Study protocol of the HYPER-LIV01 trial: a multicenter phase II, prospective and randomized study comparing simultaneous portal and hepatic vein embolization to portal vein embolization for hypertrophy of the future liver remnant before major hepatectomy for colo-rectal liver metastases.

BACKGROUND: In patients undergoing major liver resection, portal vein embolization (PVE) has been widely used to induce hypertrophy of the non-embolized liver in order to prevent post-hepatectomy liver failure. PVE is a safe and effective procedure, but does not always lead to sufficient hypertrophy of the future liver remnant (FLR). Hepatic vein(s) embolization has been proposed to improve FLR regeneration when insufficient after PVE. The sequential right hepatic vein embolization (HVE) after right PVE demonstrated an incremental effect on the FLR but it implies two different procedures with no time gain as compared to PVE alone. We have developed the so-called liver venous deprivation (LVD), a combination of PVE and HVE during the same intervention, to optimize the phase of liver preparation before surgery. The main objective of this randomized phase II trial is to compare the percentage of change in FLR volume at 3 weeks after LVD or PVE. METHODS: Patients eligible to this multicenter prospective randomized phase II study are subjects aged from 18 years old suffering from colo-rectal liver metastases considered as resectable and with non-cirrhotic liver parenchyma. The primary objective is the percentage of change in FLR volume at 3 weeks after LVD or PVE using MRI or CT-Scan. Secondary objectives are assessment of tolerance, post-operative morbidity and mortality, post-hepatectomy liver failure, rate of non-respectability due to insufficient FLR or tumor progression, per-operative difficulties, blood loss, R0 resection rate, post-operative liver volume and overall survival. Objectives of translational research studies are evaluation of pre- and post-operative liver function and determination of biomarkers predictive of liver hypertrophy. Sixty-four patients will be included (randomization ratio 1:1) to detect a difference of 12% at 21 days in FLR volumes between PVE and LVD. DISCUSSION: Adding HVE to PVE during the same procedure is an innovative and promising approach that may lead to a rapid and major increase in volume and function of the FLR, thereby increasing the rate of resectable patients and limiting the risk of patient's drop-out. TRIAL REGISTRATION: This study was registered on clinicaltrials.gov on 15th February 2019 (NCT03841305).

Long-term prognostic significance of right bundle-branch morphology ventricular ectopy induced during stress test in patients with intermediate to high probability of coronary artery disease.

Aims: Stress-induced right bundle-branch block morphology ventricular ectopy (SI-RBVE) may be caused by left ventricular myocardial anomalies. While frequent ventricular ectopy (FVE) has been linked to poor outcomes, the prognostic value of SI-RBVE has not been established. The study aims to determine whether SI-RBVE is associated with increased mortality. Methods and results: Three hundred forty-three patients with an intermediate to high probability of coronary artery disease were prospectively included. Patients were referred for a single-photon emission computed tomography and underwent a stress test according to standard protocols. Stress-induced right bundle-branch block morphology ventricular ectopy (VE) was defined as one or more induced premature beats with positive predominance in V1. Frequent VE was defined as the presence of seven or more ventricular premature beats per minute or any organized ventricular arrhythmia. During a mean follow-up of 4.5 ± 1.3 years, 59 deaths occurred. The death rate was higher in the SI-RBVE group (23.4% vs. 14.0%, P = 0.021). Age [odds ratio (OR) = 1.09 (95% CI: 1.06-1.13), P < 0.001] and peripheral artery disease [OR = 2.47 (95% CI: 1.35-4.50) P = 0.003] were independent factors of mortality, but single-photon emission computed tomography findings were not. There was an interaction between SI-RBVE and left ventricular ejection fraction (LVEF). In patients with LVEF > 50%, SI-RBVE was an incremental risk factor for mortality [OR = 2.83 (95% CI: 1.40-5.74), P = 0.004]. Stress-induced right bundle-branch block morphology VE patients also presented higher rates of known coronary artery disease, ischaemia, scar, and ST-segment changes. Frequent VE was not related to mortality. Conclusion: Stress-induced right bundle-branch block morphology VE is associated with an increased mortality in patients with preserved LVEF.

Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study).

See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18F-misonidazole (18F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-ß = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the 18F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the 18F-FMISO-negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.

For avid glucose tumors, the SUV peak is the most reliable parameter for [(18)F]FDG-PET/CT quantification, regardless of acquisition time.

BACKGROUND: This study is an assessment of the impact of acquisition times on SUV with [(18)F]FDG-PET/CT on healthy livers (reference organ with stable uptake over time) and on tumors. METHODS: One hundred six [(18)F]FDG-PET/CT were acquired in list mode over a single-bed position (livers (n = 48) or on tumors (n = 58)). Six independent datasets of different durations were reconstructed (from 1.5 to 10 min). SUVmax (hottest voxel), SUVpeak (maximum average SUV within a 1-cm(3) spherical volume), and SUVaverage were measured within a 3-cm-diameter volume of interest (VOI) in the right lobe of the liver. For [(18)F]FDG avid tumors (SUVmax ≥ 5), the SUVmax, SUVpeak, and SUV41% (isocontour threshold method) were computed. RESULTS: For tumors, SUVpeak values did not vary with acquisition time. SUVmax displayed significant differences between 1.5- and 5-10-min reconstruction times. SUV41% was the most time-dependent parameter. For the liver, the SUVaverage was the sole parameter that did not vary over time. CONCLUSIONS: For [(18)F]FDG avid tumors, with short acquisition times, i.e., with new generations of PET systems, the SUVpeak may be more robust than the SUVmax. The SUVaverage over a 3-cm-diameter VOI in the right lobe of the liver appears to be a good method for a robust and reproducible assessment of the hepatic metabolism.

[¹8F]FDG positron emission tomography within two weeks of starting erlotinib therapy can predict response in non-small cell lung cancer patients.

PURPOSE: The aim of this prospective study was to evaluate whether [¹8F]FDG-PET/CT, performed within two weeks of starting erlotinib therapy can predict tumor response defined by RECIST 1.1 criteria after 8 weeks of treatment in patients with inoperable (stage IIIA to IV) non-small cell lung cancer patients. PATIENTS AND METHODS: Three [¹8F]FDG-PET/CT scans were acquired in 12 patients before (5±4 days) and after 9±3 days (early PET) and 60±6 days (late PET) of erlotinib therapy. Conventional evaluation, including at least chest CT (baseline versus after 8 weeks of treatment), was performed according to RECIST 1.1 criteria. Change in [¹8F]FDG uptake was compared with conventional response, progression-free survival (PFS), and overall survival (OS). RESULTS: By using ROC analysis, the Area Under the Curve for prediction of metabolic non-progressive disease (mNP) by early PET was 0.86 (95% CI, 0.62 to 1.1; P = 0.04) at a cut-off of 21.6% reduction in maximum Standardized Uptake Value (SUVmax). This correctly classified 11/12 patients (7 with true progressive disease; 4 with true non-progressive disease; 1 with false progressive disease). Non-progressive disease after 8 weeks of treatment according to RECIST 1.1 criteria was significantly more frequent in patients classified mNP (P = 0.01, Fisher's exact test). mNP patients showed prolonged PFS (HR = 0.27; 95% CI, 0.04 to 0.59; P<0.01) and OS (HR = 0.34; 95% CI, 0.06 to 0.84; P = 0.03). Late PET analysis provided concordant results. CONCLUSION: Morphologic response, PFS and OS survival in non-small cell lung cancer patients can be predicted by [¹8F]FDG-PET/CT scan within 2 weeks after starting erlotinib therapy.

Interobserver agreement of qualitative analysis and tumor delineation of 18F-fluoromisonidazole and 3'-deoxy-3'-18F-fluorothymidine PET images in lung cancer.

