Comparison of three diagnostic strategies for suspicion of pulmonary embolism: planar ventilation-perfusion scan (V/Q), CT pulmonary angiography (CTPA) and single photon emission CT ventilation-perfusion scan (SPECT V/Q): a protocol of a randomised controlled trial.

INTRODUCTION: Pulmonary embolism (PE) is a challenge to diagnose and when missed, exposes patients to potentially fatal recurrent events. Beyond CT pulmonary angiography (CTPA) and planar ventilation/perfusion (V/Q) scan, single photon emission CT (SPECT) V/Q emerged a new diagnostic modality of scintigraphic acquisition that has been reported to improve diagnostic performances. To date, no management outcome study or randomised trial evaluated an algorithm based on SPECT V/Q for PE diagnosis. We present the design of a randomised multicentre, international management study comparing SPECT V/Q with validated strategies. MATERIAL AND METHODS: We will include a total of 3672 patients with suspected PE requiring chest imaging, randomised into three different groups, each using a different diagnostic strategy based on SPECT V/Q, CTPA and planar V/Q scan. Randomisation will be unbalanced (2:1:1), with twice as many patients in SPECT V/Q arm (n=1836) as in CTPA and planar V/Q arms (n=918 in each). Our primary objective will be to determine whether a diagnostic strategy based on SPECT V/Q is non-inferior to previously validated strategies in terms of diagnostic exclusion safety as assessed by the 3-month risk of thromboembolism in patients with a negative diagnostic workup. Secondary outcomes will be the proportion of patients diagnosed with PE in each arm, patients requiring additional tests, the incidence of major and clinically relevant non-major bleeding and the incidence and cause of death in each arm. ETHICS AND DISSEMINATION: This trial is funded by a grant from Brest University Hospital and by INVENT. The study protocol was approved by Biomedical Research Ethics Committee. The investigator or delegate will obtain signed informed consent from all patients prior to inclusion in the trial. Our results will inform future clinical practice guidelines and solve the current discrepancy between nuclear medicine guidelines and clinical scientific society guidelines. TRIAL REGISTRATION NUMBER: NCT02983760.

[18F]DCFPyL PET/CT versus [18F]fluoromethylcholine PET/CT in Biochemical Recurrence of Prostate Cancer (PYTHON): a prospective, open label, cross-over, comparative study.

PURPOSE: Primary objective was to compare the per-patient detection rates (DR) of [18F]DCFPyL versus [18F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT), in patients with first prostate cancer (PCa) biochemical recurrence (BCR). Secondary endpoints included safety and impact on patient management (PM). METHODS: This was a prospective, open label, cross-over, comparative study with randomized treatment administration of [18F]DCFPyL (investigational medicinal product) or [18F]fluoromethylcholine (comparator). Men with rising prostate-specific antigen (PSA) after initial curative therapy were enrolled. [18F]DCFPyL and [18F]fluoromethylcholine PET/CTs were performed within a maximum time interval of 12 days. DR was defined as the percentage of positive PET/CT scans identified by 3 central imaging readers. PM was assessed by comparing the proposed pre-PET/CT treatment with the local treatment", defined after considering both PET/CTs. RESULTS: A total of 205 patients with first BCR after radical prostatectomy (73%; median PSA = 0.46 ng/ml [CI 0.16;27.0]) or radiation therapy (27%; median PSA = 4.23 ng/ml [CI 1.4;98.6]) underwent [18F]DCFPyL- and/or [18F]fluoromethylcholine -PET/CTs, between July and December 2020, at 22 European sites. 201 patients completed the study. The per-patient DR was significantly higher for [18F]DCFPyL- compared to [18F]fluoromethylcholine -PET/CTs (58% (117/201 patients) vs. 40% (81/201 patients), p < 0.0001). DR increased with higher PSA values for both tracers (PSA ≤ 0.5 ng/ml: 26/74 (35%) vs. 22/74 (30%); PSA 0.5 to ≤ 1.0 ng/ml: 17/31 (55%) vs. 10/31 (32%); PSA 1.01 to < 2.0 ng/ml: 13/19 (68%) vs. 6/19 (32%);PSA > 2.0: 50/57 (88%) vs. 39/57 (68%) for [18F]DCFPyL- and [18F]fluoromethylcholine -PET/CT, respectively). [18F]DCFPyL PET/CT had an impact on PM in 44% (90/204) of patients versus 29% (58/202) for [18F]fluoromethylcholine. Overall, no drug-related nor serious adverse events were observed. CONCLUSIONS: The primary endpoint of this study was achieved, confirming a significantly higher detection rate for [18F]DCFPyL compared to [18F]fluoromethylcholine, in men with first BCR of PCa, across a wide PSA range. [18F]DCFPyL was safe and well tolerated.

