Reporting of interventional clinical trial results in an academic center: a survey of completed studies.

BACKGROUND: The dissemination of clinical trial results is an important scientific and ethical endeavour. This survey of completed interventional studies in a French academic center describes their reporting status. METHODS: We explored all interventional studies sponsored by Rennes University Hospital identified on the French Open Science Monitor which tracks trials registered on EUCTR or clinicaltrials.gov, and provides an automatic assessment of the reporting of results. For each study, we ascertained the actual reporting of results using systematic searches on the hospital internal database, bibliographic databases (Google Scholar, PubMed), and by contacting all principal investigators (PIs). We describe several features (including total budget and numbers of trial participants) of the studies that did not report any results. RESULTS: The French Open Science Monitor identified 93 interventional studies, among which 10 (11%) reported results. In contrast, our survey identified 36 studies (39%) reporting primary analysis results and an additional 18 (19%) reporting results for secondary analyses (without results for their primary analysis). The overall budget for studies that did not report any results was estimated to be €5,051,253 for a total of 6,735 trial participants. The most frequent reasons for the absence of results reported by PIs were lack of time for 18 (42%), and logistic difficulties (e.g. delay in obtaining results or another blocking factor) for 12 (28%). An association was found between non-publication and negative results (adjusted Odds Ratio = 4.70, 95% Confidence Interval [1.67;14.11]). CONCLUSIONS: Even allowing for the fact that automatic searches underestimate the number of studies with published results, the level of reporting was disappointingly low. This amounts to a waste of trial participants' implication and money. Corrective actions are needed. TRIAL REGISTRATION: https://osf.io/q5hcs.

[A survey on French hospital physicians'certification to the good clinical practices]. / Enquête sur la certification aux bonnes pratiques cliniques en recherche académique.

Good clinical practice (GCP) is an international ethical and scientific quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials. Before the start of a clinical trial, investigators commit to perform the research in accordance with GCPs, regulatory dispositions and protocol. The sponsors are responsible for investigators' selection and for controlling their skills. Whereas industrial sponsors systematically require a certificate of GCP training, academic sponsors seem to be less demanding. We have carried out two surveys between April and June 2018. A first questionnaire was sent to the 40 French academic directions of clinical research and innovation in order to determine their requirements about the GCP training of the investigators participating in their trials. The second questionnaire was transmitted to physicians of the "Bretagne recherche clinique hospitalière network": Rennes, Saint-Malo, Saint-Brieuc, Vannes, Lorient and Pontivy hospitals, in order to determine the GCP certification rate, and their needs in terms of clinical research training. Twenty-eight (70%) directions of clinical research answered the first survey, among which 18 (64%) required systematically the investigators' GCP certification in case of category 1 interventional studies. This rate decreased for category 2 (50%) and non-interventional category 3 (18%) studies. A total of 345 physicians answered the second survey, among which 263 (76%) had already been clinical trial investigators. However, only 29% of all physicians and 54% of those who had been principal investigator were certified for GCP training. These results support the need for large campaigns of GCP training in public hospitals.

The added value of quality of life (QoL) for prognosis of overall survival in patients with palliative hepatocellular carcinoma.

BACKGROUND & AIMS: Several prognostic classifications (PCs) have been developed for use in palliative care in patients with hepatocellular carcinoma (HCC). We have recently suggested that CLIP combined with WHO PS has the greatest discriminative power. We evaluated the prognostic value of quality of life (QoL) data and whether the latter could improve classification of palliative HCC patients. METHODS: This was a reanalysis from the CHOC trial with an evaluation of the discriminative power for overall survival (OS) of the established CLIP/GRETCH/BCLC/BoBar prognostic systems alone and then in association with each of the following groups of parameters: selected clinical factors, QoL as continuous variables, dichotomized QoL, selected clinical factors and continuous QoL, selected clinical factors and dichotomized QoL. Baseline QoL was assessed using the EORTC QLQ-C30. Discriminative power was evaluated with the Harrell's C-index and net reclassification improvement. RESULTS: Quality of life was available in 79% of the patients (n=271). Univariate analysis revealed that better role functioning (HR=0.991 [0.987-0.995]) and better physical functioning (0.991 [0.984-0.997]) scores were associated with longer survival. In contrast, poorer score for fatigue (1.011 [1.006-1.015]) and diarrhoea (1.008 [1.002-1.013]) were associated with shorter survival. After adjustment for clinical and sociodemographic variables, only better role functioning score (0.993 [0.988-0.998]) was associated with longer survival. Adding oedema, hepatomegaly, fatigue and diarrhoea QoL scales to CLIP resulted in the best performance. CONCLUSIONS: Our results confirm that QoL scales are independent prognostic factors of OS in palliative HCC patients. Incorporation of QoL data improved all the studied PCs.

