Relevance of 18F-DOPA visual and semi-quantitative PET metrics for the diagnostic of Parkinson disease in clinical practice: a machine learning-based inference study.

PURPOSE: To decipher the relevance of visual and semi-quantitative 6-fluoro-(18F)-L-DOPA (18F-DOPA) interpretation methods for the diagnostic of idiopathic Parkinson disease (IPD) in hybrid positron emission tomography (PET) and magnetic resonance imaging. MATERIAL AND METHODS: A total of 110 consecutive patients (48 IPD and 62 controls) with 11 months of median clinical follow-up (reference standard) were included. A composite visual assessment from five independent nuclear imaging readers, together with striatal standard uptake value (SUV) to occipital SUV ratio, striatal gradients and putamen asymmetry-based semi-quantitative PET metrics automatically extracted used to train machine learning models to classify IPD versus controls. Using a ratio of 70/30 for training and testing sets, respectively, five classification models-k-NN, LogRegression, support vector machine, random forest and gradient boosting-were trained by using 100 times repeated nested cross-validation procedures. From the best model on average, the contribution of PET parameters was deciphered using the Shapley additive explanations method (SHAP). Cross-validated receiver operating characteristic curves (cv-ROC) of the most contributive PET parameters were finally estimated and compared. RESULTS: The best machine learning model (k-NN) provided final cv-ROC of 0.81. According to SHAP analyses, visual PET metric was the most important contributor to the model overall performance, followed by the minimum between left and right striatal to occipital SUV ratio. The 10-time cv-ROC curves of visual, min SUVr or both showed quite similar performance (mean area under the ROC of 0.81, 0.81 and 0.79, respectively, for visual, min SUVr or both). CONCLUSION: Visual expert analysis remains the most relevant parameter to predict IPD diagnosis at 11 months of median clinical follow-up in 18F-FDOPA. The min SUV ratio appears interesting in the perspective of simple semi-automated diagnostic workflows.

Head-to-Head Comparison Between Rabbit Sign and EANM/SNMMI Criteria for the 18F-DOPA Visual Assessment of Parkinsonian Syndromes in PET/MRI: A Multiple Expert-Based and Blinded Controlled Study.

PURPOSE: The aim of this study was to compare the diagnostic performance of the rabbit visual pattern versus the one endorsed by the EANM/SNMMI for the diagnosis of parkinsonian syndromes in PET/MRI. PATIENTS AND METHODS: The 18F-DOPA PET images of 129 consecutive patients (65 Park+ and 64 controls) with 1 year of clinical follow-up were reviewed independently by 5 experienced readers on the same imaging workstation, blinded to the final clinical diagnosis. Two visual methods were assessed independently, with several days to months of interval: the criteria endorsed by EANM/SNMMI and the "rabbit" shape of the striate assessed on 3D MIP images. The sensitivities, specificities, likelihood ratios, and predictive values of the 2 diagnostic tests were estimated simultaneously by using the "comparison of 2 binary diagnostic tests to a paired design" method. RESULTS: The estimated 95% confidence interval (CI) of sensitivities and specificities ranged from 49.4% to 76.5% and from 83.2% to 97.7%, respectively. The 95% CI estimates of positive and negative likelihood ratios ranged from 3.8 to 26.7 and from 0.26 to 0.56, respectively. The 95% CI estimates of the positive and negative predictive values ranged from 78.1% to 96.7% and from 60.3% to 81.4%, respectively. For all the parameters, no statistical difference was observed between the 2 methods (P > 0.05). The rabbit sign reduced the readers' discrepancies by 25%, while maintaining the same performance. CONCLUSIONS: The rabbit visual pattern appears at least comparable to the current EANM/SNMMI reference procedure for the assessment of parkinsonian syndromes in daily clinical practice, without the need of any image postprocessing. Further multicenter prospective studies would be of relevance to validate these findings.

PET Molecular Imaging: A Holistic Review of Current Practice and Emerging Perspectives for Diagnosis, Therapeutic Evaluation and Prognosis in Clinical Oncology.

PET/CT molecular imaging has been imposed in clinical oncological practice over the past 20 years, driven by its two well-grounded foundations: quantification and radiolabeled molecular probe vectorization. From basic visual interpretation to more sophisticated full kinetic modeling, PET technology provides a unique opportunity to characterize various biological processes with different levels of analysis. In clinical practice, many efforts have been made during the last two decades to standardize image analyses at the international level, but advanced metrics are still under use in practice. In parallel, the integration of PET imaging with radionuclide therapy, also known as radiolabeled theranostics, has paved the way towards highly sensitive radionuclide-based precision medicine, with major breakthroughs emerging in neuroendocrine tumors and prostate cancer. PET imaging of tumor immunity and beyond is also emerging, emphasizing the unique capabilities of PET molecular imaging to constantly adapt to emerging oncological challenges. However, these new horizons face the growing complexity of multidimensional data. In the era of precision medicine, statistical and computer sciences are currently revolutionizing image-based decision making, paving the way for more holistic cancer molecular imaging analyses at the whole-body level.