Characterization of the First Animal Toxin Acting as an Antagonist on AT1 Receptor.

The renin-angiotensin system (RAS) is one of the main regulatory systems of cardiovascular homeostasis. It is mainly composed of angiotensin-converting enzyme (ACE) and angiotensin II receptors AT1 and AT2. ACE and AT1 are targets of choice for the treatment of hypertension, whereas the AT2 receptor is still not exploited due to the lack of knowledge of its physiological properties. Peptide toxins from venoms display multiple biological functions associated with varied chemical and structural properties. If Brazilian viper toxins have been described to inhibit ACE, no animal toxin is known to act on AT1/AT2 receptors. We screened a library of toxins on angiotensin II receptors with a radioligand competition binding assay. Functional characterization of the selected toxin was conducted by measuring second messenger production, G-protein activation and ß-arrestin 2 recruitment using bioluminescence resonance energy transfer (BRET) based biosensors. We identified one original toxin, A-CTX-cMila, which is a 7-residues cyclic peptide from Conus miliaris with no homology sequence with known angiotensin peptides nor identified toxins, displaying a 100-fold selectivity for AT1 over AT2. This toxin shows a competitive antagonism mode of action on AT1, blocking Gαq, Gαi3, GαoA, ß-arrestin 2 pathways and ERK1/2 activation. These results describe the first animal toxin active on angiotensin II receptors.

Residual pulmonary vascular obstruction and recurrence after acute pulmonary embolism: a systematic review and meta-analysis of individual participant data.

We aimed to assess the relationship between residual pulmonary vascular obstruction (RPVO) on planar lung scan after completion of at least 3 months of anticoagulant therapy for acute pulmonary embolism (PE) and the risk of recurrent venous thromboembolism (VTE) or death due to PE one year after treatment discontinuation. The systematic review was registered with the International Prospective Registry of Systematic Reviews (PROSPERO: CRD42017081080). The primary outcome measure was to generate a pooled estimate of the rate of recurrent VTE at one year in patient with RPVO diagnosed on planar lung scan after discontinuation of at least 3 months of anticoagulant treatment for an acute PE. Individual data were obtained for 809 patients. RPVO (ie, obstruction >0%) was found in 407 patients (50.3%) after a median of 6.6 months of anticoagulant therapy for a first acute PE. Recurrent VTE or death due to PE occurred in 114 patients (14.1%), for an annual risk of 6.4% (95% confidence interval, 4.7%-8.6%). Out of the 114 recurrent events, 63 occurred within one year after discontinuation of anticoagulant therapy corresponding to a risk of 8.1% (6.4%-9.8%) at 1 year. The risk of recurrent VTE at one year was 5.8% (4.4-7.2) in participants with RPVO <5%, vs 11.7% (9.5-13.8) in participants with RPVO ≥5%. RPVO is a significant predictor of the risk of recurrent venous thromboembolism. However, the risk of recurrent events remains too high in patients without residual perfusion defect for it to be used as a stand-alone test to decide on anticoagulation discontinuation.

PSMA-11 PET/CT for Detection of Recurrent Prostate Cancer in Patients With Negative Choline PET/CT.