Improved imaging of intrahepatic colorectal metastases with 18F-fluorodeoxyglucose respiratory-gated positron emission tomography.

BACKGROUND: In 18F-fluorodeoxyglucose PET/CT, respiratory motion induces bias in image interpretations (i.e. organ misregistration or lesion omission/underestimation). OBJECTIVE: The present study applied our custom gating method (referred to as 'CT-based gated PET' and that has already been validated by our research group) to PET imaging of the liver and compared its per lesion sensitivity with that of standard clinical (i.e. ungated) PET. METHODS: A total of 13 patients scheduled for liver surgery were referred to our department for PET/CT imaging. Each patient underwent both ungated and CT-based gated PET imaging protocols. Two independent, blinded observers interpreted the two sets of PET images and reached a consensus when necessary. Image interpretations were combined with histological analysis and/or intraoperative ultrasound examination to compute each method's per lesion sensitivity and true positive fraction. Analyses were also performed by considering lesions according to their size (longest axis over 10 mm or over 15 mm). RESULTS: Forty-eight lesions were confirmed by pathology reports. When considering all the uptakes, the ungated and the CT-based gated PET methods had sensitivities of 54.2 and 64.6% (P=0.025) and true positive fractions of 83.9 and 86.1%, respectively. When considering uptakes greater than 10 mm in size, ungated and CT-based gated PET had sensitivities of 74.3 and 88.6% (P=0.025), respectively. For lesions greater than 15 mm in size, the corresponding sensitivities were 85.2 and 100% (P=0.046). CONCLUSION: CT-based gated PET yielded a higher lesion-based sensitivity than routine, ungated PET did. Hence, this method improves the detection of intrahepatic colorectal metastases--especially for lesions that are close in size to the detection limit of the PET gantry.

Respiratory-gated 18F-FDG PET imaging in lung cancer: effects on sensitivity and specificity.

BACKGROUND: Respiratory motion is known to deteriorate positron emission tomography (PET) images and may lead to potential diagnostic errors when a standardized uptake value (SUV) cut-off threshold is used to discriminate between benign and malignant lesions. PURPOSE: To evaluate and compare ungated and respiratory-gated 18F-fluorodeoxyglucose PET/computed tomography (CT) methods for the characterization of pulmonary nodules. MATERIAL AND METHODS: The list-mode acquisition during respiratory-gated PET was combined with a short breath-hold CT scan to form the CT-based images. We studied 48 lesions in 43 patients. PET images were analyzed in terms of the maximum SUV (SUV(max)) and the lesion location. RESULTS: Using receiver-operating characteristic (ROC) curves, the optimal SUV cut-off thresholds for the ungated and CT-based methods were calculated to be 2.0 and 2.2, respectively. The corresponding sensitivity values were 83% and 92%, respectively, with a specificity of 67% for both methods. The two methods gave equivalent performance levels for the upper and middle lobes (sensitivity 93%, specificity 62%). They differed for the lower lobes, where the CT-based method outperformed the ungated method (sensitivity values of 90% and 70%, respectively, and a specificity of 73% with both methods) - especially for lesions smaller than 15 mm. CONCLUSION: The CT-based method increased sensitivity and did not diminish specificity, compared with the ungated method. It was more efficient than the ungated method for imaging the lower lobes and smallest lesions, which are most affected by respiratory motion.

Preliminary clinical applications of a device-dedicated whole-body positron emission tomography reconstruction method: impact on standardized uptake values.

BACKGROUND: ¹8F-fluorodeoxyglucose positron emission tomography has proven relevance in oncological diagnosis, staging and follow-up. The standardized uptake value (SUV) is one of the most widely used semi-quantitative criteria in PET imaging. However, factors such as noise and image resolution affect the measurement of the SUV. We reported earlier that a device-dedicated projector [attenuation-weighted ordered-subsets expectation maximization detector response (AW-OSEM DR), based on point-source measurements] introduces less noise than a geometrical model (AW-OSEM). OBJECTIVE: The aim of this study was to investigate the AW-OSEM DR method's impact on SUV measurements under clinical conditions. METHODS: We first performed a bias analysis to assess the accuracy of the quantitation for the two reconstruction methods as a function of target size and the number of iterations, with 14 acquisitions of the NEMA IEC/2001 phantom. We then used each method to calculate the maximum and average SUVs, respectively for 32 lesions. RESULTS: For all spheres and all iterations, the bias was significantly lower with AW-OSEM DR than with AW-OSEM (P=0.012). Moreover, a paired Student's t-test showed significant intermethod differences for maximum SUV and average SUV (both P<0.001) in cancer patients. Conversely, the two methods did not differ significantly in terms of the mean SUV and signal-to-noise ratio calculated in the liver for each patient (P=0.5 and 0.08, respectively). CONCLUSION: Phantom and patient studies were performed to quantify the effects of AW-OSEM DR on PET images. The phantom study highlighted the fact that our method produces more accurate images in terms of the SUV, which is an essential quality for ensuring correct diagnosis, follow-up and treatment planning.

