Towards an optimal clinical protocol for the treatment of moving targets with pencil beam scanned proton therapy

At the University Medical Center Groningen (UMCG) Proton Therapy Center (GPTC), a novel and advantageous form of radiotherapy for the treatment of cancer is available. This treatment technique, referred as proton therapy, uses charged particles (protons) to irradiate, and consequently, damage the tumour. Due to the physical properties of protons, proton therapy allows to successfully kill the tumour, while sparing the adjacent healthy tissue from any damaging radiation. The tumours within liver, lung, and oesophageal cancer patients move due to the patients’ respiration. These moving tumours are surrounded by organs (heart, lung, spinal cord, and oesophagus), which need to be spared from radiation. This is why proton therapy is particularly valuable for these patients. However, the interference of the movement of these tumours with the highly precise proton therapy machine, brings a challenge for the execution of their treatments at the GPTC, and other proton centres. The work performed throughout this thesis focuses on achieving optimal and safe proton treatments for moving tumours. To complete this, we performed comprehensive and representative analysis with clinical patient data and proton machine specific information of our department. The tools developed and the results obtained contributed to the start of the treatment of moving tumours at the GPTC, and therefore we believe they will play an important role for the proton therapy community in general. We aim to extend our gained experience to all proton centres worldwide, so that moving tumours can take advantage of the clinical benefits expected from proton therapy

Evaluation of continuous beam rescanning versus pulsed beam in pencil beam scanned proton therapy for lung tumours

The treatment of moving targets with pencil beam scanned proton therapy (PBS-PT) may rely on rescanning strategies to smooth out motion induced dosimetric disturbances. PBS-PT machines, such as Proteus (R) Plus (PPlus) and Proteus (R) One (POne), deliver a continuous or a pulsed beam, respectively. In PPlus, scaled (or no) rescanning can be applied, while POne implies intrinsic 'rescanning' due to its pulsed delivery. We investigated the efficacy of these PBS-PT delivery types for the treatment of lung tumours. In general, clinically acceptable plans were achieved, and PPlus and POne showed similar effectiveness

NOVOS EMPREENDIMENTOS: DIFICULDADES E BARREIRAS INSTITUCIONAIS PARA ABERTURA DE MICRO E PEQUENAS INDÚSTRIAS EM VITÓRIA DA CONQUISTA-BA

Las micro y pequeñas empresas corresponden a la mayoría de los establecimientos en Brasil, así como en Vitória da Conquista, asumiendo gran importancia económica y social. Esta investigación objetivó identificar las dificultades de los empresarios de las micro y pequeñas industrias,  en cuanto a los procesos de apertura de empresas fundadas en los años de 2015 y 2016. El estudio tuvo carácter exploratorio y descriptivo, utilizando el estudio de caso múltiple. Se observó alto grado de insatisfacción en relación a las etapas de apertura de las empresas, sobre todo en relación al exceso de burocracia, lo que implicó en mayor morosidad de las acciones. Se evidenció, por lo tanto, la necesidad de mejoras, a ejemplo de la evolución de normativas y estructuras burocráticas, en el sentido de promover la celeridad de los procesos de apertura de empresas.As micro e pequenas empresas correspondem à maioria dos estabelecimentos no Brasil, assim como em Vitória da Conquista, assumindo grande importância econômica e social. Esta pesquisa objetivou identificar as dificuldades dos empresários das micro e pequenas indústrias, quanto aos processos de abertura de empresas fundadas nos anos de 2015 e 2016. O estudo teve caráter exploratório e descritivo, utilizando-se o estudo de caso múltiplo. Observou-se alto grau de insatisfação em relação às etapas de abertura das empresas, sobretudo em relação ao excesso de burocracia, o que implicou em maior morosidade das ações. Evidenciou-se, portanto, a necessidade de melhorias, a exemplo da evolução de normatizações e estruturas burocráticas, no sentido de promover a celeridade dos processos de abertura de empresas.Micro and small enterprises correspond to most establishments in Brasil, as well as in Vitória da Conquista, assuming great economic and social importance. This study aimed to identify the difficulties faced by entrepreneurs in micro- and small-scale industries in the opening of companies founded in the years 2015 and 2016. The study was exploratory and descriptive, using the multiple case study. There was a high degree of dissatisfaction with the opening stages of the companies, especially in relation to the excess of bureaucracy, which implied a greater slowness of actions. The need for improvements, such as the evolution of regulations and bureaucratic structures, has been evidenced in order to promote the speed of business start-up

Robustness assessment of clinical adaptive proton and photon radiotherapy for oesophageal cancer in the model-based approach

Purpose In the Netherlands, oesophageal cancer (EC) patients are selected for intensity modulated proton therapy (IMPT) using the expected normal tissue complication probability reduction (ΔNTCP) when treating with IMPT compared to volumetric modulated arc therapy (VMAT). In this study, we evaluate the robustness of the first EC patients treated with IMPT in our clinic in terms of target and organs-at-risk (OAR) dose with corresponding NTCP, as compared to VMAT. Materials and Methods For 20 consecutive EC patients, clinical IMPT and VMAT plans were created on the average planning 4DCT. Both plans were robustly evaluated on weekly repeated 4DCTs and if target coverage degraded, replanning was performed. Target coverage was evaluated for complete treatment trajectories with and without replanning. The planned and accumulated mean lung dose (MLD) and mean heart dose (MHD) were additionally evaluated and translated into NTCP. Results Replanning in the clinic was performed more often for IMPT (15x) than would have been needed for VMAT (8x) (p = 0.11). Both adaptive treatments would have resulted in adequate accumulated target dose coverage. Replanning in the first week of treatment had most clinical impact, as anatomical changes resulting in insufficient accumulated target coverage were already observed at this stage. No differences were found in MLD between the planned dose and the accumulated dose. Accumulated MHD differed from the planned dose (p < 0.001), but since these differences were similar for VMAT and IMPT (1.0 and 1.5 Gy, respectively), the ΔNTCP remained unchanged. Conclusion Following an adaptive clinical workflow, adequate target dose coverage and stable OAR doses with corresponding NTCPs was assured for both IMPT and VMAT

Towards the clinical implementation of intensity-modulated proton therapy for thoracic indications with moderate motion:Robust optimised plan evaluation by means of patient and machine specific information

PURPOSE: Compared to volumetric modulated arc therapy (VMAT), clinical benefits are anticipated when treating thoracic tumours with intensity-modulated proton therapy (IMPT). However, the current concern of plan robustness as a result of motion hampers its wide clinical implementation. To define an optimal protocol to treat lung and oesophageal cancers, we present a comprehensive evaluation of IMPT planning strategies, based on patient 4DCTs and machine log files. MATERIALS AND METHODS: For ten lung and ten oesophageal cancer patients, a planning 4DCT and weekly repeated 4DCTs were collected. For these twenty patients, the CTV volume and motion were assessed based on the 4DCTs. In addition to clinical VMAT plans, layered rescanned 3D and 4D robust optimised IMPT plans (IMPT_3D and IMPT_4D respectively) were generated, and approved clinically, for all patients. The IMPT plans were then delivered in dry runs at our proton facility to obtain log files, and subsequently evaluated through our 4D robustness evaluation method (4DREM). With this method, for each evaluated plan, fourteen 4D accumulated scenario doses were obtained, representing 14 possible fractionated treatment courses. RESULTS: From VMAT to IMPT_3D, nominal Dmean(lungs-GTV) decreased 2.75 ± 0.56 GyRBE and 3.76 ± 0.92 GyRBE over all lung and oesophageal cancer patients, respectively. A more pronounced reduction was verified for Dmean(heart): 5.38 ± 7.36 GyRBE (lung cases) and 9.51 ± 2.25 GyRBE (oesophagus cases). Target coverage robustness of IMPT_3D was sufficient for 18/20 patients. Averaged dose in critical structures over all 4DREM scenarios changed only slightly for both IMPT_3D and IMPT_4D. Relative to IMPT_3D, no gain in IMPT_4D was observed. CONCLUSION: The dosimetric superiority of IMPT over VMAT has been established. For most thoracic tumours, our IMPT_3D planning protocol showed to be robust and clinically suitable. Nevertheless, accurate patient positioning and adapting to anatomical variations over the course of treatment remain compulsory

Improving the prediction of overall survival for head and neck cancer patients using image biomarkers in combination with clinical parameters

Purpose: To develop and validate prediction models of overall survival (OS) for head and neck cancer (HNC) patients based on image biomarkers (IBMs) of the primary tumor and positive lymph nodes (Ln) in combination with clinical parameters. Material and methods: The study cohort was composed of 289 nasopharyngeal cancer (NPC) patients from China and 298 HNC patients from the Netherlands. Multivariable Cox-regression analysis was performed to select clinical parameters from the NPC and HNC datasets, and IBMs from the NPC dataset. Final prediction models were based on both IBMs and clinical parameters. Results: Multivariable Cox-regression analysis identified three independent IBMs (tumor Volume density, Run Length Non-uniformity and Ln Major-axis-length). This IBM model showed a concordance (c)-index of 0.72 (95%Cl: 0.65-0.79) for the NPC dataset, which performed reasonably with a c-index of 0.67 (95%Cl: 0.62-0.72) in the external validation HNC dataset. When IBMs were added in clinical models, the c-index of the NPC and HNC datasets improved to 0.75 (95%Cl: 0.68-0.82; p = 0.019) and 0.75 (95%Cl: 0.70-0.81; p <0.001), respectively. Conclusion: The addition of IBMs from the primary tumor and Ln improved the prognostic performance of the models containing clinical factors only. These combined models may improve pre-treatment individualized prediction of OS for HNC patients. (C) 2017 The Authors. Published by Elsevier Ireland Ltd

Assessment of dosimetric errors induced by deformable image registration methods in 4D pencil beam scanned proton treatment planning for liver tumours

PURPOSE: Respiratory impacts in pencil beam scanned proton therapy (PBS-PT) are accounted by extensive 4D dose calculations, where deformable image registration (DIR) is necessary for estimating deformation vector fields (DVFs). We aim here to evaluate the dosimetric errors induced by different DIR algorithms in their resulting 4D dose calculations by using ground truth(GT)-DVFs from 4DMRI. MATERIALS AND METHODS: Six DIR methods: ANACONDA, Morfeus, B-splines, Demons, CT Deformable, and Total Variation, were respectively applied to nine 4DCT-MRI liver data sets. The derived DVFs were then used as input for 4D dose calculation. The DIR induced dosimetric error was assessed by individually comparing the resultant 4D dose distributions to those obtained with GT-DVFs. Both single-/three-field plans and single/rescanned strategies were investigated. RESULTS: Differences in 4D dose distributions among different DIR algorithms, and compared to the results using GT-DVFs, were pronounced. Up to 40 % of clinically relevant dose calculation points showed dose differences of 10 % or more between the GT. Differences in V95(CTV) reached up to 11.34 ± 12.57 %. The dosimetric errors became in general less substantial when applying multiple-field plans or using rescanning. CONCLUSION: Intrinsic geometric errors by DIR can influence the clinical evaluation of liver 4D PBS-PT plans. We recommend the use of an error bar for correctly interpreting individual 4D dose distributions

Cohort profile: the 100 million Brazilian cohort

The creation of The 100 Million Brazilian Cohort was motivated by the availability of high quality but dispersed social and health databases in Brazil and the need to integrate data and evaluate the impact of policies aiming to improve the social determinants of health (e.g. social protection policies) on health outcomes, overall and in subgroups of interest in a dynamic cohort. • The baseline of The 100 Million Brazilian Cohort comprises 131 697 800 low-income individuals in 35 358 415 families from 2011 to 2018. The Cohort population is mostly composed of children and young adults, with a higher proportion of females than the general Brazilian population, who identify themselves as Brown and live in the urban area of the country. • Exposure to social protection and the follow-up of individuals are obtained through: (i) deterministic linkage using the Social Identification Number (NIS) to link the Cohort baseline to social protection programmes and to periodically renewed socioeconomic information in Cadatro U ́ nico datasets; and/or (ii) non-deterministic linkage using the CIDACS-RL non-deterministic linkage tool, to link the Cohort baseline to administrative health care datasets such as mortality (Mortality Information System, SIM), disease notification (Information System for Notifiable Diseases, SINAN), birth information (Live Birth Information System, SINASC) and nutrition status (Food and Nutrition Surveillance System, SISVAN). • So far, studies have used The 100 Million Brazilian Cohort to investigate the socioeconomic and demographic determinants of leprosy, leprosy treatment outcomes and low birthweight and to evaluate the impact of the Bolsa Familia Programme (BFP) on leprosy and child mortality. Other studies are now being conducted that are of utmost relevance to the health inequalities of Brazil and many low- and middle-income countries, and many research opportunities are being opened up with the linkage of a range of health outcomes

Differences in risk factors for incident and recurrent preterm birth: a population-based linkage of 3.5 million births from the CIDACS birth cohort.

BACKGROUND: Preterm birth (PTB) is a syndrome resulting from a complex list of underlying causes and factors, and whether these risk factors differ in the context of prior PTB history is less understood. The aim of this study was to explore whether PTB risk factors in a second pregnancy were different in women with versus without previous PTB. METHODS: We conducted a population-based cohort study using data from the birth cohort of the Center for Data and Knowledge Integration for Health (CIDACS) for the period 2001 to 2015. We used longitudinal transition models with multivariate logistic regression to investigate whether risk factors varied between incident and recurrent PTB. RESULTS: A total of 3,528,050 live births from 1,764,025 multiparous women were analyzed. We identified different risk factors (Pdifference <0.05) between incident and recurrent PTB. The following were associated with an increased chance for PTB incidence, but not recurrent: household overcrowding (OR 1.09), maternal race/ethnicity [(Black/mixed-OR 1.04) and (indigenous-OR 1.34)], young maternal age (14 to 19 years-OR 1.16), and cesarean delivery (OR 1.09). The following were associated with both incident and recurrent PTB, respectively: single marital status (OR 0.85 vs 0.90), reduced number of prenatal visits [(no visit-OR 2.56 vs OR 2.16) and (1 to 3 visits-OR 2.44 vs OR 2.24)], short interbirth interval [(12 to 23 months-OR 1.04 vs OR 1.22) and (<12 months, OR 1.89, 95 vs OR 2.58)], and advanced maternal age (35-49 years-OR 1.42 vs OR 1.45). For most risk factors, the point estimates were higher for incident PTB than recurrent PTB. CONCLUSIONS: The risk factors for PTB in the second pregnancy differed according to women's first pregnancy PTB status. The findings give the basis for the development of specific prevention strategies for PTB in a subsequent pregnancy

IFNG +874T/A polymorphism is not associated with American tegumentary leishmaniasis susceptibility but can influence Leishmania induced IFN-γ production

<p>Abstract</p> <p>Background</p> <p>Interferon-gamma is a key cytokine in the protective responses against intracellular pathogens. A single nucleotide polymorphism (SNP) located in the first intron of the human IFN-γ gene can putatively influence the secretion of cytokine with an impact on infection outcome as demonstrated for tuberculosis and other complex diseases. Our aim was to investigate the putative association of IFNG+874T/A SNP with American tegumentary leishmaniasis (ATL) and also the influence of this SNP in the secretion of IFN-γ <it>in vitro</it>.</p> <p>Methods</p> <p>Brazilian ATL patients (78 cutaneous, CL, and 58 mucosal leishmaniasis, ML) and 609 healthy volunteers were evaluated. The genotype of +874 region in the IFN-γ gene was carried out by Amplification Refractory Mutational System (ARMS-PCR). <it>Leishmania</it>-induced IFN-γ production on peripheral blood mononuclear cell (PBMC) culture supernatants was assessed by ELISA.</p> <p>Results</p> <p>There are no differences between +874T/A SNP frequency in cases and controls or in ML versus CL patients. Cutaneous leishmaniasis cases exhibiting AA genotype produced lower levels of IFN-γ than TA/TT genotypes. In mucosal cases, high and low IFN-γ producers were clearly demonstrated but no differences in the cytokine production was observed among the IFNG +874T or A carriers.</p> <p>Conclusion</p> <p>Our results suggest that +874T/A polymorphism was not associated with either susceptibility or severity to leishmaniasis. Despite this, IFNG +874T/A SNP could be involved in the pathogenesis of leishmaniasis by influencing the amount of cytokine released by CL patients, although it could not prevent disease development. On the other hand, it is possible that in ML cases, other potential polymorphic regulatory genes such as TNF-α and IL-10 are also involved thus interfering with IFN-γ secretion.</p