Trastuzumab induced in vivo tissue remodelling associated in vitro with inhibition of the active forms of AKT and PTEN and RhoB induction in an ovarian carcinoma model.

BACKGROUND: The incidence of ovarian cancer has been increasing worldwide and it is currently the leading cause of death from gynaecological malignancy. Unlike breast cancer, the prognostic role of the human epidermal growth factor receptor-2 (HER-2) in ovarian carcinoma remains controversial. METHODS: The aim of this preclinical study was to further characterise the biological, molecular and cellular effects of trastuzumab (Herceptin) using NIH-OVCAR-3 and derived cell lines both in vitro and in vivo. RESULTS: In vitro assessments have shown that trastuzumab treatment inhibited total and phosphorylated HER-2. This was associated with inhibition of the phosphorylated form of phosphatase and tensin homologue (PTEN), mitogen-activated protein kinase and AKT, and the total level of p27(kip). Inhibition of PTEN is associated with phosphorylated MEK1/2 upregulation, suggesting a specific inhibition of the protein phosphatase function of PTEN. Moreover, trastuzumab induced the upregulation of RhoB. These molecular modifications promote inhibition of cell migration and potentially restoration of tumour cell contact inhibition. RhoB induction in NIH-OVCAR-3 control cell lines mimics the molecular and cellular trastuzumab long-time exposition effects. RhoB inhibition in NIH-OVCAR-3 long-time exposed to trastuzumab cell line reverses the cellular and molecular effects observed in this model. In vivo examinations have shown that these changes are also associated with the restoration of structural, morphological and normal functions of the peritoneum of an ovarian carcinoma mouse model. CONCLUSION: These results provide an indication of the mechanisms underlying the anti-tumour activity of trastuzumab that strongly implicate RhoB in an ovarian carcinoma model that does not show HER-2 amplification or overexpression. These findings highlight that trastuzumab effects involve a possible cross-talk between RhoB and PTEN in the early stages of tumour re-growth in a model of micrometastatic ovarian cancer.

[The impact of 18F-fluorodeoxyglucose positron emission tomography on the 3D conformal radiotherapy planning in patients with non-small cell lung cancer]. / Intérêt de la tomographie par émission de positons au [18F]-fluoro-2-désoxyglucose dans la détermination des volumes cibles de radiothérapie. Application à l'irradiation conformationnelle des cancers bronchiques non à petites cellules.

Traditional radiation treatment planning relies on density imaging such as Computed Tomography for anatomic information of various structures of interest including target and normal tissues. However, the difficulties to distinguish malignant from normal tissue on CT slides often leads to inaccurate outlining of the GTV and/or to geographic misses. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has shown an increase in both sensitivity and specificity over CT in locoregional staging of patients with non-small cell lung cancer (NSCLC). The co registration of FDG-PET images to the data of the CT planning offers the radiation oncologist the possibility to include functional information into the target outlining. For the treatment of patients with NSCLC, it has been shown that the use of FDG-PET images: 1) modified the shape and volume of radiation fields in 22-62% of cases, mainly due to a better nodal staging and distinction of atelectasis from tumor and; 2) significatively reduced the interobserver and intraobserver variability. This paper reviews the results reported in the literature. Challenges and proposed solutions are discussed.

Validation of reconstructed bremsstrahlung spectra between 6 MV and 25 MV from measured transmission data.

We have previously investigated a method of high-energy x-ray spectral reconstruction from transmission data by direct resolution of a matrix system. This technique uses the spectral vectorial algebra formalism. The resolution has previously been tested on a 12 MV photon beam. To extend and to test the validity of the results to the entire radiotherapy energy range, we have performed the method on photon beams with nominal energies of 6, 12, 15, and 25 MV. The influence on the 6 MV spectrum of a 60 degrees built-in wedge has also been investigated to test the sensitivity of the method and the results are reported. To validate our reconstructed spectra, dosimetric quantities such as tissue phantom ratios (TPR), water-to-air stopping power ratios (S/p) air water, and quality indexes TPR 10 (20) have been calculated. The results show good agreement between the measured and calculated data. Mean mass energy absorption coefficient ratios for different materials have also been computed and compared to data published recently and the results are very close (within +/- 0.5%). Primary depth dose functions in water have also been computed to deduce primary dose attenuation coefficients.

Improvement of the Cockcroft-Gault equation for predicting glomerular filtration in cancer patients.

In order to determine the morphological and biological covariables which better predict the glomerular filtration rate in cancer patients, we performed the present study in a population of 123 patients (78 men, 45 women) with various tumor types; 55 of these patients had previously received cisplatin, and 12 had undergone unilateral nephrectomy. The 51Cr-EDTA plasma concentration versus time data of 80 patients were analysed according to a population pharmacokinetic approach by using the Nonlinear Mixed Effects Model (Nonmem) program. The best fit for 51Cr-EDTA clearance estimation was given by the following formula: [formula: see text] (with ABW for actual body weight in kg, age in years, sex = 0 if male and sex = 1 if female, and Scr for serum creatinine in mumol/l). Actual body weight was the most predictive morphologic parameter, and the adjustment was not improved by taking into account the ideal body weight. The GFR of patients previously treated with cisplatin was 18% lower than that of untreated patients age for age. However, this covariable was not present in the final model because it was redundant with other covariables, likely Scr. The formula was then prospectively evaluated with the data of 43 other patients. The mean (+/- SD) ratio between GFR predicted according the Nonmem formula and the observed GFR was 0.95 +/- 0.23 which did not differ significantly from unity. Conversely, the mean ratio between creatinine clearance calculated according to the Cockcroft-Gault equation and the observed GFR (0.86 +/- 0.21) differed significantly from unity. This study shows that in cancer patients the formula to calculate GFR drawn from Nonmem analysis is more accurate than the Cockcroft-Gault equation. However, an accurate determination of GFR requires specific techniques as 51Cr-EDTA clearance investigation.