INTRODUCTION: Prostate adenocarcinoma (CaP) is the leading cancer in men. After curative treatment, from 27% to 53% of patients will experience biochemical recurrence (BR). With the development of focal therapies, precise early identification of recurrence's sites is of utmost importance in order to deliver individualized treatment on positive lesions. The aim of this study was to assess the detection rate (DR) of 68Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT) in selected patients with prostate cancer BR and recent negative 18F-choline PET/CT. PATIENTS AND METHODS: We performed a retrospective analysis including all patients with CaP referred for BR with a negative 18F-choline PET/CT, and who underwent 68Ga-PSMA-11 PET/CT between October, 2018 and December, 2019. The overall DR of 68Ga-PSMA-11 PET/CT was calculated, and described according to BR characteristics especially PSA levels and velocity. Patients were followed up for at least 1 year. Patient management following 68Ga-PSMA-11 PET/CT and PSA levels evolution after treatment were also recorded. RESULTS: One hundred fifty-nine patients comprising 164 examinations were analyzed. The overall DR of 68Ga-PSMA-11 PET/CT for BR was 65.9% (95CI, 58.6-73.1). The DR was 52.5% (95CI, 39.9-65.0), 70.6% (95CI, 55.3-85.9), 70.4% (95CI, 53.1-87.6), and 78.6% (95CI, 66.2-91.0) for PSA levels between 0.2 and 0.49 ng/mL, 0.5 to 0.99 ng/mL, 1 to 1.99 ng/mL and PSA ≥ 2 ng/mL, respectively. The DR was 70.7% (95CI, 59.0-82.4) with a PSA doubling time (PSA-DT) ≤6 months and 65.2% (95CI, 55.5-74.9) with a PSA-DT >6 months. Around 3/4 of patients (75.9%) with a positive 68Ga-PSMA-11 PET/CT initiated treatment, including surgery (2.4%), stereotactic radiotherapy ± androgen deprivation therapy (ADT) (22%) or external conformational radiotherapy ± ADT (46.3%). Patient management changed in 43 cases (39.8%). CONCLUSION: Our study confirmed the ability of 68Ga-PSMA-11 PET/CT to detect occult biochemical recurrence, even in a selected population of CaP patients with negative 18F-choline PET/CT, even at low PSA levels.

Radiation exposure to nuclear medicine technologists performing a V/Q PET: Comparison with conventional V/Q scintigraphy, [18F]FDG PET and [68Ga]Ga DOTATOC PET procedures.

Introduction: Ventilation/Perfusion (V/Q) PET/CT is an emerging imaging modality for regional lung function evaluation. The same carrier molecules as conventional V/Q scintigraphy are used but they are radiolabelled with gallium-68 (68Ga) instead of technetium-99m (99mTc). A recurrent concern regarding V/Q PET imaging is the radiation dose to the healthcare workers. The aim of this study was to evaluate the total effective dose and the finger dose received by the technologist when performing a V/Q PET procedure, and to compare them with the radiations doses received with conventional V/Q scintigraphy, FDG PET and Ga DOTATOC PET procedures. Materials and methods: The whole body dose measurement was performed 10 times for each of the evaluated procedures using an electronic personal dosimeter (ED). For V/Q PET and V/Q scintigraphy procedures, ventilation and perfusion stages were separately evaluated. Internal exposure was measured for ventilation procedures. Finger dose measurements were performed 5 times for each of the PET procedures using Thermoluminescence (TL) pellets. Results: The technologist effective dose when performing a V/Q PET procedure was 2.83 ± 0.67 µSv, as compared with 1.16 ± 0.34 µSv for conventional V/Q scintigraphy, 2.13 ± 0.77 µSv for [68Ga]Ga-DOTATOC, and 2.86 ± 1.79 µSv for FDG PET procedures, respectively. The finger dose for the V/Q PET procedure was similar to the dose for a [68Ga]Ga-DOTATOC scan (0.35 mSv and 0.32 mSv, respectively). Conclusion: The technologist total effective dose for a V/Q PET procedure is ~2.4 higher than the dose for a conventional V/Q scintigraphy, but in the same range than the radiation exposure when performing common PET procedures, both in terms of total effective dose or finger dose. These results should be reassuring for the healthcare workers performing a V/Q PET procedure.

Quantification of the pulmonary vascular obstruction index on ventilation/perfusion lung scintigraphy: Comparison of a segmental visual scoring to the Meyer score.

Introduction: Quantifying the pulmonary vascular obstruction index (PVOI) is essential for the management of patients with pulmonary embolism or chronic thromboembolic pulmonary hypertension (CTEPH). The reference method for quantifying the PVOI with planar lung ventilation/perfusion (V/Q) scintigraphy is the Meyer score, which was validated using pulmonary angiography as a reference standard. However, it is complex to use in daily practice. In contrast, a rapid and fast quantification method consists in estimating the PVOI based on the number of segmental perfusion defects. However, the accuracy of this method has never been evaluated. In this study, we aimed to compare PVOI quantification on planar V/Q scintigraphy assessed by a segmental visual scoring (SVS) to the Meyer score. Materials and methods: The eligible study population consisted of consecutive patients who underwent planar V/Q scan for CTEPH screening. A central review was performed by three nuclear medicine physicians. PVOI was assessed by summing the number of segmental perfusion defects or equivalent (2 sub-segments = 1 segment = 5%) and by Meyer's method. The two interpretations were performed 6 months apart. A Spearman rank correlation coefficient was calculated to evaluate correlation between the two measurement methods. An intra-class correlation (ICC) was calculated to assess agreement. A Bland et Altman plot analysis was used to evaluate agreement between the two measurements. Results: A total of 226 V/Q scans were interpreted. Spearman rank correlation coefficient between SVS and Meyer was 0.963 (95%CI 0.952-0.971) for mismatched perfusion defects and 0.963 (95%CI 0.953-0.972) for perfusion defects regardless of ventilation. Intra-class correlation (ICC) for agreement was 0.978 (95%CI 0.972-0.983) for mismatched perfusion defects and 0.968 (95%CI 0.959-0.976) for perfusion defects regardless of ventilation. In Bland & Altmann analysis, the mean difference between the SVS method and the Meyer score was 0.42 and 0.61 for the mismatched or matched evaluation, respectively. Conclusion: Our study shows a high correlation, and low differences in PVOI quantification when using a segmental visual scoring (SVS) as compared to the Meyer score. The SVS has the great advantage to be easy and rapid to apply in daily practice.

18F-Fluorodeoxyglucose positron emission/computed tomography for occult cancer among patients with unprovoked venous thromboembolism: What do we know?

18F-Fluorodeoxyglucose Positron Emission/Computed Tomography (FDG PET/CT) is a non-invasive whole-body imaging modality that has the potential for replacing multiple cancer screening tests by one. Previous studies showed that FDG PET/CT has an excellent sensitivity and negative predictive value for occult cancer screening in patients with unprovoked venous thromboembolism (VTE). In this patient population, FDG PET/CT is a reproducible imaging procedure with a kappa value estimated at 0.75. Although false positive results may lead to unnecessary investigations, it seems from recent evidence that invasive procedures triggered by a positive scan often resulted in cancer diagnosis. Trials assessing use of FDG PET/CT for occult cancer screening in patients with VTE at high risk for occult cancer diagnosis are ongoing.

Frequency and predictors for chronic thromboembolic pulmonary hypertension after a first unprovoked pulmonary embolism: Results from PADIS studies.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication of a pulmonary embolism (PE) whose incidence and predictors are not precisely determined. OBJECTIVE: To determine the frequency and predictors for CTEPH after a first unprovoked PE. PATIENTS/METHODS: In a randomized trial comparing an additional 18-month warfarin versus placebo in patients after a first unprovoked PE initially treated with vitamin K antagonist for 6 months, we applied recommended CTEPH screening strategies through an 8-year follow-up to determine cumulative incidence of CTEPH. CTEPH predictors were estimated using Cox models. Pulmonary vascular obstruction (PVO) and systolic pulmonary arterial pressure (sPAP) at PE diagnosis and 6 months were studied by receiver operating curves analysis. All CTEPH cases and whether they were incident or prevalent were adjudicated. RESULTS: During a median follow-up of 8.7 years, nine CTEPH cases were diagnosed among 371 patients, with a cumulative incidence of 2.8% (95% confidence interval [CI] 0.95-4.64), and of 1.31% (95% CI 0.01-2.60) after exclusion of five cases adjudicated as prevalent. At PE diagnosis, PVO > 45% and sPAP > 56 mmHg were associated with CTEPH with a hazard ratio (HR) of 33.00 (95% CI 1.64-667.00, p = .02) and 12.50 (95% CI 2.10-74.80, p < .01), respectively. Age > 65 years, lupus anticoagulant antibodies and non-O blood groups were also predictive of CTEPH. PVO > 14% and sPAP > 34 mmHg at 6 months were associated with CTEPH (HR 63.90 [95% CI 3.11-1310.00, p < .01]and HR 17.2 [95% CI 2.75-108, p < .01]). CONCLUSION: After a first unprovoked PE, CTEPH cumulative incidence was 2.8% during an 8-year follow-up. PVO and sPAP at PE diagnosis and at 6 months were the main predictors for CTEPH diagnosis.

