Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

A peripheral dose calculation model for estimating second cancer risk after breast radiotherapy

AbstractBreast cancer is one of the most common cancers affecting one in eight women during their lives. Survival rates have increased steadily thanks to early diagnosis with mammography screening and more efficient treatment strategies. Post-operative radiation therapy is a standard of care in the management of breast cancer and has been shown to reduce efficiently both local recurrence rate and breast cancer mortality. Radiation therapy is however associated with some late effects for long-term survivors. Radiation-induced secondary cancer is a relatively rare but severe late effect of radiation therapy. Currently, radiotherapy plans are essentially optimized to maximize tumor control and minimize late deterministic effects (tissue reactions) that are mainly associated with high doses (» 1 Gy). With improved cure rates and new radiation therapy technologies, it is also important to evaluate and minimize secondary cancer risks for different treatment techniques. This is a particularly challenging task due to the large uncertainties in the dose-response relationship.In contrast with late deterministic effects, secondary cancers may be associated with much lower doses and therefore out-of-field doses (also called peripheral doses) that are typically inferior to 1 Gy need to be determined accurately. Out-of-field doses result from patient scatter and head scatter from the treatment unit. These doses are particularly challenging to compute and we characterized it by Monte Carlo (MC) calculation. A detailed MC model of the Siemens Primus linear accelerator has been thoroughly validated with measurements. We investigated the accuracy of such a model for retrospective dosimetry in epidemiological studies on secondary cancers. Considering that patients in such large studies could be treated on a variety of machines, we assessed the uncertainty in reconstructed peripheral dose due to the variability of peripheral dose among various linac geometries. For large open fields (> 10x10 cm2), the uncertainty would be less than 50%, but for small fields and wedged fields the uncertainty in reconstructed dose could rise up to a factor of 10. It was concluded that such a model could be used for conventional treatments using large open fields only.The MC model of the Siemens Primus linac was then used to compare out-of-field doses for different treatment techniques in a female whole-body CT-based phantom. Current techniques such as conformai wedged-based radiotherapy and hybrid IMRT were investigated and compared to older two-dimensional radiotherapy techniques. MC doses were also compared to those of a commercial Treatment Planning System (TPS). While the TPS is routinely used to determine the dose to the contralateral breast and the ipsilateral lung which are mostly out of the treatment fields, we have shown that these doses may be highly inaccurate depending on the treatment technique investigated. MC shows that hybrid IMRT is dosimetrically similar to three-dimensional wedge-based radiotherapy within the field, but offers substantially reduced doses to out-of-field healthy organs.Finally, many different approaches to risk estimations extracted from the literature were applied to the calculated MC dose distribution. Absolute risks varied substantially as did the ratio of risk between two treatment techniques, reflecting the large uncertainties involved with current risk models. Despite all these uncertainties, the hybrid IMRT investigated resulted in systematically lower cancer risks than any of the other treatment techniques. More epidemiological studies with accurate dosimetry are required in the future to construct robust risk models. In the meantime, any treatment strategy that reduces out-of-field doses to healthy organs should be investigated. Electron radiotherapy might offer interesting possibilities with this regard.RésuméLe cancer du sein affecte une femme sur huit au cours de sa vie. Grâce au dépistage précoce et à des thérapies de plus en plus efficaces, le taux de guérison a augmenté au cours du temps. La radiothérapie postopératoire joue un rôle important dans le traitement du cancer du sein en réduisant le taux de récidive et la mortalité. Malheureusement, la radiothérapie peut aussi induire des toxicités tardives chez les patients guéris. En particulier, les cancers secondaires radio-induits sont une complication rare mais sévère de la radiothérapie. En routine clinique, les plans de radiothérapie sont essentiellement optimisées pour un contrôle local le plus élevé possible tout en minimisant les réactions tissulaires tardives qui sont essentiellement associées avec des hautes doses (» 1 Gy). Toutefois, avec l'introduction de différentes nouvelles techniques et avec l'augmentation des taux de survie, il devient impératif d'évaluer et de minimiser les risques de cancer secondaire pour différentes techniques de traitement. Une telle évaluation du risque est une tâche ardue étant donné les nombreuses incertitudes liées à la relation dose-risque.Contrairement aux effets tissulaires, les cancers secondaires peuvent aussi être induits par des basses doses dans des organes qui se trouvent hors des champs d'irradiation. Ces organes reçoivent des doses périphériques typiquement inférieures à 1 Gy qui résultent du diffusé du patient et du diffusé de l'accélérateur. Ces doses sont difficiles à calculer précisément, mais les algorithmes Monte Carlo (MC) permettent de les estimer avec une bonne précision. Un modèle MC détaillé de l'accélérateur Primus de Siemens a été élaboré et validé avec des mesures. La précision de ce modèle a également été déterminée pour la reconstruction de dose en épidémiologie. Si on considère que les patients inclus dans de larges cohortes sont traités sur une variété de machines, l'incertitude dans la reconstruction de dose périphérique a été étudiée en fonction de la variabilité de la dose périphérique pour différents types d'accélérateurs. Pour de grands champs (> 10x10 cm ), l'incertitude est inférieure à 50%, mais pour de petits champs et des champs filtrés, l'incertitude de la dose peut monter jusqu'à un facteur 10. En conclusion, un tel modèle ne peut être utilisé que pour les traitements conventionnels utilisant des grands champs.Le modèle MC de l'accélérateur Primus a été utilisé ensuite pour déterminer la dose périphérique pour différentes techniques dans un fantôme corps entier basé sur des coupes CT d'une patiente. Les techniques actuelles utilisant des champs filtrés ou encore l'IMRT hybride ont été étudiées et comparées par rapport aux techniques plus anciennes. Les doses calculées par MC ont été comparées à celles obtenues d'un logiciel de planification commercial (TPS). Alors que le TPS est utilisé en routine pour déterminer la dose au sein contralatéral et au poumon ipsilatéral qui sont principalement hors des faisceaux, nous avons montré que ces doses peuvent être plus ou moins précises selon la technTque étudiée. Les calculs MC montrent que la technique IMRT est dosimétriquement équivalente à celle basée sur des champs filtrés à l'intérieur des champs de traitement, mais offre une réduction importante de la dose aux organes périphériques.Finalement différents modèles de risque ont été étudiés sur la base des distributions de dose calculées par MC. Les risques absolus et le rapport des risques entre deux techniques de traitement varient grandement, ce qui reflète les grandes incertitudes liées aux différents modèles de risque. Malgré ces incertitudes, on a pu montrer que la technique IMRT offrait une réduction du risque systématique par rapport aux autres techniques. En attendant des données épidémiologiques supplémentaires sur la relation dose-risque, toute technique offrant une réduction des doses périphériques aux organes sains mérite d'être étudiée. La radiothérapie avec des électrons offre à ce titre des possibilités intéressantes.

Recurrence pattern after [(18)F]fluoroethyltyrosine-positron emission tomography-guided radiotherapy for high-grade glioma: a prospective study.

PURPOSE: To assess the failure pattern observed after (18)F fluoroethyltyrosine (FET) planning after chemo- and radiotherapy (RT) for high-grade glioma. METHODS: All patients underwent prospectively RT planning using morphological gross tumour volumes (GTVs) and biological tumour volumes (BTVs). The post-treatment recurrence tumour volumes (RTVs) of 10 patients were transferred on their CT planning. First, failure patterns were defined in terms of percentage of RTV located outside the GTV and BTV. Second, the location of the RTV with respect to the delivered dose distribution was assessed using the RTV's DVHs. Recurrences with >95% of their volume within 95% isodose line were considered as central recurrences. Finally, the relationship between survival and GTV/BTV mismatches was assessed. RESULTS: The median percentages of RTV outside the GTV and BTV were 41.8% (range, 10.5-92.4) and 62.8% (range, 34.2-81.1), respectively. The majority of recurrences (90%) were centrally located. Using a composite target volume planning formalism, the degree of GTV and BTV mismatch did not correlate with survivorship. CONCLUSIONS: The observed failure pattern after FET-PET planning and chemo-RT is primarily central. The target mismatch-survival data suggest that using FET-PET planning may counteract the possibility of BTV-related progression, which may have a detrimental effect on survival.

