Retrospective evaluation of the performance of the electrical impedance spectroscopy system Nevisense in detecting keratinocyte cancers.

BACKGROUND: Keratinocyte cancers, also referred to as non-melanoma skin cancers (NMSCs), are one of the most common malignant skin tumors. We performed a retrospective analysis of lesions from patients of a private dermatology practice to evaluate the use of electrical impedance spectroscopy (EIS) in detecting keratinocyte malignancies. The aim of the study is to assess the accuracy of the technique and to rate its use as supportive tool in NMSC diagnosis. MATERIAL AND METHODS: The period evaluated ranges from September 2015 to November 2019. In total, 1712 lesions from 951 patients were included. All lesions suspicious for malignancy were gauged with the Nevisense device. Excised lesions were sent in for histopathological classification, and the results were compared to the Nevisense score. RESULTS: A total of 767 lesions (44.8%) received a negative score (0-3) from the Nevisense system and 945 lesions (55.2%) a positive score (4-10). The combination of the dermatologist's visual assessment plus the technical determined Neviscore resulted in the excision of 52.5% of all 1712 suspicious lesions whereof 15% were found to be malignant. The sensitivity of Nevisense was 98.4% for NMSC detection. CONCLUSION: Electrical impedance spectroscopy was found to be a valuable adjunct support tool in clinical decisions for cases with suspicion for NMSC.

Fatigue in Cancer and Neuroinflammatory and Autoimmune Disease: CNS Arousal Matters.

The term fatigue is not only used to describe a sleepy state with a lack of drive, as observed in patients with chronic physical illnesses, but also a state with an inhibition of drive and central nervous system (CNS) hyperarousal, as frequently observed in patients with major depression. An electroencephalogram (EEG)-based algorithm has been developed to objectively assess CNS arousal and to disentangle these pathophysiologically heterogeneous forms of fatigue. The aim of this study was to test the hypothesis that fatigued patients with CNS hyperarousal score higher on depressive symptoms than those without this neurophysiological pattern. METHODS: Subjects with fatigue (Multidimensional Fatigue Inventory sum-score > 40) in the context of cancer, neuroinflammatory, or autoimmune diseases were drawn from the 60+ cohort of the Leipzig Research Center for Civilization Diseases. CNS arousal was assessed by automatic EEG-vigilance stage classification using the Vigilance Algorithm Leipzig (VIGALL 2.1) based on 20 min EEG recordings at rest with eyes closed. Depression was assessed by the Inventory of Depressive Symptomatology (IDS-SR). RESULTS: Sixty participants (33 female; median age: 67.5 years) were included in the analysis. As hypothesized, fatigued patients with CNS hyperarousal had higher IDS-SR scores than those without hyperarousal (F1,58 = 18.34; p < 0.0001, η2 = 0.240). CONCLUSION: hyperaroused fatigue in patients with chronic physical illness may be a sign of comorbid depression.

Multiple Eruptive Epithelioid Hemangiomas: A Subset of Cutaneous Cellular Epithelioid Hemangioma With Expression of FOS-B.

There is a wide clinicopathologic spectrum of vascular proliferations characterized by the presence of epithelioid endothelial cells, comprising epithelioid hemangioma (EH)-pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma (PM-HAE), epithelioid hemangioendothelioma, and epithelioid angiosarcoma. Immunohistochemical FOS-B expression as well as FOS-B rearrangement (fluorescent in situ hybridization [FISH]) have recently been described as diagnostically relevant underpinnings of EH (restricted to osseous lesions) and PM-HAE. The aim of this study was to clinicopathologically characterize and to elucidate FOS-B expression in patients with eruptive lesions of the cellular variant of cutaneous EH. All cases of cutaneous cellular EH (n=16) showed strong diffuse immunohistochemical expression of FOS-B, in conjunction with positivity for ERG and nestin. Expression of MYC, CAMTA-1, AE1/3, and MNF116 was negative in all cases. FISH investigations did not show any sign of rearrangements for CAMTA-1 or MYC amplification. Negative-control cases included 15 lobular hemangiomas, 5 epithelioid angiosarcomas, and 5 nodular Kaposi sarcomas, all of which were negative for FOS-B. Positive-control cases included 15 angiolymphoid hyperplasia with eosinophilia cases, all of them being positive. In contrast with what has been published so far, cutaneous variants of cellular EH exhibit positive immunostaining for FOS-B. Remarkably, FOS-B expression is not restricted to the intraosseous subset of EH. For differential diagnosis of epithelioid vascular tumors, we therefore suggest a helpful panel of antibodies including CAMTA-1, TFE-3, FOS-B, and AE1/AE3. We point out the telltale immunophenotypes: angiolymphoid hyperplasia with eosinophilia and EH (FOS-B/others negative), PM-HAE (FOS-B/AE1/AE3/others negative), epithelioid hemangioendothelioma (CAMTA-1 or TFE-3/others negative). Remarkably, MYC is not expressed in these tumors, neither is there an MYC amplification by FISH. We suggest the term multiple eruptive EHs for this subset of cutaneous vascular tumors.

