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Phylogenomics has the power to uncover complex phylogenetic scenarios across the genome. In most cases, no single topology is reflected across the entire genome as the phylogenetic signal differs among genomic regions due to processes, such as introgression and incomplete lineage sorting. Baleen whales are among the largest vertebrates on Earth with a high dispersal potential in a relatively unrestricted habitat, the oceans. The fin whale (Balaenoptera physalus) is one of the most enigmatic baleen whale species, currently divided into four subspecies. It has been a matter of debate whether phylogeographic patterns explain taxonomic variation in fin whales. Here we present a chromosome-level whole genome analysis of the phylogenetic relationships among fin whales from multiple ocean basins. First, we estimated concatenated and consensus phylogenies for both the mitochondrial and nuclear genomes. The consensus phylogenies based upon the autosomal genome uncovered monophyletic clades associated with each ocean basin, aligning with the current understanding of subspecies division. Nevertheless, discordances were detected in the phylogenies based on the Y chromosome, mitochondrial genome, autosomal genome and X chromosome. Furthermore, we detected signs of introgression and pervasive phylogenetic discordance across the autosomal genome. This complex phylogenetic scenario could be explained by a puzzle of introgressive events, not yet documented in fin whales. Similarly, incomplete lineage sorting and low phylogenetic signal could lead to such phylogenetic discordances. Our study reinforces the pitfalls of relying on concatenated or single locus phylogenies to determine taxonomic relationships below the species level by illustrating the underlying nuances which some phylogenetic approaches may fail to capture. We emphasize the significance of accurate taxonomic delineation in fin whales by exploring crucial information revealed through genome-wide assessments.
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PURPOSE: The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC). PATIENTS AND METHODS: The study was a phase 2 randomized trial with Simon's optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage. RESULTS: Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6-47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group. CONCLUSIONS: Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC.
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Neoplasias del Sistema Biliar , Ipilimumab , Nivolumab , Radiocirugia , Humanos , Radiocirugia/métodos , Radiocirugia/efectos adversos , Nivolumab/administración & dosificación , Nivolumab/uso terapéutico , Femenino , Masculino , Neoplasias del Sistema Biliar/patología , Neoplasias del Sistema Biliar/terapia , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/mortalidad , Ipilimumab/administración & dosificación , Ipilimumab/uso terapéutico , Anciano , Persona de Mediana Edad , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más Años , Terapia CombinadaRESUMEN
Teverelix drug product (DP) is a parenteral gonadotropin-releasing hormone (GnRH) antagonist that has been successfully tested in phase 2 trials for hormone-sensitive advanced prostate cancer (APC) and benign prostatic hyperplasia (BPH). In previous APC trials, teverelix DP was administered as intramuscular (IM) and subcutaneous (SC) injections, using a loading dose and (in a single trial) a maintenance dose. Our objective was to derive an optimal dosing regimen for phase 3 clinical development, using a pharmacometrics modeling approach. Data from 9 phase 2 studies (229 patients) was utilized to develop a population pharmacokinetic (PK) model that described the concentration profile accommodating both IM and SC routes of administration. A 2-compartment model with sequential first-order absorption (slow and fast) and lag times best described the PK profiles of teverelix following SC and IM administration. An indirect response model with inhibition of production rate was fit to describe testosterone (T) concentrations based on physiological relevance. The final population PK-pharmacodynamic model was used to conduct simulations of various candidate dosing regimens to select the optimal dosing regimen to achieve clinical castration (T < 0.5 ng/mL by day 28) and to sustain clinical castration for 26 weeks. Model simulation showed that a loading dose of 360 mg SC and 180 mg IM with a maintenance dose of 360 mg SC 6-weekly (Q6W) starting at day 28 can achieve a ≥95% castration rate up to 52 weeks. This dose regimen was selected for phase 3 clinical development, which includes cardiovascular safety assessment in comparison to a GnRH agonist.