Risk of Bronchiolitis Obliterans Syndrome Is Twice as High in Cyclosporine Treated Patients in Comparison to Tacrolimus 3 Years after Lung Transplantation: Results of a Prospective Randomized International Trial of 248 Patients

Purpose: In this prospective randomized study efficacy and safety of two immunosuppressive regimens (Tac, MMF, Steroids vs. CsA, MMF, Steroids) after Lung Transplantation were compared. Primary objective was the incidence of bronchiolitis obliterans syndrome (BOS). Secondary objectives were incidence of acute rejection and infection, survival and adverse events. 248 patients with a complete 3 year follow-up were included in the analysis. Methods and Materials: Patients were randomized to treatment group A: Tac (0.01-0.03 mg/kg/d iv-0.05-0.3 mg/kg/d po) or B: CsA (1-3 mg/kg/d iv-2-8 mg/kg/d po). MMF dose was1-4 mg/d in both groups. No induction therapy was given. Patients were stratified for cystic fibrosis. Intention to treat analysis was performed in patients who were switched to a different immunosuppressive regimen. Results: 3 of 123 Tac patients and 41 of 125 CsA patients were switched to another immunosuppressive regimen and were analyzed as intention to treat. Three year follow-up data of the complete patient cohort were included in this final analysis. Groups showed no difference in demographic data. Kaplan Meier analysis revealed significantly less BOS in Tac treated patients (p=0.033, log rank test, pooled over strata). Cox regression showed a twice as high risk for BOS in the CsA group (factor 2.003). Incidence of acute rejection was 67.5% (Tac) and 75.2% (CsA) (p=0.583). One- and 3-year-survival-rates were not different (85.4% Tac vs. 88.8% CsA, and 80.5% Tac vs. 83.2% CsA, p=n.s.). Incidence of infections and renal failure was similar (p=n.s.). Conclusions: Tac significantly reduced the risk for BOS after 3 years in this intention to treat analysis. Both regimens have a good immunosuppressive potential and offer a similar safety profile with excellent one and three year survival rates. Acute rejection rates were similar in both groups. Incidence of infections and renal failure showed no difference.

High antigen concentration inhibits T cell proliferation but not interleukin 2 production: examination of limiting dilution microcultures and T cell clones.

The effect of high antigen dose on the activation of cytochrome c peptide-primed lymph node cells was determined in several strains of mice by a limiting dilution analysis. It was found that proliferation of cytochrome c peptide-specific T cells was completely inhibited at high antigen concentration in C57BL/6 but only partially in DBA mice and had no effect in SJL mice. Clones derived from DBA mice showed a differential capacity to be inhibited by high antigen dose. On the other hand, interleukin 2 production by these clones was not impaired regardless of the antigen concentrations used.

Replacement of (R)-methadone by a double dose of (R,S)-methadone in addicts: interindividual variability of the (R)/(S) ratios and evidence of adaptive changes in methadone pharmacokinetics.

METHODS: Twenty-two patients receiving (R)-methadone maintenance treatment were switched to a double dose of (R,S)-methadone: blood samples were collected before and after the change, and the concentrations of the enantiomers were measured. In the second period, during racemic methadone treatment, important interindividual variability in the stereoselective disposition of the enantiomers of methadone was measured, with (R)/(S) ratios ranging from 0.63 to 2.40. This point should be taken into account particularly with respect to therapeutic drug monitoring of racemic methadone. RESULTS: A significant decrease P < 0.005 in the mean serum concentration/dose ratios of the active (R)-enantiomer before and after the change was measured (mean 3.97 and 3.33). CONCLUSION: Although of small amplitude (16%), this decrease confirms previously described adaptive changes in methadone pharmacokinetics during racemic methadone maintenance treatment and may necessitate, in some patients, a dose adjustment.

Objective comparison of image quality and dose between conventional and synchrotron radiation mammography.

The shape of the energy spectrum produced by an x-ray tube has a great importance in mammography. Many anode-filtration combinations have been proposed to obtain the most effective spectrum shape for the image quality-dose relationship. On the other hand, third generation synchrotrons such as the European Synchrotron Radiation Facility in Grenoble are able to produce a high flux of monoenergetic radiation. It is thus a powerful tool to study the effect of beam energy on image quality and dose in mammography. An objective method was used to evaluate image quality and dose in mammography with synchrotron radiation and to compare them to standard conventional units. It was performed systematically in the energy range of interest for mammography through the evaluation of a global image quality index and through the measurement of the mean glandular dose. Compared to conventional mammography units, synchrotron radiation shows a great improvement of the image quality-dose relationship, which is due to the beam monochromaticity and to the high intrinsic collimation of the beam, which allows the use of a slit instead of an anti-scatter grid for scatter rejection.

Low-dose multidetector computed tomography of the cervical spine: optimization of iterative reconstruction strength levels.

BACKGROUND: Iterative reconstruction (IR) techniques reduce image noise in multidetector computed tomography (MDCT) imaging. They can therefore be used to reduce radiation dose while maintaining diagnostic image quality nearly constant. However, CT manufacturers offer several strength levels of IR to choose from. PURPOSE: To determine the optimal strength level of IR in low-dose MDCT of the cervical spine. MATERIAL AND METHODS: Thirty consecutive patients investigated by low-dose cervical spine MDCT were prospectively studied. Raw data were reconstructed using filtered back-projection and sinogram-affirmed IR (SAFIRE, strength levels 1 to 5) techniques. Image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured at C3-C4 and C6-C7 levels. Two radiologists independently and blindly evaluated various anatomical structures (both dense and soft tissues) using a 4-point scale. They also rated the overall diagnostic image quality using a 10-point scale. RESULTS: As IR strength levels increased, image noise decreased linearly, while SNR and CNR both increased linearly at C3-C4 and C6-C7 levels (P < 0.001). For the intervertebral discs, the content of neural foramina and dural sac, and for the ligaments, subjective image quality scores increased linearly with increasing IR strength level (P ≤ 0.03). Conversely, for the soft tissues and trabecular bone, the scores decreased linearly with increasing IR strength level (P < 0.001). Finally, the overall diagnostic image quality scores increased linearly with increasing IR strength level (P < 0.001). CONCLUSION: The optimal strength level of IR in low-dose cervical spine MDCT depends on the anatomical structure to be analyzed. For the intervertebral discs and the content of neural foramina, high strength levels of IR are recommended.

Irradiation corporelle totale : présent et avenir [Total body irradiation: present and future]

Total body irradiation (TBI) has an established role as preparative regimen for bone-marrow transplantation in the treatment of hematological malignancies. Many randomized trials demonstrated that the clinical outcomes obtained from the association of TBI and cyclophosphamide are equivalent, or, sometimes, better than those based on chemotherapeutic agents. Despite the therapeutic progress of the last years, and the consequent improvement in the overall survival, this preparative regimen remains always associated with a relatively high rate of acute and late toxicity. In this article, we review the actual indications of TBI in clinical practice, and analyze the technological progress in this domain. We focus on the hypothesis that a selective irradiation of the hematopoietic or lymphoid organs is actually possible with intensity-modulated radiotherapy. Technical limits and preliminary results in terms of acute and late toxicities of intensity-modulated TBI are analyzed. With these new technologies, treatment-related toxicity is not anymore a major limiting factor in the preparative regimens for bone-marrow transplantation, allowing for a larger spectrum of TBI indications, a possible extension to patients older than 50 years, or a dose escalation. Preliminary results warrant, however, further evaluation in clinical trials to better assess the impact of this new approach on disease control and the long-term toxicity.

