Evaluation of response after SBRT for liver tumors

Stereotactic body radiotherapy (SBRT) has developed over the last few years for the treatment of primary and metastatic hepatic tumors. The tumoral and adjacent peritumoral modifications caused by this radiosurgery limit the evaluation of response by anatomic imaging and dimensional criteria alone, such as with RECIST. This suggests that it is of interest to also take into account the residual enhancement and hyper metabolism of these hepatic targets. We have reviewed the English language literature regarding the response of hepatic lesions treated by SBRT, and found that only seven articles were specifically concerned with this problem.The response of the hepatocellular carcinoma after SBRT has been studied specifically with multiphase enhanced CT-scan. Criteria set by the European Association of Study of the Liver better estimate response at each time point of follow up than RECIST does. Non-enhancement, reflecting tumor necrosis, is additionally an early indicator of response with extended response in time and a best non-enhancement percentage is observed at 12 months. The response after treatment by SBRT of cholangiocarcinoma has not yet generated a specific report.Use of RECIST criteria is also inadequate in the evaluation of response after SBRT for hepatic metastases. Response of liver metastases to SBRT is better assessed with a combination of size and enhancement pattern. The occurrence of a lobulated enhancement during follow up is efficient to predict local progression in a specific, reproducible, and sensitive way. Patients with FDG-avid hepatic metastases are also better evaluated with PET-CT and functional criteria than routine imaging and metric evaluation alone

Detecting the molecular scars of evolution in the Mycobacterium tuberculosis complex by analyzing interrupted coding sequences

<p>Abstract</p> <p>Background</p> <p>Computer-assisted analyses have shown that all bacterial genomes contain a small percentage of open reading frames with a frameshift or in-frame stop codon We report here a comparative analysis of these interrupted coding sequences (ICDSs) in six isolates of <it>M. tuberculosis</it>, two of <it>M. bovis </it>and one of <it>M. africanum </it>and question their phenotypic impact and evolutionary significance.</p> <p>Results</p> <p>ICDSs were classified as "common to all strains" or "strain-specific". Common ICDSs are believed to result from mutations acquired before the divergence of the species, whereas strain-specific ICDSs were acquired after this divergence. Comparative analyses of these ICDSs therefore define the molecular signature of a particular strain, phylogenetic lineage or species, which may be useful for inferring phenotypic traits such as virulence and molecular relationships. For instance, <it>in silico </it>analysis of the W-Beijing lineage of <it>M. tuberculosis</it>, an emergent family involved in several outbreaks, is readily distinguishable from other phyla by its smaller number of common ICDSs, including at least one known to be associated with virulence. Our observation was confirmed through the sequencing analysis of ICDSs in a panel of 21 clinical <it>M. tuberculosis </it>strains. This analysis further illustrates the divergence of the W-Beijing lineage from other phyla in terms of the number of full-length ORFs not containing a frameshift. We further show that ICDS formation is not associated with the presence of a mutated promoter, and suggest that promoter extinction is not the main cause of pseudogene formation.</p> <p>Conclusion</p> <p>The correlation between ICDSs, function and phenotypes could have important evolutionary implications. This study provides population geneticists with a list of targets, which could undergo selective pressure and thus alters relationships between the various lineages of <it>M. tuberculosis </it>strains and their host. This approach could be applied to any closely related bacterial strains or species for which several genome sequences are available.</p

ICDS database: interrupted CoDing sequences in prokaryotic genomes

Unrecognized frameshifts, in-frame stop codons and sequencing errors lead to Interrupted CoDing Sequence (ICDS) that can seriously affect all subsequent steps of functional characterization, from in silico analysis to high-throughput proteomic projects. Here, we describe the Interrupted CoDing Sequence database containing ICDS detected by a similarity-based approach in 80 complete prokaryotic genomes. ICDS can be retrieved by species browsing or similarity searches via a web interface (). The definition of each interrupted gene is provided as well as the ICDS genomic localization with the surrounding sequence. Furthermore, to facilitate the experimental characterization of ICDS, we propose optimized primers for re-sequencing purposes. The database will be regularly updated with additional data from ongoing sequenced genomes. Our strategy has been validated by three independent tests: (i) ICDS prediction on a benchmark of artificially created frameshifts, (ii) comparison of predicted ICDS and results obtained from the comparison of the two genomic sequences of Bacillus licheniformis strain ATCC 14580 and (iii) re-sequencing of 25 predicted ICDS of the recently sequenced genome of Mycobacterium smegmatis. This allows us to estimate the specificity and sensitivity (95 and 82%, respectively) of our program and the efficiency of primer determination

One-tissue compartment model for myocardial perfusion quantification with N-13 ammonia PET provides matching results: A cross-comparison between Carimas, FlowQuant, and PMOD

