1H-NMR plasma lipoproteins profile analysis reveals lipid metabolism alterations in HER2-positive breast cancer patients

The lipid tumour demand may shape the host metabolism adapting the circulating lipids composition to its growth and progression needs. This study aims to exploit the straightforward 1 H-NMR lipoproteins analysis to investigate the alterations of the circulating lipoproteins’ fractions in HER2-positive breast cancer and their modulations induced by treatments. The baseline1H-NMR plasma lipoproteins profiles were measured in 43 HER2-positive breast cancer patients and compared with those of 28 healthy women. In a subset of 32 patients, longitudinal measurements were also performed along neoadjuvant chemotherapy, after surgery, adjuvant treatment, and during the two-year follow-up. Differences between groups were assessed by multivariate PLS-DA and by univariate analyses. The diagnostic power of lipoproteins subfractions was assessed by ROC curve, while lipoproteins time changes along interventions were investigated by ANOVA analysis. The PLS-DA model distinguished HER2-positive breast cancer patients from the control group with a sensitivity of 96.4% and specificity of 90.7%, mainly due to the differential levels of VLDLs subfractions that were significantly higher in the patients' group. Neoadjuvant chemotherapy-induced a significant drop in the HDLs after the first three months of treatment and a specific decrease in the HDL-3 and HDL-4 subfractions were found significantly associated with the pathological complete response achievement. These results indicate that HER2-positive breast cancer is characterized by a significant host lipid mobilization that could be useful for diagnostic purposes. Moreover, the lipoproteins profiles alterations induced by the therapeutic interventions could predict the clinical outcome supporting the application of1H-NMR lipoproteins profiles analysis for longitudinal monitoring of HER2-positive breast cancer in large clinical studies

In-room test results at CNAO of an innovative PT treatments online monitor (Dose Profiler)

The use of C, He and O ions as projectiles in Particle Therapy (PT) treatments is getting more and more widespread as a consequence of their enhanced relative biological effectiveness and oxygen enhancement ratio, when compared to the protons one. The advantages related to the incoming radiation improved efficacy are requiring an accurate online monitor of the dose release spatial distribution. Such monitor is necessary to prevent unwanted damage to the tissues surrounding the tumour that can arise, for example, due to morphological changes occurred in the patient during the treatment with respect to the initial CT scan. PT treatments with ions can be monitored by detecting the secondary radiation produced by the primary beam interactions with the patient body along the path towards the target volume. Charged fragments produced in the nuclear process of projectile fragmentation can be emitted at large angles with respect to the incoming beam direction and can be detected with high efficiency in a nearly background-free environment. The Dose Profiler (DP) detector, developed within the INSIDE project, is a scintillating fibre tracker that allows an online reconstruction and backtracking of such secondary charged fragments. The construction and preliminary in-room tests performed on the DP, carried out using the 12C ions beam of the CNAO treatment centre using an anthropomorphic phantom as a target, will be reviewed in this contribution. The impact of the secondary fragments interactions with the patient body will be discussed in view of a clinical application. Furthermore, the results implications for a pre-clinical trial on CNAO patients, foreseen in 2019, will be discussed

Scintillating fiber devices for particle therapy applications

Particle Therapy (PT) is a radiation therapy technique in which solid tumors are treated with charged ions and exploits the achievable highly localized dose delivery, allowing to spare healthy tissues and organs at risk. The development of a range monitoring technique to be used on-line, during the treatment, capable to reach millimetric precision is considered one of the important steps towards an optimization of the PT efficacy and of the treatment quality. To this aim, charged secondary particles produced in the nuclear interactions between the beam particles and the patient tissues can be exploited. Besides charged secondaries, also neutrons are produced in nuclear interactions. The secondary neutron component might cause an undesired and not negligible dose deposition far away from the tumor region, enhancing the risk of secondary malignant neoplasms that can develop even years after the treatment. An accurate neutron characterization (flux, energy and emission profile) is hence needed for a better evaluation of long-term complications. In this contribution two tracker detectors, both based on scintillating fibers, are presented. The first one, named Dose Profiler (DP), is planned to be used as a beam range monitor in PT treatments with heavy ion beams, exploiting the charged secondary fragments production. The DP is currently under development within the INSIDE (Innovative Solutions for In-beam DosimEtry in hadrontherapy) project. The second one is dedicated to the measurement of the fast and ultrafast neutron component produced in PT treatments, in the framework of the MONDO (MOnitor for Neutron Dose in hadrOntherapy) project. Results of the first calibration tests performed at the Trento Protontherapy center and at CNAO (Italy) are reported, as well as simulation studies

Effect of the exposure to maternal smoking during pregnancy and childhood on the body mass index until adolescence

OBJETIVO Analisar se a exposição ao tabagismo materno durante a gravidez e no início da infância afeta as mudanças no índice de massa corporal entre o nascimento e a adolescência. MÉTODOS Realizado estudo de coorte de base populacional com 2.405 crianças (0 a 5 anos) nascidas em Cuiabá, Brasil, e avaliadas de 1999 a 2000. De 2009 a 2011, esse grupo foi reavaliado. Peso ao nascer foi obtido a partir de registros médicos e a exposição ao tabagismo durante a gravidez e infância foi avaliada na primeira entrevista. Modelos lineares de efeitos mistos foram utilizados para estimar a associação entre a exposição ao tabagismo materno, durante a gravidez e a fase pré-escolar, e o índice de massa corporal das crianças ao nascer e durante a infância e adolescência. RESULTADOS Apenas 11,3% das mães relataram fumar durante a gravidez, sendo que a maioria delas (78,2%) também fumou durante a fase pré-escolar da criança. Entre as mães que fumaram exclusivamente durante a gravidez (n = 59), 97,7% fumaram somente no primeiro trimestre. As mudanças de índice de massa corporal entre o nascimento e a infância foram semelhantes entre as crianças expostas e não expostas ao tabagismo materno. Entretanto, entre a infância e a adolescência, a taxa de variação do índice de massa corporal foi maior entre os expostos ao tabagismo materno apenas durante a gravidez quando comparado aos não expostos. CONCLUSÕES A exposição ao fumo apenas durante a gravidez, especialmente no primeiro trimestre, pode afetar as mudanças no índice de massa corporal até a adolescência, apoiando a recomendação de cessação do tabagismo entre as mulheres em idade fértil.OBJECTIVE: Investigate the effect of exposure to smoking during pregnancy and early childhood on changes in the body mass index (BMI) from birth to adolescence. METHODS: A population-based cohort of children (0-5 years old) from Cuiabá, Midwest Brazil, was assessed in 1999-2000 (n = 2,405). Between 2009 and 2011, the cohort was re-evaluated. Information about birth weight was obtained from medical records, and exposure to smoking during pregnancy and childhood was assessed at the first interview. Linear mixed effects models were used to estimate the association between exposure to maternal smoking during pregnancy and preschool age, and the body mass index of children at birth, childhood and adolescence. RESULTS: Only 11.3% of the mothers reported smoking during pregnancy, but most of them (78.2%) also smoked during early childhood. Among mothers who smoked only during pregnancy (n = 59), 97.7% had smoked only in the first trimester. The changes in body mass index at birth and in childhood were similar for children exposed and those not exposed to maternal smoking. However, from childhood to adolescence the rate of change in the body mass index was higher among those exposed only during pregnancy than among those who were not exposed. CONCLUSIONS: Exposure to smoking only during pregnancy, especially in the first trimester, seems to affect changes in the body mass index until adolescence, supporting guidelines that recommend women of childbearing age to stop smokin

Measurement of secondary particle production induced by particle therapy ion beams impinging on a PMMA target

Particle therapy is a technique that uses accelerated charged ions for cancer treatment and combines a high irradiation precision with a high biological effectiveness in killing tumor cells [1]. Informations about the secondary particles emitted in the interaction of an ion beam with the patient during a treatment can be of great interest in order to monitor the dose deposition. For this purpose an experiment at the HIT (Heidelberg Ion-Beam Therapy Center) beam facility has been performed in order to measure fluxes and emission profiles of secondary particles produced in the interaction of therapeutic beams with a PMMA target. In this contribution some preliminary results about the emission profiles and the energy spectra of the detected secondaries will be presente

Clinical relevance of the combined analysis of circulating tumor cells and anti-tumor T-cell immunity in metastatic breast cancer patients

Background: Metastatic breast cancer (mBC) is a heterogeneous disease with varying responses to treatments and clinical outcomes, still requiring the identification of reliable predictive biomarkers. In this context, liquid biopsy has emerged as a powerful tool to assess in real-time the evolving landscape of cancer, which is both orchestrated by the metastatic process and immune-surveillance mechanisms. Thus, we investigated circulating tumor cells (CTCs) coupled with peripheral T-cell immunity to uncover their potential clinical relevance in mBC. Methods: A cohort of 20 mBC patients was evaluated, before and one month after starting therapy, through the following liquid biopsy approaches: CTCs enumerated by a metabolism-based assay, T-cell responses against tumor-associated antigens (TAA) characterized by interferon-γ enzyme-linked immunosorbent spot (ELISpot), and the T-cell receptor (TCR) repertoire investigated by a targeted next-generation sequencing technique. TCR repertoire features were characterized by the Morisita’s overlap and the Productive Simpson Clonality indexes, and the TCR richness. Differences between groups were calculated by Fisher’s, Mann-Whitney or Kruskal-Wallis test, as appropriate. Prognostic data analysis was estimated by Kaplan-Meier method. Results: Stratifying patients for their prognostic level of 6 CTCs before therapy, TAA specific T-cell responses were detected only in patients with a low CTC level. By analyzing the TCR repertoire, the highest TCR clonality was observed in the case of CTCs under the cut-off and a positive ELISpot response (p=0.03). Whereas, at follow-up, patients showing a good clinical response coupled with a low number of CTCs were characterized by the most elevated TCR clonality (p<0.05). The detection of CTCs≥6 in at least one time-point was associated with a lower TCR clonality (p=0.02). Intriguingly, by combining overall survival analysis with TCR repertoire, we highlighted a potential prognostic role of the TCR clonality measured at follow-up (p=0.03). Conclusion: These data, whether validated in a larger cohort of patients, suggest that the combined analysis of CTCs and circulating anti-tumor T-cell immunity could represent a valuable immune-oncological biomarker for the liquid biopsy field. The clinical application of this promising tool could improve the management of mBC patients, especially in the setting of immunotherapy, a rising approach for BC treatment requiring reliable predictive biomarkers

The hadronic models for cosmic ray physics: the FLUKA code solutions

FLUKA is a general purpose Monte Carlo transport and interaction code used for fundamental physics and for a wide range of applications. These include Cosmic Ray Physics (muons, neutrinos, EAS, underground physics), both for basic research and applied studies in space and atmospheric flight dosimetry and radiation damage. A review of the hadronic models available in FLUKA and relevant for the description of cosmic ray air showers is presented in this paper. Recent updates concerning these models are discussed. The FLUKA capabilities in the simulation of the formation and propagation of EM and hadronic showers in the Earth's atmosphere are shown.Comment: 8 pages, 9 figures. Invited talk presented by M.V. Garzelli at ISVHECRI2006, International Symposium on Very High Energy Cosmic Rays, Weihai, China, August 15 - 22 200

Emerging concepts and challenges in implementing the exposome paradigm in allergic diseases and asthma.

Exposome research can improve the understanding of the mechanistic connections between exposures and health to help mitigate adverse health outcomes across the life span. The exposomic approach provides a risk profile instead of single predictors and thus is particularly applicable to allergic diseases and asthma. Under the PRACTALL collaboration between the European Academy of Allergy and Clinical Immunology (EAACI) and the American Academy of Allergy, Asthma, and Immunology (AAAAI), we evaluated the current concepts and the unmet needs on the role of the exposome in allergic diseases and asthma