An LC-MS/MS-based method for the simultaneous quantification of melatonin, cortisol and cortisone in saliva.

Disturbances in the diurnal pattern are associated with several clinical and psychological conditions, including depression and fatigue. Salivary sampling for melatonin, cortisol and cortisone provides a non-invasive method for frequent sampling and obtaining biochemical insight into the diurnal pattern of individuals. Therefore, a new liquid chromatography-tandem mass spectrometry-based method for the measurement of salivary melatonin, cortisol and cortisone was developed and validated. The method required 250 µl saliva, used isotope dilution methodology and was based on a liquid-liquid extraction for sample preparation, reversed-phase chromatography and multiple reaction monitoring on a mass spectrometer for quantitation. The lower limits of quantification obtained were 0.010 nmol/L for melatonin, 0.5 nmol/L for cortisol and 1.00 nmol/L for cortisone and the limits of detection were 0.003 nmol/L, 0.15 nmol/L and 0.1 nmol/L respectively. The method imprecision was ≤14% for all measurands, and the method comparison showed highly comparable results with high correlation coefficients (all ≥0.964). Potential interference of cortisol and cortisone by prednisolone was observed and could be detected by chromatogram review. Typical diurnal patterns for melatonin, cortisol and cortisone were observed in the saliva of 20 cancer survivors who collected saliva throughout the day.

Single-item chronotype is associated with dim light melatonin onset in lymphoma survivors with fatigue.

Chronotype is frequently assessed in human observational studies using various morningness-eveningness questionnaires. An alternative single-item chronotype question has been proposed for its reduced administration time and its accessibility to all types of populations. We investigated whether this single-item chronotype is associated with dim light melatonin onset, the "gold standard" for estimating the endogenous circadian phase. We used data from a randomised trial in 166 (non-)Hodgkin lymphoma survivors with cancer-related fatigue. All participants completed a questionnaire, including a single-item chronotype question. A subsample of 47 participants also provided saliva samples before sleep onset for melatonin measurement. Using multiple linear regression, we examined whether chronotype based on a single question was associated with dim light melatonin onset. The subsample of 47 participants had a mean age of 44.6 years. The mean (SD) dim light melatonin onset was at 8:42 (1:19) p.m. and the most common chronotype was more evening than morning person (29.2%). A gradual increase in dim light melatonin onset with later chronotype (i.e. evening preference) was observed, with a mean ranging from 7:45 p.m. in definite morning persons to 9:16 p.m. in definite evening persons. Our study shows that single-item chronotype is associated with dim light melatonin onset as a marker of the endogenous circadian phase of fatigued lymphoma survivors. This type of chronotype assessment can therefore be a useful alternative for more extensive morningness-eveningness questionnaires.

Light therapy as a treatment of cancer-related fatigue in (non-)Hodgkin lymphoma survivors (SPARKLE trial): study protocol of a multicenter randomized controlled trial.

BACKGROUND: Cancer related fatigue (CRF) is one of the most prevalent and distressing long-term complaints reported by (non-) Hodgkin survivors. To date there has been no standard treatment for CRF in this population. A novel and promising approach to treat CRF is exposure to bright white light therapy. Yet, large scale randomized controlled trials testing its efficacy in these patients and research on potential mechanisms is lacking. The objective of the current study is to investigate the efficacy of light therapy as a treatment for CRF and to explore potential mechanisms. METHODS/DESIGN: In a multicenter, randomized controlled trial we are evaluating the efficacy of two intensities of light therapy in reducing CRF complaints and restrictions caused by CRF in survivors of Hodgkin lymphoma or diffuse large B-cell lymphoma. Secondary outcomes include sleep quality, depression, anxiety, quality of life, cognitive complaints, cancer worries, fatigue catastrophizing, self-efficacy to handle fatigue, biological circadian rhythms of melatonin, cortisol and activity, and biomarkers of inflammation. We will recruit 128 survivors, with fatigue complaints, from academic and general hospitals. Survivors are randomized to either an intervention (exposure to bright white light) or a comparison group (exposure to dim white light). The longitudinal design includes four measurement points at baseline (T0), post-intervention at 3.5 weeks (T1), 3 months post-intervention (T2) and 9 months post-intervention (T3). Each measurement point includes self-reported questionnaires and actigraphy (10 days). T0 and T1 measurements also include collection of blood and saliva samples. DISCUSSION: Light therapy has the potential to be an effective treatment for CRF in cancer survivors. This study will provide insights on its efficacy and potential mechanisms. If proven to be effective, light therapy will provide an easy to deliver, low-cost and low-burden intervention, introducing a new era in the treatment of CRF. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov on August 8th 2017( NCT03242902 ).