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Hormona Liberadora de Gonadotropina , Modelos Biológicos , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Desarrollo de Medicamentos/métodos , Anciano , Inyecciones Subcutáneas , Ensayos Clínicos Fase III como Asunto , Inyecciones Intramusculares , Persona de Mediana Edad , Factores de Riesgo de Enfermedad Cardiaca , Enfermedades Cardiovasculares , Relación Dosis-Respuesta a Droga , OligopéptidosRESUMEN
BACKGROUND: Teverelix drug product (DP) is a novel injectable gonadotropin-releasing hormone antagonist. METHODS: An adaptive phase 2, open-label, multicenter trial was conducted in patients with advanced prostate cancer to evaluate the efficacy and safety of a combined subcutaneous (SC) and intramuscular (IM) loading dose regimen of teverelix DP of 120 mg SC + 120 mg IM (Group 1; N = 9) or 180 mg SC + 180 mg IM (Group 2; N = 41) administered at a single visit, followed by 6-weekly SC maintenance doses of 120 mg (Group 1) or 180 mg (Group 2), up to Day 168. The primary endpoint was the proportion of patients achieving castration levels with serum testosterone <0.5 ng/mL at Day 28 with a target castration rate of 90%. Injection sites were inspected by the investigator at every visit and reactions (ISRs) were proactively recorded. RESULTS: The target castration rate was reached in Group 2 (97.5%) but not in Group 1 (62.5%). The castration rates were not maintained to Day 42 (Group 2: 82.5%; Group 1: 50.0%). Suppression of testosterone to castrate levels occurred rapidly (median time: 2 days for both groups). Suppression of testosterone, prostate-specific antigen, follicle-stimulating hormone, and luteinizing hormone was sustained throughout the treatment period, being more prominent with the higher dose. The adverse event (AE) profile was similar between groups. The most common AEs were injection-site induration (n = 40: 80.0%), injection-site erythema (n = 35: 70.0%), and hot flush (n = 21: 42.0%). Most ISRs were Grade 1. CONCLUSION: Overall, the teverelix DP doses were generally well-tolerated but did not adequately maintain castration levels.
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Neoplasias de la Próstata , Humanos , Masculino , Hormona Liberadora de Gonadotropina , Oligopéptidos , Antígeno Prostático Específico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía , Testosterona/sangreRESUMEN
OBJECTIVES: Prolonged or excessive stress can have a negative impact on health and well-being, and stress therefore constitutes a major public health issue. A central question is what are the main sources of stress in contemporary societies? This study examines the effects of work-related and non-work-related stressors and perceived social support on perceived stress within a causal framework. METHODS: Panel data were drawn from two waves (2013 and 2017) of the population-based health survey "How are you?" conducted in the Central Denmark Region. The analytical sample comprised 9,194 subjects who had responded to both surveys. Work-related and non-work-related stressors included major life events, chronic stressors, daily hassles and lack of social support. Perceived stress was measured with the 10-item Perceived Stress Scale (PSS). Data were analysed using fixed effects regression in a fully balanced design. RESULTS: The largest effects on PSS were seen in own disease, work situation and lack of social support. Other stressors affecting the perceived stress level were financial circumstances, relationship with partner, relationship with family and friends, and disease among close relatives. Most variables had a symmetrical effect on PSS. CONCLUSIONS: The results point to the need for comprehensive policies to promote mental health that span life domains and include both the individual and the group as well as organizational and societal levels. The study indicates that there are multiple potential entry points for stress prevention and stress management. However, it also shows that disease, work situation and social support weigh heavily in the overall picture. This points to the healthcare system and workplace as key institutional venues for action.
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Amigos , Instituciones de Salud , Humanos , Causalidad , Encuestas Epidemiológicas , Estrés PsicológicoRESUMEN
Phylogeny-based estimates suggesting a low germline mutation rate (µ) in baleen whales have influenced research ranging from assessments of whaling impacts to evolutionary cancer biology. We estimated µ directly from pedigrees in four baleen whale species for both the mitochondrial control region and nuclear genome. The results suggest values higher than those obtained through phylogeny-based estimates and similar to pedigree-based values for primates and toothed whales. Applying our estimate of µ reduces previous genetic-based estimates of preexploitation whale abundance by 86% and suggests that µ cannot explain low cancer rates in gigantic mammals. Our study shows that it is feasible to estimate µ directly from pedigrees in natural populations, with wide-ranging implications for ecological and evolutionary research.
