Correction to: Impact of a combined multimodal-aerobic and multimodal intervention compared to standard aerobic treatment in breast cancer survivors with chronic cancer-related fatigue - results of a three-armed pragmatic trial in a comprehensive cohort design.

An amendment to this paper has been published and can be accessed via the original article.

Impact of a combined multimodal-aerobic and multimodal intervention compared to standard aerobic treatment in breast cancer survivors with chronic cancer-related fatigue - results of a three-armed pragmatic trial in a comprehensive cohort design.

BACKGROUND: Cancer-related fatigue (CRF) and insomnia are major complaints in breast cancer survivors (BC). Aerobic training (AT), the standard therapy for CRF in BC, shows only minor to moderate treatment effects. Other evidence-based treatments include cognitive behavioral therapy, e.g., sleep education/restriction (SE) and mindfulness-based therapies. We investigated the effectiveness of a 10-week multimodal program (MT) consisting of SE, psycho-education, eurythmy- and painting-therapy, administered separately or in combination with AT (CT) and compared both arms to AT alone. METHODS: In a pragmatic comprehensive cohort study BC with chronic CRF were allocated randomly or by patient preference to (a) MT, (b) CT (MT + AT) or (c) AT alone. Primary endpoint was a composite score of the Pittsburgh Sleep Quality Index and the Cancer Fatigue Scale after 10 weeks of intervention (T1); a second endpoint was a follow-up assessment 6 months later (T2). The primary hypothesis stated superiority of CT and non-inferiority of MT vs. AT at T1. A closed testing procedure preserved the global α-level. The intention-to-treat analysis included propensity scores for the mode of allocation and for the preferred treatment, respectively. RESULTS: Altogether 126 BC were recruited: 65 were randomized and 61 allocated by preference; 105 started the intervention. Socio-demographic parameters were generally balanced at baseline. Non-inferiority of MT to AT at T1 was confirmed (p < 0.05), yet the confirmative analysis stopped as it was not possible to confirm superiority of CT vs. AT (p = 0.119). In consecutive exploratory analyses MT and CT were superior to AT at T1 and T2 (MT) or T2 alone (CT), respectively. CONCLUSIONS: The multimodal CRF-therapy was found to be confirmatively non-inferior to standard therapy and even yielded exploratively sustained superiority. A randomized controlled trial including a larger sample size and a longer follow-up to evaluate multimodal CRF-therapy is highly warranted. TRIAL REGISTER: DRKS-ID: DRKS00003736 . Recruitment period June 2011 to March 2013. Date of registering 19 June 2012.

Viscum Album Lipophilic Extract in Actinic Keratosis, Cutaneous Squamous Cell Carcinoma, and Basal Cell Carcinoma: A Retrospective Case Series.

