[PET-CT for evaluation of the solitary pulmonary nodule: an update]. / TEP-TDM pour l'exploration du nodule pulmonaire solitaire: acquis et perspectives.

INTRODUCTION: Positron emission tomography (PET) with 18F-FDG has become an important tool for the characterization of solitary pulmonary nodules (SPN). BACKGROUND: The results of the main meta-analyses show that the sensitivity and specificity of 18F-FDG PET for determining malignancy of SPN are close to 95% and 80% respectively. The limits of the technology are now well known. False negative results are mainly due to certain histological types with low metabolic activity (such as bronchiolo-alveolar carcinoma and typical carcinoid), or small size (nodules less than 8 mm). False positives are mainly represented by granulomatous and infectious processes. VIEWPOINTS: A gain in accuracy occurred with the advent of hybrid PET/CT machines that combine the functional data from 18FDG-PET and the morphological data of computed tomography. Improved imaging protocols (eg. injection of iodinated contrast media) could further enhance the performance of PET-CT. Further improvements will rely on respiratory synchronization protocols and on the advent of new PET tracers. CONCLUSION: 18F-FDG PET-CT should be performed for any nodule over 8 mm in size when the pre-test probability of malignancy is not deemed negligible.

[PET/CT in breast cancer: an update]. / Différents rôles de la TEP-TDM en sénologie : mise au point.

The authors discuss the various roles of 18F-FDG PET/CT in the management of breast cancer. Roles of new tracers such as F-18 fluoro-L-thymidine (a marker of cell proliferation), 18-fluoro-17-B-estradiol (marker of estrogen receptor) and sodium fluoride (marker of bone matrix) are also mentioned. There is little justification for the use of FDG-PET/CT in patient with clinically T1 (< or = 2 cm) N0 tumours. Notably, it cannot be used as a substitute to SLNB "sentinel lymph node biopsy" for axillary staging due to limited sensitivity for the detection of small metastases. The case is different in higher risk patients, and especially so in patients with locally advanced disease. FDG-PET/CT in these patients might depict lymph node involvement in the level III of Berg or in supraclavicular or internal mammary basins. It might also uncover occult distant metastases, notably, early osteomedullary infiltration. Thus, for these tumors, initial PET/CT can enable better intramodality treatment planning or a change in treatment. PET/CT as a whole-body examination is also very efficient in case of suspicion of recurrence. On the other hand, many studies show that this functional imaging could be used to assess early response to neoadjuvant chemotherapy or to chemotherapy of metastatic disease. 18FDG-PET/CT could thus become an unavoidable modality to answer various clinical situations.

[Sentinel node biopsy in breast cancer]. / La technique du ganglion sentinelle dans le cancer du sein: quelques considérations récentes.

As compared to conventional axillary dissection, the sentinel node technique is accompanied by reduced morbidity and shorter hospital stay. Based on available data, the use of this technique does not seem to yield higher rates of axillary recurrence. A combination of both radioisotope detection and blue dye increases the identification rate, while also reducing false-negative rate. Surgical results are optimized when preoperative lymphoscintigraphy mapping is obtained in addition to peroperative probe detection. Considering the site of injection, the subareolar injection can be easy to apply even in case of non-palpable tumours, and gives higher count rates. However, the intraparenchymal, peritumoral, injection is necessary to evidence cases of extra-axillary drainage (internal mammary, infra- or supraclavicular) that is present in about 20% of patients. With the advent of hybrid cameras (SPECT-CT), the topography of these extra-axillary nodes can be given with high precision. Use of the sentinel node technique has been accompanied by an increase in the percent of patients with node involvement, due to an increased detection of micrometastases inferior or equal to 2 mm. Following an overview of basic principles, and of the main results with the sentinel node technique we focus the discussion on several points that are still open to debate, such as: 1) which group of patients can benefit from the sentinel node technique? 2) What is the optimal methodology? 3) What is the prognostic significance of micrometastases and of isolated tumour cells? 4) What attention should be given to extra-axillary drainage?

