Review of the results of the in vivo dosimetry during total skin electron beam therapy

This work reviews results of in vivo dosimetry (IVD) for total skin electron beam (TSEB) therapy, focusing on new methods, data emerged within 2012. All quoted data are based on a careful review of the literature reporting IVD results for patients treated by means of TSEB therapy. Many of the reviewed papers refer mainly to now old studies and/or old guidelines and recommendations (by IAEA, AAPM and EORTC), because (due to intrinsic rareness of TSEB-treated pathologies) only a limited number of works and reports with a large set of numerical data and proper statistical analysis is up-to-day available in scientific literature. Nonetheless, a general summary of the results obtained by the now numerous IVD techniques available is reported; innovative devices and methods, together with areas of possible further and possibly multicenter investigations for TSEB therapies are highlighted

Naphthofuranone derivatives as specific inhibitors of thymidylate synthases

Synthetic compounds of 1, 2 -naphthalein molecules (I) having specific inhibitory properties of the enzymatic activity of thymidylate synthases of bacterial species, their preparation, their pharmaceutical composition and use in the treatment and prophylaxis of infectious pathologies are disclosed

Transvaginal ultrasound assessment of uterine scar after previous caesarean section: comparison with 3T-magnetic resonance diffusion tensor imaging

This study aimed to evaluate 3-T magnetic resonance imaging in the analysis of caesarean scars in women with prior caesarean section (pCS) and investigate the potential added value of diffusion tensor imaging (3T-MR-DTI) with fibre tracking reconstruction, compared with transvaginal ultrasound (TVUS). Thirty women who had previously undergone elective CS in a singleton pregnancy at term were examined (19 women with one pCS formed group 1 and 11 women with two pCS formed group 2). Patients underwent TVUS and 3T-MR-DTI within 2 days. Twelve women with prior vaginal delivery served as controls and underwent only 3T-MR. Uterine fibre architecture was depicted by MR-DTI with 3D tractography reconstruction providing quali-quantitative analysis of fibre, described as the reduction of number of longitudinal fibres that run through the uterine scar. Six subjects were excluded. According to 3T-MR morphology, scars were described as linear (n = 12) and retracting (n = 12); disagreement with TVUS was 54 %. The thickness of myometrium at the scar level was found to be significantly greater with 3T-MR compared to TVUS in linear scars (p = 0.01). No difference was found among retracting scars. In controls, according to 3T-MR-DTI, longitudinal myometrial fibres running in the anterior wall were similar to those in the posterior wall at same level -2 %; -27 % + 22 %). In groups 1 and 2 there was significant reduction in anterior fibres compared to posterior ones (-53 %; -77 % - 34 %; p = 0.0001). Among retracting scars, fibre reduction was significantly higher compared to linear scars, p < 0.016. The added value of 3T-MR with DTI lies in the prompt evaluation of muscle fibre remaining at scar level

New Thymidylate synthase inhibitor induces apoptosis in melanoma cell lines.

Malignant melanoma is an aggressive disease and its rapidly increasing world-wide. This type of tumor is particularly resistant to conventional chemotherapy and radiotherapy. For this reason in the last years has been developed a variety of a new chemotherapeutic agents. We investigated the action in vitro of four experimental antifolate substances (MR7, MR2, MR36 and NMR707) with a critical target for thymidylate synthase (TS), an essential enzyme for DNA synthesis. These compounds behave as antifolate but show a new structure with respect to all know antifolato agents. We studied how these substances may influence apoptosis in melanoma cell lines SK-MEL-2 (derived from malignant melanoma metastasis) and SK-MEL-28 (derived from primary malignant melanoma).The antifolate agents induced apoptosis in SK-MEL-2 and SK-MEL-28 cells as confirmed by TUNEL technique and Comet Assay. Western-blot analysis showed down regulation of Bcl-2 protein level, up-regulation of p21 and Bax protein level and PARP cleavage especially for MR36, MR7 and MR21. Moreover, these antifolate-induced apoptosis was accompanied by caspase-9 and -8 activation. In addition, a different sensibility for apoptosis was observed for the two cell lines. In fact, in primary melanoma cells, apoptosis occurred also at low concentrations especially for MR7 and MR36. Our results show that TS inhibitors are able to induce apoptosis and for this reason may play a potential role as new therapeutic agents for melanoma, but further studies are necessary to understand their molecular mechanism

TSI INDUCES APOPTOSIS WITH A P53 INDIPENDENT PATHWAY IN MELANOMA CELL LINES AND IN NORMAL HUMAN MELANOCITES

Melanoma patients have a very poor prognosis and this type of tumor is particular resistant toconventional chemotherapy and radiotherapy. For this reason in the last years has beendeveloped a variety of new therapeutic agents. We investigated four experimental antifolatesubstances (MR7, MR36, MR21 and NMR707) with a critical target for thymidylate synthase(TS), an essential enzyme for DNA synthesis and repair. All the compounds were tested fortheir inhibitory properties against TS enzymes from different species: Lactobacillus casei,Pneumocystis carinii, Cryptococcus neoformans and human. These compounds behave asantifolates but show new structure with respect to all known antifolate agents. We studiedhow these substances may influence apoptosis in melanoma cell lines SKmel 2 (derived frommalignant melanoma metastasis) and SKmel 28 (derived from primary malignant melanoma)and normal human melanocytes. The antifolate agents induced apoptosis in Skmel 2 andSkmel 28 cells. These results were confirmed by Comet Assay. Western blot analysis showeddown regulation of the level of Bcl2 and PARP clivage especially for MR36, MR7 and MR21.Moreover a different apoptotic behaviour for the two cell lines was observed, in fact inprimary melanoma cells apoptosis occurred also at low concentrations especially for MR7.After chemotherapeutic treatment with all the tested compounds p53 was not modulatedindicating a p53 independent pathway for apoptosis. Caspases 8 and 9 clearly mediateantifolate agents apoptosis independent of the status of p53. Our results show that TSinhibitors inducing apoptosis may play a future potential role as new therapeutic agents formelanoma, but further studies are necessary to understand their molecular mechanism

Pharmacological and toxicological evaluation of a new series of thymidylate synthase inhibitors as anticancer agents

Thymidylate synthase (TS) is responsible for catalysing the de novo biosynthesis of doexythymidine monophosphate and is a target for many anticancer drugs. A series of thymidylate synthase inhibitors (TSIs), synthesised in our laboratory, were submitted to primary anticancer screening by the National Cancer Institute (NCI). Four compounds, 3,3bis(4-methoxyphenyl)-1H, 3H-naphtho[1,8-cd]pyran-1-one (MR7), 6-chloro-3,3-bis(4-hydroxyphenyl)-]H,3H-naphtho[1,8cdjpyran-1-one (MR21), 3,3-bis(3-fluoro-4-hydroxyphenyl)IH,3H-naphtho[1,8-cd]pyran-l-one (MR35) and 6-bromo-3,3bis(3-chloro-4-hydro.xyphenyl)-1H,3H-naphtho[1,8-cd]pyran-l- one (MR36), passed the criteria and were automatically scheduled for evaluation against the full panel of 60 human tumour cell lines. In this study, the antiproliferative activity of the substances against SK-MEL-2 cells (from metastatic tissue) and SK-MEL-28 cells (from primary malignant melanoma cells) was investigated. Neutral Red uptake and the MTT test were performed to confirm the results of the NCI, and [H-3]thymidine incorporation was performed as a test of the proliferation rate. Our results indicated that compounds MR21 and MR36 were the most active agents and the [H-3]-thymidine test was the best in predicting toxicity against melanoma cells

A support vector machine tool for adaptive tomotherapy treatments: Prediction of head and neck patients criticalities

Adaptive radiation therapy (ART) is an advanced field of radiation oncology. Image-guided radiation therapy (IGRT) methods can support daily setup and assess anatomical variations during therapy, which could prevent incorrect dose distribution and unexpected toxicities. A re-planning to correct these anatomical variations should be done daily/weekly, but to be applicable to a large number of patients, still require time consumption and resources. Using unsupervised machine learning on retrospective data, we have developed a predictive network, to identify patients that would benefit of a re-planning.1200 MVCT of 40 head and neck (H&N) cases were re-contoured, automatically, using deformable hybrid registration and structures mapping. Deformable algorithm and MATLAB(®) homemade machine learning process, developed, allow prediction of criticalities for Tomotherapy treatments.Using retrospective analysis of H&N treatments, we have investigated and predicted tumor shrinkage and organ at risk (OAR) deformations. Support vector machine (SVM) and cluster analysis have identified cases or treatment sessions with potential criticalities, based on dose and volume discrepancies between fractions. During 1st weeks of treatment, 84% of patients shown an output comparable to average standard radiation treatment behavior. Starting from the 4th week, significant morpho-dosimetric changes affect 77% of patients, suggesting need for re-planning. The comparison of treatment delivered and ART simulation was carried out with receiver operating characteristic (ROC) curves, showing monotonous increase of ROC area.Warping methods, supported by daily image analysis and predictive tools, can improve personalization and monitoring of each treatment, thereby minimizing anatomic and dosimetric divergences from initial constraints

Expert system classifier for adaptive radiation therapy in prostate cancer

A classifier-based expert system was developed to compare delivered and planned radiation therapy in prostate cancer patients. Its aim is to automatically identify patients that can benefit from an adaptive treatment strategy. The study predominantly addresses dosimetric uncertainties and critical issues caused by motion of hollow organs. 1200 MVCT images of 38 prostate adenocarcinoma cases were analyzed. An automatic daily re-contouring of structures (i.e. rectum, bladder and femoral heads), rigid/deformable registration and dose warping was carried out to simulate dose and volume variations during therapy. Support vector machine, K-means clustering algorithms and similarity index analysis were used to create an unsupervised predictive tool to detect incorrect setup and/or morphological changes as a consequence of inadequate patient preparation due to stochastic physiological changes, supporting clinical decision-making. After training on a dataset that was considered sufficiently dosimetrically stable, the system identified two equally sized macro clusters with distinctly different volumetric and dosimetric baseline properties and defined thresholds for these two clusters. Application to the test cohort resulted in 25% of the patients located outside the two macro clusters thresholds and which were therefore suspected to be dosimetrically unstable. In these patients, over the treatment course, mean volumetric changes of 30 and 40% for rectum and bladder were detected which possibly represents values justifying adjustment of patient preparation, frequent re-planning or a plan-of-the-day strategy. Based on our research, by combining daily IGRT images with rigid/deformable registration and dose warping, it is possible to apply a machine learning approach to the clinical setting obtaining useful information for a decision regarding an individualized adaptive strategy. Especially for treatments influenced by the movement of hollow organs, this could reduce inadequate treatments and possibly reduce toxicity, thereby increasing overall RT efficacy

Intra-fraction motion in IMRT, VMAT and helical tomotherapy: In vivo dosimetry using TLD and LEGO phantom

Introduction: During free-breathing arbitrary phase, a mean motion reconstruction is acquired using not gated CT. The lack of knowledge of the tumor and organs at risk (OAR) location can generate possible random/systematic errors during RT treatment. A home-made anthropomorphic dynamic phantom was developed to assess, by TLD, the breathing of the lung district and to quantify the dose variation due to intra-fraction motion. Materials and Methods: Respiratory motion was simulated by a LEGO Mindstorms phantom, programmed in LabVIEW and equipped by 8 ribs, 1 OAR and 1 target with 4 degree of freedom. Within a treatment of 40 cGy, 3 planning strategies were compared. Static (S): CT acquired and plan delivered with phantom in static mode. Static-Real (SR): equal to the S condition but plan delivered with human breathing condition. Dynamic (D): 4DCT with breathing phantom and plan based on Maximum Intensity Projection (MIP) and the ITV generated by the junction of the target contoured in each phases. For each CT were planned and delivered an IMRT, VMAT and Helical plan to uniformly irradiate the target. Dosimetry was made using TLD GR-200 (LiF:Mg,Cu,P). Results: For each technique, data were normalized to the S IMRT plan. In SR condition, the dose delivered to the target was 89.2 ± 6.6%. Due to the motion of the target, TLD measure confirms the uncorrected dose distribution related with the plan. Between the 3 techniques, the Helical plan allows reaching a greater coverage probably due to the kinetic behavior with slow machine rotation. In D condition, the dose delivered to the target was 93.5 ± 5.1%. The internal motion was partially accounted with ITV density re-assignment. Conclusions: Respiratory motion is often assumed to be the same during CT and RT cycles. However, due to contraction of the thoracic diaphragm muscle, it can be slightly different. In this study, a dynamic phantom and TLD measures have quantified the error and dose distribution in a simulated lung treatment