INTRODUCTION: Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC) belong to the group of keratinocyte carcinomas (KC). Actinic keratosis (AK) is a precursor lesion of cSCC. The incidences of cSCC, BCC, and AK are currently strongly increasing. Different standard therapies exist for these conditions but are not always applicable or successful. Hydrophilic Viscum album extracts have been used in anthroposophic cancer therapy since 1917. Viscum album lipophilic extract (VALE) is prepared by means of supercritical CO2 extraction. This retrospective case series assessed the safety and clinical effects of a topical application of 10% VALE in individual cases of cSCC, BCC, and AK. METHODS: For this retrospective case series, a positive vote was obtained from the Ethics Committee of the University of Witten/Herdecke (No. 146/2020). Eligible patients signed a declaration of consent prior to inclusion in the study. The main outcome parameters were the clinical response to treatment with VALE and adverse drug reactions. Risk factors, concomitant therapies and diseases, further diagnostic and therapeutic information were documented where available. Data analysis was performed on the level of patients and of individual lesions. RESULTS: The study population consisted of 55 patients with 74 skin lesions. Individual case analysis accompanied by photographic documentation revealed typical and promising treatment courses. Clinical response rates (complete + partial remissions) for individual lesions were 78% for cSCC, 70% for BCC, and 71% for AK. Complete remission rates for individual lesions were 56% for cSCC, 35% for BCC, and 15% for AK. In cSCC and BCC, shorter times to best clinical response were observed. Adverse drug reactions were reported in 5 patients including erythema and inflammatory reactions of mostly moderate severity that resolved completely. In one case, therapy was temporarily paused, in four cases it was continued without interruption. DISCUSSION/CONCLUSION: The results of this study suggest that VALE is a safe and tolerable extract under whose application complete and partial remissions of KC could be observed. To improve and assess the efficacy of VALE, prospective investigations are necessary.Das kutane Plattenepithelkarzinom (cSCC) und das Basalzellkarzinom (BCC) gehören zur Gruppe der Keratinozytenkarzinome (KC). Die aktinische Keratose (AK) ist eine Vorstufe des cSCC. Die Häufigkeit von cSCC, BCC und AK ist derzeit stark im Steigen begriffen. Es gibt verschiedene Standardtherapien für diese Erkrankungen, die jedoch nicht immer anwendbar oder erfolgreich sind. Hydrophile Viscum album-Extrakte werden seit 1917 in der anthroposophischen Krebstherapie eingesetzt. Viscum album Lipophilic Extract (VALE) wird mittels überkritischer CO2-Extraktion hergestellt. In dieser retrospektiven Fallserie wurden die Sicherheit und die klinischen Auswirkungen einer topischen Anwendung von 10% VALE bei einzelnen Fällen von cSCC, BCC und AK untersucht.Für diese retrospektive Fallserie wurde ein positives Votum der Ethikkommission der Universität Witten/Herdecke eingeholt (Nr. 146/2020). Die in Frage kommenden Patienten unterzeichneten vor der Aufnahme in die Studie eine Einverständniserklärung. Die wichtigsten Ergebnisparameter waren das klinische Ansprechen auf die Behandlung mit VALE und unerwünschte Arzneimittelwirkungen. Risikofaktoren, Begleittherapien und -erkrankungen sowie weitere diagnostische und therapeutische Informationen wurden, soweit vorhanden, dokumentiert. Die Datenanalyse wurde für jeden einzelnen Patienten und jeder einzelnen Läsion durchgeführt.Die Studienpopulation bestand aus 55 Patienten mit 74 Hautläsionen. Die Einzelfallanalyse mit Fotodokumentation ergab typische und vielversprechende Behandlungsverläufe. Die klinischen Ansprechraten (vollständige + partielle Remissionen) für einzelne Läsionen lagen bei 78% für cSCC, 70% für BCC und 71% für AK. Die Komplettremissionsraten für einzelne Läsionen lagen bei 56% für cSCC, 35% für BCC und 15% für AK. Bei cSCC und BCC wurden kürzere Zeiten bis zum besten klinischen Ansprechen beobachtet. Bei fünf Patienten wurden unerwünschte Arzneimittelwirkungen gemeldet, darunter Erytheme und Entzündungsreaktionen von meist mäßigem Schweregrad, die vollständig abklangen. In einem Fall wurde die Therapie vorübergehend pausiert, in vier Fällen wurde sie ohne Unterbrechung fortgesetzt.Die Ergebnisse dieser Studie deuten darauf hin, dass VALE ein sicherer und verträglicher Extrakt ist, bei dessen Anwendung vollständige und partielle Remissionen von KC beobachtet werden konnten. Um die Wirksamkeit der Therapie mit VALE weiterzuentwickeln und eingehender zu beurteilen, sind prospektive Untersuchungen erforderlich.

A randomized placebo-controlled double-blinded study comparing oral and subcutaneous administration of mistletoe extract for the treatment of equine sarcoid disease.

BACKGROUND: Equine sarcoids (ES) are the most common cutaneous tumors in equids. Systemic treatment options are sparse. Subcutaneous (SC) injections of Viscum album extract (VAE) demonstrate efficacy as a systemic treatment directed against ES. OBJECTIVES/AIM: To critically assess the therapeutic efficacy of orally administered VAE. ANIMALS: Forty-five ES-affected, privately owned, 3-12 year-old horses. METHODS: A 3-armed randomized placebo-controlled, double-blinded study was conducted in a double-dummy design. Horses were subjected to oral administration and SC injections of either VAE or placebo (VAE oral/placebo SC, VAE SC/placebo oral, placebo oral/placebo SC) over a 7-month treatment period. Primary endpoint was the change of baseline of a composite index of ES number and ES area after 14 months. Second endpoint was the clinical response. RESULTS: No statistically significant difference in the composite endpoint between the 3 study arms was found. The primary endpoint showed 4 (27%) horses in the VAE oral group with complete ES regression, 3 (21%) in the VAE SC injection group, and 2 (13%) in the placebo group. The clinical response revealed complete or partial regression in 6 horses of the oral VAE group (40%), 4 of the SC injection group (29%), and 4 of the placebo group (25%). Direct comparison of oral VAE and placebo showed an odds ratio, stratified for prognosis of 2.16 (95%-CI: 0.45-10.42) and a P-value of 0.336. CONCLUSION AND CLINICAL IMPORTANCE: Oral administration of VAE is well tolerated. No statistically significant difference in the effectiveness of systemic VAE versus placebo against ES was found.

Fatigue and quality of life during neoadjuvant chemotherapy of early breast cancer: a prospective multicenter cohort study.