The course of fear of cancer recurrence: Different patterns by age in breast cancer survivors.

OBJECTIVE: To examine the time course and predictors of fear of cancer recurrence (FCR) in breast cancer survivors over a period of 18 months after initial surgery. METHODS: Breast cancer patients (n = 267) were followed until 18 months after primary breast surgery. Shortly after surgery, participants completed the Life Orientation Test-Revised to measure optimism and the Concerns about Recurrence Scale to measure FCR. Mixed regression analysis was performed with age, optimism, marital status, education, type of surgery, with or without lymphectomy, chemotherapy, hormonal therapy, or radiotherapy, time since surgery, and all interactions with time as predictors of FCR. RESULTS: The final model included a significant interaction between age and time since surgery and a main effect for optimism. CONCLUSION: These results suggest that the course of FCR depends on the age of breast cancer survivors. Younger survivors showed an increase of fear during the first 1.5 years after breast surgery, whereas older survivors showed stable levels during the first 6 months after which it declined. Also, less optimistic survivors reported higher levels of FCR. Health care providers should pay (extra) attention to FCR in younger and less optimistic patients and offer psychological help when needed.

Comparing Smartphone Virtual Reality Exposure Preparation to Care as Usual in Children Aged 6 to 14 Years Undergoing Magnetic Resonance Imaging: Protocol for a Multicenter, Observer-Blinded, Randomized Controlled Trial.

BACKGROUND: A magnetic resonance imaging (MRI) procedure can cause preprocedural and periprocedural anxiety in children. Psychosocial interventions are used to prepare children for the procedure to alleviate anxiety, but these interventions are time-consuming and costly, limiting their clinical use. Virtual reality (VR) is a promising way to overcome these limitations in the preparation of children before an MRI scan. OBJECTIVE: The objective of this study is (1) to develop a VR smartphone intervention to prepare children at home for an MRI procedure; and (2) to examine the effect of the VR intervention in a randomized controlled trial, in which the VR intervention will be compared to care as usual (CAU). CAU involves an information letter about an MRI examination. The primary outcome is the child's procedural anxiety during the MRI procedure. Secondary outcomes include preprocedural anxiety and parental anxiety. We hypothesize that the VR preparation will result in a higher reduction of the periprocedural anxiety of both parents and children as compared to CAU. METHODS: The VR intervention provides a highly realistic and child-friendly representation of an MRI environment. In this randomized controlled trial, 128 children (aged 6 to 14 years) undergoing an MRI scan will be randomly allocated to the VR intervention or CAU. Children in the VR intervention will receive a log-in code for the VR app and are sent cardboard VR glasses. RESULTS: The VR smartphone preparation app was developed in 2020. The recruitment of participants is expected to be completed in December 2022. Data will be analyzed, and scientific papers will be submitted for publication in 2023. CONCLUSIONS: The VR smartphone app is expected to significantly reduce pre- and periprocedural anxiety in pediatric patients undergoing an MRI scan. The VR app offers a realistic and child-friendly experience that can contribute to modern care. A smartphone version of the VR app has the advantage that children, and potentially their parents, can get habituated to the VR environment and noises in their own home environment and can do this VR MRI preparation as often and as long as needed. TRIAL REGISTRATION: ISRCTN Registry ISRCTN20976625; https://www.isrctn.com/ISRCTN20976625. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41080.

A questionable factor structure of the multidimensional fatigue inventory in the general Dutch population.

OBJECTIVE: One of the most commonly used tools to measure fatigue is the Multidimensional Fatigue Inventory (MFI). Studies into the scale structure of the MFI show discrepant findings. The objective of this study was to investigate the scale structure of the MFI in the general Dutch population. STUDY DESIGN AND SETTING: Using data from a Dutch probability-based internet panel (n = 2512), the original 5-factor model, a 4-factor, and a 5- and 4-bifactor model of the MFI were tested with confirmatory factor analyses. Additional models were investigated using exploratory factor analysis. RESULTS: Results neither confirmed a 5-factor (RMSEA = 0.120, CFI = 0.933, TLI = 0.920) nor a 4-factor model (RMSEA = 0.122, CFI = 0.928, TLI = 0.917). The two bi-factor models also showed a poor fit (bi-4-factor: RMSEA = 0.151, CFI = 0.895, TLI = 0.873; bi-5-factor: RMSEA = 0.153, CFI = 0.894, TLI = 0.871). Exploratory factor analysis did not support an alternative model, but seemed to show robustness in the loading of the original general fatigue items. CONCLUSION: Our results did not provide empirical support for a four or five (bi-)factor structure of the MFI, nor for an alternative model. The most reliable scale of the MFI seems to be the general fatigue scale that could be used as a general indicator of fatigue.

Cancer-related Fatigue in Relation to Chronotype and Sleep Quality in (Non-)Hodgkin Lymphoma Survivors.

Cancer-related fatigue has been related to circadian disruptions and lower levels of sleep quality. However, it is unknown whether the circadian phase, which is associated with chronotype and timing of sleep, is related to fatigue after cancer. The aims of this study were to investigate the associations between (1) chronotype and cancer-related fatigue and (2) sleep quality and cancer-related fatigue. In this cross-sectional questionnaire study, 458 (non-)Hodgkin lymphoma survivors (n = 231 female, mean age 49.7 years) completed a Visual Analogue Scale for fatigue (VAS-fatigue) from 0 (no fatigue) to 10 (worst imaginable fatigue), the Munich Chronotype Questionnaire (MCTQ), and the Pittsburgh Sleep Quality Index (PSQI) between October 2018 and July 2019. A hierarchical linear regression analysis was used to evaluate the associations between the dependent variable fatigue and chronotype (based on early, intermediate, or late average midsleep) in Model 1, and fatigue and sleep quality in Model 2. The results showed no indications for an association between chronotype and fatigue (all p values ≥ 0.50). There were associations between two (out of seven) aspects of sleep quality and fatigue: subjective sleep quality (p < 0.001) and daily dysfunctioning (p < 0.001). Therefore, it is more likely that fatigue is associated with self-reported sleep quality rather than with chronotype. However, experimental studies with objective, physiological data on circadian phase and sleep quality are necessary to confirm the conclusions of this cross-sectional study.

Earlier chronotype in patients with rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) patients show an earlier circadian rhythm (i.e. serum melatonin peaks earlier during the night, indicating an earlier timing of the internal circadian pacemaker). In the current study, we examined whether the chronotype, which is influenced by the circadian rhythm, is also earlier. In addition, we explored whether chronotype is related to disease activity and patient-reported outcomes. METHODS: The chronotype (Munich Chronotype Questionnaire) of patients with RA (n = 121; mean age 60 years, 73% female) was compared with that of subjects from the general population (norm group; n = 1695) with a one-sample t test. In addition, we investigated chronotype in relation to disease activity (Disease Activity Score; DAS), reported morning stiffness, fatigue (Checklist Individual Strength), and health-related quality of life (RAND-36). RESULTS: The chronotype of patients with RA was, on average, 23 min (95% CI, 15 to 31 min) earlier than that of the norm group (t(115) = - 5.901, p < 0.001, d = 0.55). Chronotype was not related to disease activity or patient-reported outcomes (p > 0.05). CONCLUSION: As expected, chronotype was earlier in RA patients. However, in this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm has a positive influence on these outcomes. This insight could improve our understanding of the pathophysiology of RA and contribute to exploring new treatment possibilities. Key Points • This is the first study examining chronotype in patients with rheumatoid arthritis, and how chronotype relates to disease activity and patient-reported outcomes. • We found an earlier chronotype in patients with rheumatoid arthritis than in subjects from the general population. • In this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm positively influences these outcomes.

Light Therapy for Cancer-Related Fatigue in (Non-)Hodgkin Lymphoma Survivors: Results of a Randomized Controlled Trial.

PURPOSE: To evaluate the short- and long-term effects of light therapy on fatigue (primary outcome) and sleep quality, depression, anxiety, quality of life, and circadian rhythms (secondary outcomes) in survivors of (non-)Hodgkin lymphoma presenting with chronic cancer-related fatigue. METHODS: We randomly assigned 166 survivors (mean survival 13 years) to a bright white light intervention (BWL) or dim white light comparison (DWL) group. Measurements were completed at baseline (T0), post-intervention (T1), at three (T2), and nine (T3) months follow-up. A mixed-effect modeling approach was used to compare linear and non-linear effects of time between groups. RESULTS: There were no significant differences between BWL and DWL in the reduction in fatigue over time. Both BWL and DWL significantly (p < 0.001) improved fatigue levels during the intervention followed by a slight reduction in this effect during follow-up (EST0-T1 = -0.71; EST1-T3 = 0.15). Similar results were found for depression, sleep quality, and some aspects of quality of life. Light therapy had no effect on circadian rhythms. CONCLUSIONS: BWL was not superior in reducing fatigue compared to DWL in HL and DLBCL survivors. Remarkably, the total sample showed clinically relevant and persistent improvements on fatigue not commonly seen in longitudinal observational studies in these survivors.

Chronotherapy Network Netherlands (CNN).

Information is provided about the Chronotherapy Network Netherlands (CNN).