 patients, brain, kidneys, liver, spleen, lungs, and bone marrow were delineated. Patlak analysis was used to account for differences in plasma activity concentration and to quantify irreversible uptake (Ki). To identify target engagement, Ki values were compared to ns-baseline Ki values previously reported, and the effect of increasing mass doses on Ki was investigated. RESULTS: All mAbs, except ipilimumab, showed Ki values in spleen above the ns-baseline for the lowest administered mass dose, in addition to decreasing Ki values with higher mass doses, both indicative of target engagement. For bone marrow, no ns-baseline was established previously, but a similar pattern was observed. For kidneys, most mAbs showed Ki values within the ns-baseline for both low and high mass doses. However, with high mass doses, some saturation effects were seen, suggestive of a lower ns-baseline value. Ki values were near zero in brain tissue for all mass doses of all mAbs. CONCLUSION: Using Patlak analysis and the established ns-baseline values, evidence for target engagement in (lymphoid) organs for several immune checkpoint inhibitors could be demonstrated. A decrease in the Ki values with increasing mass doses supports the applicability of Patlak analysis for the assessment of target engagement for PET ligands with irreversible uptake behavior.
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BACKGROUND: Convolutional neural networks (CNNs), applied to baseline [18F]-FDG PET/CT maximum intensity projections (MIPs), show potential for treatment outcome prediction in diffuse large B-cell lymphoma (DLBCL). The aim of this study is to investigate the robustness of CNN predictions to different image reconstruction protocols. Baseline [18F]FDG PET/CT scans were collected from 20 DLBCL patients. EARL1, EARL2 and high-resolution (HR) protocols were applied per scan, generating three images with different image qualities. Image-based transformation was applied by blurring EARL2 and HR images to generate EARL1 compliant images using a Gaussian filter of 5 and 7 mm, respectively. MIPs were generated for each of the reconstructions, before and after image transformation. An in-house developed CNN predicted the probability of tumor progression within 2 years for each MIP. The difference in probabilities per patient was then calculated between both EARL2 and HR with respect to EARL1 (delta probabilities or ΔP). We compared these to the probabilities obtained after aligning the data with ComBat using the difference in median and interquartile range (IQR). RESULTS: CNN probabilities were found to be sensitive to different reconstruction protocols (EARL2 ΔP: median = 0.09, interquartile range (IQR) = [0.06, 0.10] and HR ΔP: median = 0.1, IQR = [0.08, 0.16]). Moreover, higher resolution images (EARL2 and HR) led to higher probability values. After image-based and ComBat transformation, an improved agreement of CNN probabilities among reconstructions was found for all patients. This agreement was slightly better after image-based transformation (transformed EARL2 ΔP: median = 0.022, IQR = [0.01, 0.02] and transformed HR ΔP: median = 0.029, IQR = [0.01, 0.03]). CONCLUSION: Our CNN-based outcome predictions are affected by the applied reconstruction protocols, yet in a predictable manner. Image-based harmonization is a suitable approach to harmonize CNN predictions across image reconstruction protocols.
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Investigating prognostic factors in patients with relapsed or primary refractory classical Hodgkin lymphoma (R/R cHL) is essential to optimize risk-adapted treatment strategies. We built a prognostic model using baseline quantitative 18F-fluorodeoxyglucose positron emission tomography (PET) radiomics features and clinical characteristics to predict the progression-free survival (PFS) among patients with R/R cHL treated with salvage chemotherapy followed by autologous stem cell transplantation. Metabolic tumor volume and several novel radiomics dissemination features, representing interlesional differences in distance, volume, and standard uptake value, were extracted from the baseline PET. Machine learning using backward selection and logistic regression were applied to develop and train the model on a total of 113 patients from 2 clinical trials. The model was validated on an independent external cohort of 69 patients. In addition, we validated 4 different PET segmentation methods to calculate radiomics features. We identified a subset of patients at high risk for progression with significant inferior 3-year PFS outcomes of 38.1% vs 88.4% for patients in the low-risk group in the training cohort (P < .001) and 38.5% vs 75.0% in the validation cohort (P = .015), respectively. The overall survival was also significantly better in the low-risk group (P = .022 and P < .001). We provide a formula to calculate a risk score for individual patients based on the model. In conclusion, we developed a prognostic model for PFS combining radiomics and clinical features in a large cohort of patients with R/R cHL. This model calculates a PET-based risk profile and can be applied to develop risk-stratified treatment strategies for patients with R/R cHL. These trials were registered at www.clinicaltrials.gov as #NCT02280993, #NCT00255723, and #NCT01508312.
