Radiobiological considerations in combining doses from external beam radiotherapy and brachytherapy for cervical cancer

The recommended radio-therapeutic treatment for cervix cancer consists of a first phase of external beam radiotherapy (EBRT) plus a second phase of brachytherapy (BT), the combined treatment being delivered within 8 weeks.In order to assess a comprehensive dosimetry of the whole treatment, it is necessary to take into account that these two phases are characterized by different spatial and temporal dosimetric distributions, which complicates the task of the summation of the two contributions, EBRT and BT. Radiobiology allows to tackle this issue pragmatically by means of the LQ model and, in fact, this is the usual tool currently in use for this matter.In this work, we describe the rationale behind the summation of the dosimetric contributions of the two phases of the treatment, EBRT and BT, for cervix cancer, as carried out with the LQ model.Besides, we address, from a radiobiological point of view, several important considerations regarding the use of the LQ model for this task. One of them is the analysis of the effect of the overall treatment time in the result of the global treatment. Another important question considered is related to the fact that the capacity of LQ to predict the treatment outcomes is deteriorated when the dose per fraction of the radiotherapic scheme exceeds 6–10Gy, which is a typical brachytherapy fractionation. Finally, we analyze the influence of the uncertainty and the variability of the main parameters utilized in the LQ model formulation in the assessment of the global dosimetry

A radiobiological study of the schemes with a low number of fractions in high-dose-rate brachytherapy as monotherapy for prostate cancer

Purpose Schemes with high doses per fraction and small number of fractions are commonly used in high-dose-rate brachytherapy (HDR-BT) for prostate cancer. Our aim was to analyze the differences between published clinical results and the predictions of radiobiological models for absorbed dose required in a single fraction monotherapy HDR-BT. Material and methods Published HDR-BT clinical results for low- and intermediate-risk patients with prostate cancer were revised. For 13 clinical studies with 16 fractionation schedules between 1 and 9 fractions, a dose-response relation in terms of the biochemical control probability (BC) was established using Monte Carlo-based statistical methods. Results We obtained a value of α/β = 22.8 Gy (15.1-60.2 Gy) (95% CI) much larger than the values in the range 1.5-3.0 Gy that are usually considered to compare the results of different fractionation schemes in prostate cancer radiotherapy using doses per fraction below 6 Gy. The doses in a single fraction producing BC = 90% and 95% were 22.3 Gy (21.5-24.2 Gy) and 24.3 Gy (23.0-27.9 Gy), respectively. Conclusions The α/β obtained in our analysis of 22.8 Gy for a range of dose per fraction between 6 and 20.5 Gy was much greater than the one currently estimated for prostate cancer using low doses per fraction. This high value of α/β explains reasonably well the data available in the region of high doses per fraction considered.Spanish Ministerio de Ciencia y Competitividad FPA2015-67694-PEuropean Union (EU)Junta de Andalucía FQM038

Fibromyalgia: Evidence for Deficits in Positive Psychology Resources. A Case-Control Study from the Al-Ándalus Project

Positive psychology is the study of positive subjective experience and individual traits. Identifying deficits in positive psychology regarding fibromyalgia may inform targets for management. Therefore, the aim of the present case–control study was to compare the levels of positive affect, negative affect, satisfaction with life, optimism and emotional repair in a large sample of women with fibromyalgia (cases) and age-matched peers without fibromyalgia (controls). This case–control study included 437 women with fibromyalgia (51.6 ± 7.1 years old) and 206 age-matched women without fibromyalgia (50.6 ± 7.2 years old). Participants self-reported their levels of (i) subjective well-being on the Positive and Negative Affect Schedule and the Satisfaction with Life Scale, (ii) dispositional optimism on the Life Orientation Test-Revised and (iii) emotional repair on the Trait Meta-Mood Scale. Women with fibromyalgia showed lower levels of positive affect, satisfaction with life, optimism and emotional repair and higher levels of negative affect. Large effect sizes were found for positive affect, negative affect and satisfaction with life (all, Cohen’s d ≥ 0.80) and small-to-moderate for emotional repair and optimism (both, Cohen’s d ≥ 0.50). Women with fibromyalgia experience deficits of positive psychology resources. Thus, developing tailored therapies for fibromyalgia focusing on reducing deficits in positive psychology resources may be of clinical interest, though this remains to be corroborated in future researchThis work was supported by the Spanish Ministry of Economy and Competitiveness (I+D+i DEP2010-15639, I+D+I DEP2013-40908); the Spanish Ministry of Education (FPU15/00002), Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES). F.E.-L. has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 707404. The funders of this study did not have any role in the study design, data collection and analyses, decision to publish or preparation of the manuscript We would like to thank the researchers of the cts-1018 research group, particularly Manuel Delgado-Fernández, and acknowledge the “Fibromyalgia, Chronic Fatigue Syndrome and Chemistry Sensibility Federation” (“ALBA ANDALUCIA”, association of fibromyalgia, Andalucía, southern Spai