[Advantages of PET-CT in the work-up of cervical cancer]. / Intérêts de la TEP-TDM pour le cancer du col de l'utérus.

The present paper addresses the advantages and limits of PET-CT in the work-up of cervical cancer. PET-CT is not to be overlooked in initial staging. It is useful to assess involvement of pelvic and lumbar lymph nodes. It can improve staging accuracy and help guide initial treatment such as optimisation of radiation therapy fields. Given its limited spatial resolution however, PET does not seem so adequate to document tumours less than 5 mm in diameter. It is not warranted for staging carcinoma in situ (FIGO stage 0) or preclinical carcinoma (FIGO stage 1A1 and 1A2). Furthermore MRI performances are best as far as local extension and tumour volume measurement are concerned. PET brings prognostic information. High initial uptake in tumour tissue or persistent increased uptake at completion of treatment indicates rather poor prognosis. PET is useful to evaluate therapy, but its exact role in this issue remains to be further refined. Finally, PET-CT can document early recurrence of disease.

[Benign schwannoma with high uptake of 18 fluorodeoxglucose (PET-Scan)]. / Un cas de schwannome bénin avec hypermétabolisme sur la tomoscintigraphie TEP au 18fluorodésoxyglucose.

INTRODUCTION: In patients with a previous history of malignancy, the occurrence of a mediastinal mass with significant uptake of 18 Fluorodeoxyglucose on a PET-scan may lead to biopsy or resection. CASE REPORT: We report the case of a posterior mediastinal mass, with significant uptake of 18 Fluorodeoxyglucose on PET- scan, in a patient with a previous history of testicular seminoma. The lesion was actually a benign schwannoma. CONCLUSIONS: In the case of a mediastinal mass with conventional imaging being in favour of a neurogenic tumour a PET scan cannot confirm benignity or malignancy.

Update on the diagnosis and therapy of distant metastases of differentiated thyroid carcinoma.

Differentiated thyroid cancer, when adequately treated, has an overall good prognosis. However, 10-15% of patients develop distant metastases. The presence of metastases is an important prognostic factor that negatively affects survival. For (131)I-avid distant metastases, (131)I therapy is a very effective treatment modality that induces complete remission in about a third of patients. These figures may be even higher in case of early diagnosis, when tumor burden is still limited. Additional measures may include surgery and/or external beam radiation therapy. Cytotoxic chemotherapy is largely ineffective in patients with progressive, poorly differentiated cancer. These patients should be candidates for trials with new molecularly targeted therapeutic agents. In this paper, a review of diagnostic modalities, prognostic factors and therapeutic options for patients with distant metastases is proposed. In particular, the prognostic value of the early discovery of metastatic disease will be underlined.

Cerebrospinal fluid MR dynamics and risk of falls in the elderly.

RATIONALE AND OBJECTIVES: To investigate the relationship between CSF dynamics and risk of falls of unknown origin in the elderly. POPULATION AND METHODS: Phase contrast MR studies allowed CSF aqueductal flow quantification on 23 community-dwelling older people initially explored for mild cognitive impairment. Mobility assessment included report of falls, talking walking test, stance test, one leg standing test, up and go test, and measurement of fast gait speed. RESULTS: History of falls was associated with larger aqueduct, steeper diastolic slopes higher ratios RDV/SD of diastolic volume/CSF systole duration (p

[Cerebral metastasis for the identification of carcinomas of the lung: the use of mulimodality medical images. A case repport]. / Metastase cerebrale revelatrice d'un carinome epidermoide pulmonaire: apport de l'imagerie multinodalite.

INTRODUCTION: Diagnosis of carcinomas of unknown primary site has proved to be difficult for many reasons. PATIENT AND METHODS: In this study, case in which cerebral metastasis is confirmed by biopsy technique with no identified primary site at the onset of treatment is presented here in. RESULTS: The multimolity medical images was used to detect pulmonary hearths compatibles with a malignant histology. Further analysis diagnosed a primitive neoplasm. CONCLUSION: This study illustrates the interest of this technology in medical imagery in the early detection of primitive cancers on which the forecast depends.