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Tasa de Mutación , Ballenas , Animales , Linaje , Ballenas/genéticaRESUMEN
Background and objectives: Teverelix drug product (DP) is a gonadotropin-releasing hormone antagonist in development for the treatment of patients with prostate cancer in whom androgen deprivation therapy is indicated. The aim of this paper is to present the results of five Phase 2 studies that assessed the pharmacokinetics, pharmacodynamics, efficacy and safety of different loading dose regimens of teverelix DP. Methods: Five single-arm, uncontrolled clinical trials were conducted in patients with advanced prostate cancer. The five different loading dose regimens of teverelix DP tested were (a) a single 90 mg subcutaneous (SC) injection of teverelix DP given on 3 consecutive days (Days 0, 1 and 2); (b) a single 90 mg intramuscular (IM) injection of teverelix DP given 7 days apart (Days 0 and 7); (c) a single 120 mg SC injection of teverelix DP given on 2 consecutive days (Days 0 and 1); (d) 2 × 60 mg SC injections of teverelix DP given on 3 consecutive days (Days 0, 1 and 2), and (e) 2 × 90 mg SC injections of teverelix DP given on 3 consecutive days (Days 0, 1 and 2). The primary efficacy parameter was the duration of action of an initial loading dose regimen in terms of suppression of testosterone to below the castration level (0.5 ng/mL). Results: Eighty-two patients were treated with teverelix DP. Two regimens (90 mg and 180 mg SC on 3 consecutive days) had a mean duration of castration of 55.32 days and 68.95 days with >90% of patients having testosterone levels < 0.5 ng/mL at Day 28. The mean onset of castration for the SC regimens ranged from 1.10 to 1.77 days, while it was slower (2.4 days) with IM administration. The most common adverse event (AE) was injection site reaction. No AEs of severe intensity were reported. Conclusions: Teverelix DP is safe and well tolerated. Castrate levels of testosterone can be rapidly achieved following the subcutaneous injection of teverelix DP on 3 consecutive days. Streamlining of the administration of the loading dose and identifying a suitable maintenance dose will be investigated in future trials.
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Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Hormona Liberadora de Gonadotropina/uso terapéutico , Leuprolida/efectos adversos , Antagonistas de Andrógenos/uso terapéutico , Testosterona/uso terapéuticoRESUMEN
BACKGROUND & AIMS: Late diagnosis is a critical factor undermining clinical management of patients with biliary tract cancer (BTC). While biliary tumours display extensive inter-patient heterogeneity, the host immune response may be comparatively homogenous, providing diagnostic opportunities. Herein, we investigated whether cancer-associated systemic reprogramming could be detected non-invasively to improve diagnosis of BTC. METHODS: In this prospective Danish study, whole blood (WB) microRNA (miRNA) profiling was performed in samples from 218 patients with BTC, 99 healthy participants, and 69 patients with differential diagnoses split into discovery (small RNA-sequencing) and validation (RT-qPCR) cohorts. miRNA expression and activity were further investigated in 119 and 660 BTC tissues, respectively. RESULTS: Four WB miRNAs (let-7a-3p, miR-92b-5p, miR-145-3p, miR-582-3p) were identified and validated as diagnostic of BTC on univariable analysis. Two diagnostic miRNA indexes were subsequently identified that were elevated in patients with BTC and in patients with differential diagnoses, compared to healthy participants. The combination of these miRNA indexes with serum CA 19-9 significantly improved the diagnostic performance of CA 19-9 alone, consistently achieving superior AUC values irrespective of clinical setting (minimum AUC >0.84) or tumour location (minimum AUC >0.87). The diagnostic information captured by miRNA indexes was not recapitulated by routine clinical measurements. Index miRNA expression in BTC tissues was associated with distinct pathobiological and immune features. CONCLUSIONS: WB miRNA profiles are altered in patients with BTC. Quantification of miRNA indexes in combination with serum CA 19-9 has the potential to improve early diagnosis of BTC, pending further validation. LAY SUMMARY: Surgery is currently the only curative intervention for patients with biliary tract cancer (BTC). However, resection is not possible for most patients who are diagnosed with late-stage disease. With the aim of identifying new early diagnostic opportunities, we analysed circulating microRNAs (small non-coding RNAs whose role in cancer is being increasingly recognised) in whole blood samples. We identified a microRNA signature that could distinguish patients with BTC from healthy participants. These miRNAs significantly improved the diagnostic potential of the routinely measured biomarker, CA 19-9, and were implicated in distinct immune processes in tumour tissues.
