Genetic variants found in paediatric oncology patients with severe chemotherapy-induced toxicity: A case series.

Paediatric oncology patients who develop severe chemotherapy-induced toxicity that requires dose reduction, delay or termination of treatment are at risk of decreased treatment efficacy. Previous research has provided evidence that genetic variants in TPMT, NUDT15, UGT1A1 and DPYD are associated with toxicity of anticancer drugs. This led to pharmacogenetic guidelines that are integrated into clinical practice in paediatric oncology. Recently, novel genetic variants have been associated with a higher risk of developing chemotherapy-induced toxicity. In this case series, we selected 21 novel variants and genotyped these in nine patients with excessive chemotherapy-induced toxicity using whole exome sequencing or micro-array data. We observed that six out of nine patients carried at least one variant that, according to recent studies, potentially increased the risk of developing methotrexate- or vincristine-induced toxicity. As patient-derived genetic data are becoming widely accessible in paediatric oncology, these variants could potentially enter clinical practice to mitigate chemotherapy-induced toxicity.

[RCT about mindfulness-based cognitive therapy for psychological distress in cancer patients]. / RCT naar mindfulness-based cognitieve therapie voor psychische klachten bij oncologische patiënten.

BACKGROUND: Cancer patients may experience psychological distress, like anxiety and depressive symptoms. Mindfulness-based cognitive therapy (MBCT) has been shown to alleviate this psychological distress. However, patients experience barriers in participating in face-to-face MBCT. Individual internet-based MBCT (eMBCT) could be an alternative.
AIM: To compare MBCT and eMBCT to treatment as usual (TAU) for psychological distress in cancer patients.
METHOD: 245 cancer patients with psychological distress were randomly allocated to MBCT (n = 77), eMBCT (n = 90) or TAU (n = 78). Patients completed baseline (T0) and post-intervention (T1) assessments. The primary outcome was psychological distress on the Hospital Anxiety and Depression Scale. Outcomes were analyzed using linear mixed modeling on the intention-to-treat sample. Since both interventions were compared to TAU, the type I error rate was set to p < 0.025.
RESULTS: Compared to TAU, patients reported significantly less psychological distress after both MBCT (Cohen's d = 0.43, p < 0.001) and eMBCT (Cohen's d = 0.63, p < 0.001).
CONCLUSION: Compared to TAU, MBCT and eMBCT were similarly effective in reducing psychological distress in a sample of distressed heterogeneous cancer patients.

Consolidation and prediction of long-term treatment effect of group and online mindfulness-based cognitive therapy for distressed cancer patients.

BACKGROUND: Group face-to-face and individual internet-based mindfulness-based cognitive therapy (MBCT and eMBCT) have been demonstrated to reduce psychological distress for distressed cancer patients in a randomized controlled trial (RCT). This study focused on the long-term effects of this RCT during the nine-month follow-up period, and on possible predictors, moderators and working mechanisms. METHODS: Distressed cancer patients (n = 245) were randomized to MBCT or eMBCT. Data were collected at baseline, post-treatment, three- and nine-month follow-up. Data were analyzed with linear mixed effect models and (hierarchical) linear regressions. RESULTS: Analyses revealed long-term reductions in psychological distress and rumination, and long-term increases in positive mental health and mental health-related quality of life (QoL) in both interventions over the course of the nine-month follow-up. Interestingly, patients reported less psychological distress in the follow-up period after eMBCT in comparison to MBCT. Less psychological distress, rumination and neuroticism, and more extraversion and agreeableness at baseline predicted less psychological distress at the nine-month follow-up after both interventions. Less mindful and conscientious patients at baseline benefited more from eMBCT than from MBCT. Regarding working mechanisms, changes in mindfulness skills, fear of cancer recurrence and rumination during both interventions predicted less psychological distress at follow-up. CONCLUSIONS: Our findings suggest most improvements in cancer patients' increase over time after both interventions. Furthermore, patients seemed to benefit more from eMBCT than MBCT based on psychological distress levels, especially those patients with low levels of mindfulness skills and conscientiousness.

Detection of titanium particles in human liver and spleen and possible health implications.

BACKGROUND: Titanium dioxide (TiO2) is produced at high volumes and applied in many consumer and food products. Recent toxicokinetic modelling indicated the potential of TiO2 to accumulate in human liver and spleen upon daily oral exposure, which is not routinely investigated in chronic animal studies. A health risk from nanosized TiO2 particle consumption could not be excluded then. RESULTS: Here we show the first quantification of both total titanium (Ti) and TiO2 particles in 15 post-mortem human livers and spleens. These low-level analyses were enabled by the use of fully validated (single particle) inductively coupled plasma high resolution mass spectrometry ((sp)ICP-HRMS) detection methods for total Ti and TiO2 particles. The presence of TiO2 in the particles in tissues was confirmed by Scanning Electron Microscopy with energy dispersive X-ray spectrometry. CONCLUSIONS: These results prove that TiO2 particles are present in human liver and spleen, with ≥24% of nanosize (< 100 nm). The levels are below the doses regarded as safe in animals, but half are above the dose that is deemed safe for liver damage in humans when taking into account several commonly applied uncertainty factors. With these new and unique human data, we remain with the conclusion that health risks due to oral exposure to TiO2 cannot be excluded.