FDG-PET biomarkers associated with long-term benefit from first-line immunotherapy in patients with advanced non-small cell lung cancer.

OBJECTIVE: To determine FDG-PET biomarkers associated with long-term benefit (LTB) and survival in advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy. METHODS: In this multicenter study, we retrospectively analyzed advanced NSCLC patients with a PD-L1 tumor proportion score (TPS) ≥ 50%, who underwent FDG-PET/CT before first-line pembrolizumab, received from August 2017 to September 2019. Parameters extracted were SUVmax, SUVmean, TMTV (total metabolic tumor volume) and TLG (total lesion glycolysis). LTB was defined as objective (complete or partial) response or stable disease as best overall response, maintained for ≥ 12 months. A multivariate prediction model was developed using logistic regression for LTB and Cox models for progression-free survival (PFS) and overall survival (OS). RESULTS: On the 63 eligible patients, with a median follow-up of 13.4 (range, 1.5-29.1) months, 17 (27%) had LTB. Median PFS and OS were 7.7 months (95%CI 5.0-10.5) and 12.1 months (95%CI 8.6-15.6). In multivariate analyses, high TMTV (> 84cm3) and high tumor SUVmean (> 10.1) remained independent factors for predicting LTB (OR 0.2; p = 0.03 and OR 3.7; p = 0.04) and PFS (HR 2.2; p = 0.02 and HR 0.5; p = 0.045). High TMTV was significantly associated with poor OS (HR 3.1; p = 0.03). No association was observed between tumor SUVmax or TLG and clinical outcomes. CONCLUSIONS: In patients with advanced NSCLC and PD-L1 TPS ≥ 50%, baseline low TMTV and high tumor SUVmean correlate with survival and LTB from upfront pembrolizumab. Beyond the initial staging, FDG-PET/CT scan could provide relevant biomarkers associated with clinical outcomes that should be taken into account when considering first-line treatment options.

Association of the Metabolic Score Using Baseline FDG-PET/CT and dNLR with Immunotherapy Outcomes in Advanced NSCLC Patients Treated with First-Line Pembrolizumab.

Background: We aimed to assess the clinical utility of a previously published score combining the total metabolic tumor volume (TMTV) on baseline FDG-PET/CT and pretreatment derived from the neutrophils to lymphocytes ratio (dNLR) for prognostication in NSCLC patients undergoing first-line immunotherapy (IT). Methods: In this multicenter retrospective study, 63 advanced NSCLC patients with a PD-L1 tumor proportion score (TPS) ≥50%, who underwent FDG-PET/CT before first-line IT, treated from January 2017 to September 2019, were enrolled. Associations between this score and the progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and overall response rate (ORR) were evaluated. Results: The median (m) PFS and mOS were 7.7 (95% CI 4.9-10.6) and 12.1 (8.6-15.6) months, respectively, and DCR and ORR were 65% and 58%, respectively. mOS was 17.9 months (14.6 not reached) for the good group versus 13.8 (95%CI 8.4-18.9) and 6.6 (CI 2.0-11.2) months for the intermediate and poor groups, respectively. mPFS was 15.1 (95%CI 12.1-20.0) months for the good group versus 5.2 (1.9-8.5) and 1.9 (95%CI 1.3-2.5) months for the intermediate and poor groups, respectively. The poor prognosis group was associated with DCR and ORR (p < 0.05). Conclusions: The metabolic score combining TMTV on the baseline FDG-PET/CT scan and pretreatment dNLR was associated with the survival and response in a cohort of advanced NSCLC patients with ≥50% PD-L1 receiving frontline IT.

Late onset of nivolumab-induced severe gastroduodenitis and cholangitis in a patient with stage IV melanoma.

Antiprogramed cell death-1 protein agents represent a therapeutic approach based on stimulating the host's immune response through blockade of immune checkpoints, inhibitory pathways that dampen the physiological peripheral T-cell immune response and are essential for maintaining self-tolerance. We describe the late onset of severe gastroduodenitis and cholangitis in a nivolumab-treated, metastatic melanoma patient in complete remission. Positron-emission tomography with computed tomography scans showed diffuse fluorodeoxyglucose (FDG) uptake in the stomach preceding upper digestive tract symptoms. Hence, positron-emission tomography with computed tomography might as well be a useful tool for early diagnosis of subclinical gastric toxicity as recently shown for colitis. Furthermore, physicians must be aware and remain vigilant to antiprogramed cell death-1 protein-related digestive toxicity that may appear very late during treatment.