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Neoplasias del Sistema Biliar , MicroARN Circulante , MicroARNs , Neoplasias del Sistema Biliar/diagnóstico , Neoplasias del Sistema Biliar/genética , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , Humanos , MicroARNs/genética , Estudios ProspectivosRESUMEN
Denmark has a 35-year history of monitoring health status in the general population through health surveys. In this commentary, we outline the development of health surveys in Denmark from the beginning in 1987 to the present time. We describe how the current systematic framework for the Danish National Health Survey (DNHS) developed. We discuss the methodological basis for the DNHS and describe its application in public health practice and research. Over the years, the DNHS has become an important part of the Danish public health environment. Challenges for the DNHS in the future are to adapt to new trends in public health and at the same time to be able to monitor important changes consistently over time.
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Estado de Salud , Práctica de Salud Pública , Dinamarca/epidemiología , Encuestas Epidemiológicas , Humanos , Encuestas y CuestionariosRESUMEN
Global warming is affecting the population dynamics and trophic interactions across a wide range of ecosystems and habitats. Translating these real-time effects into their long-term consequences remains a challenge. The rapid and extreme warming period that occurred after the Last Glacial Maximum (LGM) during the Pleistocene-Holocene transition (7-12 thousand years ago) provides an opportunity to gain insights into the long-term responses of natural populations to periods with global warming. The effects of this post-LGM warming period have been assessed in many terrestrial taxa, whereas insights into the impacts of rapid global warming on marine taxa remain limited, especially for megafauna. In order to understand how large-scale climate fluctuations during the post-LGM affected baleen whales and their prey, we conducted an extensive, large-scale analysis of the long-term effects of the post-LGM warming on abundance and inter-ocean connectivity in eight baleen whale and seven prey (fish and invertebrates) species across the Southern and the North Atlantic Ocean; two ocean basins that differ in key oceanographic features. The analysis was based upon 7032 mitochondrial DNA sequences as well as genome-wide DNA sequence variation in 100 individuals. The estimated temporal changes in genetic diversity during the last 30,000 years indicated that most baleen whale populations underwent post-LGM expansions in both ocean basins. The increase in baleen whale abundance during the Holocene was associated with simultaneous changes in their prey and climate. Highly correlated, synchronized and exponential increases in abundance in both baleen whales and their prey in the Southern Ocean were indicative of a dramatic increase in ocean productivity. In contrast, the demographic fluctuations observed in baleen whales and their prey in the North Atlantic Ocean were subtle, varying across taxa and time. Perhaps most important was the observation that the ocean-wide expansions and decreases in abundance that were initiated by the post-LGM global warming, continued for millennia after global temperatures stabilized, reflecting persistent, long-lasting impacts of global warming on marine fauna.
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Ecosistema , Calentamiento Global , Animales , Océano Atlántico , Dinámica Poblacional , Ballenas/fisiologíaRESUMEN
OBJECTIVE: To validate the Danish Multimorbidity Treatment Burden Questionnaire (MTBQ) and obtain a population-based evaluation of treatment burden. DESIGN: Mixed-methods. SETTING: Danish population-based survey. PARTICIPANTS: Translation by professional translators and an expert group. The scale was tested by 13 407 participants (aged ≥25 years) in treatment. MEASURES: The 10-item MTBQ was translated into Danish using forward-backward translation and used in a large population health survey. A global MTBQ score was calculated and factor analysis and Cronbach's alpha assessed dimensional structure and internal consistency reliability, respectively. Spearman's rank correlations between global MTBQ scores and scores of self-rated health, health-related quality of life and the number of long-term conditions, respectively, assessed construct validity. MTBQ scores were grouped into four categories (no, low, medium, high burden) to assess interpretability and population-based evaluation of treatment burden. RESULTS: The scale showed high internal consistency (α=0.87), positive skewness and large floor effects. Factor analysis supported a one-dimensional structure of the scale with a three-dimensional structure as a less parsimonious alternative. The MTBQ score was negatively associated with self-rated health (rS-0.45, p<0.0001) and health-related quality of life (rS-0.46/-0.51, p<0.0001), and positively associated with the number of long-term conditions (rS 0.26, p<0.0001) and perceived stress (rS 0.44, p<0.0001). Higher treatment burden was associated with young age, male sex, high educational level, unemployment, being permanently out of work, not living with a spouse/cohabitant, living with child(ren) and long-term conditions (eg, heart attack, stroke, diabetes and mental illness). CONCLUSION: The Danish MTBQ is a valid measure of treatment burden with good construct validity and high internal reliability. This is the first study to explore treatment burden at a population level and provides important evidence to policy makers and clinicians about sociodemographic groups at risk of higher treatment burden.