Review of strategies for MRI based reconstruction of endocavitary and interstitial applicators in brachytherapy of cervical cancer

Brachytherapy plays an essential role in the curative intent management of locally advanced cervical cancer. The introduction of the magnetic resonance (MR) as a preferred image modality and the development of new type of applicators with interstitial components have further improved its benefits.The aim of this work is to review the current status of one important aspect in the cervix cancer brachytherapy procedure, namely catheter reconstruction.MR compatible intracavitary and interstitial applicators are described. Considerations about the use of MR imaging (MRI) regarding appropriate strategies for applicator reconstruction, technical requirements, MR sequences, patient preparation and applicator commissioning are included.It is recommendable to perform the reconstruction process in the same image study employed by the physician for contouring, that is, T2 weighted (T2W) sequences. Nevertheless, a clear identification of the source path inside the catheters and the applicators is a challenge when using exclusively T2W sequences. For the intracavitary component of the implant, sometimes the catheters may be filled with some substance that produces a high intensity signal on MRI. However, this strategy is not feasible for plastic tubes or titanium needles, which, moreover, induce magnetic susceptibility artifacts. In these situations, the use of applicator libraries available in the treatment planning system (TPS) is useful, since they not only include accurate geometrical models of the intracavitary applicators, but also recent developments have made possible the implementation of the interstitial component. Another strategy to improve the reconstruction process is based on the incorporation of MR markers, such as small pellets, to be used as anchor points.Many institutions employ computed tomography (CT) as a supporting image modality. The registration of CT and MR image sets should be carefully performed, and its uncertainty previously assessed. Besides, an important research work is being carried out regarding the use of ultrasound and electromagnetic tracking technologies

Longitudinal analysis of blood DNA methylation identifies mechanisms of response to tumor necrosis factor inhibitor therapy in rheumatoid arthritis

[Abstract] Background: Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory disease of the joints that has been associated with variation in the peripheral blood methylome. In this study, we aim to identify epigenetic variation that is associated with the response to tumor necrosis factor inhibitor (TNFi) therapy. Methods: Peripheral blood genome-wide DNA methylation profiles were analyzed in a discovery cohort of 62 RA patients at baseline and at week 12 of TNFi therapy. DNA methylation of individual CpG sites and enrichment of biological pathways were evaluated for their association with drug response. Using a novel cell deconvolution approach, altered DNA methylation associated with TNFi response was also tested in the six main immune cell types in blood. Validation of the results was performed in an independent longitudinal cohort of 60 RA patients. Findings: Treatment with TNFi was associated with significant longitudinal peripheral blood methylation changes in biological pathways related to RA (FDR<0.05). 139 biological functions were modified by therapy, with methylation levels changing systematically towards a signature similar to that of healthy controls. Differences in the methylation profile of T cell activation and differentiation, GTPase-mediated signaling, and actin filament organization pathways were associated with the clinical response to therapy. Cell type deconvolution analysis identified CpG sites in CD4+T, NK, neutrophils and monocytes that were significantly associated with the response to TNFi. Interpretation: Our results show that treatment with TNFi restores homeostatic blood methylation in RA. The clinical response to TNFi is associated to methylation variation in specific biological pathways, and it involves cells from both the innate and adaptive immune systems

HLA association with the susceptibility to anti-synthetase syndrome.