A practical way to improve contrast-to-noise ratio and quantitation for statistical-based iterative reconstruction in whole-body PET imaging.

In whole-body positron emission tomography (PET) imaging, the detection of small uptake foci (i.e., around two or three times the tomograph's spatial resolution) is a critical issue. Indeed, spatial resolution is altered by postreconstruction smoothing operations used to reduce the noise introduced by (among other things) an inaccurate system matrix. The authors previously proposed a device-dedicated projector, easily applicable on a clinical gantry, based on point-source measurements, which introduces less noise than a geometrical model. In the present study, they took advantage of the lower noise levels by reducing the postfilter and then quantified the approach's impact on image quality. This study was performed on an IEC Body Phantom Set filled with 18F (sphere-to-background activity ratio: 4:1). The same 3 min acquisition was reconstructed with either (i) a clinical system based on a geometrical tomographic operator (OSEM_CL) or (ii) an OSEM algorithm using the suggested system matrix (OSEM_DR). In order to compare the resulting images, they set the 3D Gaussian postfilter (3DGPF) for OSEM_DR so as to obtain similar background signal-to-noise ratio (SNR) to that of OSEM_CL with a Gaussian postfilter full width at half maximum of 5 mm (as recommended for whole-body imaging on a Biograph6). They then assessed the contrast-to-noise ratio (CNR) and quantitation [contrast recovery (CR)] for the phantom's four smallest spheres (with internal diameters of 10, 13, 17, and 22 mm). Evaluation of 3DGPFs ranging from 2.2 to 2.6 mm showed that a value of 2.4 mm in OSEM_DR gave the closest background SNR to that of OSEM_CL with a 3DGPF of 5 mm. For all studied targets, the CNR was higher with OSEM_DR than with OSEM_CL. For the 10 and 13 mm spheres, OSEM_DR increased the size of the CNR peaks by 37% and 20%, relative to OSEM_CL. The OSEM_DR technique yielded higher CR values than OSEM_CL did. For the 10, 13, 17, and 22 mm spheres, the CR values at eight iterations were 0.5, 0.6, 1.1, and 1.0 for OSEM_DR and 0.3, 0.4, 0.9, and 0.8 for OSEM_CL. They evaluated a practical method for determining a device-dedicated system matrix based on point-source acquisitions. This tomographic operator is more realistic than geometrical system matrix and introduces less noise into PET images during statistical reconstruction; it thus reduces the extent of postfiltering operations required. Thus, spatial resolution is better maintained with OSEM_DR than with clinical reconstruction. They showed that this method improves the contrast-to-noise ratio and quantification of uptake foci (especially those that are at the system's limit of detection) and, in a clinical context, could allow better detection and earlier diagnosis.

Motion correction based on an appropriate system matrix for statistical reconstruction of respiratory-correlated PET acquisitions.

Respiratory motion correction in positron emission tomography (PET) seeks to incorporate motion information into an image reconstruction algorithm by using the full counting statistics of an acquisition to generate a single, motion-free volume. Here, we present a motion-incorporated ordered subsets expectation maximization (MOSEM) reconstruction based on a device-dedicated tomographic projector in which each matrix element is calculated directly from the voxels' Cartesian coordinates alone. The motion is corrected by updating this projector as a function of the respiratory level. The performance of the reconstruction method was investigated with three datasets: two simulations of a transaxially or axially moving lesion on a patient acquisition and a third acquisition of a moving sphere. After the 16th sub-iteration, the normalized mean square error (NMSE, with a motionless acquisition as reference) was 0.20 for the non-corrected (ungated) image and 0.01 for the MOSEM image with transaxial motion simulation. Likewise, NMSE was 0.30 for the ungated image and 0.03 for MOSEM image with axial motion simulation. For the phantom, ungated reconstruction yielded an error of 0.78, whereas MOSEM yielded 0.43. The error reduction resulted from enhancement and reduced spreading of the moving uptake. Our results show that MOSEM reconstruction yields motion-corrected images which are similar to motionless reference images.

Improved attenuation correction via appropriate selection of respiratory-correlated PET data.

