[Can positron emission tomography assessment of response to treatment help to individualize use of erlotinib in non-small cell lung cancer?] / L'imagerie par émission de positons à la 3'-désoxy-3'-[18F]-fluorothymidine ([18F]FLT) peut-elle avoir un rôle théranostique lors du traitement par erlotinib dans le cancer bronchique non à petites cellules ?

Erlotinib can be prescribed in the treatment of locally advanced or metastatic non-small lung cancer cell (NSCLC) after failure of at least one prior chemotherapy regimen on the basis of the BR-21 study. Several publications have recently questioned these results. The metabolic imaging of solid tumours by positron emission tomography is a research field that could help customize the treatment of NSCLC and so complement the treatment approaches allowed by genetic analyses. This strategy is part of an innovative "early metabolic look" approach. The primary objective of this study is to determine if metabolic progression observed between the 7th and 14th day after initiation of treatment with erlotinib by 3'-Deoxy-3'-[18F]-Fluorothymidine PET in patients with EGFR naive NSCLC is predictive for morphological progression after 6 to 8 weeks of treatment. A health economic analysis will be conducted. This study is particularly innovative because it begins the exploration of the era of metabolic evaluation of therapeutic response in NSCLC.

[Prognostic value of the metabolically active tumour volume]. / Valeur pronostique du volume tumoral métabolique sur la TEP au ((18)F)-fluorodésoxyglucose préthérapeutique pour le cancer de l'œsophage localisé.

PURPOSE: The purpose of this study was to assess the prognostic value of different parameters on pretreatment fluorodeoxyglucose [((18)F)-FDG] positron emission tomography-computed tomography (PET-CT) in patients with localized oesophageal cancer. PATIENTS AND METHOD: We retrospectively reviewed 83 cases of localised oesophageal cancer treated in our institution. Patients were treated with curative intent and have received chemoradiotherapy alone or followed by surgery. Different prognostic parameters were correlated to survival: cancer-related factors, patient-related factors and parameters derived from PET-CT (maximum standardized uptake value [SUV max], metabolically active tumor volume either measured with an automatic segmentation software ["fuzzy locally adaptive bayesian": MATVFLAB] or with an adaptive threshold method [MATVseuil] and total lesion glycolysis [TLGFLAB and TLGseuil]). RESULTS: The median follow-up was 21.8 months (range: 0.16-104). The median overall survival was 22 months (95% confidence interval [95%CI]: 15.2-28.9). There were 67 deaths: 49 associated with cancer and 18 from intercurrent causes. None of the tested factors was significant on overall survival. In univariate analysis, the following three factors affected the specific survival: MATVFLAB (P=0.025), TLGFLAB (P=0.04) and TLGseuil (P=0.04). In multivariate analysis, only MATVFLAB had a significant impact on specific survival (P=0.049): MATVFLAB<18 cm(3): 31.2 months (95%CI: 21.7-not reached) and MATVFLAB>18 cm(3): 20 months (95%CI: 11.1-228.9). CONCLUSION: The metabolically active tumour volume measured with the automatic segmentation software FLAB on baseline PET-CT was a significant prognostic factor, which should be tested on a larger cohort.

A starch-based microparticulate system dedicated to diagnostic and therapeutic nuclear medicine applications.

The aim of this work was to develop a new microparticulate system able to form a complex with radionuclides with a high yield of purity for diagnostic or therapeutic applications. Owing to its properties potato starch was chosen as starting material and modified by oxidization and coupling of a ligand (polyamine) enabling modified starch to chelate radionuclides. The choice of suitable experiments was based on a combination of a Rechtschaffner experimental design and a surface response design to determine the influence of experimental parameters and to optimize the final product. Starch-based microparticle formulations from the experimental plans were compared and characterized through particle size analysis, scanning electron microscopy, elemental analysis and, for the most promising formulations, by in vitro labeling stability studies and determination of free polyamine content or in vivo imaging studies. The mechanism of starch-based microparticle degradation was identified by means of size measurements. The results of the Rechtschaffner design showed the positive qualitative effect of the temperature and the duration of coupling reaction whereas surface response analysis clearly showed that, by increasing the oxidization level and starch concentration, the nitrogen content in the final product is increased. In vitro and in vivo characterization led to identification of the best formulation. With a size around 30 µm, high radiochemical purity (over 95%) and a high signal-to-noise ratio (over 600), the new starch-based microparticulate system could be prepared as ready-to-use kits and sterilized without modification of its characteristics, and thus meet the requirement for in vivo diagnostic and therapeutic applications.