BACKGROUND: Few measurements of fatigue and quality of life have been performed during neoadjuvant chemotherapy of early breast cancer. This study evaluates fatigue and quality of life experienced by early breast cancer patients during neoadjuvant chemotherapy and their association with different clinical parameters. METHODS: Fifty-four stage I-III patients' responses to the Multidimensional Fatigue Inventory (MFI) and to the Functional Assessment of Cancer Therapy-Breast (FACT-B) were analyzed by a linear covariance pattern model. Chemotherapy regimen, age, baseline fatigue level, body-mass-index and cancer stage were added to the model to estimate their impact on both outcomes. RESULTS: All fatigue dimensions worsened in clinically relevant levels. Physical fatigue worsened the most, mental fatigue the least. For quality of life, physical and functional well-being worsened the most. Only emotional well-being improved during chemotherapy. Physical well-being worsened more during standard than during dose-dense chemotherapy, and more during anthracycline than during taxane cycles. Age, body-mass-index and cancer stage had no impact. The higher the fatigue levels at baseline, the less they worsened during chemotherapy. CONCLUSIONS: Further actions to reduce fatigue and improve quality of life during neoadjuvant chemotherapy of early breast cancer are needed. Focus should be laid on the physical dimension. Future research should also investigate the impact of different chemotherapy sequences and densities on fatigue and quality of life. STUDY REGISTRATION: The study was registered in the German Clinical Trials Register in May 2019 (DRKS00016761).

Validation of the Internal Coherence Scale (ICS) in Healthy Geriatric Individuals and Patients Suffering from Diabetes Mellitus Type 2 and Cancer.

BACKGROUND: With increased life expectancy, the coexistence of functional impairment and multimorbidity can negatively impact life quality and coherence in geriatric individuals. The self-report 10-item Internal Coherence (ICS) measures how individuals cope with and make sense of disease-specific life challenges. The aim of this study was to validate the ICS in a sample of geriatric individuals. METHODS AND PROCEDURE: In a cross-sectional study, geriatric individuals with and without chronic diseases were recruited. A factor analysis with principal component extraction (PCA) and a structural equation model (SEM) was conducted to assess the ICS factor structure in a geriatric sample. To measure convergent validity, the following scales were used: Short Health Survey (SF-12), Karnofsky Performance Index (KPI), Trait autonomic regulation (Trait aR), Sense of Coherence Scale (SOC), and Geriatric Depression Scale (GDS). RESULTS: A sample of n = 104 (70-96 years of age) patients with Diabetes Mellitus Type 2 (n = 22), cancer diseases (n = 31) and healthy controls (n = 51) completed the ICS. PCA and SEM yielded the original two-factor solution: 1. Inner resilience and coherence and 2. Thermo coherence. Overall internal consistency for this cohort was satisfying (Cronbach's α with rα = 0.72), and test-retest reliability was moderate (rrt = 0.53). ICS scores were significantly correlated to all convergent criteria ranging between r = 0.22 * and 0.49 ** (p < 0.05 *; p < 0.01 **). CONCLUSION: Study results suggest that the ICS appears to be a reliable and valid tool to measure internal coherence in a geriatric cohort (70-96 years). However, moderate test-retest reliability prompts the consideration of potential age-effects that may bias the reliability for this specific cohort.

Influence of Multimodal Treatment on Rest/Activity and Autonomic Regulation in Breast Cancer Patients with Cancer-Related Fatigue: Results of a Tri-Centre Trial with a Comprehensive Cohort Design.

INTRODUCTION: Breast cancer patients with cancer-related fatigue (BC-CRF) often have lower physical activity. To investigate how this could be improved, we evaluated a multimodal treatment (MT) and a combination of MT with aerobic training (CT) and compared these with aerobic training (AT) regarding rest/activity rhythm and state autonomic regulation (State aR). METHODS: In this pragmatic comprehensive cohort design study, the explorative analysis focused on actigraphy and State aR including the rest/activity regulation subscale (State aR-R/A) which were assessed at baseline (T0), after 10 weeks of intervention (T1), and State aR additionally 6 months later (T2). STATISTICS: General linear modelling including propensity scores. RESULTS: 65 BC-CRF were randomized, and 61 were allocated by preference to the treatment arms. 105 patients started the intervention. At T1, State aR-R/A improved the most in MT (+3.49, CI [2.42; 4.55]) compared to AT (+1.59, CI [0.13; 3.06]) and CT (+1.68, CI [0.83; 2.52]), showing superiority of MT to AT (p = 0.048). At T2 MT was sustainably superior to AT regarding State aR-R/A (+3.61, CI [2.38; 4.83] p < 0.01) and State aR also showed superiority of MT to AT (p = 0.006). AT T1 24-h activity was higher in MT compared to AT (p = 0.029). CONCLUSIONS: MT was superior to AT regarding State aR total score after 6 months, State aR-R/A after 10 weeks, and after 6 months. Actigraphically measured total activity also improved after 10 weeks.