Folliculotropic mycosis fungoides.

Accepted by the WHO and EORTC as a variant of classic mycosis fungoides, folliculotropic (syn.: follicular or pilotropic) mycosis fungoides (FMF) is characterized by a broad clinical and histological spectrum with numerous differential diagnoses. Recent studies have shown that FMF can be divided into two prognostically different subgroups, both marked by histological as well as clinical differences. Treatment should therefore be tailored to the various subtypes and clinical courses. The present review highlights the clinical and histological manifestations of FMF as well as the new subclassification. Moreover, important differential diagnoses and therapeutic options are discussed.

Physical activity in depressed and non-depressed patients with obesity.

PURPOSE: Obesity and depression have both been shown to be associated with reduced physical activity (PA). However, most studies have not applied objective measures to determine PA in patients. Moreover, to our knowledge, no studies are available comparing depressed and non-depressed patients with regard to PA. METHODS: We investigated PA in 47 patients with both obesity and depression, 70 non-depressed patients with obesity, and 71 non-depressed and non-obese healthy control participants using the SenseWear™ Armband (SWA) with walked steps per day and metabolic equivalents (MET) as parameters for PA. RESULTS: Depressed as well as non-depressed patients with obesity showed a significantly reduced PA as reflected by walked steps as well as reduced METs. Healthy controls walked a mean of 11,586 ± 3731 (SD) steps per day, whereas non-depressed patients with obesity accumulated 7283 ± 3547 and patients with both obesity and depression recorded only 6177 ± 3291 steps per day. However, the difference between depressed and non-depressed patients with obesity did not reach statistical significance either in terms of walked steps or with regard to METs. CONCLUSIONS: Obesity seems to be associated with a substantial reduction of PA and energy expenditure, whereas the effect of an additional depressive disorder was comparably small. Even though depression did not have any statistically significant effect on steps and METs per day in this study with obese patients, it could be clinically relevant for an individual patient.

Pro- and anti-inflammatory cytokines, but not CRP, are inversely correlated with severity and symptoms of major depression.

To clarify findings of elevated cytokine levels in major depression (MD), this study aimed to investigate the relationship between serum levels of cytokines, symptoms of MD and antidepressant treatment outcome. At baseline (T0) and 4 weeks following initiation of antidepressant treatment (T1), levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage-colony-stimulating-factor (GM-CSF), CRP and depression ratings HAMD-17 and BDI-II were assessed in 30 patients with MD and 30 age-and sex-matched controls. At T0, in the patient group, cytokines, but not CRP, negatively correlated with individual BDI-II-items, factors and severities and showed both negative and positive correlations with HAMD-17 items. At T1 and within the controls, no such relationships were observed. At T0 and T1, levels of both pro- and anti-inflammatory cytokines were significantly higher in treatment responders (ΔHAMD-17T0-T1≥50%,n=15) compared to non-responders. When controlled for baseline BDI, differences between groups were only found significant for IL-2 at T0. The results suggest cytokines are not generally pro-depressive but rather relate to more specific regulation of symptoms and severities in MD. Together with the association between cytokines and treatment responder status, these data support cytokines as a promising but still controversial biomarker of depression.

Normative values of the Epworth Sleepiness Scale (ESS), derived from a large German sample.

PURPOSE: Daytime sleepiness is associated with several medical problems. The aim of this paper is to provide normative values for one of the most often used questionnaires measuring daytime sleepiness, the Epworth Sleepiness Scale (ESS). METHODS: A large sample of 9711 people from the German general population took part in this study. In addition to the ESS, several other questionnaires were used, and sociodemographic and behavioral factors were recorded. RESULTS: Normative values for the ESS are given. According to the generally accepted criterion ESS > 10, 23 % of the sample showed excessive daytime sleepiness. Males reported significantly more daytime sleepiness than females (effect size d = 0.19). In the age range of 40-80 years, a continuous decline of daytime sleepiness was observed. Psychometric properties of the ESS were good. Alcohol intake and nicotine consumption were marginally associated with daytime sleepiness, and obese people reported significantly more sleepiness than people of normal weight (OR = 1.39). CONCLUSIONS: The normative tables allow clinicians and researchers to assess the degree of their patients' daytime sleepiness, especially in the upper range of scores.

Tobacco use is associated with reduced amplitude and intensity dependence of the cortical auditory evoked N1-P2 component.

RATIONALE: Tobacco use is linked to cerebral atrophy and reduced cognitive performance in later life. However, smoking-related long-term effects on brain function remain largely uncertain. Previous studies suggest that nicotine affects serotonergic signaling, and the intensity dependence (alias loudness dependence) of the auditory evoked N1-P2 potential has been proposed as a marker of serotonergic neurotransmission. OBJECTIVE: In the present study, we assesed the effects of chronic smoking on amplitude and intensity dependence of the auditory evoked N1-P2 potential. METHODS: Subjects underwent a 15-min intensity dependence of auditory evoked potentials (IAEP) paradigm. From N = 1739 eligible subjects (40-79 years), we systematically matched current smokers, ex-smokers, and never-smokers by sex, age, alcohol and caffeine consumption, and socioeconomic status. Between-group differences and potential dose-dependencies were evaluated. RESULTS: Analyses revealed higher N1-P2 amplitudes and intensity dependencies in never-smokers relative to ex- and current smokers, with ex-smokers exhibiting intermediate intensity dependencies. Moreover, we observed pack years and number of cigarettes consumed per day to be inversely correlated with amplitudes in current smokers. CONCLUSIONS: According to the IAEP serotonin hypothesis, our results suggest serotonin activity to be highest in current smokers, intermediate in ex-smokers, and lowest in never-smokers. To our knowledge, the present study is the first providing evidence for a dose-dependent reduction in N1-P2 amplitudes. Further, we extend prior research by showing reduced amplitudes and intensity dependencies in ex-smokers even 25 years, on average, after cessation. While we can rule out several smoking-related confounders to bias observed associations, causal inferences remain to be established by future longitudinal studies.

Impact of Serum Cytokine Levels on EEG-Measured Arousal Regulation in Patients with Major Depressive Disorder and Healthy Controls.

BACKGROUND: In major depressive disorder (MDD), findings include hyperstable regulation of brain arousal measured by electroencephalography (EEG) vigilance analysis and alterations in serum levels of cytokines. It is also known that cytokines affect sleep-wake regulation. This study investigated the relationship between cytokines and EEG vigilance in participants with MDD and nondepressed controls, and the influence of cytokines on differences in vigilance between the two groups. METHODS: In 60 patients with MDD and 129 controls, 15-min resting-state EEG recordings were performed and vigilance was automatically assessed with the VIGALL 2.0 (Vigilance Algorithm Leipzig). Serum levels of the wakefulness-promoting cytokines interleukin (IL)-4, IL-10, IL-13 and somnogenic cytokines tumor necrosis factor-α, interferon-x03B3; and IL-2 were measured prior to the EEG. RESULTS: Summed wakefulness-promoting cytokines, but not somnogenic cytokines, were significantly associated with the time course of EEG vigilance in the MDD group only. In both groups, IL-13 was significantly associated with the course of EEG vigilance. In MDD compared to controls, a hyperstable EEG vigilance regulation was found, significant for group and group × time course interaction. After controlling for wakefulness-promoting cytokines, differences in vigilance regulation between groups remained significant. CONCLUSIONS: The present study demonstrated a relationship between wakefulness-promoting cytokines and objectively measured EEG vigilance as an indicator for brain arousal. Altered brain arousal regulation in MDD gives support for future evaluation of vigilance measures as a biomarker in MDD. Since interactions between cytokines and EEG vigilance only moderately differed between the groups and cytokine levels could not explain the group differences in EEG vigilance regulation, cytokines and brain arousal regulation are likely to be associated with MDD in independent ways.

Dynamics of melanin-concentrating hormone (MCH) serum levels in major depressive disorder during antidepressant treatment.

BACKGROUND: In preclinical studies, the hypothalamic polypeptide melanin-concentrating hormone (MCH) has been shown to be involved in depression-like behavior and modulations of MCH and MCH-receptors were proposed as potential new antidepressant drug targets. METHODS: For the first time, MCH serum levels were explored in 30 patients with major depressive disorder (MDD) prior to (T1) and after 2 (T2) and 4 weeks (T3) of antidepressant treatment and in 30 age- and sex-matched healthy controls by applying a fluorescence immunoassay. RESULTS: Levels of MCH did not differ significantly between un-medicated patients (444.11±174.63pg/mL SD) and controls (450.68±210.03pg/mL SD). In MDD patients, MCH levels significantly decreased from T1 to T3 (F=4.663; p=0.013). Post-hoc analyses showed that these changes were limited to patients treated with mirtazapine but not escitalopram and female but not male patients. MCH-levels showed high correlations from T1 to T3 (r≥0.964, p<0.001) and were found to correlate significantly with parameters of sleep within the controls. LIMITATIONS: Small sample size. No follow-up measures were performed within the control group. CONCLUSIONS: Our findings suggest peripheral MCH-levels not to be altered in depression but possibly reflecting depression-related state properties that can be modulated by sleep, medication and sex.

