Pierre-Yves Salaun

Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial

IMPORTANCE The optimal duration of anticoagulation after a first episode of unprovoked pulmonary embolism is uncertain. OBJECTIVES To determine the benefits and harms of an additional 18-month treatment with warfarin vs placebo, after an initial 6-month nonrandomized treatment period on a vitamin K antagonist. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind trial (treatment period, 18 months; median follow-up, 24 months); 371 adult patients who had experienced a first episode of symptomatic unprovoked pulmonary embolism (ie, with no major risk factor for thrombosis) and had been treated initially for 6 uninterrupted months with a vitamin K antagonist were randomized and followed up between July 2007 and September 2014 in 14 French centers. INTERVENTIONS Warfarin or placebo for 18 months. MAIN OUTCOMES AND MEASURES The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months after randomization. Secondary outcomes were the composite at 42 months (treatment period plus 24-month follow-up), as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. RESULTS After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event. During the 18-month treatment period, the primary outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 (13.5%) in the placebo group (hazard ratio [HR], 0.22; 95% CI, 0.09-0.55; P = .001). Recurrent venous thromboembolism occurred in 3 patients in the warfarin group and 25 patients in the placebo group (HR, 0.15; 95% CI, 0.05-0.43); major bleeding occurred in 4 patients in the warfarin group and in 1 patient in the placebo group (HR, 3.96; 95% CI, 0.44 to 35.89). During the 42-month entire study period (including the study treatment and follow-up periods), the composite outcome occurred in 33 patients (20.8%) in the warfarin group and in 42 (24.0%) in the placebo group (HR, 0.75; 95% CI, 0.47-1.18). Rates of recurrent venous thromboembolism, major bleeding, and unrelated death did not differ between groups. CONCLUSIONS AND RELEVANCE Among patients with a first episode of unprovoked pulmonary embolism who received 6 months of anticoagulant treatment, an additional 18 months of treatment with warfarin reduced the composite outcome of recurrent venous thrombosis and major bleeding compared with placebo. However, benefit was not maintained after discontinuation of anticoagulation therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00740883.

Noninvasive Diagnosis of Pulmonary Embolism

BACKGROUND We designed a simple and integrated diagnostic algorithm for acute pulmonary embolism (PE). Diagnosis was based on clinical probability assessment, plasma D-dimer testing, then sequential testing to include lower limb venous compression ultrasonography, ventilation perfusion lung scan, and chest multidetector CT (MDCT) imaging. METHODS We included 321 consecutive patients presenting at Brest University Hospital in Brest, France, with clinically suspected PE and positive d-dimer or high clinical probability. Patients in whom VTE was deemed absent were not given anticoagulants and were followed up for 3 months. RESULTS Detection of DVT by ultrasonography established the diagnosis of PE in 43 (13%). Lung scan associated with clinical probability was diagnostic in 243 (76%) of the remaining patients. MDCT scan was required in only 35 (11%) of the patients. The 3-month thromboembolic risk in patients not given anticoagulants, based on the results of the diagnostic protocol, was 0.53% (95% CI, 0.09-2.94). CONCLUSIONS A diagnostic strategy combining clinical assessment, d-dimer, ultrasonography, and lung scan gave a noninvasive diagnosis in the majority of outpatients with suspected PE and appeared to be safe.

Phase II Trial of Anticarcinoembryonic Antigen Pretargeted Radioimmunotherapy in Progressive Metastatic Medullary Thyroid Carcinoma: Biomarker Response and Survival Improvement

The prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival based on such prognostic factors as serum calcitonin and carcinoembryonic antigen (CEA) doubling times (DTs). This prospective phase II multicenter trial evaluated the efficacy and safety of anti-CEA pretargeted radioimmunotherapy (pRAIT) in rapidly progressing metastatic MTC patients and also how serum biomarker DTs correlate with clinical outcome. Methods: From June 2004 to January 2008, 42 patients were treated with anti-CEA × anti–diethylenetriaminepentaacetic acid (DTPA) bispecific antibody (hMN-14 × m734) (40 mg/m2), followed by 131I-di-DTPA-indium bivalent hapten (1.8 GBq/m2) 4–6 d later. Results: The disease control rate (durable stabilization plus objective response) was 76.2%. Grade 3–4 hematologic toxicity was observed in 54.7% of patients and myelodysplastic syndrome in 2, including 1 heavily treated previously. After pRAIT, 21 of 37 assessed patients (56.7%) showed a significant impact on DT (≥100% increase of pre-pRAIT calcitonin or CEA DT or prolonged decrease of the biomarker concentration after pRAIT). Pre-pRAIT DT and post-pRAIT DT were significant independent predictors for overall survival (OS) from pRAIT (pre-pRAIT: hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24–0.86; P = 0.016; and post-pRAIT: HR, 5.32; 95% CI, 1.63–17.36; P = 0.006) and OS from diagnosis (pre-pRAIT: HR, 0.21; 95% CI, 0.08–0.51; P = 0.001; and post-pRAIT: HR, 6.16; 95% CI, 1.81–20.98; P = 0.004). Conclusion: pRAIT showed antitumor activity, with manageable hematologic toxicity in progressive MTC. Increased biomarker DT after treatment correlated with increased OS.

Limited screening with versus without (18)F-fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open-label randomised controlled trial.

BACKGROUND Clear guidelines for the investigation of occult malignancy after unprovoked venous thromboembolism are not yet available. (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT could serve as a comprehensive screening strategy for occult malignancy in this context. We aimed to compare a screening strategy based on (18)F-FDG PET/CT with a limited screening strategy for detection of malignant disease in patients with unprovoked venous thromboembolism. METHODS In an open-label, multicentre, randomised study we enrolled patients from four French university hospitals. Patients aged 18 years or older, diagnosed with unprovoked venous thromboembolism (not provoked by a major inherited or acquired risk factor) were invited to participate. Patients were randomly assigned in a 1:1 ratio to a limited screening strategy (physical examination, usual laboratory tests, and basic radiographs) or a screening strategy consisting of the limited strategy plus an (18)F-FDG PET/CT scan. Randomisation was done with a dedicated central web-based randomisation system, in block sizes of six, stratified by centre, and concealed from the investigators. Patients and investigators were not masked to study group assignment. Patients were followed up for 2 years. The primary outcome was the proportion of patients with a cancer diagnosis in each group after the initial screening assessment. Analyses were conducted in modified intention-to-test and per-protocol populations. This trial is completed and registered with ClinicalTrials.gov, number NCT00964275. FINDINGS Between March 3, 2009, and Aug 18, 2012, we enrolled and randomly assigned 399 patients; five withdrew consent, leaving 197 in each group for the modified intention-to-test analysis. After initial screening assessment, cancer was diagnosed in 11 (5·6%) patients in the (18)F-FDG PET/CT group and four (2·0%) patients in the limited screening group (absolute risk difference 3·6%, 95% CI -0·4 to 7·9; p=0·07). At the initial screening assessment, seven (64%) of the 11 cancers diagnosed in the (18)F-FDG PET/CT group were early-stage compared with two of four cancers diagnosed in the limited screening group (p=1·00). One (0·5%) occult malignancy was detected in 186 patients who had negative initial screening in the (18)F-FDG PET/CT group, compared with nine (4·7%) in 193 patients in the limited screening group (absolute risk difference 4·1%, 95% CI 0·8 to 8·4, p=0·01). Overall, five (42%) of the 12 cancers diagnosed in the (18)F-FDG PET/CT group were advanced stage, compared with seven (54%) of the 13 cancers diagnosed in the limited screening group (p=0·70). 16 patients died during follow-up, eight (4·1%) in each group. Two (1·0%) patients in the (18)F-FDG PET/CT group and five (2·5%) in the limited screening group had cancer-related deaths. INTERPRETATION A strategy including limited screening and a (18)F-FDG PET/CT was not associated with a significantly higher rate of cancer diagnosis after unprovoked venous thromboembolism. The risk of subsequent cancer diagnosis was, however, lower in patients who had negative initial screening that included (18)F-FDG PET/CT than in patients who had negative initial limited screening. Whether or not (18)F-FDG PET/CT might be useful in a more selected population of patients with a high risk of cancer remains to be determined. FUNDING Programme Hospitalier de Recherche Clinique (French Department of Health).

FDG-positron-emission tomography for staging and therapeutic assessment in patients with plasmacytoma

Plasmacytoma can be confined to bone (solitary bone plasmacytoma) or occur in extramedullary sites (extramedullary plasmacytoma).[1][1]–[4][2] Diagnostic criteria are a biopsy-proven lesion of bone or soft tissue with evidence of clonal plasma cells, normal bone marrow with no evidence of clonal

Diagnostic Accuracy of Single-Photon Emission Tomography Ventilation/Perfusion Lung Scan in the Diagnosis of Pulmonary Embolism

BACKGROUND Planar ventilation/perfusion (V/Q) lung scintigraphy is a validated tool for the diagnosis of pulmonary embolism (PE). Nevertheless, given the high rate of nonconclusive V/Q, further investigation is often necessary. V/Q single-photon emission CT (SPECT) scan could improve V/Q performance, but sparse data are available on its accuracy. This study assessed the diagnostic performance of V/Q SPECT scan in a cohort of consecutive patients with suspected PE. METHODS Three hundred twenty-one consecutive patients with a clinical suspicion of PE were prospectively included. Patients suspected of having PE were managed according to a reference diagnostic strategy validated by a 3-month follow-up. In addition to the reference strategy, patients had a V/Q SPECT scan, the results of which were compared with the initial work-up results. RESULTS Prevalence of PE was 0 of 41 (0%; 95% CI, 0%-9%), six of 134 (4%; 95% CI, 2%-9%),15 of 36 (42%; 95% CI, 27%-58%), and 28 of 32 (88%; 95% CI, 72%-95%) in the normal, low,intermediate, and high V/Q SPECT scan probability groups, respectively. The combination of V/Q SPECT scan with clinical probability was diagnostic in 88% of patients. CONCLUSIONS V/Q SPECT scan results show satisfactory accuracy for PE diagnosis. Validation of dedicated interpretation criteria is required, followed by outcome studies that use V/Q SPECT scan as part of a diagnostic strategy to rule out PE. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01183026; URL: www.clinicaltrials.gov

Prognostic value of dual-time-point 18F-FDG PET-CT imaging in patients with head and neck squamous cell carcinoma.

ObjectiveThe objective of this study was to investigate the independent prognostic value of dual-time-point 18F-fluorodeoxyglucose (18F-FDG) PET-CT imaging in patients with head and neck squamous cell carcinoma (HNSCC). MethodsPatients referred to our department to undergo 18F-FDG PET-CT for staging of HNSCC were prospectively included. Each patient was scanned using a Philips Gemini PET-CT system 1 h (early acquisition) and 2 h (delayed acquisition) after injection. An intratumoral retention index (RI) of 18F-FDG was measured for each examination by the dual-time-point method. Event-free survival (EFS) and overall survival (OS) were determined by the Kaplan–Meier method and compared with the conventional maximum standardized uptake value (SUVmax) at 60 min, SUVmax at 120 min, and RI in univariate and multivariate analyses including the usual prognostic factors such as age, sex, primary site, SCC histologic grade, and American Joint Committee on Cancer stage (I, II, III, and IV). ResultsSixty-six consecutive patients (60 men and six women; mean age=61±9 years) were included in the study. In univariate analysis, besides age and stage, RI was predictive of EFS (P=0.01) but not of OS (P=0.1), whereas SUVmax at 60 min was not predictive of EFS (P=0.18) or OS (P=0.08) and SUVmax at 120 min was predictive of OS (P=0.02) but not of EFS (P=0.05). In multivariate analysis, RI persisted as an independent predictive factor for EFS (P=0.02) but not SUVmax at 120 min for OS (P=0.12). ConclusionOur results suggest an additional prognostic interest of RI measured by dual-time-point 18F-FDG PET-CT, independent of usual prognostic factors, in patients with HNSCC.

Toxicity and efficacy of combined radioimmunotherapy and bevacizumab in a mouse model of medullary thyroid carcinoma

Significant antitumor effects were previously observed with radioimmunotherapy (RIT) using an anti‐carcinoembryonic antigen (CEA) monoclonal antibody (F6) labeled with iodine‐131 in medullary thyroid cancer (MTC)‐bearing nude mice. Nevertheless, no complete response was achieved. Because angiogenesis is critical for tumor growth, bevacizumab is used to treat solid tumor in clinical practice. The present pilot study evaluated toxicity and efficacy of RIT combined with bevacizumab in mice subcutaneously grafted with TT MTC cells.

V/Q SPECT Interpretation for Pulmonary Embolism Diagnosis: Which Criteria to Use?

Ventilation–perfusion (V/Q) SPECT has been reported to improve the diagnostic performance of V/Q imaging for the diagnosis of pulmonary embolism (PE). However, only sparse data based on an objective reference test are available, and the criteria used for interpretation have varied widely. Therefore, the aim of our study was to assess the performance of V/Q SPECT using various criteria for interpretation, in comparison with a validated independent diagnostic strategy. Methods: The SPECT study included patients for whom V/Q SPECT data were compared with the results of an independent and validated diagnostic algorithm for PE. V/Q SPECT scans were performed after intravenous injection of 99mTc-macroaggregated albumin and simultaneous ventilation with 81mKr gas. Interpretation was performed independently by 2 nuclear medicine physicians who were not aware of the clinical history, diagnostic strategy conclusion, or patient’s outcome. Sensitivity, specificity, and likelihood ratios were evaluated for various combinations of mismatched defect numbers and sizes (segmental or subsegmental). Generation of receiver-operating-characteristic curves was based on the number of mismatch defects and the number of subsegmental mismatch defects or equivalent. Results: Of the 249 patients who were analyzed, the diagnosis of PE was confirmed in 49 and ruled out in 200 according to the previously validated independent strategy. Of all the tested criteria, the best performance was achieved using a diagnostic cutoff of at least 1 segmental or 2 subsegmental mismatches, with sensitivity and specificity of 0.92 (95% confidence interval, 0.84–1) and 0.91 (95% confidence interval, 0.87–0.95), respectively. With a negative V/Q SPECT result, the posttest probability of PE was 0.010, 0.037, and 0.119 for a low, intermediate, and high clinical probability. With a positive V/Q SPECT result, the posttest probability of PE was 0.531, 0.814, and 0.939 for a low, intermediate, and high probability. Conclusion: For V/Q SPECT interpretation, a diagnostic cutoff of 1 segmental or 2 subsegmental mismatches seems best for confirming or excluding acute PE.

Prognostic value of fluorine-18 fluorodeoxyglucose positron-emission tomography imaging in patients with head and neck squamous cell carcinoma

High tumor uptake of fluorodeoxyglucose (FDG) is associated with an unfavorable outcome in patients with cancer. We evaluated FDG uptake as a prognostic factor in patients with head and neck squamous cell carcinoma.