In vivo evaluation of lipid nanocapsules as a promising colloidal carrier for paclitaxel.

Paclitaxel-loaded lipid nanocapsules (PX-LNC) exhibit interesting in vitro characteristics with improved antitumoral activity compared with free PX formulation. Biodistribution studies were realized with the use of (14)C-trimyristin ((14)C-TM) or (14)C-phosphatidylcholine ((14)C-PC) whereas antitumoral activity of PX-LNC formulations was based on the animal survival in a chemically induced hepatocellular carcinoma (HCC) model in Wistar rats. Blood concentration-time profiles for both labeled (14)C-TM-LNC and (14)C-PC-LNC were similar; the t(1/2) and MRT values (over 2h and close to 3h, respectively, for both formulations) indicated the long circulating properties of the LNC carrier with a slow distribution and elimination phase. Survival curves of paclitaxel treated groups showed a statistical significant difference compared to the control survival curve (P=0.0036 and 0.0408). Animals treated with 4x 70 mg/m(2) of PX-LNC showed the most significant increase in mean survival times compared to the controls (IST(mean) 72%) and cases of long-term survivors were preferentially observed in the PX-LNC treated group (37.5%; 3/8). These results demonstrate the great interest to use LNC as drug delivery system for paclitaxel, permitting with an equivalent therapeutic efficiency to avoid the use of excipients such as polyoxyethylated castor oil for its formulation.

Comparison of positron emission tomography and lymphangiography in the diagnosis of infradiaphragmatic Hodgkin's disease.

PURPOSE: To evaluate the respective roles of positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) and lymphangiography (LAG) in staging Hodgkin's disease (HD) patients with negative contrast-enhanced infradiaphragmatic computed tomography (CT). MATERIAL AND METHODS: 28 patients underwent FDG-PET and LAG at initial staging. Concordant positive findings on both tests were regarded as actual HD locations and concordant negative findings as true negative. In case of discrepancy, the reference was biopsy or magnetic resonance imaging (MRI). RESULTS: Concordant results were obtained in 26 patients (24 negative, two positive). In two of the 24 negative patients, PET showed additional lesions in the spleen and one celiac lymph node (one patient), and in the right kidney and the right iliac crest (one patient). Discordant results were obtained in two patients. Both methods indicated infradiaphragmatic involvement in different locations in one patient. In the other, PET was falsely positive (PET done within 24 hours after a negative LAG), which was confirmed by biopsy (benign inflammatory, probably due to LAG medium). CONCLUSION: FDG-PET and LAG gave comparable results, making invasive LAG unnecessary. Furthermore, LAG, when performed before PET, can be responsible for false-positive PET results.

[Does semi-quantitative analysis of FDG-PET have any additional value in the diagnosis of mesial temporal sclerosis?]. / Qual o valor da análise semi-quantitativa dos exames de FDG-PET no diagnóstico da esclerose mesial temporal?

UNLABELLED: The aim of this study was to compare qualitative visual analysis with semi-quantitative analysis in the diagnosis of mesial temporal sclerosis (MTS) using FDG-PET. METHODS: This study included 21 patients with histopathological confirmation of MTS. FDG-PET visual analysis data were based on clinical reports generated soon after the completion of the scan. FDG-PET images were semi-quantitatively analyzed using regions of interest (ROIs) in 19 slices perpendicular to the longest axis of the temporal lobe. These ROIs divided each temporal lobe into three regions (lateral, inferior and medial). An asymmetry index was calculated for each region. RESULTS: The visual analysis of the FDG-PET studies demonstrated asymmetric hypometabolism in all patients. All but 1 patient underwent standard lobectomy of the same side described as hypometabolic by the PET report. Using an asymmetry index equal or greater than 9% in at least one of the regions as a threshold, the FDG-PET semi-quantitative analysis showed significant asymmetry in 18 patients. These also matched the side of lobectomy and were confirmed as sclerotic in all but one patient (same patient as above). CONCLUSION: The semi-quantitative analysis did not provide additional information over visual interpretation in this series of patients.