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Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluordesoxiglucose F18 , Doença de Hodgkin/terapia , Doença de Hodgkin/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Intervalo Livre de Progressão , Transplante Autólogo , Ensaios Clínicos como AssuntoRESUMO
Convolutional neural networks (CNNs) may improve response prediction in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to investigate the feasibility of a CNN using maximum intensity projection (MIP) images from 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) baseline scans to predict the probability of time-to-progression (TTP) within 2 years and compare it with the International Prognostic Index (IPI), i.e. a clinically used score. 296 DLBCL 18F-FDG PET/CT baseline scans collected from a prospective clinical trial (HOVON-84) were analysed. Cross-validation was performed using coronal and sagittal MIPs. An external dataset (340 DLBCL patients) was used to validate the model. Association between the probabilities, metabolic tumour volume and Dmaxbulk was assessed. Probabilities for PET scans with synthetically removed tumors were also assessed. The CNN provided a 2-year TTP prediction with an area under the curve (AUC) of 0.74, outperforming the IPI-based model (AUC = 0.68). Furthermore, high probabilities (> 0.6) of the original MIPs were considerably decreased after removing the tumours (< 0.4, generally). These findings suggest that MIP-based CNNs are able to predict treatment outcome in DLBCL.
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Fluordesoxiglucose F18 , Linfoma Difuso de Grandes Células B , Humanos , Inteligência Artificial , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ensaios Clínicos como AssuntoRESUMO
Rational: Deep learning (DL) has demonstrated a remarkable performance in diagnostic imaging for various diseases and modalities and therefore has a high potential to be used as a clinical tool. However, current practice shows low deployment of these algorithms in clinical practice, because DL algorithms lack transparency and trust due to their underlying black-box mechanism. For successful employment, explainable artificial intelligence (XAI) could be introduced to close the gap between the medical professionals and the DL algorithms. In this literature review, XAI methods available for magnetic resonance (MR), computed tomography (CT), and positron emission tomography (PET) imaging are discussed and future suggestions are made. Methods: PubMed, Embase.com and Clarivate Analytics/Web of Science Core Collection were screened. Articles were considered eligible for inclusion if XAI was used (and well described) to describe the behavior of a DL model used in MR, CT and PET imaging. Results: A total of 75 articles were included of which 54 and 17 articles described post and ad hoc XAI methods, respectively, and 4 articles described both XAI methods. Major variations in performance is seen between the methods. Overall, post hoc XAI lacks the ability to provide class-discriminative and target-specific explanation. Ad hoc XAI seems to tackle this because of its intrinsic ability to explain. However, quality control of the XAI methods is rarely applied and therefore systematic comparison between the methods is difficult. Conclusion: There is currently no clear consensus on how XAI should be deployed in order to close the gap between medical professionals and DL algorithms for clinical implementation. We advocate for systematic technical and clinical quality assessment of XAI methods. Also, to ensure end-to-end unbiased and safe integration of XAI in clinical workflow, (anatomical) data minimization and quality control methods should be included.