Purpose To cross-compare three software packages (SPs)-Carimas, FlowQuant, and PMOD-to quantify myocardial perfusion at global, regional, and segmental levels. Materials and Methods Stress N-13 ammonia PET scans of 48 patients with HCM were analyzed in three centers using Carimas, FlowQuant, and PMOD. Values agreed if they had an ICC > 0.75 and a difference < 20% of the median across all observers. Results When using 1TCM on the global level, the agreement was good, and the maximum difference between 1TCM MBF values was 17.2% (ICC = 0.83). On the regional level, the agreement was acceptable except in the LCx region (25.5% difference, ICC = 0.74) between FlowQuant and PMOD. Carimas-1TCM agreed well with PMOD-1TCM and FlowQuant-1TCM. Values obtained with FlowQuant-1TCM had a somewhat lesser agreement with PMOD-1TCM, especially at the segmental level. Conclusions The global and regional MBF values (with one exception) agree well between the different software packages. There is significant variability in segmental values, mainly located in the LCx region and segments. Out of the studied tools, Carimas can be used interchangeably with both PMOD and FlowQuant for 1TCM implementation on all levels-global, regional, and segmental.</p

Myocardial perfusion quantification with Rb-82 PET: good interobserver agreement of Carimas software on global, regional, and segmental levels

PurposeTo estimate the interobserver agreement of the Carimas software package (SP) on global, regional, and segmental levels for the most widely used myocardial perfusion PET tracer-Rb-82.Materials and methodsRest and stress Rb-82 PET scans of 48 patients with suspected or known coronary artery disease (CAD) were analyzed in four centers using the Carimas SP. We considered values to agree if they simultaneously had an intraclass correlation coefficient (ICC) > 0.75 and a difference ResultsThe median values on the segmental level were 1.08 mL/min/g for rest myocardial blood flow (MBF), 2.24 mL/min/g for stress MBF, and 2.17 for myocardial flow reserve (MFR). For the rest MBF and MFR, all the values at all the levels fulfilled were in excellent agreement. For stress MBF, at the global and regional levels, all the 24 comparisons showed excellent agreement. Only 1 out of 102 segmental comparisons (seg. 14) was over the adequate agreement limit-23.5% of the median value (ICC = 0.95).ConclusionInterobserver agreement for Rb-82 PET myocardial perfusion quantification analyzed with Carimas is good at any LV segmentation level-global, regional, and segmental. It is good for all the estimates-rest MBF, stress MBF, and MFR.</p

Theranostic approach in ovarian cancer with anti-AMHR2 radiolabelled antibodies

Le cancer de l’ovaire est la première cause de décès par cancer gynécologique en France et il présente un fort taux de récidive justifiant la recherche de nouvelles thérapeutiques. Notre projet consiste à développer et à explorer sur des modèles expérimentaux précliniques de carcinose péritonéale de nouveaux agents thérapeutiques radiopharmaceutiques et des voies d’administration innovantes ciblant plus particulièrement la maladie résiduelle micro-métastatique présente après chirurgie de cytoréduction. Nous utilisons des anticorps monoclonaux internalisants spécifiques d’un récepteur membranaire surexprimé dans le cancer de l’ovaire et d’autres cancers gynécologiques, le récepteur de type 2 de l’hormone anti-müllerienne (AMHR2). Ces anticorps sont couplés à des radionucléides aux propriétés thérapeutiques : le Lutecium-177 (un émetteur de particules beta moins) et le Bismuth-213 (un émetteur de particules alpha) réalisant un traitement de radioimmunothérapie. Ils sont évalués après injection intrapéritonéale mais également en utilisant la technique RadioImmunoThérapie Intrapéritonéale Brève (BIP-RIT) consistant à instiller de fortes activités d’anticorps radiomarqués dans le péritoine avant d’en réaliser un rinçage abondant, à l’image de la chimiothérapie hyperthermique intrapéritonéale (CHIP). Sont étudiés sur différents modèles la biodistribution, la dosimétrie, la toxicité et l’efficacité thérapeutique des différentes combinaisons de radionucléides et de voies d’administration. La BIP-RIT présente un profil de biodistribution et de dosimétrie toujours favorable, quel que soit le radionucléide utilisé même si l’utilisation du Bismuth-213 apparait plus particulièrement adaptée à cette technique (bonne efficacité thérapeutique avec absence de toxicité). L’imagerie PET/CT de la biodistribution in-vivo de ces anticorps a été réalisée à l’aide de l’émetteur de positrons Zirconium-89 ouvrant la voie à une approche théragnostique du traitement des cancers gynécologiques AMHR2+ par (radio)immunothérapie. Les mécanismes d’action thérapeutique d’une version humanisée de l’anticorps anti-AMHR2 sont également étudiés. Ce travail ouvre des perspectives cliniques intéressantes dans la prise en charge du cancer de l’ovaire.Ovarian cancer is the first cause of cancer death from gynaecologic malignancy in France and it has high rate of recurrence justifying the development of new therapeutic tools. Our project aims at developing new radiopharmaceuticals and innovative route of administration to target the small volume residual disease after complete cytoreductive surgery of peritoneal carcinomatosis on preclinical models. We use internalising monoclonal antibodies specific of the anti-müllerian hormone type 2 receptor (AMHR2), overexpressed in ovarian cancer and gynaecologic malignancies. Antibodies are radiolabelled with Lutecium-177, a beta minus emitter, and Bismuth-213, an alpha emitter, to perform radioimmunotherapy. Radiolabelled antibodies are injected intraperitoneally but also after Brief IntraPeritoneal RadioImmunoTherapy (BIP-RIT), a technique delivering high activities in the peritoneal cavity for a short time before washing, like Hyperthermic IntraPEritoneal Chemotherapy (HIPEC). We studied biodistribution, dosimetry, toxicity and therapeutic efficacy on various models and combinaison of radionuclides and route of administration. BIP-RIT appears to be always favourable in term of biodistribution and dosimetry (especially for the tumour-over-blood ratio) whatever the radionuclide used. Bismuth-213 is particularly adapted for radioimmunotherapy of small residual tumours, showing therapeutic efficacy with no toxicity. PET/CT imaging of radiolabelled antibodies with Zirconium-89 was performed and may be used as a theranostic tool for (radio)immunotherapy with anti-AMHR2 antibodies. The anti-tumour efficacy mechanisms of a humanized version of anti-AMHR2 antibody are also presented. This work may lead to realistic theranostic options in ovarian cancer in clinic