Detection of circulating tumor cells in blood of metastatic breast cancer patients using a combination of cytokeratin and EpCAM antibodies.

BACKGROUND: Circulating tumor cells (CTCs) are detectable in peripheral blood of metastatic breast cancer patients (MBC). In this paper we evaluate a new CTC separation method based on a combination of anti-EpCAM- and anti-cytokeratin magnetic cell separation with the aim to improve CTC detection with low target antigen densities. METHODS: Blood samples of healthy donors spiked with breast cancer cell line HCC1937 were used to determine accuracy and precision of the method. 10 healthy subjects were examined to evaluate specificity. CTC counts in 59 patients with MBC were measured to evaluate the prognostic value on overall survival. RESULTS: Regression analysis of numbers of recovered vs. spiked HCC1937 cells yielded a coefficient of determination of R(2) = 0.957. The average percentage of cell recovery was 84%. The average within-run coefficient of variation for spiking of 185, 85 and 30 cells was 14%. For spiking of 10 cells the within-run CV was 30%. No CTCs were detected in blood of 10 healthy subjects examined. A standard threshold of 5 CTC/7.5 ml blood as a cut-off point between risk groups led to a highly significant prognostic marker (p < 0.001). To assess the prognostic value of medium CTC levels we additionally considered a low (CTC-L: 0 CTC), a medium (CTC-M: 1-4 CTC) and a high risk group (CTC-H: ≥5 CTC). The effect of this CTC-LMH marker on overall survival was significant as well (p < 0.001). A log-ratio test performed to compare the model with 3 vs. the model with 2 risk groups rejected the model with 2 risk groups (p = 0.026). For CTC as a count variable, we propose an offset reciprocal transformation 1/(1 + x) for overall survival prediction (p < 0.001). CONCLUSIONS: We show that our CTC detection method is feasible and leads to accurate and reliable results. Our data suggest that a refined differentiation between patients with different CTC levels is reasonable.

Does self-regulation and autonomic regulation have an influence on survival in breast and colon carcinoma patients? results of a prospective outcome study.

BACKGROUND: Cancer Related Fatigue (CRF) and circadian rhythm have a great impact on the quality of life (HRQL) of patients with breast (BC) and colon cancer (CRC). Other patient related outcomes in oncology are measured by new instruments focusing on adaptive characteristics such as sense of coherence or self-regulation, which could be more appropriate as a prognostic tool than classical HRQL. The aim of this study was to assess the association of autonomic regulation (aR) and self-regulation (SR) with survival. METHODS: 146 cancer patients and 120 healthy controls took part in an initial evaluation in 2000/2001. At a median follow up of 5.9 years later, 62 of 95 BC, 17 of 51 CRC patients, and 85 of 117 healthy controls took part in the follow-up study. 41 participants had died. For the follow-up evaluation, participants were requested to complete the standardized aR and SR questionnaires. RESULTS: On average, cancer patients had survived for 10.1 years with the disease. Using a Cox proportional hazard regression with stepwise variables such as age, diagnosis group, Charlson co-morbidity index, body mass index (BMI)) aR and SR. SR were identified as independent parameters with potential prognostic relevance on survival While aR did not significantly influence survival, SR showed a positive and independent impact on survival (OR = 0.589; 95%-CI: 0.354 - 0.979). This positive effect persisted significantly in the sensitivity analysis of the subgroup of tumour patients and in the subscale 'Achieve satisfaction and well-being' and by tendency in the UICC stages nested for the different diagnoses groups. CONCLUSIONS: Self-regulation might be an independent prognostic factor for the survival of breast and colon carcinoma patients and merits further prospective studies.

Anthroposophic supportive treatment in children with medulloblastoma receiving first-line therapy.

BACKGROUND: The use of anthroposophic medicine (AM) is popular in Central Europe, especially in German-speaking countries. Although these therapies are judged to be beneficial by many patients, there are few data with regard to the safety and efficacy in pediatric oncology. Several theoretical concerns have been published with regard to tumor enhancement or promotion of metastatic dissemination due to mistletoe. To test the indirect safety of supportive anthroposophic treatment accompanying the first-line treatment in children with medulloblastoma in this respect we performed a retrospective matched-pair analysis of patients with medulloblastoma treated by standard first-line radiochemotherapy with or without a concomitantly applied panel of AM including mistletoe. The question was whether the effectiveness of the first-line therapy is altered by AM. PROCEDURE: Seventeen patients with AM were matched in a 1:2 ratio with 34 patients from the database of the German HIT study group with regard to the criteria of diagnosis, age, status of metastatic dissemination, resection status, and first-line therapy. RESULTS: The overall survival after 10 years was 58.33% for the AM group and 57.14% for the control group, that is, showing no statistically significant difference (stratified Cox regression; P=0.6023). Event-free survival (including metastases) also did not differ between the groups (stratified Cox regression; P=0.4275). CONCLUSIONS: AM consisting of different combinations of specific pharmacologic and nonpharmacologic interventions seems to be safe with respect to any potential negative impact on the first-line therapy. There is no evidence with regard to tumor enhancement. The effectiveness of the supportive AM cannot be assessed on the basis of these data.