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Multimorbilidad , Salud Poblacional , Adulto , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Psicometría/métodos , Calidad de Vida , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
Phase transitions in molecular crystals are often determined by intermolecular interactions. The cage complex of [Co(C12 H30 N8 )]3+ â
3 NO3 - is reported to undergo a disorder-order phase transition at Tc1 ≈133â
K upon cooling. Temperature-dependent neutron and synchrotron diffraction experiments revealed satellite reflections in addition to main reflections in the diffraction patterns below Tc1 . The modulation wave vector varies as function of temperature and locks in at Tc3 ≈98â
K. Here, we demonstrate that the crystal symmetry lowers from hexagonal to monoclinic in the incommensurately modulated phases in Tc1
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BACKGROUND: Older patients with cancer are at risk of physical decline and impaired quality of life during oncological treatment. Exercise training has the potential to reduce these challenges. The study aim was to investigate the feasibility and effect of a multimodal exercise intervention in older patients with advanced cancer (stages III/IV). PATIENTS AND METHODS: Eighty-four older adults (≥65 years) with advanced pancreatic, biliary tract, or non-small cell lung cancer who received systemic oncological treatment were randomized 1:1 to an intervention group or a control group. The intervention was a 12-week multimodal exercise-based program including supervised exercise twice weekly followed by a protein supplement, a home-based walking program, and nurse-led support and counseling. The primary endpoint was change in physical function (30-second chair stand test) at 13 weeks. RESULTS: Median age of the participants was 72 years (interquartile range [IQR] 68-75). Median adherence to the exercise sessions was 69% (IQR 21-88) and 75% (IQR 33-100) for the walking program. At 13 weeks, there was a significant difference in change scores of 2.4 repetitions in the chair stand test, favoring the intervention group (p < .0001). Furthermore, significant beneficial effects were seen for physical endurance (6-minute walk test), hand grip strength, physical activity, symptom burden, symptoms of depression and anxiety, global health status (quality of life), and lean body mass. No effects were seen for dose intensity, hospitalizations, or survival. CONCLUSION: A 12-week multimodal exercise intervention with targeted support proved effective in improving physical function in older patients with advanced cancer during oncological treatment.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Terapia por Ejercicio , Fuerza de la Mano , Humanos , Neoplasias Pulmonares/terapia , Calidad de VidaRESUMEN
Teverelix trifluoroacetate is a decapeptide, gonadotropin-releasing hormone antagonist that binds competitively and reversibly to gonadotropin-releasing hormone receptors in the pituitary gland, resulting in immediate suppression of luteinizing hormone and follicle-stimulating hormone, which in turn causes a very rapid decrease in testosterone production in the Leydig cells of the testes in men and in estradiol in the ovaries in women. This phase 1 clinical study was an open-label, parallel-design, single-center, single-dose study in older, healthy male subjects. Following injection, teverelix is released into the systemic circulation in a biphasic manner. An initial rapid phase is followed by a slow-release phase thought to be due to the formation of a depot, which limits the diffusion of teverelix into the blood. The release characteristics differ significantly for the subcutaneous (SC) and intramuscular (IM) routes. Teverelix maximum concentration and exposure increased in an approximately dose-proportional manner across the 60 to 120 mg SC doses. All 3 pharmacodynamic end points (luteinizing hormone, follicle-stimulating hormone, and total testosterone) showed reductions that were more prolonged following the 90 mg IM administration compared to 90 mg SC administration.