T-cell activation by treatment of cancer patients with EMD 521873 (Selectikine), an IL-2/anti-DNA fusion protein.

ABSTRACT: BACKGROUND: EMD 521873 (Selectikine or NHS-IL2LT) is a fusion protein consisting of modified human IL-2 which binds specifically to the high-affinity IL-2 receptor, and an antibody specific for both single- and double-stranded DNA, designed to facilitate the enrichment of IL-2 in tumor tissue. METHODS: An extensive analysis of pharmacodynamic (PD) markers associated with target modulation was assessed during a first-in-human phase I dose-escalation trial of Selectikine. RESULTS: Thirty-nine patients with metastatic or locally advanced tumors refractory to standard treatments were treated with increasing doses of Selectikine, and nine further patients received additional cyclophosphamide. PD analysis, assessed during the first two treatment cycles, revealed strong activation of both CD4+ and CD8+ T-cells and only weak NK cell activation. No dose response was observed. As expected, Treg cells responded actively to Selectikine but remained at lower frequency than effector CD4+ T-cells. Interestingly, patient survival correlated positively with both high lymphocyte counts and low levels of activated CD8+ T-cells at baseline, the latter of which was associated with enhanced T-cell responses to the treatment. CONCLUSIONS: The results confirm the selectivity of Selectikine with predominant T-cell and low NK cell activation, supporting follow-up studies assessing the clinical efficacy of Selectikine for cancer patients.

Single-dose oral amoxicillin or linezolid for prophylaxis of experimental endocarditis due to vancomycin-susceptible and vancomycin-resistant Enterococcus faecalis.

Endocarditis prophylaxis following genitourinary or gastrointestinal procedures targets Enterococcus faecalis. Prophylaxis recommendations advocate oral amoxicillin (2 g in the United States and 3 g in the United Kingdom) in moderate-risk patients and intravenous amoxicillin (2 g) or vancomycin (1 g) plus gentamicin in high-risk patients. While ampicillin-resistant (or amoxicillin-resistant) E. faecalis is still rare, there is a concern that these regimens might fail against vancomycin-resistant and/or aminoglycoside-resistant isolates. The present study tested oral linezolid as an alternative. Rats with catheter-induced aortic vegetations were given prophylaxis simulating human pharmacokinetics of oral amoxicillin (2- to 3-g single dose), oral linezolid (600 mg, single or multiple oral doses every 12 h), or intravenous vancomycin (1-g single dose). Rats were then inoculated with the minimum inoculum infecting 90% of the animals (90% infective dose [ID(90)]) or with 10 times the ID(90) of the vancomycin-susceptible E. faecalis strain JH2-2 or the vancomycin-resistant (VanA phenotype) E. faecalis strain UCN41. Amoxicillin was also tested with two additional vancomycin-susceptible E. faecalis strains, 309 and 1209. Animals were sacrificed 3 days later. All the tested bacteria were susceptible to amoxicillin and gentamicin. Single-dose amoxicillin provided 100% protection against all four isolates at both the ID(90) and 10 times the ID(90). In contrast, linezolid required up to four consecutive doses to provide full protection against the vancomycin-resistant isolate. Vancomycin protected only against the vancomycin-susceptible strain. The high efficacy of single-dose oral amoxicillin suggests that this regimen could be used for prophylaxis in both moderate-risk and high-risk patients without additional aminoglycosides. Linezolid appears to be less reliable, at least against the vancomycin-resistant strain.

Dose reconstruction in the context of tomotherapy

In vivo dosimetry is a way to verify the radiation dose delivered to the patient in measuring the dose generally during the first fraction of the treatment. It is the only dose delivery control based on a measurement performed during the treatment. In today's radiotherapy practice, the dose delivered to the patient is planned using 3D dose calculation algorithms and volumetric images representing the patient. Due to the high accuracy and precision necessary in radiation treatments, national and international organisations like ICRU and AAPM recommend the use of in vivo dosimetry. It is also mandatory in some countries like France. Various in vivo dosimetry methods have been developed during the past years. These methods are point-, line-, plane- or 3D dose controls. A 3D in vivo dosimetry provides the most information about the dose delivered to the patient, with respect to ID and 2D methods. However, to our knowledge, it is generally not routinely applied to patient treatments yet. The aim of this PhD thesis was to determine whether it is possible to reconstruct the 3D delivered dose using transmitted beam measurements in the context of narrow beams. An iterative dose reconstruction method has been described and implemented. The iterative algorithm includes a simple 3D dose calculation algorithm based on the convolution/superposition principle. The methodology was applied to narrow beams produced by a conventional 6 MV linac. The transmitted dose was measured using an array of ion chambers, as to simulate the linear nature of a tomotherapy detector. We showed that the iterative algorithm converges quickly and reconstructs the dose within a good agreement (at least 3% / 3 mm locally), which is inside the 5% recommended by the ICRU. Moreover it was demonstrated on phantom measurements that the proposed method allows us detecting some set-up errors and interfraction geometry modifications. We also have discussed the limitations of the 3D dose reconstruction for dose delivery error detection. Afterwards, stability tests of the tomotherapy MVCT built-in onboard detector was performed in order to evaluate if such a detector is suitable for 3D in-vivo dosimetry. The detector showed stability on short and long terms comparable to other imaging devices as the EPIDs, also used for in vivo dosimetry. Subsequently, a methodology for the dose reconstruction using the tomotherapy MVCT detector is proposed in the context of static irradiations. This manuscript is composed of two articles and a script providing further information related to this work. In the latter, the first chapter introduces the state-of-the-art of in vivo dosimetry and adaptive radiotherapy, and explains why we are interested in performing 3D dose reconstructions. In chapter 2 a dose calculation algorithm implemented for this work is reviewed with a detailed description of the physical parameters needed for calculating 3D absorbed dose distributions. The tomotherapy MVCT detector used for transit measurements and its characteristics are described in chapter 3. Chapter 4 contains a first article entitled '3D dose reconstruction for narrow beams using ion chamber array measurements', which describes the dose reconstruction method and presents tests of the methodology on phantoms irradiated with 6 MV narrow photon beams. Chapter 5 contains a second article 'Stability of the Helical TomoTherapy HiArt II detector for treatment beam irradiations. A dose reconstruction process specific to the use of the tomotherapy MVCT detector is presented in chapter 6. A discussion and perspectives of the PhD thesis are presented in chapter 7, followed by a conclusion in chapter 8. The tomotherapy treatment device is described in appendix 1 and an overview of 3D conformai- and intensity modulated radiotherapy is presented in appendix 2. - La dosimétrie in vivo est une technique utilisée pour vérifier la dose délivrée au patient en faisant une mesure, généralement pendant la première séance du traitement. Il s'agit de la seule technique de contrôle de la dose délivrée basée sur une mesure réalisée durant l'irradiation du patient. La dose au patient est calculée au moyen d'algorithmes 3D utilisant des images volumétriques du patient. En raison de la haute précision nécessaire lors des traitements de radiothérapie, des organismes nationaux et internationaux tels que l'ICRU et l'AAPM recommandent l'utilisation de la dosimétrie in vivo, qui est devenue obligatoire dans certains pays dont la France. Diverses méthodes de dosimétrie in vivo existent. Elles peuvent être classées en dosimétrie ponctuelle, planaire ou tridimensionnelle. La dosimétrie 3D est celle qui fournit le plus d'information sur la dose délivrée. Cependant, à notre connaissance, elle n'est généralement pas appliquée dans la routine clinique. Le but de cette recherche était de déterminer s'il est possible de reconstruire la dose 3D délivrée en se basant sur des mesures de la dose transmise, dans le contexte des faisceaux étroits. Une méthode itérative de reconstruction de la dose a été décrite et implémentée. L'algorithme itératif contient un algorithme simple basé sur le principe de convolution/superposition pour le calcul de la dose. La dose transmise a été mesurée à l'aide d'une série de chambres à ionisations alignées afin de simuler la nature linéaire du détecteur de la tomothérapie. Nous avons montré que l'algorithme itératif converge rapidement et qu'il permet de reconstruire la dose délivrée avec une bonne précision (au moins 3 % localement / 3 mm). De plus, nous avons démontré que cette méthode permet de détecter certaines erreurs de positionnement du patient, ainsi que des modifications géométriques qui peuvent subvenir entre les séances de traitement. Nous avons discuté les limites de cette méthode pour la détection de certaines erreurs d'irradiation. Par la suite, des tests de stabilité du détecteur MVCT intégré à la tomothérapie ont été effectués, dans le but de déterminer si ce dernier peut être utilisé pour la dosimétrie in vivo. Ce détecteur a démontré une stabilité à court et à long terme comparable à d'autres détecteurs tels que les EPIDs également utilisés pour l'imagerie et la dosimétrie in vivo. Pour finir, une adaptation de la méthode de reconstruction de la dose a été proposée afin de pouvoir l'implémenter sur une installation de tomothérapie. Ce manuscrit est composé de deux articles et d'un script contenant des informations supplémentaires sur ce travail. Dans ce dernier, le premier chapitre introduit l'état de l'art de la dosimétrie in vivo et de la radiothérapie adaptative, et explique pourquoi nous nous intéressons à la reconstruction 3D de la dose délivrée. Dans le chapitre 2, l'algorithme 3D de calcul de dose implémenté pour ce travail est décrit, ainsi que les paramètres physiques principaux nécessaires pour le calcul de dose. Les caractéristiques du détecteur MVCT de la tomothérapie utilisé pour les mesures de transit sont décrites dans le chapitre 3. Le chapitre 4 contient un premier article intitulé '3D dose reconstruction for narrow beams using ion chamber array measurements', qui décrit la méthode de reconstruction et présente des tests de la méthodologie sur des fantômes irradiés avec des faisceaux étroits. Le chapitre 5 contient un second article intitulé 'Stability of the Helical TomoTherapy HiArt II detector for treatment beam irradiations'. Un procédé de reconstruction de la dose spécifique pour l'utilisation du détecteur MVCT de la tomothérapie est présenté au chapitre 6. Une discussion et les perspectives de la thèse de doctorat sont présentées au chapitre 7, suivies par une conclusion au chapitre 8. Le concept de la tomothérapie est exposé dans l'annexe 1. Pour finir, la radiothérapie «informationnelle 3D et la radiothérapie par modulation d'intensité sont présentées dans l'annexe 2.

Managing hypertension in high-risk patients: lessons and promises from the STRATHE and ADVANCE trials.

Pharmacological treatment of hypertension represents a cost-effective way of preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment, blood pressure should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Such targets cannot usually be reached using monotherapies. This is especially true in patients who present with a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases the blood pressure control rate. Such combinations are not only efficacious, but are also well tolerated, and some fixed low-dose combinations even have a placebo-like tolerability. This is the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has been shown in controlled trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving the stiffness of large arteries. Using this combination to initiate antihypertensive therapy has been shown in a double-blind trial (Strategies of Treatment in Hypertension: Evaluation; STRATHE) to normalize blood pressure (< 140/90 mmHg) in significantly more patients (62%) than a sequential monotherapy approach based on atenolol, losartan and amlodipine (49%) and a stepped-care strategy based on valsartan and hydrochlorothiazide (47%), with no difference between the three arm groups in terms of tolerability. An ongoing randomized trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ADVANCE) is a study with a 2 x 2 factorial design assessing the effects of the fixed-dose perindopril-indapamide combination and of the intensive gliclazide modified release-based glucose control regimen in type 2 diabetic patients, with or without hypertension. A total of 11 140 patients were randomly selected. Within the first 6 weeks of treatment (run-in phase), the perindopril-indapamide combination lowered blood pressure from 145/81 +/- 22/11 mmHg (mean +/- SD) to 137/78 +/- 20/10 mmHg. Fixed-dose combinations are becoming more and more popular for the management of hypertension, and are even proposed by hypertension guidelines as a first-line option to treat hypertensive patients.