Impact of a Multimodal and Combination Therapy on Self-Regulation and Internal Coherence in German Breast Cancer Survivors With Chronic Cancer-Related Fatigue: A Mixed-Method Comprehensive Cohort Design Study.

Background: Recent studies have proved the relevance of salutogenetic variables for fatigue management in breast cancer survivors with cancer-related fatigue (CRF). This comprehensive cohort design study is the first to examine the impact of 2 multimodal therapies, multimodal therapy (MT) and combined therapy (CT), compared with standard aerobic training (AT) on salutogenetic variables (self-regulation and internal coherence) and distress in breast cancer survivors with CRF. Methods: A total of 105 patients started the therapies and n = 84 completed the Self-regulation Scale, the Internal Coherence Scale, the Cancer Fatigue Scale, and the Hospital Anxiety and Depression Scale at baseline, 10 weeks after treatment (T1) and n = 81 after 6 months (T2). Patient satisfaction and qualitative feedback regarding therapy quality was assessed at T1. A general linear model including allocation type, therapy arm (MT/CT/AT), and bias-adjusting propensity scores tested the superiority of both multimodal therapies versus AT for all questionnaires at T1 and T2. Results: MT and CT were superior to AT to improve self-regulation and patients' satisfaction at T1. Additionally, CT showed superiority for self-regulation at T2 (all P < .05). Compared with AT, internal coherence was significantly higher for patients in the MT arms at T2, respectively (all P < .01). Pearson's correlations between self-regulation, internal coherence, and CRF improved from baseline to T2 (Mean r = -0.60). Qualitative feedback confirmed patients' benefits in several health-related categories. Conclusions: Self-regulation and internal coherence are manipulable variables with relevant CRF associations. They can be positively affected by multimodal therapies. Alongside patients' satisfaction and qualitative feedback they help refine treatment.

Reliability and validity of a new scale on internal coherence (ICS) of cancer patients.

BACKGROUND: Current inventories on quality of life used in oncology mainly focus on functional aspects of patients in the context of disease adaptation and treatments (side) effects (EORTC QLQ C30) or generically the status of common functions (Medical Outcome Study SF 36). Beyond circumscribed dimensions of quality of life (i.e., physical, emotional, social, cognitive etc.), there is a lack of inventories which also address other relevant dimensions such as the 'sense of coherence' (SOC) in cancer patients. SOC is important because of its potential prognostic relevance in cancer patients, but the current SOC scale has mainly been validated for psychiatric and psychosomatic patients. Our two-step validation study addresses the internal coherence (ICS) scale, which is based on expert rating, using specific items for oncological patients, with respect to its reliability, validity and sensitivity to chemotherapy. METHODS: The items were tested on 114 participants (57 cancer patients and a matched control group), alongside questions on autonomic regulation (aR), the Hospital Anxiety and Depression Scale (HADS), self-regulation (SRQ) and Karnofsky the Performance-Index (KPI). A retest of 65 participants was carried out after a median time span of four weeks.In the second part of the study, the ICS was used to assess internal coherence during chemotherapy in 25 patients with colorectal carcinoma (CRC) and 17 breast cancer patients. ICS was recorded before, during and 4-8 weeks after treatment. RESULTS: The 10-item scale of 'internal coherence' (ICS) shows good to very good reliability: Cronbach-alpha r = 0.91, retest-reliability r = 0.80. The ICS correlates with r = 0.43-0.72 to the convergence criteria (all p < 0.001). We are able to show decreased ICS-values after the third cycle for CRC and breast cancer patients, with a subsequent increase of ICS scores after the end of chemotherapy. CONCLUSION: The ICS has good to very good reliability, validity and sensitivity to chemotherapy.

Influence of a Multimodal and Multimodal-Aerobic Therapy Concept on Health-Related Quality of Life in Breast Cancer Survivors.