Inflammatory cytokines in general and central obesity and modulating effects of physical activity.

CONTEXT: Chronic systemic inflammation in obesity originates from local immune responses in visceral adipose tissue. However, assessment of a broad range of inflammation-mediating cytokines and their relationship to physical activity and adipometrics has scarcely been reported to date. OBJECTIVE: To characterize the profile of a broad range of pro- and anti-inflammatory cytokines and the impact of physical activity and energy expenditure in individuals with general obesity, central obesity, and non-obese subjects. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study comprising 117 obese patients (body mass index (BMI) ≥ 30) and 83 non-obese community-based volunteers. MAIN OUTCOMES MEASURES: Serum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured. Physical activity and energy expenditure (MET) were assessed with actigraphy. Adipometrics comprised BMI, weight, abdominal-, waist- and hip-circumference, waist to hip ratio (WHR), and waist-to-height-ratio (WHtR). RESULTS: General obesity was associated with significantly elevated levels of IL-5, IL-10, IL-12, IL-13, IFN-γ and TNF-α, central obesity with significantly elevated IL-5, IL-10, IL-12, IL-13 and IFN-γ-levels. In participants with general obesity, levels of IL-4, IL-10 and IL-13 were significantly elevated in participants with low physical activity, even when controlled for BMI which was negatively associated with physical acitivity. Cytokines significantly correlated with adipometrics, particularly in obese participants. CONCLUSIONS: Results confirm up-regulation of certain pro- and anti-inflammatory cytokines in obesity. In obese subjects, physical activity may lower levels and thus reduce pro-inflammatory effects of cytokines that may link obesity, insulin resistance and diabetes.

Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity.

In major depressive disorder, changes in cytokine levels have been reported to play a role in pathogenesis. Therefore, we sought to investigate a broad range of cytokines in depression. We compared serum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (INF-γ) and tumor necrosis factor (TNF)-α in 64 subjects with current depression and 206 non-depressed subjects. Depressed patients had higher levels of IL-2, IL-5, IL-12, IL-13, GM-CSF, INF-γ and TNF-α, compared to non-depressed subjects. Splitting groups into non-obese (BMI < 30) and obese (BMI ≥ 30), the non-obese depressed patients (n = 40) showed elevated IL-5, IL-12, IL-13, GM-CSF, INF-γ and TNF-α levels compared to non-obese and non-depressed subjects (n = 85). The obese and depressed patients (n = 24) showed elevated levels of IL-5, IL-12 and INF-γ compared to obese but not depressed subjects (n = 121). Levels of several cytokines were found to be associated with physical activity, employment status and presence of daily naps. The results support over-expression of pro-inflammatory cytokines in depression and extend the range of cytokines potentially associated with depression to include GM-CSF, IL-5 and IL-13. Changes in these cytokines may contribute to co-morbidity between depression and allergic and asthmatic diseases. The results also suggest inflammatory processes associated with obesity, and support an interaction between cytokine serum concentrations and behavioral aspects of both obesity and depression.

Towards open-source, low-cost haptics for surgery simulation.

In minimally invasive surgery (MIS), virtual reality (VR) training systems have become a promising education tool. However, the adoption of these systems in research and clinical settings is still limited by the high costs of dedicated haptics hardware for MIS. In this paper, we present ongoing research towards an open-source, low-cost haptic interface for MIS simulation. We demonstrate the basic mechanical design of the device, the sensor setup as well as its software integration.

Malignant melanoma S3-guideline "diagnosis, therapy and follow-up of melanoma".

This first German evidence-based guideline for cutaneous melanoma was developed under the auspices of the German Dermatological Society (DDG) and the Dermatologic Cooperative Oncology Group (DeCOG) and funded by the German Guideline Program in Oncology. The recommendations are based on a systematic literature search, and on the consensus of 32 medical societies, working groups and patient representatives. This guideline contains recommendations concerning diagnosis, therapy and follow-up of melanoma. The diagnosis of primary melanoma based on clinical features and dermoscopic criteria. It is confirmed by histopathologic examination after complete excision with a small margin. For the staging of melanoma, the AJCC classification of 2009 is used. The definitive excision margins are 0.5 cm for in situ melanomas, 1 cm for melanomas with up to 2 mm tumor thickness and 2 cm for thicker melanomas, they are reached in a secondary excision. From 1 mm tumor thickness, sentinel lymph node biopsy is recommended. For stages II and III, adjuvant therapy with interferon-alpha should be considered after careful analysis of the benefits and possible risks. In the stage of locoregional metastasis surgical treatment with complete lymphadenectomy is the treatment of choice. In the presence of distant metastasis mutational screening should be performed for BRAF mutation, and eventually for CKIT and NRAS mutations. In the presence of mutations in case of inoperable metastases targeted therapies should be applied. Furthermore, in addition to standard chemotherapies, new immunotherapies such as the CTLA-4 antibody ipilimumab are available. Regular follow-up examinations are recommended for a period of 10 years, with an intensified schedule for the first three years.

The influence of cytokines on wakefulness regulation: clinical relevance, mechanisms and methodological problems.

Sleep-wake-regulation has been shown to be substantially influenced by cytokines. The clinical relevance of this issue arises from (1) the frequency of accidents, injuries and impairment in social functioning due to sleepiness, (2) the occurrence of fatigue syndromes associated with inflammatory diseases, cancer or obesity, (3) the role of wakefulness regulation for the pathophysiology of affective and sleep disorders and (4) sedation as a side effect of psychopharmacological therapy. Experimental studies confirm the somnogenic influence of pro-inflammatory cytokines such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α (TNF-α). These cytokines modulate centers of wakefulness regulation located in the hypothalamus, the basal forebrain and the brain stem by influencing substances involved in sleep-wake-behavior such as adenosine, nitric oxide (NO), nuclear factor-κB (NF-κB), prostaglandin D2 (PGD2), the neurotransmitters γ-aminobutyric acid (GABA), glutamate and norepinephrine, as well as hormones such as growth hormone-releasing hormone (GHRH) and corticotropin-releasing hormone (CRH). Clinical studies of the influence of cytokines on wakefulness regulation are underrepresented in the research literature and objective measures of wakefulness such as the Multiple Sleep Latency Test (MSLT) are seldom reported.

EEG vigilance regulation patterns and their discriminative power to separate patients with major depression from healthy controls.

BACKGROUND/AIM: Recently, a framework has been presented that links vigilance regulation, i.e. tonic brain arousal, with clinical symptoms of affective disorders. Against this background, the aim of this study was to deepen the knowledge of vigilance regulation by (1) identifying different patterns of vigilance regulation at rest in healthy subjects (n = 141) and (2) comparing the frequency distribution of these patterns between unmedicated patients with major depression (MD; n = 30) and healthy controls (HCs; n = 30). METHOD: Each 1-second segment of 15-min resting EEGs from 141 healthy subjects was classified as 1 of 7 different vigilance stages using the Vigilance Algorithm Leipzig. K-means clustering was used to distinguish different patterns of EEG vigilance regulation. The frequency distribution of these patterns was analyzed in independent data of 30 unmedicated MD patients and 30 matched HCs using a χ² test. RESULTS: The 3-cluster solution with a stable, a slowly declining and an unstable vigilance regulation pattern yielded the highest mathematical quality and performed best for separation of MD patients and HCs (χ² = 13.34; p < 0.001). Patterns with stable vigilance regulation were found significantly more often in patients with MD than in HCs. CONCLUSION: A stable vigilance regulation pattern, derived from a large sample of HCs, characterizes most patients with MD and separates them from matched HCs with a sensitivity between 67 and 73% and a specificity between 67 and 80%. The pattern of vigilance regulation might be a useful biomarker for delineating MD subgroups, e.g. for treatment prediction.

Primary cutaneous B-cell lymphomas.

Cutaneous B-cell lymphomas (CBCL) are the second most common form of primary cutaneous lymphomas. The cutaneous follicle center lymphoma and the cutaneous marginal zone lymphoma (extranodal MALT type lymphoma) account for the vast majority of CBCL and manifest with nodules. These two lymphoma entities have an indolent, slowly progressive course and an excellent prognosis despite a high rate of recurrences. In contrast, cutaneous diffuse large B-cell lymphoma, leg type, and other rare forms of CBCL display an impaired prognosis and therefore require to be treated with multiagent chemotherapy and anti-CD20 monoclonal antibodies in most cases. Clinico-pathologic correlation, histology with immunohistochemical profile and genotyping as well as staging examinations are crucial diagnostic elements in the work-up of CBCL.