Liver function: homogenous or not?

International audienc

De l'utilisation du 99mTC-Glucarate comme marqueur de l'efficacité thérapeutique de la chimiothérapie sur un modèle animal de tumeur du sein

LYON1-BU Santé (693882101) / SudocSudocFranceF

Evaluation of response after SBRT for liver tumors

International audienceStereotactic body radiotherapy (SBRT) has developed over the last few years for the treatment of primary and metastatic hepatic tumors. The tumoral and adjacent peritumoral modifications caused by this radiosurgery limit the evaluation of response by anatomic imaging and dimensional criteria alone, such as with RECIST. This suggests that it is of interest to also take into account the residual enhancement and hyper metabolism of these hepatic targets. We have reviewed the English language literature regarding the response of hepatic lesions treated by SBRT, and found that only seven articles were specifically concerned with this problem. The response of the hepatocellular carcinoma after SBRT has been studied specifically with multiphase enhanced CT-scan. Criteria set by the European Association of Study of the Liver better estimate response at each time point of follow up than RECIST does. Non-enhancement, reflecting tumor necrosis, is additionally an early indicator of response with extended response in time and a best non-enhancement percentage is observed at 12 months. The response after treatment by SBRT of cholangiocarcinoma has not yet generated a specific report. Use of RECIST criteria is also inadequate in the evaluation of response after SBRT for hepatic metastases. Response of liver metastases to SBRT is better assessed with a combination of size and enhancement pattern. The occurrence of a lobulated enhancement during follow up is efficient to predict local progression in a specific, reproducible, and sensitive way. Patients with FDG-avid hepatic metastases are also better evaluated with PET-CT and functional criteria than routine imaging and metric evaluation alone

AAZTA-Derived Chelators for the Design of Innovative Radiopharmaceuticals with Theranostic Applications

International audienceWith the development of 68Ga and 177Lu radiochemistry, theranostic approaches in modern nuclear medicine enabling patient-centered personalized medicine applications have been growing in the last decade. In conjunction with the search for new relevant molecular targets, the design of innovative chelating agents to easily form stable complexes with various radiometals for theranostic applications has gained evident momentum. Initially conceived for magnetic resonance imaging applications, the chelating agent AAZTA features a mesocyclic seven-membered diazepane ring, conferring some of the properties of both acyclic and macrocyclic chelating agents. Described in the early 2000s, AAZTA and its derivatives exhibited interesting properties once complexed with metals and radiometals, combining a fast kinetic of formation with a slow kinetic of dissociation. Importantly, the extremely short coordination reaction times allowed by AAZTA derivatives were particularly suitable for short half-life radioelements (i.e., 68Ga). In view of these particular characteristics, the scope of this review is to provide a survey on the design, synthesis, and applications in the nuclear medicine/radiopharmacy field of AAZTA-derived chelators