CONTEXT: Cancer-related fatigue (CRF) is one of the most burdensome symptoms in breast cancer survivors (BCSs), accompanied by reduced health-related quality of life (HRQOL). OBJECTIVES: This study investigated the influence of a multimodal therapy (MT; psychoeducation, eurythmy therapy, painting therapy, and sleep education/restriction), or a combination therapy (CT; MT plus aerobic training [AT]) on HRQOL in BCS with chronic CRF in comparison with AT alone. METHODS: One hundred and twenty-six BCSs with CRF were included in a pragmatic comprehensive cohort study and allocated either per randomization or by preference to MT, CT, or AT. The EORTC QLQ-C30 core questionnaire was used to measure HRQOL. All analyses on HRQOL parameters were done in an explorative intention. RESULTS: Patients were assigned to MT (n = 44), CT (n = 54), or AT (n = 28). CT was significantly superior to AT after 10 weeks of intervention (T1) in improving physical function. MT was found to have significant superiority over AT at T1 and T2 for physical functioning, emotional functioning, insomnia, and financial problems as well as role functioning, cognitive, social functioning, and fatigue 6 months later (T2). CONCLUSION: A multimodal approach appears to be a suitable concept for BCS with chronic CRF. A confirmatory study with larger samples should demonstrate the superiority of MT and adapted CT in HRQOL compared with the current treatment AT found in these explorative analyses.

Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers.

BACKGROUND: Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with Delta-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia. METHODS: The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing Delta-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain. RESULTS: Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered. CONCLUSION: To conclude, no analgesic or antihyperalgesic activity of cannabis extract was found in the experiments. Moreover, the results even point to the development of a hyperalgesic state under cannabinoids. Together with previous data, the current results suggest that cannabinoids are not effective analgesics for the treatment of acute nociceptive pain in humans.

[Kombinierte Anwendung von Strahlentherapie und adjuvanter Therapie mit einem Mistelextrakt (Viscum album L.) zur Behandlung des oralen malignen Melanoms beim Hund: Eine retrospektive Studie].

Hintergrund: Orale maligne Melanome (OMM) des Hundes zeichnen sich durch schnelles Wachstum, lokale Invasion und hohe Metastasierungsraten aus. Extrakte auf Basis von Viscum album L. (VAE) werden zunehmend in der Krebstherapie sowohl in der Human- als auch in der Veterinärmedizin eingesetzt. Ziel unserer Studie war es zu untersuchen, inwieweit die adjuvante Therapie mit VAE eine therapeutische Option zur Behandlung von OMM ist. Besonderes Augenmerk galt dabei der Überlebenszeit und möglichen Nebenwirkungen. Tiere und Methoden: 26 Hunde mit OMM, die in einem der größten veterinäronkologischen Zentren der Schweiz allesamt eine Strahlentherapie erhielten (teilweise nach operativer Tumorresektion) wurden in die retrospektive Studie eingeschlossen: 18 Hunde wurden mit VAE behandelt (1 ml VAE (Iscador®) in ansteigenden Konzentrationen von 0,1 bis 20 mg/ml subkutan 3-mal pro Woche (VAE-Gruppe), 8 erhielten keine adjuvante Behandlung (Vergleichsgruppe). Wir verglichen die Größenentwicklung der OMM sowie die Überlebenszeit. Ergebnisse: Patienten mit Bestrahlung und adjuvanter VAE-Therapie zeigten mit 236 Tagen eine signifikant längere mediane Überlebenszeit im Vergleich zu Patienten mit Bestrahlung, aber ohne adjuvante VAE-Therapie (49 Tage; Log-Rank-Test: p = 0,0047). Die VAE-Therapie verlängerte die Überlebenszeit um mehr als zwei Drittel (Hazard Ratio (HR) = 0,30, 95%-Konfidenzintervall (KI) 0,11-0,86; p = 0,024), während ein höheres Tumorstadium gemäß UICC (Union internationale contre le cancer) einen statistischen Trend zur Verdopplung des Sterberisikos zeigte (UICC-Stadium III/IV vs. I/II: HR = 2,12, 95%-KI 0,88-5,12; p = 0,095). Zwei Patienten zeigten milde Nebenwirkungen während der VAE-Behandlung. Einer der beiden zeigte 1 Tag lang ein selbstlimitiertes Fieber, bei dem anderen Patienten reduzierten wir die Dosis von einem konzentrierteren zu einem weniger konzentrierten VAE (Serie 0) aufgrund von Müdigkeit, die daraufhin verschwand. Schlussfolgerungen: VAE ist eine sichere, nebenwirkungsarme Behandlung und scheint sich positiv auf die Überlebenszeit von Hunden mit OMM auszuwirken. Somit ist dieser therapeutische Ansatz es wert, vermehrt bei der adjuvant zur Strahlentherapie eingesetzten Behandlung des OMM in Betracht gezogen zu werden. Die verglichenen Gruppen waren jedoch klein, divers und nicht konsistent hinsichtlich aller prognostischen Parameter. Eine prospektive Studie mit einer größeren Studienpopulation wäre daher von Interesse.

[Postoperative adjuvante Therapie mit einem Mistelextrakt (Viscum album ssp. album) bei Hündinnen mit Mammatumoren].

Hintergrund: Canine Mammatumoren (CMT) sind wegen ihrer Häufigkeit und hohen Malignitätsrate eine Herausforderung für die Veterinärmedizin. Bisher ist noch keine postoperative adjuvante Therapie als wirksamer Standard etabliert und in den nächsten Jahren wohl auch nicht zu erwarten. Zusätzlich ist die Frage nach der Verträglichkeit einer adjuvanten Therapie mit Erhaltung oder Verbesserung der Lebensqualität (LQ) wichtig. Die Therapie mit Mistelextrakten (Viscum album L.; VAE) ist in der Humanonkologie nach adjuvanter Tumorbasistherapie (Chemotherapie und Bestrahlung) eine sehr häufig verwendete, zusätzliche adjuvante Behandlungsmethode. Auch bei verschiedenen Tierarten werden inzwischen Mistelpräparate in der Onkologie erfolgreich angewendet. Methoden: Überprüfung von Wirkung und Nutzen einer postoperativen, adjuvanten Misteltherapie beim CMT sowie Erfassung der LQ unter der VAE-Behandlung. Ausgewertet wurden 56 Hündinnen mit Mammaadenokarzinom, 33 ausschließlich operierte Kontrolltiere und 23 operierte Tiere, die adjuvant VAE erhielten. Ergebnisse: Die mediane Überlebenszeit (MST) aller Tiere (n = 56) betrug 32 Monate (Interquartilbereich 13-51 Monate). Im deskriptiven Vergleich der Überlebenszeiten (ST) nach Kaplan-Meier waren nach 12, 24, 36 bzw. 48 Monaten noch 24, 20, 15 bzw. 5 Hündinnen (entsprechend 72,7%, 60,6%, 45,1%, 12,4%) der Kontrollgruppe sowie 19, 14, 11 und 1 Hündin (82,6%, 60,9%, 47,8%, 4,3%) der VAE-Gruppe am Leben. Die VAE-Therapie führte zu einem geringeren Gesamtversterberisiko, das statistisch nicht signifikant war (Hazard Ratio (HR) 0,530, 95%-Konfidenzintervall (KI) 0,222-1,262; p = 0,15). Tendenziell (p = 0,07) zeigte sich eine Verringerung des tumorbedingten Sterberisikos auf 25% (HR 0,251, 95%-KI 0,056-1,122). Schlussfolgerungen: Es kann eine Tendenz zur Senkung des tumorbedingten Sterberisikos der VAE-Gruppe bei guter Verträglichkeit der Therapie angenommen werden. Die LQ der Tiere blieb über die gesamte Beobachtungszeit auf hohem Niveau stabil.

[Evidenzbasierte Leitlinien, Anspruch und Wirklichkeit].

Mit der Konzeption der «Evidenzbasierten Medizin¼ und den «Evidenzbasierten Leitlinien¼ soll mithilfe von Formalisierungsprozeduren die ärztliche Irrtumsanfälligkeit kalkulierbar gemacht werden. Quantifizierte objektive Aussagen über die therapeutische Wirksamkeit einer Behandlung sollen die individuelle ärztliche Beurteilung der therapeutischen Wirksamkeit überflüssig machen. Damit kommt der Befolgung von formalen Regeln die entscheidende Rolle bei der Beantwortung der Frage nach dem Wahrheitsgehalt und dem Wirklichkeitsbezug zu. Im Rahmen evidenzbasierter Leitlinien werden vorrangig die Ergebnisse randomisierter kontrollierter Studien (RCT) oder Meta-Analysen solcher Studien herangezogen. Am Beispiel der S3-Leitlinie «Malignes Melanom¼ wird hier eine evidenzbasierte Urteilsbildung zur Wirksamkeit einer unkonventionellen Therapie - hier mit einem Mistelpräparat - analytisch nachvollzogen. Die für die Beurteilung dieser unkonventionellen Therapie herangezogene randomisierte Studie wird genauer methodisch analysiert. Obwohl sie keine statistisch basierte Aussage zulässt, wurde eine Leitlinienempfehlung auf Basis dieser Studie abgeleitet. Es wird gezeigt, dass 1) allein die Existenz einer einzigen RCT mit hoher Evidenz gleichgesetzt wird, 2) die Ergebnisse trotz beträchtlicher Fehlinterpretationen in eine S3-Leitlinie einfließen und 3) Meinungen anstelle kritischer wissenschaftlicher Analysen verarbeitet werden. Unsere Untersuchung zeigt, dass noch so ausgefeilte epistemologische und methodologische Formalien den Arzt nicht von der Pflicht entbinden, auf Basis seiner ärztlichen Erfahrung und professionellen Kompetenz den Realitätswert der ihm zur Verfügung stehenden Information zu beurteilen.