Spontaneous mitochondrial membrane potential change during apoptotic induction by quercetin in K562 and K562/adr cells.

Natural products from plants such as flavonoids are potential drugs to overcome multidrug resistance (MDR) in cancer treatments. However, their modes of action are still unclear. In this study, the effects of quercetin on mitochondrial membrane potential (DeltaPsim) change as well as quercetin's ability to induce apoptosis and inhibit Pgp-mediated efflux of 99mTc-MIBI in K562/adr cells were investigated. Quercetin exhibits cytotoxicity against erythroleukemic cells: IC50 are 11.0 +/- 2.0 micromol/L and 5.0 +/- 0.4 micromol/L for K562 and K562/adr, respectively. Quercetin induces cell death via apoptosis in both K562 and K562/adr cells and does not inhibit Pgp-mediated efflux of 99mTc-MIBI. Quercetin (10 micromol/L, 3 h) and etoposide (100 micromol/L, 24 h) induce similar levels of apoptosis in K562 and K562/adr cells. Quercetin induces an increase followed by a decrease in |DeltaPsim| value depending on its concentration. A decrease in the |DeltaPsim| value is associated with an increase in the percentage of early apoptotic cells. It is clearly shown that quercetin results in a spontaneous DeltaPsim change during apoptotic induction. Therefore, quercetin is potentially an apoptotic-inducing agent, which reacts at the mitochondrial level.

Calcitonin precursor levels in human medullary thyroid carcinoma.

DESIGN: The hormonal serum marker for the presence and course of patients with medullary thyroid cancer (MTC) is the mature calcitonin (CT) peptide. Other CALC-1 gene products such as the 116-amino acid polypeptide prohormone, procalcitonin, as well as its component calcitonin precursors (CTpr) may also be increased in their sera. We performed a study to evaluate the clinical utility of serum levels CTpr in these patients. METHODS: Twenty-one patients with MTC (9 males, 12 females; 23-76 years of age) were evaluated. The diagnosis was confirmed by histologic examination, except for 2 (a proven RET mutation plus an abnormal pentagastrin-stimulated CT level). Nine patients had postoperative hypercalcitoninemia and 3 of these died. The specific assay for mature CT was a commercial immunoradiometric assay (hCT-IRMA); the immunoluminometric assay for CTpr (B.R.A.H.M.S Diagnostica, Berlin, Germany) detects intact procalcitonin and the free CT:CT carboxypeptide-1. RESULTS: All patients had detectable serum CTpr. These levels considerably exceeded those of mature CT, averaging 7.6-fold greater. CTpr levels correlated positively with mature CT (r = 0.61; p < 0.001). After pentagastrin administration, there was a parallelism of response between the two assays. Whenever there were known metastases, CTpr increased markedly. CONCLUSION: This study demonstrates the universal presence of CTpr in the blood of patients with MTC. The measurement of these peptides may offer a new dimension to the clinical evaluation of this malignancy.

Spatial organization of three-dimensional cocultures of adriamycin-sensitive and -resistant human breast cancer MCF-7 cells.

Genetic and cellular heterogeneity is one of mechanisms involved in increasing tumour aggressiveness during neoplastic progression. Development of drug-resistant tumour cell subpopulations is a major problem in clinical oncology. Multi-drug resistant tumour cells survive when exposed to cytotoxic agents. Here, we studied in a three-dimensional (3D) coculture system, called "ex vivo nodules", how drug-resistant and sensitive tumour cells settle down in a 3D space. For this, we cocultured adriamycin-sensitive (MCF-7S) and -resistant (MCF-7R) human breast cancer cells in long term nodules. We showed that both types of cells are able to grow separately or in coculture until five weeks in spheroidal forms. MCF-7R cells did not loose their multi-drug resistance when cultured in nodules as measured by RT-PCR. Curiously, the exterior aspects of mixed (MCF-7S/ MCF-7R) nodules and MCF-7R nodules were similar whereas MCF-7S nodules were completely different. Nevertheless, morphologically these three nodule types were distinct, in particular in their density. Immunostaining showed that in mixed nodules, MCF-7R cells were arranged at the periphery, whereas the MCF-7S cells are in the central part of the nodules. Even if the mechanism of this arrangement remained unclear, this work shows that three-dimensional cell culture is well adapted to the study of the relationships between adhesion mechanisms and drug-resistance.

The role of 99mTc-MIBI scintigraphy in the assessment of MDR1 overexpression in patients with musculoskeletal sarcomas: comparison with therapy response.

The occurrence of multidrug resistance (MDR), which is in part due to the overexpression of P-glycoprotein (Pgp), is a major problem in neoadjuvant therapy of malignant musculoskeletal tumours. The aim of this study was to investigate the role of technetium-99m hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy for functional imaging of the MDR1 phenotype in patients with musculoskeletal sarcomas. We aimed to compare 99mTc-MIBI uptake and washout kinetics with the expression of Pgp and with chemotherapy response. Twenty-five patients (16 males and 9 females, aged between 8 and 65 years) with malignant musculoskeletal tumours were studied. After injection of 555-740 MBq 99mTc-MIBI, dynamic flow images of the involved area were obtained for 3 min, and planar images were acquired at 10 min and 1 h. From the dynamic images, a tumour perfusion index (TPI) was obtained using Patlak-Rutland analysis. Tumour to background (T/B) ratios of both early and delayed images and percent wash-out rate (WR%) of 99mTc-MIBI were calculated. Immunohistochemical analysis of Pgp was performed on biopsy specimens and the degree of expression was graded according to a semiquantitative scoring system, from 0 to 6. After neoadjuvant therapy, tumour response was assessed by examining the ratio of viable cells and by detecting percent necrosis. Scintigraphic results were compared with Pgp status and therapy response. Irrespective of the Pgp status, all patients showed significant perfusion and 99mTc-MIBI uptake in early images. There was not a significant correlation between T/B ratios of early and delayed images and Pgp expression. We observed a positive correlation between WR% and Pgp status (r=0.61, P<0.01), and the wash-out rate of 99mTc-MIBI was significantly higher in patients with high Pgp expression than in those with a low Pgp score (33% +/- 9% vs 17% +/- 9%). Therapy response was determined in 21 of 25 patients, and in only 5 of 21 cases was the percent necrosis more than 90%. Neither Pgp expression rate nor WR% was found to show a significant correlation with percent necrosis in the bulk tumour specimens. In conclusion, the initial uptake of 99mTc-MIBI in bone and soft tissue sarcomas did not correlate with Pgp expression. A relationship was found between the wash-out rate of 99mTc-MIBI and the Pgp score, with a significant difference in WR% being observed between patients with high and patients with low Pgp expression.

Could 99mTc-MIBI be used to visualize the apoptotic MCF7 human breast cancer cells?

Defects in key components of apoptotic pathways provide a survival advantage to cells and have been implicated as important factors in tumorogenesis. As therapeutic drug-induced apoptosis is a key component in treatment of most cancers, alterations in apoptotic pathways may be critical to drug resistance. The question is: would it be possible to distinguish apoptotic cells and resistant cells with a same radiotracer? In this study, we investigated the ability of sodium phenylacetate (NaPa), a natural cytostatic proapoptotic metabolite, to induce apoptosis in MCF7 human breast cancer cells. Then, we tested the 99mTc-MIBI accumulation in these apoptotic cells. Annexin V-FITC was used to identify apoptotic cells by flow cytometry. Ours results demonstrated that a 72 hr treatment of MCF7 cells with 40 mM NaPa induced apoptosis in 60% of cells. In a parallel way, 99mTc-MIBI accumulation in NaPa treated cells decreased for concentrations higher than 20 mM NaPa. Thus, 99mTc-MIBI accumulation decreased correlatively with the increasing percentage of apoptotic cells obtained by treatment of MCF7 cells with NaPa. These data demonstrate that NaPa induced apoptosis in MCF7 cells and that 99mTc-MIBI is a negative tracer of apoptosis: the more MCF7 cells were engaged in the apoptotic pathway, the more 99mTc-MIBI accumulation decreased in these MCF7 apoptotic cells.