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Antagonistas de Hormonas , Oligopéptidos , Anciano , Hormona Liberadora de Gonadotropina , Antagonistas de Hormonas/efectos adversos , Humanos , Masculino , Oligopéptidos/efectos adversos , Ácido TrifluoroacéticoRESUMEN
BACKGROUND: In colorectal cancer, the inflamed tumour microenvironment with its angiogenic activities is immune- tolerant and incites progression to liver metastasis. We hypothesised that angiogenic and inflammatory factors in serum samples from patients with non-metastatic rectal cancer could inform on liver metastasis risk. METHODS: We measured 84 angiogenic and inflammatory markers in serum sampled at the time of diagnosis within the population-based cohort of 122 stage I-III patients. In a stepwise manner, the statistically strongest proteins associated with time to development of liver metastasis were analysed in the corresponding serum samples from 273 stage II-III rectal cancer patients in three independent cohorts. RESULTS: We identified the soluble form of the costimulatory immune checkpoint receptor cluster of differentiation molecule 40 (sCD40) as a marker of liver metastasis risk across all patient cohorts-the higher the sCD40 level, the shorter time to liver metastasis. In patients receiving neoadjuvant treatment, the sCD40 value remained an independent variable associated with progression to liver metastasis along with the local treatment response. Of note, serum sCD40 was not associated with progression to lung metastasis. CONCLUSIONS: Circulating sCD40 is a marker of liver metastasis risk in rectal cancer and may be developed for use in clinical practice.
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Biomarcadores de Tumor/sangre , Antígenos CD40/sangre , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/secundario , Neoplasias del Recto/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/inmunología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Neoplasias del Recto/sangre , Neoplasias del Recto/patología , Microambiente TumoralRESUMEN
BACKGROUND: High levels of perceived stress have a negative bearing on health and well-being, and stress is a major public health issue. According to the Stress Process Model, stressors are socially patterned and combine to produce strain. Despite this, most studies on stress have focused on work-related stressors leaving non-work determinants under-investigated. The aim of the present study was to determine the relative importance of work-related and non-work-related stressors and perceived social support for the overall perceived stress level. METHODS: Self-reported data were drawn from the 2017 population-based health survey "How are you?" conducted in the Central Denmark Region (N = 32,417). Data were linked with data drawn from national administrative registers. Work- and non-work-related stressors assessed included major life events, chronic stressors and daily hassles. Perceived social support was assessed using a single question. Overall perceived stress was assessed by the 10-item Perceived Stress Scale. We conducted dominance analyses based on a multiple linear regression model to determine the most important explanatory variables of overall perceived stress. Analyses were weighted and adjusted. RESULTS: Work- and non-work-related stressors along with perceived social support explained 42.5% of the total variance (R2) in overall perceived stress. The most important explanatory variables were disease, perceived social support and work situation. The stratified analyses produced slightly varying results ("dominance profiles") of perceived stress between subgroups. Work situation was the most important explanatory variable in the employed group. However, adding non-work-related explanatory variables to the analysis tripled the explained variance. CONCLUSIONS: The overall level of perceived stress can be statistically explained by a combination of work- and non-work-related stressors and perceived social support both at population level and in subgroups. The most important explanatory variables of overall perceived stress are disease, perceived social support and work situation. Results indicate that public health strategies aiming to reduce stress should take a comprehensive approach and address a variety of stressor domains rather than focus on a single domain. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency (r. no. 2012-58-0006) and registered in the Central Denmark Region (r. no. 1-16-02-593-16).