Exploring associations between psychiatric disorder, psychological distress, and health care utilization in cancer patients.

OBJECTIVE: The mental burden of cancer might elicit additional health care utilization. However, it is unclear how psychiatric disorder and psychological distress relate to health care utilization. Therefore, this study explores associations between psychiatric disorder, psychological distress, and health care utilization. It was hypothesized that presence of psychiatric disorder and psychological distress was associated with increased health care utilization and costs. METHODS: The current study consisted of secondary analyses of baseline data of a larger randomized controlled trial. Two hundred forty-five mixed-cancer patients with at least mild symptoms of psychological distress (Hospital Anxiety and Depression Scale-T ≥ 11) were mainly recruited via online media, participating centers and patient associations. Patients were assessed with Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I) for depressive, anxiety, and/or adjustment disorder. Psychological distress was measured by the Hospital Anxiety and Depression Scale. Retrospective self-reported health care utilization in the past 3 months was collected. Associations between predictors and health care utilization in terms of incidence rate ratios (IRR) and costs per category (mental, primary, somatic, and complementary) were assessed by negative binomial, logistic, and gamma regression. RESULTS: Eighty-nine (36.3%) patients suffered from psychiatric disorder, which was associated with mental health care utilization (IRR = 1.63) and costs (OR = 3.11). We observed a nonsignificant trend of somatic health care utilization in patients with psychiatric disorder. Psychological distress was associated with mental health care utilization (IRR = 1.09) and costs (OR = 1.09). Psychological distress was also associated with complementary health care utilization (IRR = 1.03). CONCLUSION: Psychiatric disorder and psychological distress were associated with mental health care use and costs. Psychological distress was associated with complementary health care use. Adequate assessment and referral to mental health care might prevent unnecessary health care utilization.

Atopic dermatitis characteristics and medication-use patterns in school-age children with AD and asthma symptoms.

BACKGROUND: Atopic dermatitis (AD) and asthma often coexist. Both diseases can have a major impact on the lives of children with AD and their caregivers. AIM: To investigate the association of patient characteristics, comorbidities and impact of AD on children who have both asthma and AD. METHODS: Children with AD (n = 140) were selected from a larger cohort of children with a reported use of asthma medication. The Children's Dermatology Life Quality Index (CDLQI) was used to assess Quality of Life (QoL), and the Self-Assessed Eczema Area and Severity Index (SA-EASI) was used to measure AD severity. Characteristics assessed included: age, sex, and the number and type of atopic comorbidities. Medication use for AD was defined using the total number of AD prescriptions, the number of different topical AD prescriptions and the highest potency topical corticosteroid (TCS) used. Determinants of AD severity and QoL were evaluated using Spearman rank tests. RESULTS: The following factors were most strongly associated with a lower QoL: characteristics of AD lesions (Spearman Rs = 0.61-0.69, P < 0.01), a higher SA-EASI score (Rs = 0.54, P < 0.01) and a larger number of different topical AD prescriptions (Rs = 0.38, P < 0.01). The following factors were correlated with more severe AD: age (Rs = -0.36, P < 0.01), larger number of different TCS preparations used (Rs = 0.27, P < 0.05) and larger number of TCS prescriptions (Rs = 0.25, P < 0.05). CONCLUSION: In children with asthma and AD, the number of TCS preparations used is associated with lower QoL and increased AD severity.

Uptake of Cadmium, Lead and Arsenic by Tenebrio molitor and Hermetia illucens from Contaminated Substrates.

Insects have potential as a novel source of protein in feed and food production in Europe, provided they can be used safely. To date, limited information is available on the safety of insects, and toxic elements are one of the potential hazards of concern. Therefore, we aimed to investigate the potential accumulation of cadmium, lead and arsenic in larvae of two insect species, Tenebrio molitor (yellow mealworm) and Hermetia illucens (black soldier fly), which seem to hold potential as a source of food or feed. An experiment was designed with 14 treatments, each in triplicate, per insect species. Twelve treatments used feed that was spiked with cadmium, lead or arsenic at 0.5, 1 and 2 times the respective maximum allowable levels (ML) in complete feed, as established by the European Commission (EC). Two of the 14 treatments consisted of controls, using non-spiked feed. All insects per container (replicate) were harvested when the first larva in that container had completed its larval stage. Development time, survival rates and fresh weights were similar over all treatments, except for development time and total live weight of the half of the maximum limit treatment for cadmium of the black soldier fly. Bioaccumulation (bioaccumulation factor > 1) was seen in all treatments (including two controls) for lead and cadmium in black soldier fly larvae, and for the three arsenic treatments in the yellow mealworm larvae. In the three cadmium treatments, concentrations of cadmium in black soldier fly larvae are higher than the current EC maximum limit for feed materials. The same was seen for the 1.0 and 2.0 ML treatments of arsenic in the yellow mealworm larvae. From this study, it can be concluded that if insects are used as feed materials, the maximum limits of these elements in complete feed should be revised per insect species.

No Negative Impact of Palliative Sedation on Relatives' Experience of the Dying Phase and Their Wellbeing after the Patient's Death: An Observational Study.

BACKGROUND: Palliative sedation is the widely-used intervention of administering sedating agents to induce a state of unconsciousness to take away a dying patient's perception of otherwise irrelievable symptoms. However, it remains questionable whether this ethically complex intervention is beneficial for patients and whether the associated lack of communication in the last phase of life has a negative impact on relatives' wellbeing. METHODS: An observational questionnaire study was conducted among relatives of a consecutive sample of patients who died a non-sudden death in the Erasmus MC Cancer Institute or in the hospice 'Laurens Cadenza' (both in Rotterdam) between 2010 and 2013. RESULTS: Relatives filled in questionnaires regarding 151 patients who had been sedated and 90 patients who had not been sedated. The median time since all patients had passed away was 21 (IQR 14-32) months. No significant differences were found in relatives´ assessments of the quality of end-of-life care, patients´ quality of life in the last week before death and their quality of dying, between patients who did and did not receive sedation, or in relatives' satisfaction with their own life, their general health and their mental wellbeing after the patient's death. CONCLUSIONS: The use of sedation in these patients appears to have no negative effect on bereaved relatives' evaluation of the patient's dying phase, or on their own wellbeing after the patient's death.

Study protocol of a multicenter randomized controlled trial comparing the effectiveness of group and individual internet-based Mindfulness-Based Cognitive Therapy with treatment as usual in reducing psychological distress in cancer patients: the BeMind study.

BACKGROUND: Mindfulness-based interventions have shown to reduce psychological distress in cancer patients. The accessibility of mindfulness-based interventions for cancer patients could be further improved by providing mindfulness using an individual internet-based format. The aim of this study is to test the effectiveness of a Mindfulness-Based Cognitive Therapy (MBCT) group intervention for cancer patients in comparison with individual internet-based MBCT and treatment as usual (TAU). METHODS/DESIGN: A three-armed multicenter randomized controlled trial comparing group-based MBCT to individual internet-based MBCT and TAU in cancer patients who suffer from at least mild psychological distress (Hospital Anxiety and Depression Scale (HADS) ≥ 11). Measurements will be conducted prior to randomization (baseline), post-treatment and at 3 months and 9 months post-treatment. Participants initially allocated to TAU are subsequently randomized to either group- or individual internet-based MBCT and will receive a second baseline measurement after 3 months. Thus, the three-armed comparison will have a time span of approximately 3 months. The two-armed intervention comparison includes a 9-month follow-up and will also consist of participants randomized to the intervention after TAU. Primary outcome will be post-treatment psychological distress (HADS). Secondary outcomes are fear of cancer recurrence (Fear of Cancer Recurrence Inventory), rumination (Rumination and Reflection Questionnaire), positive mental health (Mental Health Continuum - Short Form), and cost-effectiveness (health-related quality of life (EuroQol -5D and Short Form-12) and health care usage (Trimbos and iMTA questionnaire on Costs associated with Psychiatric illness). Potential predictors: DSM-IV-TR mood/anxiety disorders (SCID-I) and neuroticism (NEO-Five Factor Inventory) will be measured. Mediators of treatment effect: mindfulness skills, (Five-Facets of Mindfulness Questionnaire- Short Form), working alliance (Working Alliance Inventory) and group cohesion (Group Cohesion Questionnaire) will also be measured. DISCUSSION: This trial will provide valuable information on the clinical and cost-effectiveness of group versus internet-based MBCT versus TAU for distressed cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02138513. Registered 6 May 2014.

Identification and profiling of CXCR3-CXCR4 chemokine receptor heteromer complexes.