Breast carcinoma cell uptake and biodistribution of technetium-99m-carboxymethyl benzylamide dextran.

Carboxymethyl Benzylamide Dextran (CMDB7) displayed an in vitro growth inhibitory activity on breast tumor cells. CMDB7 is able to disrupt the interaction of angiogenic growth factors (FGF2, TGF beta and PDGF) with their membrane receptors. This compound blocks the angiogenesis of MDA-MB435 carcinoma xenografted in mammary fat pad and their lung metastases in nude mice. In this work, we studied the uptake of CMDB7 labeled with 99mTc in cultured human breast cancer MCF-7 cell line and the highly tumorigenic MCF-7ras cell line (Ha-ras-transfected MCF-7 cells) and the in vivo distribution in MCF-7ras tumor-bearing mice. The 99mTc-CMDB7 are stable and the intracellular concentration is time-dependent and reaches a plateau at 180 minutes. 99mTc CMDB7 uptake is much higher in MCF-7ras cells than MCF-7 cells. Since CMDB7 is internalized and could also inhibit cell proliferation by acting at nuclear sites, we investigated the MCF-7ras nuclear localization after cell fractionation. Cell fractionation revealed a cytoplasmic and nuclear internalization of CMDB7. The tumor uptakes of 99mTc-CMDB7 were 0.34%, 0.72% and 0.62% of the administrated doses per gram of tumor tissue at 1 hour, 3 hour and 5 hours respectively after their injection. The blood clearance of 99mTc CMDB7 was very rapid and the liver, spleen and kidney uptakes were very weak. These results confirm the absence of toxicity of CMDB7 and the usefulness of CMDB7 in cancer therapy by targeting breast tumors.

Improving the measurement of the 99Tc(m)-ECD brain perfusion index by temporal analysis.

Matsuda et al. have described a non-invasive method for brain perfusion quantification by computing the ratio of the cumulated counts in the cerebral hemispheres and aortic arch. The regions of interest (ROIs) are drawn manually and are observer dependent. The aim of this study was to develop a new method designed to minimize the intra- and interobserver variability when drawing the different ROIs. A dynamic study was performed as in Matsuda's method on 30 patients using technetium-99m ethyl cysteinate dimer (99Tc(m)-ECD) (ID: 800 MBq+/-33 MBq). The manual method of drawing ROIs was then compared with the following, automated one. A temporal analysis was performed on the cardiac first-pass study to obtain parametric images of the thorax. An ROI of the aortic arch was drawn automatically by means of an isocontour algorithm on the resulting views. The whole sequence was reframed and filtered by a temporal low-pass filter. Hemispheric brain ROIs were delineated on a summed image. Matsuda's algorithm was then applied. Intraobserver variability was evaluated for the classical Matsuda method. The correlation in brain perfusion index (BPI) measurements was r = 0.8976 for naive observers and r = 0.9443 for well-trained observers. Interobserver variability was also evaluated; the correlation was r = 0.7574 for naive observers and r = 0.9190 for well-trained observers. With our proposed method, the correlation in the measurements of BPI for evaluating the intraobserver variability was r = 0.9955 for naive observers and r = 0.9989 for well-trained observers. For interobserver variability, the results were r = 0.9234 for naive observers and r = 0.9230 for well-trained observers. We conclude that temporal analysis allows brain perfusion to be measured in a semi-automatic manner, and improves the reproducibility compared with the original method of Matsuda, particularly for naive observers.