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Apoyo Social , Estrés Psicológico , Estudios Transversales , Humanos , Estrés Psicológico/epidemiología , Encuestas y CuestionariosRESUMEN
Aims: This study aimed to compare health-related quality of life (HRQOL) among cancer survivors and controls in the Danish population, with special attention given to the impact of low educational attainment. Comparisons were made at population level and for subgroups stratified by education. Furthermore, comparisons were made for all cancer diagnoses combined and for the 14 most prevalent cancer sites and 'other cancer sites'. Finally, the importance of time since initial diagnosis was examined. Methods: HRQOL was measured using the physical component score (PCS) and mental component score (MCS) of the 12-item Short-Form Health Survey version 2 in a population-based survey. By linking data with the Danish Cancer Registry, 11,166 cancer survivors and 151,117 individuals with no history of cancer were identified. Results: HRQOL was reduced in cancer survivors for all cancers combined and most cancer sites. Differences were found at population level and stratified by educational attainment. PCS was reduced to a similar extent in the three educational groups, whereas MCS was reduced slightly more in the low than in the high educational attainment group. HRQOL increased with time since initial diagnosis during the first years. Conclusions: Cancer survivors had lower HRQOL than controls, and HRQOL was lower in the low than in the high educational attainment group. However, low educational attainment did not widen the gap in HRQOL following a cancer diagnosis. Despite this, the combined effect of low educational attainment and a cancer diagnosis markedly reduced HRQOL in some cancer survivors. The study identified groups of cancer survivors with low HRQOL who may have unmet rehabilitation needs.
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Supervivientes de Cáncer , Neoplasias , Escolaridad , Encuestas Epidemiológicas , Humanos , Calidad de Vida , Encuestas y CuestionariosRESUMEN
Metastatic colorectal cancer (mCRC) is treated with cetuximab 250 mg/m2 administered weekly over 1 hour or biweekly (q2w) over 3.5 hours when combined with irinotecan. This prospective study investigated cetuximab 500 mg/m2 plus irinotecan 180 mg/m2 administered q2w over 1.5 hours independent of RAS or BRAF mutation status in mCRC patients in a third-line setting. The intention-to-treat population included 181 patients. No patients had complete response, 18% had partial responses (PR) and 48% stable disease (SD). For cetuximab, a relative dose intensity of ≥90% was reached in 78% and for irinotecan in 67% of the patients. Grade 3 to 4 toxicities were pain (17%), fatigue (9%), neutropenia (8%), diarrhea (8%), rash (8%), infection (7%) and hypersensitivity (3%). No deaths occurred. Next-generation sequencing in 96.7% of the patients revealed that 50.3% had RAS and BRAFV600E wild type (WT), with a mutation type (MT) in 45.1% of the RAS and 4.4% of the BRAFV600E genes. In patients with RAS-WT and RAS-MT tumors, a PR was obtained in 32% and 4% (P = .000003) and an SD in 43% and 53%, respectively, with a superior PFS (6.2 vs 3.7 months; hazard ratio [HR] 2.12, P = .00001) and OS (12.9 vs 8.8 months; HR 1.71, P = .0008). Treatment efficacy was poor in 7.4% of patients with an RAS mutation outside KRAS exon 2 and in 38% of patients with KRAS exon 2 mutations. Administration of cetuximab and irinotecan q2w, shortening treatment time from 3.5 to 1.5 hours, is recommended as standard therapy.
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PURPOSE: Obesity is an established risk factor for venous thromboembolism (VTE), while studies on physical inactivity and VTE risk show conflicting results. We examined whether physical activity modified the association between obesity and VTE. PATIENTS AND METHODS: We conducted a population-based cohort study by combining data on outcome diagnoses, comorbidities and medication from nationwide registries with self-reported lifestyle data from an extensive Danish lifestyle questionnaire (2001-2015). We computed incidence rates (IRs) and hazard ratios (HRs) of VTE for categories of body mass index (BMI), among the total study population (n=57,523) and for physically active (n=25,387) and inactive individuals (n=30,902) separately. RESULTS: Obesity (BMI ≥30 kg/m2) was as expected associated with increased VTE risk compared with normal weight (HR 1.62, 95% confidence interval (CI): 1.26-2.09). Independent of BMI category, the rate of VTE was higher for inactive than active individuals. Thus, among obese individuals, the IR per 1000 person-years was 2.03 (95% CI: 1.60-2.57) for inactive and 1.44 (95% CI: 0.97-2.15) for active individuals. In contrast, the HR for VTE comparing obese with normal weight individuals were higher for active (HR 2.19, 95% CI: 1.35-3.58) than inactive individuals (HR 1.36, 95% CI: 1.00-1.84). CONCLUSION: Physical activity acts as an effect measure modifier of the association between obesity and VTE. Thus, physical activity reduced the absolute rate of VTE among obese individuals but increased the relative rate of VTE among obese compared with normal weight individuals.