Post-synchronized scintigraphic data to estimate antral motility.

We evaluated an improved dynamic antral scintigraphy (DAS) technique, without any frequency filtering or computation of an autocorrelation function. This DAS was performed in 15 consecutive patients and 10 healthy volunteers. Antral frequency was first estimated and was given as an input parameter to compute phase and amplitude values in each antral pixel. Motility indices were calculated by multiplying the frequency by a normalized amplitude in the whole antrum. In addition, a gastric emptying (GE) test was performed. Only 10 patients had a delayed GE when using a cut-off value of the mean of half emptying time (T +2SD) obtained in controls. Antral frequencies were significantly increased but motility indices were significantly lower in patients than in controls. These results in patients were accounted for by a retention of food in the antrum. Therefore, amplitude normalization by the antral mean count activity of each set of data was essential for discriminating between patients and controls and normalized indices appeared early predictors of hypomotility in patients with normal GE. This improved DAS technique should be a useful tool to assess antral dysmotility noninvasively, and may be of physiological and clinical interest.

Gastric emptying of solids: estimates of lag phase and constant emptying times.

There is no consensus regarding the best way to estimate the lag phase time (Tlag) and the constant emptying time (TRE) of the gastric emptying of solids. Furthermore, biphasic gastric emptying is usually described by the modified power exponential function of either Elashoff or Siegel. In an attempt to test the validity of the power exponential functions and to identify relevant parameters of biphasic gastric emptying, we followed an approach which consists of describing the power exponential function by two straight lines. The first line is horizontal and represents Tlag. The second line is tangential to the constant emptying [tangent at the maximum slope (MS) or at the half-emptying value]. Scintigraphic data of 132 patients and 15 controls were fitted by both power exponential functions. Each corresponding half-emptying time, Tlag and TRE estimated from the Elashof and Siegel power exponential functions were strongly correlated (0.93 < r < 1, P < 0.0001). The Bland and Altman statistical method demonstrated good agreement (<5% outliers). The half-emptying tangent method sometimes gave negative Tlag and should be abandoned. Tlag(MS) and TRE(MS) did not correlate and therefore were independent parameters. We conclude that the Elashoff and Siegel functions are equivalent and that the maximum slope tangent method allows a reliable description of the two independent phases of gastric emptying.

Post-synchronization of dynamic images of periodically moving organs.

The motion of periodically moving organs can be studied by acquisition of dynamic image series. When time is short, it is necessary either to find a sync signal to sum synchronous images in real time or to acquire a regular time series and to synchronize a posteriori. Dynamic acquisitions were performed (gastric and lung studies). The activity in each pixel of the moving organ can be expressed as h(t)=a0 + a1 cos(omegao0t - phi). The time-activity curve u(t) over a region of interest (ROI) of the considered organ was computed. When the ROI is well chosen, the power spectrum of u(t) exhibits a sharp peak near the characteristic frequency of the periodic motion. The DC component, amplitude and phase in each pixel can be then estimated by minimizing the following function: J=sigma[h(t) - g(t)]2, where g(t) is a noisy measurement of h(t). It is then easy to reconstruct an a posteriori gated time series by computing h(t) for various times over a single period. This approach was successful in characterizing lung and gastric motions. Dynamic series were acquired as for gastric emptying studies. The characteristic frequency of antral motility was easily and unambiguously estimated and DC, amplitude and phase images were computed. Dynamic pulmonary functional imaging was performed with 81Krm. The characteristic frequency was also easily estimated from the time-activity curve power spectrum using a ROI drawn over the lower part of the lungs. The DC, amplitude and phase images were then computed from the dynamic series and the characteristic frequency. In conclusion, a posteriori gating of dynamic series of periodically moving organs can be achieved in a simple fashion. This approach overcomes the difficulty of direct analysis of time-activity curves and provides amplitude and phase images.