Sub-cutaneous Fat Mass measured on multislice computed tomography of pretreatment PET/CT is a prognostic factor of stage IV non-small cell lung cancer treated by nivolumab.

Introduction: Our aim was to explore the prognostic value of anthropometric parameters in patients treated with nivolumab for stage IV non-small cell lung cancer (NSCLC). Methods: We retrospectively included 55 patients with NSCLC treated by nivolumab with a pretreatment 18FDG positron emission tomography coupled with computed tomography (PET/CT). Anthropometric parameters were measured on the CT of PET/CT by in-house software (Anthropometer3D) allowing an automatic multi-slice measurement of Lean Body Mass (LBM), Fat Body Mass (FBM), Muscle Body Mass (MBM), Visceral Fat Mass (VFM) and Sub-cutaneous Fat Mass (SCFM). Clinical and tumor parameters were also retrieved. Receiver operator characteristics (ROC) analysis was performed and overall survival at 1 year was studied using Kaplan-Meier and Cox analysis. Results: FBM and SCFM were highly correlated (ρ = 0.99). In ROC analysis, only FBM, SCFM, VFM, body mass index (BMI) and metabolic tumor volume (MTV) had an area under the curve (AUC) significantly higher than 0.5. In Kaplan-Meier analysis using medians as cut-offs, prognosis was worse for patients with low SCFM (<5.69 kg/m2; p = 0.04, survivors 41% vs 75%). In Cox univariate analysis using continuous values, BMI (HR = 0.84, p= 0.007), SCFM (HR = 0.75, p = 0.003) and FBM (HR = 0.80, p= 0.004) were significant prognostic factors. In multivariate analysis using clinical parameters (age, gender, WHO performance status, number prior regimens) and SCFM, only SCFM was significantly associated with poor survival (HR = 0.75, p = 0.006). Conclusions: SCFM is a significant prognosis factor of stage IV NSCLC treated by nivolumab.

Monitoring anti-PD-1-based immunotherapy in non-small cell lung cancer with FDG PET: introduction of iPERCIST.

BACKGROUND: Immunotherapy represents a new therapeutic approach in non-small cell lung carcinoma (NSCLC) with the potential for prolonged benefits. Because of the systemic nature and heterogeneity of tumoral diseases, as well as the immune restoration process induced by immunotherapy, the assessment of therapeutic efficacy is challenging, and the role of FDG PET is not well established. We evaluated the potential of FDG PET to monitor NSCLC patients treated with a checkpoint inhibitor. RESULTS: This was a retrospective analysis of 28 NSCLC patients treated with nivolumab, a programmed cell death 1 (PD-1) blocker. All patients underwent a PET scan before treatment (SCAN-1) and another scan 2 months later (SCAN-2). Disease progression was assessed by immune PET Response Criteria in Solid Tumors (iPERCIST), which was adapted from PERCIST; and the immune Response Evaluation Criteria in Solid Tumors (iRECIST). iPERCIST is a dual-time-point evaluation of "unconfirmed progressive metabolic disease" (UPMD) status at SCAN-2. UPMD at SCAN-2 was re-evaluated after 4 weeks with SCAN-3 to confirm PMD. Patients with complete/partial metabolic response (CMR or PMR) or stable metabolic disease (SMD) at SCAN-2 or -3 were considered responders. Patients with UPMD confirmed at SCAN-3 were considered non-responders. The Kaplan-Meier method was used to estimate survival. At SCAN-2, we found 9/28 cases of PMR, 4/28 cases of SMD, 2/28 cases of CMR, and 13/28 cases of UPMD. Four of the 13 UPMD patients were classified as responders at SCAN-3 (PMR n = 1, SMD n = 3). The remaining nine UPMD patients were classified as non-responders due to clinical degradation, and treatment was stopped. The median follow-up was 16.7 months [3.6-32.2]. Responders continued treatment for a mean of 10.7 months [3.8-26.3]. Overall survival was longer for responders than that for non-responders (19.9 vs. 3.6 months, log rank p = 0.0003). The 1-year survival rates were 94% for responders and 11% for non-responders. A comparison with iRECIST showed reclassification in 39% (11/28) of patients with relevant additional prognostic information. CONCLUSIONS: iPERCIST dual-time-point evaluation might be a powerful tool for evaluating anti-PD-1-based immunotherapy, with the ability to identify patients who can benefit most from treatment. The prognostic value of iPERCIST criteria should be confirmed in large prospective multicentric studies.