Objective: To investigate the human leukocyte antigen (HLA) association with anti-synthetase syndrome (ASSD). Methods: We conducted the largest immunogenetic HLA-DRB1 and HLA-B study to date in a homogeneous cohort of 168 Caucasian patients with ASSD and 486 ethnically matched healthy controls by sequencing-based-typing. Results: A statistically significant increase of HLA-DRB1*03:01 and HLA-B*08:01 alleles in patients with ASSD compared to healthy controls was disclosed (26.2% versus 12.2%, P = 1.56E–09, odds ratio–OR [95% confidence interval–CI] = 2.54 [1.84–3.50] and 21.4% versus 5.5%, P = 18.95E–18, OR [95% CI] = 4.73 [3.18–7.05]; respectively). Additionally, HLA-DRB1*07:01 allele was significantly decreased in patients with ASSD compared to controls (9.2% versus 17.5%, P = 0.0003, OR [95% CI] = 0.48 [0.31–0.72]). Moreover, a statistically significant increase of HLA-DRB1*03:01 allele in anti-Jo-1 positive compared to anti-Jo-1 negative patients with ASSD was observed (31.8% versus 15.5%, P = 0.001, OR [95% CI] = 2.54 [1.39–4.81]). Similar findings were observed when HLA carrier frequencies were assessed. The HLA-DRB1*03:01 association with anti-Jo-1 was unrelated to smoking history. No HLA differences in patients with ASSD stratified according to the presence/absence of the most representative non-anti-Jo-1 anti-synthetase autoantibodies (anti-PL-12 and anti-PL-7), arthritis, myositis or interstitial lung disease were observed. Conclusions: Our results support the association of the HLA complex with the susceptibility to ASSD.This study was partially supported by grants from the Foundation for Research in Rheumatology (FOREUM); SR-M is supported by funds of the RETICS Program [grant number RD16/0012/0009] from the `Instituto de Salud Carlos III´ (ISCIII), co-funded by the European Regional Development Fund (ERDF); BA-M is a recipient of a ‘López Albo’ Post-Residency Programme funded by Servicio Cántabro de Salud; VP-C is supported by a pre-doctoral grant from IDIVAL [grant number PREVAL 18/01]; LL-G is supported by funds of ISCIII, co-funded by ERDF [grant number PI18/00042]; OG is beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN), GPC IN607B2019/10; EAR is partially supported by Versus Arthritis [grant number 20719] and by Scleroderma and Raynaud's UK [grant number BR11]; RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, ‘Investing in your future’) [grant number CP16/00033]

Interleukin 15 Levels in Serum May Predict a Severe Disease Course in Patients with Early Arthritis

Background: Interleukin-15 (IL-15) is thought to be involved in the physiopathological mechanisms of RA and it can be detected in the serum and the synovial fluid of inflamed joints in patients with RA but not in patients with osteoarthritis or other inflammatory joint diseases. Therefore, the objective of this work is to analyse whether serum IL-15 (sIL-15) levels serve as a biomarker of disease severity in patients with early arthritis (EA). Methodology and Results: Data from 190 patients in an EA register were analysed (77.2% female; median age 53 years; 6-month median disease duration at entry). Clinical and treatment information was recorded systematically, especially the prescription of disease modifying anti-rheumatic drugs. Two multivariate longitudinal analyses were performed with different dependent variables: 1) DAS28 and 2) a variable reflecting intensive treatment. Both included sIL-15 as predictive variable and other variables associated with disease severity, including rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACPA). Of the 171 patients (638 visits analysed) completing the follow-up, 71% suffered rheumatoid arthritis and 29% were considered as undifferentiated arthritis. Elevated sIL-15 was detected in 29% of this population and this biomarker did not overlap extensively with RF or ACPA. High sIL-15 levels (β Coefficient [95% confidence interval]: 0.12 [0.06-0.18]; p&0.001) or ACPA (0.34 [0.01-0.67]; p = 0.044) were significantly and independently associated with a higher DAS28 during follow-up, after adjusting for confounding variables such as gender, age and treatment. In addition, those patients with elevated sIL-15 had a significantly higher risk of receiving intensive treatment (RR 1.78, 95% confidence interval 1.18-2.7; p = 0.007). Conclusions: Patients with EA displaying high baseline sIL-15 suffered a more severe disease and received more intensive treatment. Thus, sIL-15 may be a biomarker for patients that are candidates for early and more intensive treatmentThe work of Belen Díaz-Sánchez was supported by the RETICS Programme (Programa de Redes Temáticas de Investigación Colaborativa [Colaborative Research Thematic Network Programme]; RD08/0075 - RIER [Red de Inflamación y Enfermedades Reumáticas; Inflammation and Rheumatic Diseases Network]) from the Instituto de Salud Carlos III, Spain (URL: www.isciii.es) within the VI National Plan for I+D+I 2008–2011 (FEDER). The work of Isidoro González-Álvaro was in part supported by a grant for the Intensification of the Research Tasks in the National Health Care System from Instituto de Salud Carlos III, Spain. The consumables for measurements and data analysis were supported by a Fondo de Investigación Sanitaria grant (08/0754) from the Instituto de Salud Carlos II

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe