One-year efficacy and safety of naloxegol on symptoms and quality of life related to opioid-induced constipation in patients with cancer: KYONAL study

Cancer; Constipation; PainCàncer; Restrenyiment; DolorCáncer; Estreñimiento; DolorAbstract Objectives Naloxegol is a peripherally acting µ-opioid receptor antagonist (PAMORA) for treatment of opioid-induced constipation (OIC). The main objective was to analyse the long-term efficacy, quality of life (QOL) and safety of naloxegol in patients with cancer in a real-world study. Methods This one-year prospective study included patients older than 18 years, with active oncological disease who were under treatment with opioids for pain control and Karnofsky≥50 and OIC with inadequate response to treatment with laxative (s). All the patients received treatment with naloxegol according to clinical criteria. The main efficacy objectives were measured by the patient assessment of constipation QOL questionnaire (PAC-QOL), the PAC symptoms (PAC-SYM), the response rate at day 15, and months 1-3-6-12, and global QOL (EuroQoL-5D-5L). Results A total of 126 patients (58.7% males) with a mean age of 61.5 years (95% CI 59.4 to 63.7) were included. PAC-SYM and PAC-QOL total score and all their dimensions improved from baseline (p<0.0001). At 12 months, 77.8% of the patients were responders to naloxegol treatment. Global QOL was conserved from baseline. A total of 28 adverse reactions, mainly gastrointestinal were observed in 15.1% of the patients (19/126), being 75% (21) mild, 17.9% (5) moderate and 7.1% (2) severe. Most adverse reactions (67.9%) appeared the first 15 days of treatment. Conclusion The results of this first long-term and real-world-data study in patients with cancer, showed the sustained efficacy and safety of naloxegol for the treatment of OIC in this group of patients.This study was sponsored by Kyowa Kirin Farmacéutica S.L., Spain. The funders participated in the design of the study and the drafting of the manuscript

Development and Optimization of a Machine-Learning Prediction Model for Acute Desquamation After Breast Radiation Therapy in the Multicenter REQUITE Cohort

Breast Radiation Therapy; Machine-Learning Prediction; Acute DesquamationRaditeràpia de mama; Predicció d'aprenentatge automàtic; Descamació agudaRadioterapia de mama; Predicción de aprendizaje automático; Descamación agudaPurpose Some patients with breast cancer treated by surgery and radiation therapy experience clinically significant toxicity, which may adversely affect cosmesis and quality of life. There is a paucity of validated clinical prediction models for radiation toxicity. We used machine learning (ML) algorithms to develop and optimise a clinical prediction model for acute breast desquamation after whole breast external beam radiation therapy in the prospective multicenter REQUITE cohort study. Methods and Materials Using demographic and treatment-related features (m = 122) from patients (n = 2058) at 26 centers, we trained 8 ML algorithms with 10-fold cross-validation in a 50:50 random-split data set with class stratification to predict acute breast desquamation. Based on performance in the validation data set, the logistic model tree, random forest, and naïve Bayes models were taken forward to cost-sensitive learning optimisation. Results One hundred and ninety-two patients experienced acute desquamation. Resampling and cost-sensitive learning optimisation facilitated an improvement in classification performance. Based on maximising sensitivity (true positives), the “hero” model was the cost-sensitive random forest algorithm with a false-negative: false-positive misclassification penalty of 90:1 containing m = 114 predictive features. Model sensitivity and specificity were 0.77 and 0.66, respectively, with an area under the curve of 0.77 in the validation cohort. Conclusions ML algorithms with resampling and cost-sensitive learning generated clinically valid prediction models for acute desquamation using patient demographic and treatment features. Further external validation and inclusion of genomic markers in ML prediction models are worthwhile, to identify patients at increased risk of toxicity who may benefit from supportive intervention or even a change in treatment plan

(Pre)treatment risk factors for late fatigue and fatigue trajectories following radiotherapy for breast cancer

Breast cancer; Fatigue; RadiotherapyCáncer de mama; Fatiga; RadioterapiaCàncer de mama; Fatiga; RadioteràpiaFatigue is common in breast-cancer survivors. Our study assessed fatigue longitudinally in breast cancer patients receiving adjuvant radiotherapy (RT) and aimed to identify risk factors associated with long-term fatigue and underlying fatigue trajectories. Fatigue was measured in a prospective multicenter cohort (REQUITE) using the Multidimensional Fatigue Inventory (MFI-20) and analyzed using mixed models. Multivariable logistic models identified factors associated with fatigue dimensions at 2 years post-RT and latent class growth analysis identified individual fatigue trajectories. A total of 1443, 1302, 1203 and 1098 patients completed the MFI-20 at baseline, end of RT, after 1 and 2 years. Overall, levels of fatigue significantly increased from baseline to end of RT for all fatigue dimensions (P < .05) and returned to baseline levels after 2 years. A quarter of patients were assigned to latent trajectory high (23.7%) and moderate (24.8%) fatigue classes, while 46.3% and 5.2% to the low and decreasing fatigue classes, respectively. Factors associated with multiple fatigue dimensions at 2 years include age, BMI, global health status, insomnia, pain, dyspnea and depression. Fatigue present at baseline was consistently associated with all five MFI-20 fatigue dimensions (ORGeneralFatigue = 3.81, P < .001). From latent trajectory analysis, patients with a combination of factors such as pain, insomnia, depression, younger age and endocrine therapy had a particularly high risk of developing early and persistent high fatigue years after treatment. Our results confirmed the multidimensional nature of fatigue and will help clinicians identify breast cancer patients at higher risk of having persistent/late fatigue so that tailored interventions can be delivered.We thank all patients who participated in the REQUITE study and all the REQUITE staff involved in this project. Belgium: Ghent University Hospital; KU Leuven. France: ICM Montpellier, CHU Nîmes (Department of Radiation Oncology, CHU Nîmes, Nîmes, France). Germany: Zentrum für Strahlentherapie Freiburg (Dr. Petra Stegmaier); Städtisches Klinikum Karlsruhe (Dr. Bernhard Neu); ViDia Christliche Kliniken Karlsruhe (Prof. Johannes Claßen); Klinikum der Stadt Ludwigshafen GmbH (PD Dr. Thomas Schnabel); Universitätsklinikum Mannheim: Anette Kipke and Christiane Zimmermann; Strahlentherapie Speyer (Dr. Jörg Schäfer). The researchers at DKFZ also thank Anusha Müller, Irmgard Helmbold, Thomas Heger, Sabine Behrens, Axel Benner, Nicholas Schreck. Petra Seibold is supported by ERA PerMed 2018 funding (BMBF #01KU1912) and BfS funding (#3619S42261). Italy: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano; Candiolo Cancer Institute – FPO, IRCCS. Tiziana Rancati was partially funded by Fondazione Italo Monzino. The Netherlands: Sylvie Canisius at Maastro Clinics, Maastricht. Spain: Barcelona: Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus; VHIO acknowledge the Cellex Foundation for providing research facilities and thank CERCA Programme/Generalitat de Catalunya for institutional support. Sara Gutiérrez-Enríquez is supported by ERAPerMed JTC2018 funding (ERAPERMED2018-244 and SLT011/18/00005). Santiago: Complexo Hospitalario Universitario de Santiago. Ana Vega: supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (PI22/00589, PI19/01424; INT20/00071); the ERAPerMed JTC2018 funding (AC18/00117); the Autonomous Government of Galicia (Consolidation and structuring program: IN607B), by the Fundación Mutua Madrileña (call 2018) and by the AECC (PRYES211091VEGA); UK: University Hospitals of Leicester NHS Trust; Theresa Beaver, Kaitlin Walker and Sara Barrows. Dr Tim Rattay was funded by a National Institute of Health Research (NIHR) Clinical Lectureship (CL 2017-11-002) and is currently supported by the NIHR Leicester Biomedical Research Centre. He was previously funded by a National Institute of Health Research (NIHR) Doctoral Research Fellowship (DRF 2014-07-079). This publication presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Manchester: Catharine West and Rebecca Elliott are supported by NIHR Manchester Biomedical Research Centre and Catharine West is supported by Cancer Research UK (C1094/A18504, C147/A25254). USA: Mount Sinai Hospital, New York. Open Access funding enabled and organized by Projekt DEAL

Large-scale meta-genome-wide association study reveals common genetic factors linked to radiation-induced acute toxicities across cancer types

Meta-genome; Toxicities; CancerMetagenoma; Toxicidades; CáncerMetagenoma; Toxicitats; CàncerBackground This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). Methods A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12 042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV—formerly SNP)–based heritability of rSTATacute in all patients and for each cancer type. Results Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10‒8 < P < 1.0 × 10‒5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size ‒0.17; P = 1.7 × 10‒7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified ‘RNA splicing via endonucleolytic cleavage and ligation’ (P = 5.1 × 10‒6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). Conclusions There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta–genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.E.N. was supported by a scholarship for a PhD from the University of Groningen, Groningen, The Netherlands. T.D. is funded as an Academic Clinical Fellow by the National Institute for Health Research, UK. D.J.T. is supported by a grant from The Taylor Family Foundation and Cancer Research UK [C19941/A30286]. M.L.K.C. is supported by the National Medical Research Council Singapore Clinician Scientist Award (NMRC/CSA-INV/0027/2018), National Research Foundation Proton Competitive Research Program (NRF-CRP17-2017-05), Ministry of Education Tier 3 Academic Research Fund (MOE2016-T3-1-004), the Duke-NUS Oncology Academic Program Goh Foundation Proton Research Programme, NCCS Cancer Fund, and the Kua Hong Pak Head and Neck Cancer Research Programme. G.C.B. is supported by Cancer research UK RadNet Cambridge [C17918/A28870]. RADIOGEN research was supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (INT20/00071, INT15/00070, INT17/00133, INT16/00154; PI19/01424; PI16/00046; PI13/02030; PI10/00164); by AECC grant PRYES211091VEGA and through the Autonomous Government of Galicia (Consolidation and structuring program: IN607B). C.N.A. and L.M.H.S. received funding from the Danish Cancer Society (grant R231-A14074-B2537). T.R. was funded by a National Institutes of Health Research (NIHR) Clinical Lectureship (CL 2017-11-002) and is supported by the NIHR Leicester Biomedical Research Centre. This publication presents independent research funded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. REQUITE received funding from the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement No. 601826. S.G.E. is supported by the government of Catalonia 2021SGR01112. L.D. was supported by the European Union Horizon 2020 research and innovation programs BRIDGES (grant No. 634935)

Reproducibility of fluorescent expression from engineered biological constructs in E. coli

We present results of the first large-scale interlaboratory study carried out in synthetic biology, as part of the 2014 and 2015 International Genetically Engineered Machine (iGEM) competitions. Participants at 88 institutions around the world measured fluorescence from three engineered constitutive constructs in E. coli. Few participants were able to measure absolute fluorescence, so data was analyzed in terms of ratios. Precision was strongly related to fluorescent strength, ranging from 1.54-fold standard deviation for the ratio between strong promoters to 5.75-fold for the ratio between the strongest and weakest promoter, and while host strain did not affect expression ratios, choice of instrument did. This result shows that high quantitative precision and reproducibility of results is possible, while at the same time indicating areas needing improved laboratory practices.Peer reviewe

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially