[Myofasciitis under nivolumab treatment]. / Myofasziitis unter Nivolumab-Therapie.

We report the case of a 73-year-old female patient with malignant melanoma who developed rapidly progressive dermatosclerosis of the arms and legs as well as myalgia and flexion contractures during treatment with the immune checkpoint inhibitor nivolumab. The diagnosis of a myofasciitis was confirmed by imaging and biopsy. Following consultation with the treating dermato-oncologists nivolumab treatment was paused and treatment with methotrexate and prednisolone was initiated. Immune checkpoint inhibitors can induce a variety of immune-mediated side effects and can also imitate symptoms of rheumatological diseases. The occurrence of myofasciitis under immune checkpoint inhibition has been reported in the literature only in a few cases. Further oncological and rheumatological treatment management should be carried out in close interdisciplinary coordination.

Joint action malnutrition in the elderly (MaNuEL) knowledge hub: summary of project findings.

PURPOSE: The Joint Action Malnutrition in the Elderly (MaNuEL) Knowledge Hub was established to extend scientific knowledge, strengthen evidence-based practice, build a sustainable, transnational network of experts and harmonize research and clinical practice in the field of protein-energy malnutrition in older persons. This paper aims to summarize the main scientific results achieved during the 2-year project and to outline the recommendations derived. METHODS: 22 research groups from seven countries (Austria, France, Germany, Ireland, Spain, The Netherlands and New Zealand) worked together on 6 relevant domains of malnutrition-i.e. prevalence, screening, determinants, treatment, policy measures and education for health care professionals-making use of existing datasets, evidence and expert knowledge. RESULTS: Four systematic reviews, six secondary data analyses of existing cohort and intervention studies, two web-based surveys and one Delphi study were performed. In addition, a scoring system to rate malnutrition screening tools and a theoretical framework on the aetiology of malnutrition in older persons were developed. Based on these activities and taking existing evidence into consideration, 13 clinical practice, 9 research and 4 policy recommendations were developed. The MaNuEL Toolbox was created and made available to effectively distribute and disseminate the MaNuEL results and recommendations. CONCLUSIONS: The MaNuEL Knowledge Hub successfully achieved its aims. Results and recommendations will support researchers, healthcare professionals, policy-makers as well as educational institutes to advance their efforts in tackling the increasing problem of protein-energy malnutrition in the older population.

Definition of new cut-offs of BMI and waist circumference based on body composition and insulin resistance: differences between children, adolescents and adults.

OBJECTIVE: This study aims to determine associations between anthropometric traits, regional fat depots and insulin resistance in children, adolescents and adults to define new cut-offs of body mass index (BMI) or waist circumference (WC). DESIGN: Cross-sectional data were assessed in 433 children, adolescents and adults (aged: 6-60 years, BMI: 23.6 [21.0-27.7] kg m-2). Total adipose tissue (TAT), regional subcutaneous adipose tissue (SATtotal, SATtrunk) and visceral adipose tissue (VAT) were determined by whole-body magnetic resonance imaging, fat mass by air-displacement plethysmography. Insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR). Bivariate as well as partial correlations and regression analyses were used. Cut-off values of BMI and WC related to regional fat depots and HOMA-IR were analysed by receiver operating characteristics curve. RESULTS: In adults, TAT, SATtotal and SATtrunk increased linearly with increasing BMI and WC, whereas they followed a cubic function in children and adolescents with a steep increase at BMI and WC ≥1 standard deviation score and VAT at WC ≥2 standard deviation score. Sex differences were apparent in adults with women having higher masses of TAT and SAT and men having higher VAT. Using established BMI or WC cut-offs, correspondent masses of TAT, SATtotal, SATtrunk and VAT increased from childhood to adulthood. In all age groups, there were positive associations between BMI, WC, SATtrunk, VAT and HOMA-IR. When compared with normative cut-offs of BMI or WC, HOMA-IR-derived cut-offs of regional fat depots were lower in all age groups. CONCLUSIONS: Associations between BMI, WC and regional fat depots varied between children, adolescents, young and older adults. When compared with BMI-derived and WC-derived values, an insulin resistance-derived cut-off corresponded to lower masses of regional fat depots. Thus, established BMI and WC cut-offs are not appropriate to assess metabolic disturbances associated with obesity; therefore, new cut-offs of BMI and WC are needed for clinical practice.

Association between individual fat depots and cardio-metabolic traits in normal- and overweight children, adolescents and adults.

OBJECTIVES: To determine age-related associations between fat mass (FM), regional fat depots and cardiometabolic traits in normal- and overweight children, adolescents and adults. METHODS: Detailed body composition (regional subcutaneous and visceral adipose tissue; SAT, VAT) by whole-body magnetic resonance imaging (MRI), FM and fat-free mass by air-displacement plethysmography, systolic and diastolic blood pressure (SBP, DBP), triglycerides (TG), high-density lipoprotein cholesterol (HDL), plasma glucose and plasma insulin were measured in 433 subjects (BMI: 23.6 (21.0-27.7); 151 children and adolescents, aged 6-18 years, 150 young adults, aged 18-30 years and 132 adults, aged 30-60 years). Data were derived from pooled data of the 'Reference Center for Body Composition' in Kiel, Germany. Insulin resistance was determined by the homeostatic model assessment of insulin resistance (HOMA-IR). Partial correlations and multivariate linear regression analyses were used to evaluate the associations between body composition and cardiometabolic traits. A descriptive approach was used to demonstrate age-dependent differences in associations between body fat depots and insulin resistance, independent of BMI. RESULTS: FM, SAT, and VAT increased from childhood to adulthood with low VAT in children and adolescents. When compared to children, TG was higher in adults. HDL and DBP did not differ between age groups. Insulin resistance was highest in male adolescents and female young adults. Associations between body fat depots and cardiometabolic traits were seen after puberty with no associations in pre- and intrapubertal children. When compared to FM, SAT and VAT had the strongest association with insulin resistance in adults. This association was independent of BMI. CONCLUSIONS: Associations between individual body fat depots and most cardiometabolic traits became evident after puberty only. The strongest associations were observed between insulin resistance and abdominal fat in adults. The impact of VAT was independent of BMI.

Cross-reactivity between methylisothiazolinone, octylisothiazolinone and benzisothiazolinone using a modified local lymph node assay.

BACKGROUND: In the light of the exceptionally high rates of contact allergy to the preservative methylisothiazolinone (MI), information about cross-reactivity between MI, octylisothiazolinone (OIT) and benzisothiazolinone (BIT) is needed. OBJECTIVES: To study cross-reactivity between MI and OIT, and between MI and BIT. METHODS: Immune responses to MI, OIT and BIT were studied in vehicle and MI-sensitized female CBA mice by a modified local lymph node assay. The inflammatory response was measured by ear thickness, cell proliferation of CD4+ and CD8+ T cells, and CD19+ B cells in the auricular draining lymph nodes. RESULTS: MI induced significant, strong, concentration-dependent immune responses in the draining lymph nodes following a sensitization phase of three consecutive days. Groups of MI-sensitized mice were challenged on day 23 with 0·4% MI, 0·7% OIT and 1·9% BIT - concentrations corresponding to their individual EC3 values. No statistically significant difference in proliferation of CD4+ and CD8+ T cells was observed between mice challenged with MI compared with mice challenged with BIT and OIT. CONCLUSIONS: The data indicate cross-reactivity between MI, OIT and BIT, when the potency of the chemical was taken into account in choice of challenge concentration. This means that MI-sensitized individuals may react to OIT and BIT if exposed to sufficient concentrations.

Associations between body composition, physical capabilities and pulmonary function in healthy older adults.

BACKGROUND/OBJECTIVES: There are positive associations between pulmonary function (PF) and fat-free mass as well as muscle strength. Contrarily, negative associations were found with indirect measures of visceral adipose tissue (VAT). We aimed to differentiate between associations of body composition and PF by assessing mediating and moderating effects of physical capabilities. SUBJECTS/METHODS: Cross-sectional data were assessed among 40 healthy, free-living elderly (20 males) aged 65.1-81.2 years (mean±s.d. age: 72.2±4.3 years; body mass index: 25.6±3.7 kg/m2). Total and regional skeletal muscle (SM), and adipose tissue (AT) were measured using whole-body magnetic resonance imaging. Muscle strength by handgrip dynamometry, physical activity (PA) by questionnaire, and physical performance by gait speed and sit-to-stand test (STS). Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were assessed by spirometry. RESULTS: Positive associations between height-standardized FVC (FVCI) as well as FEV1 (FEVI), and SM (r=0.435-0.520, P<0.05) were found; subcutaneous AT (SAT) and FVCI correlated negatively (r=-0.374; P<0.05). HGS and PA correlated positively with FEVI (r=0.456-0.608, P<0.05), HGS also with FVCI (r=0.595, P<0.05). Stepwise multiple regression using FVCI and FEVI as dependent variables, and total/thoracic SM, VAT, SAT, HGS, PA and physical performance as independent variables showed that (i) only HGS entered the regression for predicting FVCI (R2=0.351; standard error of estimation (SEE)=0.32 l), and (ii) HGS and PA explained 50% of FEVI (SEE=0.23 l). HGS mediated the relationship between SM and PF; the STS moderated the relationship between SM and FVCI. CONCLUSIONS: In healthy elderly, PF is positively associated with SM; physical capabilities mediate and moderate these relationships.

From the past to future: from energy expenditure to energy intake to energy expenditure.

Although most recent research on energy balance focusses on energy intake (EI) there is still need to think about both sides of the energy balance. Current research on energy expenditure (EE) relates to metabolic adaptation to negative energy balance, mitochondrial metabolism associated with aging, obesity and type 2 diabetes mellitus, the role of EE in hunger and appetite control, non-shivering thermogenesis and brown adipose tissue activity, cellular bioenergetics as a target of obesity treatment and the evolutionary and ecological determinants of EE in humans and other primates. As far as regulation of energy balance is concerned there is recent evidence that EE rather than body weight is under tight control. Biologically, EE is maintained within a narrow physiological range. An EE-set point has been proposed as the width between the upper and lower boundaries of the individual EE range. Regulation of EE may fail in very obese patients with an EI above their upper boundary and after drastic weight loss when patients may go far below their lower EE boundary and thus are loosing control. In population studies, fat-free mass (FFM) and its composition (that is, the proportion of high to low metabolic rate organs) are major determinants of EE. It is tempting to speculate that tight biologic control of EE is related to brain energy need, which is preserved at the cost of peripheral metabolism. There is a moderate heritability of EE, which is independent of the heritability of FFM. In future, metabolic phenotyping should focus on the EE-FFM relationship rather than on EE-values alone.

Improved survival for patients diagnosed with chronic lymphocytic leukemia in the era of chemo-immunotherapy: a Danish population-based study of 10455 patients.

The treatment of chronic lymphocytic leukemia (CLL) is in rapid transition, and during recent decades both combination chemotherapy and immunotherapy have been introduced. To evaluate the effects of this development, we identified all CLL patients registered in the nation-wide Danish Cancer Register between 1978 and 2013. We identified 10 455 CLL patients and 508 995 CLL-free control persons from the general population. Compared with the latter, the relative mortality rate between CLL patients and their controls decreased from 3.4 (95% CI 3.2-3.6) to 1.9 (95% CI 1.7-2.1) for patients diagnosed in 1978-1984 and 2006-2013, respectively. The improved survival corresponded to a decreasing risk of death from malignant hematological diseases, whereas the risk of death from infections was stable during the study period. These population-based data substantiate the improved survival for patients treated with chemo-immunotherapy demonstrated in clinical studies.

Hepatic adaptations to maintain metabolic homeostasis in response to fasting and refeeding in mice.

BACKGROUND: The increased incidence of obesity and associated metabolic diseases has driven research focused on genetically or pharmacologically alleviating metabolic dysfunction. These studies employ a range of fasting-refeeding models including 4-24 h fasts, "overnight" fasts, or meal feeding. Still, we lack literature that describes the physiologically relevant adaptations that accompany changes in the duration of fasting and re-feeding. Since the liver is central to whole body metabolic homeostasis, we investigated the timing of the fast-induced shift toward glycogenolysis, gluconeogenesis, and ketogenesis and the meal-induced switch toward glycogenesis and away from ketogenesis. METHODS: Twelve to fourteen week old male C57BL/6J mice were fasted for 0, 4, 8, 12, or 16 h and sacrificed 4 h after lights on. In a second study, designed to understand the response to a meal, we gave fasted mice access to feed for 1 or 2 h before sacrifice. We analyzed the data using mixed model analysis of variance. RESULTS: Fasting initiated robust metabolic shifts, evidenced by changes in serum glucose, non-esterified fatty acids (NEFAs), triacylglycerol, and ß-OH butyrate, as well as, liver triacylglycerol, non-esterified fatty acid, and glycogen content. Glycogenolysis is the primary source to maintain serum glucose during the first 8 h of fasting, while de novo gluconeogenesis is the primary source thereafter. The increase in serum ß-OH butyrate results from increased enzymatic capacity for fatty acid flux through ß-oxidation and shunting of acetyl-CoA toward ketone body synthesis (increased CPT1 (Carnitine Palmitoyltransferase 1) and HMGCS2 (3-Hydroxy-3-Methylglutaryl-CoA Synthase 2) expression, respectively). In opposition to the relatively slow metabolic adaptation to fasting, feeding of a meal results in rapid metabolic changes including full depression of serum ß-OH butyrate and NEFAs within an hour. CONCLUSIONS: Herein, we provide a detailed description of timing of the metabolic adaptations in response to fasting and re-feeding to inform study design in experiments of metabolic homeostasis. Since fasting and obesity are both characterized by elevated adipose tissue lipolysis, hepatic lipid accumulation, ketogenesis, and gluconeogenesis, understanding the drivers behind the metabolic shift from the fasted to the fed state may provide targets to limit aberrant gluconeogenesis and ketogenesis in obesity.

Epidermal filaggrin deficiency mediates increased systemic T-helper 17 immune response.

BACKGROUND: Cellular T-helper (Th)17 infiltrates dominate skin inflammation in filaggrin-deficient flaky tail (ft/ft) mice, and Th17 cells are found in both the skin and blood of patients with acute atopic dermatitis. However, the potential role of loss-of-function mutations in the filaggrin gene (FLG) for increased peripheral Th17 cells is unclear. OBJECTIVES: To study whether mutations in FLG influence the frequency of peripheral Th17 cells. METHODS: We studied blood samples from six adults with mutations in FLG and five controls without mutations for frequencies of cytokine-producing CD4(+) T cells. We evaluated ft/ft mice and wild-type (WT) control mice for interleukin (IL)-17-producing CD4(+) T cells in naive mice and following 2,4-dinitrofluorobenzene (DNFB) challenge. In addition, the T-cell receptor (TCR) Vß-chain repertoire was analysed by flow cytometry. RESULTS: Human studies showed increased frequency of peripheral Th17 cells in FLG mutation carriers when compared with WT individuals. Mouse studies showed increased frequency of peripheral Th17 cells in adult ft/ft mice but not in 2-week-old ft/ft mice. Moreover, altered TCR Vß-chain repertoire was found in ft/ft mice when compared with WT mice. An increased frequency of CD4(+) Vß10(+) T cells producing IL-17 was found in the spleen of adult ft/ft mice when compared with WT mice. Finally, DNFB challenge induced an increased number of Th17 cells in ft/ft mice compared with WT mice. CONCLUSIONS: Deficiency of filaggrin appeared to be a driver of increased peripheral levels of Th17 cells. This increase must be acquired as peripheral Th17 cells were found in adult ft/ft mice but not in 2-week-old ft/ft mice indicating involvement of exogenous factors.

The Vitamin D Analogue Calcipotriol Reduces the Frequency of CD8+ IL-17+ T Cells in Psoriasis Lesions.

The vitamin D analogue calcipotriol is an immunomodulatory drug widely used to treat psoriasis; however, how calcipotriol affects the immune cells in psoriasis lesions is not fully understood. The aim of this study was to investigate the effect of calcipotriol on the frequency of CD4(+) and CD8(+) T cells and innate lymphoid cells (ILC) and their production of IL-17A, IFN-γ and IL-22 in psoriasis lesions in patients with chronic plaque psoriasis. Eighteen patients with psoriasis were included, and two similar psoriasis lesions were chosen for each patient. One lesion was treated with calcipotriol (50 µg/g) and the other with vehicle twice a day for 14 days. The clinical effect was measured by degree of erythema, scaling and induration in each lesion (SUM score). Skin biopsies were collected for histological and immunohistochemical analyses. Skin-derived cells were isolated and analysed by flow cytometry. After 14 days of treatment with calcipotriol, a significant clinical and histological effect was seen; however, we found no differences in the frequency of CD4(+) and CD8(+) T cells or ILC between calcipotriol- and vehicle-treated skin. The main finding was a significant decrease in CD8(+) IL-17(+) T cells in skin-derived cells from calcipotriol-treated skin, which was further supported by the absence of CD8(+) IL-17(+) T cells in immunohistochemical staining of calcipotriol-treated skin. No changes in the frequency of IL-22(+) or IFN-γ(+) cells were observed. Our findings show that the vitamin D analogue calcipotriol reduces the frequency of CD8(+) IL-17(+) T cells in psoriasis lesions concomitant with clinical improvement.

The impact of SF3B1 mutations in CLL on the DNA-damage response.

Mutations or deletions in TP53 or ATM are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with ATM aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (n=110) containing ATM, SF3B1 and TP53 gene defects. Next, we applied a newly developed multiplex assay for p53/ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly, SF3B1 mutated samples without concurrent ATM and TP53 aberrations (sole SF3B1) displayed partially defective ATM/p53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast, NOTCH1 or K/N-RAS mutated CLL displayed normal responses in p53/ATM target gene induction and apoptosis. In sole SF3B1 mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage and/or an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with SF3B1 mutations.

The EBMT/EMCL consensus project on the role of autologous and allogeneic stem cell transplantation in mantle cell lymphoma.

The role of both autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) in the management of mantle cell lymphoma (MCL) remains to be clarified. We conducted a consensus project using the RAND-modified Delphi consensus procedure to provide guidance on how SCT should be used in MCL. With regard to autoSCT, there was consensus in support of: autoSCT is the standard first-line consolidation therapy; induction therapy should include high-dose cytarabine and Rituximab; complete or partial remission should be achieved before autoSCT; Rituximab maintenance following autoSCT is not indicated; and omission of autoSCT in 'low-risk' patients is not indicated. No consensus could be reached regarding: autoSCT in the treatment of relapsed disease following non-transplant therapy; the value of positron emission tomography scanning and minimal residual disease (MRD) monitoring; in vivo purging with Rituximab; total body irradiation conditioning for autoSCT; and preemptive Rituximab after autoSCT. For alloSCT, consensus was reached in support of: alloSCT should be considered for patients relapsing after autoSCT; reduced intensity conditioning regimens should be used; allogeneic immunotherapy should be used for MRD eradication after alloSCT; and there is a lack of prognostic criteria to guide the use of alloSCT as first-line consolidation. No consensus was reached regarding the role of alloSCT for relapsed disease following non-transplant therapy.