MT9, a natural peptide from black mamba venom antagonizes the muscarinic type 2 receptor and reverses the M2R-agonist-induced relaxation in rat and human arteries.

All five muscarinic receptors have important physiological roles. The endothelial M2 and M3 subtypes regulate arterial tone through direct coupling to Gq or Gi/o proteins. Yet, we lack selective pharmacological drugs to assess the respective contribution of muscarinic receptors to a given function. We used mamba snake venoms to identify a selective M2R ligand to investigate its contribution to arterial contractions. Using a bio-guided screening binding assay, we isolated MT9 from the black mamba venom, a three-finger toxin active on the M2R subtype. After sequencing and chemical synthesis of MT9, we characterized its structure by X-ray diffraction and determined its pharmacological characteristics by binding assays, functional tests, and ex vivo experiments on rat and human arteries. Although MT9 belongs to the three-finger fold toxins family, it is phylogenetically apart from the previously discovered muscarinic toxins, suggesting that two groups of peptides evolved independently and in a convergent way to target muscarinic receptors. The affinity of MT9 for the M2R is 100 times stronger than that for the four other muscarinic receptors. It also antagonizes the M2R/Gi pathways in cell-based assays. MT9 acts as a non-competitive antagonist against acetylcholine or arecaine, with low nM potency, for the activation of isolated rat mesenteric arteries. These results were confirmed on human internal mammary arteries. In conclusion, MT9 is the first fully characterized M2R-specific natural toxin. It should provide a tool for further understanding of the effect of M2R in various arteries and may position itself as a new drug candidate in cardio-vascular diseases.

Radiopharmaceutical Labelling for Lung Ventilation/Perfusion PET/CT Imaging: A Review of Production and Optimization Processes for Clinical Use.

Lung ventilation/perfusion (V/Q) positron emission tomography-computed tomography (PET/CT) is a promising imaging modality for regional lung function assessment. The same carrier molecules as a conventional V/Q scan (i.e., carbon nanoparticles for ventilation and macro aggregated albumin particles for perfusion) are used, but they are labeled with gallium-68 (68Ga) instead of technetium-99m (99mTc). For both radiopharmaceuticals, various production processes have been proposed. This article discusses the challenges associated with the transition from 99mTc- to 68Ga-labelled radiopharmaceuticals. The various production and optimization processes for both radiopharmaceuticals are reviewed and discussed for optimal clinical use.

Lung Ventilation/Perfusion Scintigraphy for the Screening of Chronic Thromboembolic Pulmonary Hypertension (CTEPH): Which Criteria to Use?

Objective: The diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) is a major challenge as it is a curable cause of pulmonary hypertension (PH). Ventilation/Perfusion (V/Q) lung scintigraphy is the imaging modality of choice for the screening of CTEPH. However, there is no consensus on the criteria to use for interpretation. The aim of this study was to assess the accuracy of various interpretation criteria of planar V/Q scintigraphy for the screening of CTEPH in patients with PH. Methods: The eligible study population consisted of consecutive patients with newly diagnosed PH in the Brest University Hospital, France. Final diagnosis (CTEPH or non-CTEPH) was established in a referential center on the management of PH, based on the ESC/ERS guidelines and a minimum follow-up of 3 years. A retrospective central review of planar V/Q scintigraphy was performed by three nuclear physicians blinded to clinical findings and to final diagnosis. The number, extent (sub-segmental or segmental) and type (matched or mismatched) of perfusion defects were reported. Sensitivity and specificity were evaluated for various criteria based on the number of mismatched perfusion defects and the number of perfusion defects (regardless of ventilation). Receiver operating characteristic (ROC) curves were generated and areas under the curve (AUC) were calculated for both. Results: A total of 226 patients with newly diagnosed PH were analyzed. Fifty six (24.8%) were diagnosed with CTEPH while 170 patients (75.2%) were diagnosed with non-CTEPH. The optimal threshold was 2.5 segmental mismatched perfusion defects, providing a sensitivity of 100 % (95% CI 93.6-100%) and a specificity of 94.7% (95%CI 90.3-97.2%). Lower diagnostic cut-offs of mismatched perfusion defects provided similar sensitivity but lower specificity. Ninety five percent of patients with CTEPH had more than 4 segmental mismatched defects. An interpretation only based on perfusion provided similar sensitivity but a specificity of 81.8% (95%CI 75.3-86.9%). Conclusion: Our study confirmed the high diagnostic performance of planar V/Q scintigraphy for the screening of CTEPH in patients with PH. The optimal diagnostic cut-off for interpretation was 2.5 segmental mismatched perfusion defects. An interpretation only based on perfusion defects provided similar sensitivity but lower specificity.