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PURPOSE: Although lymphocyte activation gene-3 (LAG-3) directed therapies demonstrate promising clinical anti-cancer activity, only a subset of patients seems to benefit and predictive biomarkers are lacking. Here, we explored the potential use of the anti-LAG-3 antibody tracer [89Zr]Zr-BI 754111 as a predictive imaging biomarker and investigated its target specific uptake as well as the correlation of its tumor uptake and the tumor immune infiltration. METHODS: Patients with head and neck (N = 2) or lung cancer (N = 4) were included in an imaging substudy of a phase 1 trial with BI 754091 (anti-PD-1) and BI 754111 (anti-LAG-3). After baseline tumor biopsy and [18F]FDG-PET, patients were given 240 mg of BI 754091, followed 8 days later by administration of [89Zr]Zr-BI 754111 (37 MBq, 4 mg). PET scans were performed 2 h, 96 h, and 144 h post-injection. To investigate target specificity, a second tracer administration was given two weeks later, this time with pre-administration of 40 (N = 3) or 600 mg (N = 3) unlabeled BI 754111, followed by PET scans at 96 h and 144 h post-injection. Tumor immune cell infiltration was assessed by immunohistochemistry and RNA sequencing. RESULTS: Tracer uptake in tumors was clearly visible at the 4-mg mass dose (tumor-to-plasma ratio 1.63 [IQR 0.37-2.89]) and could be saturated by increasing mass doses (44 mg: 0.67 [IQR 0.50-0.85]; 604 mg: 0.56 [IQR 0.42-0.75]), demonstrating target specificity. Tumor uptake correlated to immune cell-derived RNA signatures. CONCLUSIONS: [89Zr]Zr-BI-754111 PET imaging shows favorable technical and biological characteristics for developing a potential predictive imaging biomarker for LAG-3-directed therapies. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03780725. Registered 19 December 2018.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Humanos , Radioisótopos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Tomografia por Emissão de Pósitrons/métodos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Zircônio , Linhagem Celular TumoralRESUMO
Current diagnostic criteria for myelofibrosis are largely based on bone marrow (BM) biopsy results. However, these have several limitations, including sampling errors. Explorative studies have indicated that imaging might form an alternative for the evaluation of disease activity, but the heterogeneity in BM abnormalities complicates the choice for the optimal technique. In our prospective diagnostic pilot study, we aimed to visualize all BM abnormalities in myelofibrosis before and during ruxolitinib treatment using both PET/CT and MRI. A random sample of patients was scheduled for examinations at baseline and after 6 and 18 months of treatment, including clinical and laboratory examinations, BM biopsies, MRI (T1-weighted, Dixon, dynamic contrast-enhanced (DCE)) and PET/CT ([15O]water, [18F]NaF)). At baseline, all patients showed low BM fat content (indicated by T1-weighted MRI and Dixon), increased BM blood flow (as measured by [15O]water PET/CT), and increased osteoblastic activity (reflected by increased skeletal [18F]NaF uptake). One patient died after the baseline evaluation. In the others, BM fat content increased to various degrees during treatment. Normalization of BM blood flow (as reflected by [15O]water PET/CT and DCE-MRI) occurred in one patient, who also showed the fastest clinical response. Vertebral [18F]NaF uptake remained stable in all patients. In evaluable cases, histopathological parameters were not accurately reflected by imaging results. A case of sampling error was suspected. We conclude that imaging results can provide information on functional processes and disease distribution throughout the BM. Differences in early treatment responses were especially reflected by T1-weighted MRI. Limitations in the gold standard hampered the evaluation of diagnostic accuracy.
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Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Mielofibrose Primária , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Medula Óssea/diagnóstico por imagem , Medula Óssea/patologia , Projetos Piloto , Mielofibrose Primária/diagnóstico por imagem , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/patologia , Estudos Prospectivos , Fluordesoxiglucose F18 , Imageamento por Ressonância Magnética/métodosAssuntos
Espondiloartrite Axial , Sacroileíte , Espondilartrite , Humanos , Articulação Sacroilíaca/diagnóstico por imagem , Articulação Sacroilíaca/patologia , Coluna Vertebral , Espondilartrite/diagnóstico por imagem , Espondilartrite/tratamento farmacológico , Espondilartrite/patologia , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons , Necrose , Sacroileíte/diagnóstico por imagem , Sacroileíte/tratamento farmacológico , Sacroileíte/patologiaRESUMO
PURPOSE: To relate [18F]fluoride uptake on PET with abnormalities on magnetic resonance imaging (MRI) and conventional radiography (CR) in ankylosing spondylitis (AS) patients. METHODS: Ten clinically active AS patients (female 6/10, age 38 ± 11 years) were included, and both spine and SI-joints were examined. PET scans were dichotomously scored for enhanced [18F]fluoride uptake, MRI scans were scored for fatty lesions, erosions, ankylosis, and bone marrow edema (BME), and CR was scored for erosions, syndesmophytes, and ankylosis. The overlap of lesions across all modalities was evaluated through univariate and multivariate analyses using a generalized mixed model. RESULTS: In the spine, 69 lesions with enhanced [18F]fluoride uptake, 257 MRI lesions, and 88 CR lesions were observed. PET lesions were mostly located in costovertebral and facet joints, outside the field of view (FOV) of the MRI and CR. However, PET lesions inside the FOV of MRI and CR partially showed no abnormality on MRI and CR. In lesions with abnormalities on multiple modalities, both univariate and multivariate analysis showed that PET activity had the strongest association with BME on MRI and ankylosis on CR. In the SI joints, 15 lesions (75%) with PET uptake were found, with 87% showing abnormalities on MRI and CR. CONCLUSION: [18F]fluoride PET lesions are often found outside the scope of MRI and CR, and even in the same location show only partial overlap with abnormalities on MRI (especially BME) and CR (especially ankylosis). This suggests that [18F]fluoride PET partially visualizes aspects of AS separate from MRI and CR, providing novel information. CLINICAL TRIAL REGISTRATION: NL43223.029.13 registered at 02-05-2013. https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=C1257BA2002CC066C1257B4E0049A65A.