PURPOSE: We propose a respiratory-correlated PET data processing method (called "BH-CT-based") based on breath-hold CT acquisition to reduce the smearing effect and improve the attenuation correction. The resulting images are compared with the ungated PET images acquired using a standard, free-breathing clinical protocol. METHODS: The BH-CT-based method consisted of a list-mode acquisition with simultaneous respiratory signal recording. An additional breath-hold CT acquisition was also performed in order to define a tissue position from which PET events can be selected. A phantom study featured a 0.5-ml sphere (filled with 18F-fluorodeoxyglucose ((18)F-FDG) solution) pushed onto a rubber balloon (filled with (18)F-FDG solution and iodinated contrast agent). The feasibility of the BH-CT-based method was also assessed in two patients. RESULTS: In the phantom study, the contrast-to-noise ratios (CNRs) were -1.6 for the Ungated volume and 5.1 for the BH-CT-based volume. For patients, CNRs were higher for BH-CT-based volumes than those for Ungated volumes (17.3 vs. 6.3 and 7.3 vs. 3.8, for patients 1 and 2, respectively). Bias-variance measurements were performed and yielded bias reduction of 40% with BH-CT-based. CONCLUSION: The application of a BH-CT-based method decreases motion bias in PET images. This method resolves issues related to both PET-to-CT misregistration and erroneous attenuation correction and increases lesion detectability.

Initial clinical results for breath-hold CT-based processing of respiratory-gated PET acquisitions.

PURPOSE: Respiratory motion causes uptake in positron emission tomography (PET) images of chest structures to spread out and misregister with the CT images. This misregistration can alter the attenuation correction and thus the quantisation of PET images. In this paper, we present the first clinical results for a respiratory-gated PET (RG-PET) processing method based on a single breath-hold CT (BH-CT) acquisition, which seeks to improve diagnostic accuracy via better PET-to-CT co-registration. We refer to this method as "CT-based" RG-PET processing. METHODS: Thirteen lesions were studied. Patients underwent a standard clinical PET protocol and then the CT-based protocol, which consists of a 10-min List Mode RG-PET acquisition, followed by a shallow end-expiration BH-CT. The respective performances of the CT-based and clinical PET methods were evaluated by comparing the distances between the lesions' centroids on PET and CT images. SUV(MAX) and volume variations were also investigated. RESULTS: The CT-based method showed significantly lower (p = 0.027) centroid distances (mean change relative to the clinical method = -49%; range = -100% to 0%). This led to higher SUV(MAX) (mean change = +33%; range = -4% to 69%). Lesion volumes were significantly lower (p = 0.022) in CT-based PET volumes (mean change = -39%: range = -74% to -1%) compared with clinical ones. CONCLUSIONS: A CT-based RG-PET processing method can be implemented in clinical practice with a small increase in radiation exposure. It improves PET-CT co-registration of lung lesions and should lead to more accurate attenuation correction and thus SUV measurement.

Brain hydrodynamics study by phase-contrast magnetic resonance imaging and transcranial color doppler.

PURPOSE: To evaluate the contributions of phase-contrast magnetic resonance (PCMR) and transcranial color Doppler (TCCD) imaging in the investigation of cerebral hydrodynamics. MATERIALS AND METHODS: A total of 13 healthy subjects were studied. Blood velocity measurements were performed with TCCD and gated PCMR imaging in major intracranial and extracranial arteries stages. Peak systolic velocity and end-diastolic velocity were extracted to establish correlations between TCCD and PCMR imaging. Cerebral blood flow (CBF) and intracranial volume change (IVC) during the cardiac cycle were calculated, taking into account cerebrospinal fluid (CSF) oscillations. RESULTS: Despite an underestimation of velocities with PCMR imaging, significant correlations were observed for velocity measurements between the two modalities in extracranial vessels, but were poorly correlated in intracranial vessels. PCMR data processing gave a mean CBF of 690+/-90 mL/minute. CONCLUSION: PCMR imaging provides complementary information to TCCD to assess various intracranial parameters such as instantaneous velocities, blood and CSF flow distributions, volume variation, or pressure regulation mechanisms during cardiac cycles.

Three dimensional modeling of the cerebrospinal fluid dynamics and brain interactions in the aqueduct of sylvius.

A computational fluid dynamics (CFD) method is presented to investigate the flow of cerebro-spinal fluid (CSF) in the cerebral aqueduct. In addition to former approaches exhibiting a rigid geometry, we propose a model which includes a deformable membrane as the wall of this flow channel. An anatomical shape of the aqueduct was computed from magnetic resonance images (MRI) and the resulting meshing was immersed in a marker-and-cell (MAC) staggered grid for to take into account fluid-structure interactions. The time derivatives were digitized using the Crank-Nicolson scheme. The equation of continuity was modified by introducing an artificial compressibility and digitized by a finite difference scheme. Calculations were validated with the simulation of laminar flow in a rigid tube. Then, comparisons were made between simulations of a rigid aqueduct and a deformable one. We found that the deformability of the walls has a strong influence on the pressure drop for a given flow.