Structural and Functional Diversity of Animal Toxins Interacting With GPCRs.

Peptide toxins from venoms have undergone a long evolutionary process allowing host defense or prey capture and making them highly selective and potent for their target. This has resulted in the emergence of a large panel of toxins from a wide diversity of species, with varied structures and multiple associated biological functions. In this way, animal toxins constitute an inexhaustible reservoir of druggable molecules due to their interesting pharmacological properties. One of the most interesting classes of therapeutic targets is the G-protein coupled receptors (GPCRs). GPCRs represent the largest family of membrane receptors in mammals with approximately 800 different members. They are involved in almost all biological functions and are the target of almost 30% of drugs currently on the market. Given the interest of GPCRs in the therapeutic field, the study of toxins that can interact with and modulate their activity with the purpose of drug development is of particular importance. The present review focuses on toxins targeting GPCRs, including peptide-interacting receptors or aminergic receptors, with a particular focus on structural aspects and, when relevant, on potential medical applications. The toxins described here exhibit a great diversity in size, from 10 to 80 amino acids long, in disulfide bridges, from none to five, and belong to a large panel of structural scaffolds. Particular toxin structures developed here include inhibitory cystine knot (ICK), three-finger fold, and Kunitz-type toxins. We summarize current knowledge on the structural and functional diversity of toxins interacting with GPCRs, concerning first the agonist-mimicking toxins that act as endogenous agonists targeting the corresponding receptor, and second the toxins that differ structurally from natural agonists and which display agonist, antagonist, or allosteric properties.

Risk stratification for predicting recurrent venous thromboembolism after discontinuation of anticoagulation: a post hoc analysis of a French prospective multicentre study.

BACKGROUND: We aimed to validate and to refine current recurrent venous thromboembolism (VTE) risk classification. METHODS: We performed a post hoc analysis of a multicentre cohort including 1881 patients with a first symptomatic VTE prospectively followed after anticoagulation discontinuation. The primary objective was to validate the International Society of Thrombosis and Haemostasis (ISTH) risk classification in predicting recurrence risk. The secondary objective was to evaluate a refined ISTH classification based on the recurrence risk estimate for each individual risk factor. RESULTS: During a 4.8-year median follow-up after anticoagulation discontinuation, symptomatic recurrent VTE occurred in 230 patients (12.2%). Based on the ISTH classification, patients with unprovoked VTE or VTE with minor or major persistent risk factors had a 2-fold increased recurrence risk compared with those with VTE and major transient risk factors. Recurrence risk was not increased in patients with minor transient factors (hazard ratio (HR) 1.31, 95% CI 0.84-2.06). Individual risk factors analysis identified hormone-related VTE (pregnancy: HR 0.26, 95% CI 0.08-0.82; oestrogens: HR 0.25, 95% CI 0.14-0.47) and amyotrophic lateral sclerosis (HR 5.84, 95% CI 1.82-18.70). After reclassification of these factors as major transient for the former and major persistent for the latter, the modified ISTH classification allowed us to accurately discriminate between patients at low risk of recurrence (i.e. with major transient risk factors) and those at high risk of recurrence (i.e. without major transient risk factors). CONCLUSIONS: Among patients who stopped anticoagulation after a first VTE, a refined ISTH classification based on recurrence risk intensity of individual factors allowed discrimination between patients at low recurrence risk, including hormonal exposure in women, and patients at high recurrence risk.

Automatic delineation and quantification of pulmonary vascular obstruction index in patients with pulmonary embolism using Perfusion SPECT-CT: a simulation study.

BACKGROUND: In patients with pulmonary embolism (PE), there is a growing interest in quantifying the pulmonary vascular obtruction index (PVOI), which may be an independent risk factor for PE recurrence. Perfusion SPECT/CT is a very attractive tool to provide an accurate quantification of the PVOI. However, there is currently no reliable method to automatically delineate and quantify it. The aim of this phantom study was to assess and compare 3 segmentation methods for PVOI quantification with perfusion SPECT/CT imaging. METHODS: Three hundred ninety-six SPECT/CT scans, with various PE scenarios (n = 44), anterior to posterior perfusion gradients (n = 3), and lung volumes (n = 3) were simulated using Simind software. Three segmentation methods were assesssed: (1) using an intensity threshold expressed as a percentage of the maximal voxel value (MaxTh), (2) using a Z-score threshold (ZTh) after building a Z-score parametric lung map, and (3) using a relative difference threshold (RelDiffTh) after building a relative difference parametric map. Ninety randomly selected simulations were used to define the optimal threshold, and 306 simulations were used for the complete analysis. Spacial correlation between PE volumes from the phantom data and the delineated PE volumes was assessed by computing DICEPE indices. Bland-Altman statistics were used to calculate agreement for PVOI between the phantom data and the segmentation methods. RESULTS: Mean DICEPE index was higher with the RelDiffTh method (0.85 ± 0.08), as compared with the MaxTh method (0.78 ± 0.16) and the ZTh method (0.67 ± 0.15). Using the RelDiffTh method, mean DICEPE index remained high (> 0.81) regardless of the perfusion gradient and the lung volumes. Using the RelDiffTh method, mean relative difference in PVOI was - 12%, and the limits of agreement were - 40% to 16%. Values were 3% (- 75% to 81%) for MaxTh method and 0% (- 120% to 120%) for ZTh method. Graphycal analysis of the Bland-Altman graph for the RelDiffTh method showed very close estimation of the PVOI for small and medium PE, and a trend toward an underestimation of large PE. CONCLUSION: In this phantom study, a delineation method based on a relative difference parametric map provided a good estimation of the PVOI, regardless of the extent of PE, the intensity of the anterior to posterior gradient, and the whole lung volumes.

[18F]FDG PET radiomics to predict disease-free survival in cervical cancer: a multi-scanner/center study with external validation.

PURPOSE: To test the performances of native and tumour to liver ratio (TLR) radiomic features extracted from pre-treatment 2-[18F] fluoro-2-deoxy-D-glucose ([18F]FDG) PET/CT and combined with machine learning (ML) for predicting cancer recurrence in patients with locally advanced cervical cancer (LACC). METHODS: One hundred fifty-eight patients with LACC from multiple centers were retrospectively included in the study. Tumours were segmented using the Fuzzy Local Adaptive Bayesian (FLAB) algorithm. Radiomic features were extracted from the tumours and from regions drawn over the normal liver. Cox proportional hazard model was used to test statistical significance of clinical and radiomic features. Fivefold cross validation was used to tune the number of features. Seven different feature selection methods and four classifiers were tested. The models with the selected features were trained using bootstrapping and tested in data from each scanner independently. Reproducibility of radiomics features, clinical data added value and effect of ComBat-based harmonisation were evaluated across scanners. RESULTS: After a median follow-up of 23 months, 29% of the patients recurred. No individual radiomic or clinical features were significantly associated with cancer recurrence. The best model was obtained using 10 TLR features combined with clinical information. The area under the curve (AUC), F1-score, precision and recall were respectively 0.78 (0.67-0.88), 0.49 (0.25-0.67), 0.42 (0.25-0.60) and 0.63 (0.20-0.80). ComBat did not improve the predictive performance of the best models. Both the TLR and the native models performance varied across scanners used in the test set. CONCLUSION: [18F]FDG PET radiomic features combined with ML add relevant information to the standard clinical parameters in terms of LACC patient's outcome but remain subject to variability across PET/CT devices.