Management of patient dose and image noise in routine pediatric CT abdominal examinations.

The aim was to propose a strategy for finding reasonable compromises between image noise and dose as a function of patient weight. Weighted CT dose index (CTDI(w)) was measured on a multidetector-row CT unit using CTDI test objects of 16, 24 and 32 cm in diameter at 80, 100, 120 and 140 kV. These test objects were then scanned in helical mode using a wide range of tube currents and voltages with a reconstructed slice thickness of 5 mm. For each set of acquisition parameter image noise was measured and the Rose model observer was used to test two strategies for proposing a reasonable compromise between dose and low-contrast detection performance: (1) the use of a unique noise level for all test object diameters, and (2) the use of a unique dose efficacy level defined as the noise reduction per unit dose. Published data were used to define four weight classes and an acquisition protocol was proposed for each class. The protocols have been applied in clinical routine for more than one year. CTDI(vol) values of 6.7, 9.4, 15.9 and 24.5 mGy were proposed for the following weight classes: 2.5-5, 5-15, 15-30 and 30-50 kg with image noise levels in the range of 10-15 HU. The proposed method allows patient dose and image noise to be controlled in such a way that dose reduction does not impair the detection of low-contrast lesions. The proposed values correspond to high- quality images and can be reduced if only high-contrast organs are assessed.

Therapeutic Drug Monitoring (TDM) of Imatinib: Effectiveness of Bayesian dose adjustment for CML patients enrolled in the Imatinib Concentration Monitoring (I-COME) study

Introduction: As imatinib pharmacokinetics are highly variable, plasma levels differ largely between patients under the same dosage. Retrospective studies in chronic myeloid leukemia (CML) patients showed significant correlations between low levels and suboptimal response, as well as between high levels and poor tolerability. Monitoring of trough plasma levels, targeting 1000 μg/L and above, is thus increasingly advised. Our study was launched to assess prospectively the clinical usefulness of systematic imatinib TDM in CML patients. This preliminary analysis addresses the appropriateness of the dosage adjustment approach applied in this study, which targets the recommended trough level and allows an interval of 4-24 h after last drug intake for blood sampling. Methods: Blood samples from the first 15 patients undergoing 1st TDM were obtained 1.5-25 h after last dose. Imatinib plasma levels were measured by LC-MS/MS and the concentrations were extrapolated to trough based on a Bayesian approach using a population pharmacokinetic model. Trough levels were predicted to differ significantly from the target in 12 patients (10 <750 μg/L; 2 >1500 μg/L along with poor tolerance) and individual dose adjustments were proposed. 8 patients underwent a 2nd TDM cycle. Trough levels of 1st and 2nd TDM were compared, the sample drawn 1.5 h after last dose (during distribution phase) was excluded from the analysis. Results: Individual dose adjustments were applied in 6 patients. Observed concentrations extrapolated to trough ranged from 360 to 1832 μg/L (median 725; mean 810, CV 52%) on 1st TDM and from 720 to 1187 μg/L (median 950; mean 940, CV 18%) on 2nd TDM cycle. Conclusions: These preliminary results suggest that TDM of imatinib using a Bayesian interpretation is able to target the recommended trough level of 1000 μg/L and to reduce the considerable differences in trough level exposure between patients (with CV decreasing from 52% to 18%). While this may simplify blood collection in daily practice, as samples do not have to be drawn exactly at trough, the largest possible interval to last drug intake yet remains preferable to avoid sampling during distribution phase leading to biased extrapolation. This encourages the evaluation of the clinical benefit of a routine TDM intervention in CML patients, which the randomized Swiss I-COME trial aims to.