BACKGROUND AND PURPOSE: The C-X-C chemokine receptors 3 (CXCR3) and C-X-C chemokine receptors 4 (CXCR4) are involved in various autoimmune diseases and cancers. Small antagonists have previously been shown to cross-inhibit chemokine binding to CXCR4, CC chemokine receptors 2 (CCR2) and 5 (CCR5) heteromers. We investigated whether CXCR3 and CXCR4 can form heteromeric complexes and the binding characteristics of chemokines and small ligand compounds to these chemokine receptor heteromers. EXPERIMENTAL APPROACH: CXCR3-CXCR4 heteromers were identified in HEK293T cells using co-immunoprecipitation, time-resolved fluorescence resonance energy transfer, saturation BRET and the GPCR-heteromer identification technology (HIT) approach. Equilibrium competition binding and dissociation experiments were performed to detect negative binding cooperativity. KEY RESULTS: We provide evidence that chemokine receptors CXCR3 and CXCR4 form heteromeric complexes in HEK293T cells. Chemokine binding was mutually exclusive on membranes co-expressing CXCR3 and CXCR4 as revealed by equilibrium competition binding and dissociation experiments. The small CXCR3 agonist VUF10661 impaired binding of CXCL12 to CXCR4, whereas small antagonists were unable to cross-inhibit chemokine binding to the other chemokine receptor. In contrast, negative binding cooperativity between CXCR3 and CXCR4 chemokines was not observed in intact cells. However, using the GPCR-HIT approach, we have evidence for specific ß-arrestin2 recruitment to CXCR3-CXCR4 heteromers in response to agonist stimulation. CONCLUSIONS AND IMPLICATIONS: This study indicates that heteromeric CXCR3-CXCR4 complexes may act as functional units in living cells, which potentially open up novel therapeutic opportunities.

Positive feelings among terminally ill cancer patients.

For a realistic perspective on what it is like to have cancer and be in the last months of life, it is necessary to also study the positive feelings people may still experience. We set out to describe positive feelings experienced by terminally ill patients. The Depression Adjective Checklist was completed by 96 cancer patients with an estimated life expectancy of less than 3 months. On average patients endorsed 30% (3.6/12) of the positive mood items, and 25% (5.4/22) of the negative mood items. The larger part of terminally ill cancer patients with an estimated life expectancy of less than 3 months reported one or more positive mood states. A positive mood state such as 'being interested' was endorsed by more than half (65%) of the patients, other positive feelings were endorsed by a substantial proportion of patients, for example: 38% of patients endorsed feeling 'jovial' and 35% reported being 'optimistic'. Although having incurable cancer often leads to feelings of depression, mood is variable and many patients experience at least some positive feelings.

Psychosocial factors and the course of cervical intra-epithelial neoplasia: a prospective study.

OBJECTIVE: To investigate the influence of psychosocial factors on the course of cervical intra-epithelial neoplasia (CIN). METHODS: A group of 93 patients with CIN 1 or 2 was followed for 2.25 years by half-yearly colposcopy and cytology. Negatively-rated life events, social support, and coping style were studied in relation to distress during follow-up and in relation to time till progression and regression of CIN. Human papillomavirus (HPV) infection was controlled for as well as sick role bias caused by suspicion of having cervical cancer and distress due to the abnormal cervical smear. RESULTS: During follow-up, progression was found in 20 patients (22%), stable disease in 22 patients (24%), and regression in 51 patients (55%). Negatively-rated life events and lack of social support predicted distress longitudinally. No association was found between progression or regression of CIN and negatively-rated life events, lack of social support, coping style, and distress. CONCLUSION: We found no evidence that psychosocial factors influence the course of CIN.

Risk of acute coronary events according to serum concentrations of enterolactone: a prospective population-based case-control study.

BACKGROUND: The lignan enterolactone, produced by the intestinal microflora from dietary precursors, has been implicated in protection against cancer. We investigated the association of serum enterolactone concentration with the risk of acute coronary events in a prospective nested case-control study in middle-aged men from eastern Finland. METHODS: Enterolactone was measured by time-resolved fluoroimmunoassay in serum from 167 men who had an average 7.7 years of follow-up to an acute coronary event and from 167 control men. Both cases and controls were from a cohort of 2005 men who had no clinical coronary heart disease (CHD) at baseline. The controls were matched for age, examination year, and residence. Acute coronary events were registered prospectively. FINDINGS: The mean baseline serum enterolactone concentration was lower among the cases than the controls (18.2 [SD 21.1] vs 23.5 [18.2] nmol/L, p=0.001). The men in the highest quarter of the enterolactone distribution (>30.1 nmol/L) had a 58.8% (95% CI 24.1-77.6, p=0.005) lower risk of acute coronary events than men in the lowest quarter. After adjustment for the nine most strongly predictive risk factors, men in the highest enterolactone quarter had a 65.3% (11.9-86.3, p=0.03) lower risk than men in the lowest quarter. INTERPRETATION: Healthy men with high serum concentrations of enterolactone had a lower risk of acute coronary events than men with lower concentrations. These findings support the hypothesis that plant-dominated fibre-rich food lowers the risk of CHD.