UNLABELLED: As the preparation phase of a multicenter clinical trial using (18)F-fluoro-2-deoxy-d-glucose ((18)F-FDG), (18)F-fluoromisonidazole ((18)F-FMISO), and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) in non-small cell lung cancer (NSCLC) patients, we investigated whether 18 nuclear medicine centers would score tracer uptake intensity similarly and define hypoxic and proliferative volumes for 1 patient and we compared different segmentation methods. METHODS: Ten (18)F-FDG, ten (18)F-FMISO, and ten (18)F-FLT PET/CT examinations were performed before and during curative-intent radiotherapy in 5 patients with NSCLC. The gold standards for uptake intensity and volume delineation were defined by experts. The between-center agreement (18 nuclear medicine departments connected with a dedicated network, SFMN-net [French Society of Nuclear Medicine]) in the scoring of uptake intensity (5-level scale, then divided into 2 levels: 0, normal; 1, abnormal) was quantified by κ-coefficients (κ). The volumes defined by different physicians were compared by overlap and κ. The uptake areas were delineated with 22 different methods of segmentation, based on fixed or adaptive thresholds of standardized uptake value (SUV). RESULTS: For uptake intensity, the κ values between centers were, respectively, 0.59 for (18)F-FDG, 0.43 for (18)F-FMISO, and 0.44 for (18)F-FLT using the 5-level scale; the values were 0.81 for (18)F-FDG and 0.77 for both (18)F-FMISO and (18)F-FLT using the 2-level scale. The mean overlap and mean κ between observers were 0.13 and 0.19, respectively, for (18)F-FMISO and 0.2 and 0.3, respectively, for (18)F-FLT. The segmentation methods yielded significantly different volumes for (18)F-FMISO and (18)F-FLT (P < 0.001). In comparison with physicians, the best method found was 1.5 × maximum SUV (SUVmax) of the aorta for (18)F-FMISO and 1.3 × SUVmax of the muscle for (18)F-FLT. The methods using the SUV of 1.4 and the method using 1.5 × the SUVmax of the aorta could be used for (18)F-FMISO and (18)F-FLT. Moreover, for (18)F-FLT, 2 other methods (adaptive threshold based on 1.5 or 1.6 × muscle SUVmax) could be used. CONCLUSION: The reproducibility of the visual analyses of (18)F-FMISO and (18)F-FLT PET/CT images was demonstrated using a 2-level scale across 18 centers, but the interobserver agreement was low for the (18)F-FMISO and (18)F-FLT volume measurements. Our data support the use of a fixed threshold (1.4) or an adaptive threshold using the aorta background to delineate the volume of increased (18)F-FMISO or (18)F-FLT uptake. With respect to the low tumor-on-background ratio of these tracers, we suggest the use of a fixed threshold (1.4).

American consensus recommendations for gastric scintigraphy: curve fitting with only a few points remains an easy and accurate method to obtain reliable and reproducible gastric emptying estimates.

BACKGROUND: In 2008, American consensus recommendations for performing gastric emptying (GE) scintigraphy were published. It was recommended that data are acquired only at 0, 1, 2, and 4 h and that the results are expressed as percentages of meal retention. Until now, it was established that the GE time-activity curves should have many points (every 10, 15, or 20 min) to reflect the GE process accurately and to be optimally adjusted by a mathematical model. In this study, we have evaluated the curve fitting using only a few points as proposed by the consensus protocol. MATERIALS AND METHODS: GE scintigraphy tests of 224 patients were retrospectively analyzed. Two curve fittings were done for each patient, either using data acquired every 20 min or using data acquired every hour. A comparison of these two methods was made based on the values of the computed GE parameters. RESULTS: We observed strong correlations between the two methods (r=0.81-0.99, P<0.05). Using the Bland-Altman analysis, more than 95% of the differences were included in the mean difference 95% confidence interval. The mean differences were weak with a relatively small SD and Cohen's k coefficients ranging from 0.84 to 0.93, indicating an excellent agreement between the two methods. CONCLUSION: Our results showed the feasibility and accuracy of curve fitting using only a few points. The curve fitting is easy to perform and allows the computation of reliable and reproducible parameters that reflect the whole GE process.