Assuntos
Espondilite Anquilosante , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Fluoretos , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Radiografia , Espondilite Anquilosante/diagnóstico por imagem , Espondilite Anquilosante/patologia , MasculinoRESUMO
PURPOSE: Watchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with <2 International Metastatic RCC Database Consortium criteria and ≤2 metastatic sites [referred to as watch and wait ("W&W") criteria]. The IMaging PAtients for Cancer drug SelecTion-Renal Cell Carcinoma study objective was to assess the predictive value of [18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT for WW duration in patients with mccRCC. EXPERIMENTAL DESIGN: Between February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients. RESULTS: The median WW time was 16.1 months [95% confidence interval (CI): 9.0-31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4-14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9-3.3; P = 0.13). Patients with "W&W criteria" had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9-3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the "W&W criteria" improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53). CONCLUSIONS: In patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of the "W&W criteria" for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this.
Assuntos
Carcinoma de Células Renais , Humanos , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/terapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18/uso terapêutico , Radioisótopos/uso terapêutico , Zircônio , Conduta Expectante , Prognóstico , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
INTRODUCTION: Although visual and quantitative assessments of [18F]FDG PET/CT studies typically rely on liver uptake value as a reference or normalisation factor, consensus or consistency in measuring [18F]FDG uptake is lacking. Therefore, we evaluate the variation of several liver standardised uptake value (SUV) measurements in lymphoma [18F]FDG PET/CT studies using different uptake metrics. METHODS: PET/CT scans from 34 lymphoma patients were used to calculate SUVmaxliver, SUVpeakliver and SUVmeanliver as a function of (1) volume-of-interest (VOI) size, (2) location, (3) imaging time point and (4) as a function of total metabolic tumour volume (MTV). The impact of reconstruction protocol on liver uptake is studied on 15 baseline lymphoma patient scans. The effect of noise on liver SUV was assessed using full and 25% count images of 15 lymphoma scans. RESULTS: Generally, SUVmaxliver and SUVpeakliver were 38% and 16% higher compared to SUVmeanliver. SUVmaxliver and SUVpeakliver increased up to 31% and 15% with VOI size while SUVmeanliver remained unchanged with the lowest variability for the largest VOI size. Liver uptake metrics were not affected by VOI location. Compared to baseline, liver uptake metrics were 15-18% and 9-18% higher at interim and EoT PET, respectively. SUVliver decreased with larger total MTVs. SUVmaxliver and SUVpeakliver were affected by reconstruction protocol up to 62%. SUVmax and SUVpeak moved 22% and 11% upward between full and 25% count images. CONCLUSION: SUVmeanliver was most robust against VOI size, location, reconstruction protocol and image noise level, and is thus the most reproducible metric for liver uptake. The commonly recommended 3 cm diameter spherical VOI-based SUVmeanliver values were only slightly more variable than those seen with larger VOI sizes and are sufficient for SUVmeanliver measurements in future studies. TRIAL REGISTRATION: EudraCT: 2006-005,174-42, 01-08-2008.