Automatic segmentation of breast MR images through a Markov random field statistical model.

An algorithm dedicated to automatic segmentation of breast magnetic resonance images is presented in this paper. Our approach is based on a pipeline that includes a denoising step and statistical segmentation. The noise removal preprocessing relies on an anisotropic diffusion scheme, whereas the statistical segmentation is conducted through a Markov random field model. The continuous updating of all parameters governing the diffusion process enables automatic denoising, and the partial volume effect is also addressed during the labeling step. To assess the relevance, the Jaccard similarity coefficient was computed. Experiments were conducted on synthetic data and breast magnetic resonance images extracted from a high-risk population. The relevance of the approach for the dataset is highlighted, and we demonstrate accuracy superior to that of traditional clustering algorithms. The results emphasize the benefits of both denoising guided by input data and the inclusion of spatial dependency through a Markov random field. For example, the Jaccard coefficient for the clinical data was increased by 114%, 109%, and 140% with respect to a K-means algorithm and, respectively, for the adipose, glandular and muscle and skin components. Moreover, the agreement between the manual segmentations provided by an experienced radiologist and the automatic segmentations performed with this algorithm was good, with Jaccard coefficients equal to 0.769, 0.756, and 0.694 for the above-mentioned classes.

The retrospective binning method improves the consistency of phase binning in respiratory-gated PET/CT.

This study assesses the accuracy of prospective phase-gated PET/CT data binning and presents a retrospective data binning method that improves image quality and consistency. Respiratory signals from 17 patients who underwent 4D PET/CT were analysed to evaluate the reproducibility of temporal triggers used for the standard phase-based gating method. Breathing signals were reprocessed to implement retrospective PET data binning. The mean and standard deviation of time lags between automatic triggers provided by the Real-time Position Management (RPM, Varian) gating device and inhalation peaks derived from respiratory curves were computed for each patient. The total number of respiratory cycles available for 4D PET/CT according to the binning mode (prospective versus retrospective) was compared. The maximum standardized uptake value (SUV(max)), biological tumour volume (BTV) and tumour trajectory measures were determined from the PET/CT images of five patients. Compared to retrospective binning (RB), prospective gating approach led to (i) a significant loss in breathing cycles (15%) and (ii) the inconsistency of data binning due to temporal dispersion of triggers (average 396 ms). Consequently, tumour characterization could be impacted. In retrospective mode, SUV(max) was up to 27% higher, where no significant difference appeared in BTV. In addition, prospective mode gave an inconsistent spatial location of the tumour throughout the bins. Improved consistency with breathing patterns and greater motion amplitude of the tumour centroid were observed with retrospective mode. The detection of the tumour motion and trajectory was improved also for small temporal dispersion of triggers. This study shows that the binning mode could have a significant impact on 4D PET images. The consistency of triggers with breathing signals should be checked before clinical use of gated PET/CT images, and our RB method improves 4D PET/CT image quantification.

Iodine-131 pharmacokinetics in patients on hemodialysis for end stage renal disease: clinical implications.

AIM: Curative treatment of thyroid cancer is a major issue for patients with end stage renal disease (ESRD) undergoing dialysis because they might not be included in a renal transplant protocol once they have overcome this disease. Since 131I is mostly eliminated by the kidneys, there is concern regarding the toxicity, efficacy and feasibility of 131I-therapy of anuric dialyzed patients. METHODS: This paper reports on 131I uptake and elimination from remnant thyroid tissue (T), salivary glands (SG), stomach (S) and blood, after administration of 3.7 GBq of 131I for 2 patients on twice weekly dialysis for ESRD. RESULTS: Compared to normal renal function patients, radio-iodine recirculation is observed, and SG and blood irradiation is about 6 times higher, but the dose delivered to the thyroid is not significantly enhanced. Dialysis removes more 131I from SG, S and blood than from T. Anticipated dialysis will reduce irradiation by 38% for the blood, 45% for SG and 34% for T. CONCLUSIONS: Therefore, a higher 131I amount could then be used, providing that accurate personalized dosimetry is previously performed using 131I pharmacokinetic models. Concerning radiation protection issues, no significant dialysis equipment contamination is noted, and nurses and medical staff exposure remains below 0.2 mSv.

[Contribution of a new technique of digital enhancement for the control of radiation fields]. / Apport d'une nouvelle technique de numérisation au contrôle des champs d'irradiation.

To increase geometric treatment accuracy in radiation therapy, we used a novel digitized method and original image processing. The radiographic films that are conventionally used for verifying each beam during the treatment were digitized by a Kodak digital system and then an original image enhancement was applied. For the evaluation of our technique, a clinical trial with two tests was used. The trial involved four readers doing 80 reading. The enhanced films were judged to be of higher quality than the non enhanced films (p = 0.001) and were read more accurately (p < or = 0.001). This automatic enhancement of digitized captured portal images can be easily integrated into the busy routine of a radiotherapy department.