The questionnaire on autonomic regulation: a useful concept for integrative medicine?

The concept of autonomic regulation (aR) reflects the relevance of the function of different autonomic systems for health. aR can be captured by questionnaires. We differentiate between a trait or constitutional aR questionnaire version including 12 (short-version) or 18 items, respectively, with three subscales (orthostatic-circulatory, rest/activity and digestive regulation), and an 18-item state aR questionnaire on the preceding week with four subscales (rest/activity, orthostatic-circulatory, thermo- and digestive regulation). The validated questionnaires show satisfying to good reliability and robust validity with clear construct validity. In this article, we summarized the actually available literature on aR and the use of aR questionnaires in clinical and observational studies. We described the relationship of high aR with health and in case of low aR or loss of regulation with disease and functional disorder in the three (four) different subscales and functional systems, such as rest/activity, orthostatic-circulatory or digestive regulation (thermoregulation) with the consecutive therapeutic need. Finally, we gave perspectives of its further application in clinical research.

[Reduction of endogenous regulation in internal medicine patients]. / Verlust von endogener Regulation bei internistischen Patienten.

BACKGROUND: General health-related questionnaires on quality of life do not satisfactorily distinguish between healthy and sick people. One of the reasons cited for this lack is too much mental influence. This is why we developed a questionnaire on endogenous regulation (eR) that reflects the regulatory state of various vegetative functions. OBJECTIVE: The current study examines whether the short version eR questionnaire is able to distinguish between healthy people and internal medicine patients. PATIENTS AND METHODS: 408 participants were included in the study (284 females, 124 males). Among these were patients with colorectal cancer (n = 49), breast cancer (n = 95), diabetes mellitus (type 1: n = 20, type 2: n = 40), coronary disease (n = 39), rheumatoid illnesses (n = 28) and multimorbid patients (n = 22) as well as a healthy control group (n = 115). In addition to the eR questionnaire the study also used the Hospital Anxiety and Depression Scale (HADS), the short questionnaire on self-regulation and questions on the vegetative status. RESULTS: The healthy control group showed the highest eR, with an estimated average of M = 29.8. Patients with breast cancer, diabetes mellitus type 2, coronary disease and rheumatoid illnesses reveal a significantly lowered eR. Multimorbid patients show the lowest eR. Patients with cancer of the colon and diabetes type 1 were measured at M = 27.9 and M = 27.3 respectively and showed no significantly lowered estimated average compared to the control group. A high eR significantly correlates (p < 0.002) with the following parameters: low levels of anxiety (r = 49) and depression (r = 0.36), high self-regulation (r = 0.34), morning type (r = 0.40), less congestive perspiration (r = 0.38), less shivering (r = 0.23), dysmenorrhoea (r = 0.38) and allergies (r = 0.17). CONCLUSION: Healthy people show the highest, multimorbid patients the lowest eR. Consistent relations to health, illness, heat regulation and personality presence have been shown. Further studies to clarify clinical relevance are necessary.

A randomised, controlled, single-blinded study on the impact of a single rhythmical massage (anthroposophic medicine) on well-being and salivary cortisol in healthy adults.

BACKGROUND: Rhythmical massage (RM) has evolved from classical massage and is based on the principles of Anthroposophic medicine. The goal of this randomized, single-blinded study was to assess the efficacy of a single RM intervention with either aroma oil (RA) or a neutral oil (RM) compared to a sham massage (SM) on several dimensions of well-being and salivary cortisol in a laboratory setting. METHODS: 118 healthy adults (mean age: 25.2 years; SD: 4.7) were randomized to one of three groups (RM, RA or SM). After baseline measurements, all subjects were exposed to an experimental stressful situation (Trier Social Stress Test, TSST), before receiving a single massage intervention of about 60 min including a 20-minute rest period. Well-being as the main outcome parameter was assessed by standardized questionnaires (MDBF, Bf-S, B-L) and visual analogue scales (VAS) prior to the beginning of the massage and subsequently. Salivary cortisol and heart rate variability (data are shown elsewhere) were also measured. RESULTS: Participants who received RM or RA showed no statistically significant improvements (MDBF, Bf-S, B-L) compared to the SM group after adjusting for baseline differences observed between the treatment groups. Furthermore, no statistically significant differences were found between the RM and RA groups in any of the analyses. Within a follow-up survey all participants from the RA and 82% from the RM group described the intervention as "relaxing" compared with 42% in the SM group. Salivary cortisol did not differ statistically significantly between the three groups over time. CONCLUSIONS: We found no significant effect within this trial. This may be due to the methodological complexity of massage research and especially the sham-controlled design with only one single intervention examined. The influence of the setting, and the expectations of and interaction between participant and practitioner seem to play a role that needs to be verified. Therefore the true potential of rhythmical massage intervention still needs to be validated.