13C-octanoic acid breath test for gastric emptying measurement.

OBJECTIVES: The purpose of this multicentre study was to assess the accuracy and reproducibility of the 13C-octanoic acid breath test compared to scintigraphy for measurement of gastric emptying. METHODS: Sixty-nine healthy subjects (40 men, 29 women; mean age 30 years, range 21-61) were studied at least once by using the 13C-octanoic breath test. In 34 healthy subjects, gastric emptying was simultaneously measured by gastric scintigraphy, and the 13C-octanoic breath test was then repeated in 18 of these cases. Fifty-four patients (30 men, 24 women; mean age 46 years, range 13-74) with dyspeptic or reflux symptoms were studied according to the same procedure. RESULTS: The correlation between breath test and scintigraphic values was highly significant (r = 0.744, P<0.001). The concordance of results of scintigraphy and breath test (normal versus abnormal) and the reproducibility (Bland and Altman method) of the breath test were good (CVinter = 24%, CVintra = 15%). As compared to scintigraphy, breath test detected an abnormal gastric emptying with 67% sensitivity and 80% specificity (ROC analysis). CONCLUSION: These results confirm the value of breath test as an accurate measurement of gastric emptying. Its excellent reproducibility makes it a method of choice for pharmacological studies. However, at least when scintigraphy is considered the gold standard, breath test sensitivity may be insufficient for the detection of gastroparesis in an individual patient.

Use of left ventricular pacing in heart failure: evaluation by gated blood pool imaging.

BACKGROUND: Left ventricular (LV) pacing has been suggested to complement other forms of therapy in patients with heart failure. METHODS AND RESULTS: We investigated 17 patients (15 men, 2 women, aged 68 +/- 6 years, 10 ischemic and 7 primary dilated cardiomyopathy) with heart failure (13 were in New York Heart Association class IV and 4 in class III). One month after LV pacer implantation, 12 patients reported clinical improvement (mean class 3.7 before pacing vs 2.6 with LV pacing; P = .001). We report the results of 3 equilibrium-gated blood pool studies performed in each patient, 1 before pacing and 2 after pacer implantation (1 with pacing on, and 1 after turning off the pacer). LV pacing did not modify LV ejection fraction. Phase analysis demonstrated a significant decrease of the interventricular phase shift (delta(pi)) with LV pacing (no pacing, delta(pi) = 8.99 degrees +/- 19.05 degrees; delta7n= -0.97 degrees +/- 27.85 degrees with LV pacing). Clinical improvement was observed in patients with an initial positive delta(pi) that decreased with pacing and/or an initial LV phase standard deviation >50 degrees that decreased with pacing. CONCLUSION: LV pacing induces interventricular and intraventricular synchronization. A decrease of the interventricular phase shift seems to be the most important predictor of functional recovery for paced patients with heart failure.

Validation of 213Bi-alpha radioimmunotherapy for multiple myeloma.

The efficacy of radioimmunotherapy (RIT) with beta emitters has been clinically demonstrated in the treatment of refractory forms of lymphoma. Alpha-emitting radionuclides with a short half-life are also good potential candidates for RIT directed at tumor targets easily accessible to radioimmunoconjugate molecules and small enough to benefit from the short range of alpha particles (<100 microm). The purpose of this study was to demonstrate the feasibility of ex vivo purging of multiple myeloma-invaded bone marrow. Tumor cells were targeted by a specific monoclonal antibody (B-B4) coupled to 213Bi by a chelating agent (pentaacetic triamine diethylene p-aminobenzyl acid). The efficacy of alpha-RIT was assessed in vitro by analysis of thymidine incorporation, cell mortality, apoptosis of myeloma cells, and the study of nonspecific irradiation of hematopoietic cell lines not recognized by B-B4-pentaacetic triamine diethylene p-aminobenzyl acid immunoconjugate. High dose-dependent cell mortality of myeloma cells was found with radiolabeled B-B4, and this mortality was total at 30 kBq/10(5) cells. Cells were found in apoptotic state at rates of up to 40% for a dose of 7.4 kBq/10(5) cells. Nonspecific mortality was low compared with specific mortality (up to 1%).