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Chronic psychological stress can result in physiological and mental health risks via the activation of the hypothalamic–pituitary–adrenal (HPA) axis, sympathoadrenal activity and emotion-focused coping strategies. The impact of different stress loads on cardiometabolic risk is poorly understood. This post hoc analysis of a randomized pilot study was conducted on 61 participants (18–65 years of age) with perceived chronic stress. The Perceived Stress Questionnaire (PSQ30), Psychological Neurological Questionnaire (PNF), anthropometric, clinical and blood parameters were assessed. Subjects were assigned to ‘high stress’ (HS; PSQ30 score: 0.573 ± 0.057) and ‘very high stress’ (VHS; PSQ30 score: 0.771 ± 0.069) groups based on the PSQ30. Morning salivary cortisol and CRP were elevated in both groups. Visceral adiposity, elevated blood pressure and metabolic syndrome were significantly more frequent in the HS group vs. the VHS group. The fatty liver index (FLI) was higher (p = 0.045), while the PNF score was lower (p < 0.001) in the HS group. The HS group was comprised of more smokers (p = 0.016). Energy intake and physical activity levels were similar in both groups. Thus, high chronic stress was related to visceral adiposity, FLI, elevated blood pressure and metabolic syndrome in the HS group, while very high chronic stress was associated with psychological–neurological symptoms and a lower cardiometabolic risk in the VHS group, probably due to different coping strategies.

Chronic non-communicable diseases (NCD) are the major reason for death, morbidity, loss of independency and public health cost. NCD prevalence could be significantly reduced by adopting a healthy lifestyle. This cross-sectional cohort study (online survey) in 221 women aimed to assess NCD awareness, knowledge about NCD prevention and willingness to adopt a healthier lifestyle in women. Overall, NCD awareness level was quite high with, however, information mainly originating from lay media, probably being one reason for false estimations of age groups mainly affected by NCD, impact of NCD on quality of life, NCD mortalities, and the extent of NCD prevention by lifestyle interventions, respectively. Furthermore, also due to mainly lay media, half of women knew online NCD risk calculators, most of them would like to know their NCD risk, but only few had been offered NCD risk calculation by their physician. The mean threshold for willing to adopt a healthier lifestyle was a roughly calculated 37% 5–10 years risk to develop a certain NCD. Acceptance of non-pharmacological interventions for NCD prevention was high, however, major barriers for not implementing a healthier lifestyle were lack of expert information and lack of time. In conclusion, future public health strategies should focus on distributing better understandable and correct information about NCD as well as meeting the individuals’ request for personalized NCD risk calculation. Furthermore, physicians should be better trained for personalized NCD prevention counseling.

Purpose This study aims to verify that the mental-cognitive domain of the validated generic bio-functional status (BFS)/bio-functional age (BFA) assessment tool, incorporating the concept of Active and Healthy Ageing (AHA), reflects cognitive performance. In addition, the effects of chronic stress exposure on the mental-cognitive BFS/BFA should be investigated. Methods The study was carried out as a monocenter, cross-sectional, observational, non-interventional trial (Bern Cohort Study 2014, BeCS-14) with the participation of 147 non-pediatric, non-geriatric subjects. All participants followed a standardized battery of biopsychosocial assessments consisting of BFS/BFA, a validated cognitive performance test battery (Inventar zur Gedächtnisdiagnostik; IGD) and a validated questionnaire for the assessment of chronic stress (Trier Inventory for the assessment of Chronic Stress; TICS), respectively. Results Mean cognitive performance was average and higher in younger or better educated individuals. The BFA of the participants was 7.8 ± 7.8 year-equivalents below their chronological age. The mental-cognitive BFS/BFA assessment correlated well with the validated questionnaire for cognition assessment, the IGD. Further, three TICS subdomains (work overload (r = − 0.246, p = 0.003), work discontent (r = − 0.299, p = 0.006) and pressure to succeed (r = − 0.274, p Conclusions Our study shows that the BFS/BFA assessment tool follows European Innovation Partnership on Active and Healthy Ageing (EIP-AHA) requirements. Further, we could demonstrate that higher levels of chronic work-related stress may be associated with poorer mental-cognitive performance and a pro-aging state indicating that cognitive impairments can be reduced by stress management interventions.

Patients with intestinal fat malabsorption and urolithiasis are particularly at risk of acquiring fat-soluble vitamin deficiencies. The aim of the study was to evaluate the vitamin status and metabolic profile before and after the supplementation of fat-soluble vitamins A, D, E and K (ADEK) in 51 patients with fat malabsorption due to different intestinal diseases both with and without urolithiasis. Anthropometric, clinical, blood and 24-h urinary parameters and dietary intake were assessed at baseline and after ADEK supplementation for two weeks. At baseline, serum aspartate aminotransferase (AST) activity was higher in stone formers (SF, n = 10) than in non-stone formers (NSF, n = 41) but decreased significantly in SF patients after supplementation. Plasma vitamin D and E concentrations increased significantly and to a similar extent in both groups during intervention. While plasma vitamin D concentrations did not differ between the groups, vitamin E concentrations were significantly lower in the SF group than the NSF group before and after ADEK supplementation. Although vitamin D concentration increased significantly in both groups, urinary calcium excretion was not affected by ADEK supplementation. The decline in plasma AST activity in patients with urolithiasis might be attributed to the supplementation of ADEK. Patients with fat malabsorption may benefit from the supplementation of fat-soluble vitamins ADEK.

PURPOSE It is controversial who should be recommended to undergo natural cycle IVF (NC-IVF). Therefore, objective prognostic criteria which are already known at the time of counselling were defined. METHODS A retrospective observational study was performed with 201 couples (age 34.7 ± 4.1) undergoing 311 NC-IVF treatments with 201 transfers, corresponding to a transfer rate of 65.3%. The first cycle resulting in a transfer of one embryo was further analysed. Clinical pregnancy and live birth rates were analysed. RESULTS Pregnancy rate and live birth rates per first cycle were 21.9% and 13.2%, respectively. Groupwise comparison revealed the following clinical pregnancy/live birth rates per transfer cycle: duration of infertility 1-2 years 34.3/25.7%, 3-4 years 21.8/14.9% and > 4 years 9.1/4.5%. Women's age

Background Cardiac arrhythmias (CA) are very common and may occur with or without heart disease. Causes of these disturbances can be components of the metabolic syndrome (MetS) or deficits of micronutrients especially magnesium, potassium, B vitamins and coenzyme Q10. Both causes may also influence each other. Insulin resistance (IR) is a risk factor for diastolic dysfunction. One exploratory outcome of the present pilot study was to assess the impact of a dietary intervention with specific micronutrients on the lowering of IR levels in patients with CA with the goal to improve the left ventricular (LV) function. Methods This was a post hoc analysis of the randomized double blind, placebo-controlled pilot study in patients with CA (VPBs, SVPBs, SV tachycardia), which were recruited using data from patients who were 18–75 years of age in an Outpatient Practice of Cardiology. These arrhythmias were assessed by Holter ECG and LV function by standard echocardiography. Glucose metabolism was measured by fasting glucose, fasting insulin level and the Homeostasis Model Assessment of IR (HOMA-IR) at baseline and after 6 weeks of dietary supplementation. Results A total of 54 randomized patients with CA received either a specific micronutrient combination or placebo. Dietary intervention led to a significant decrease in fasting insulin ≥58 pmol/l (p = 0.020), and HOMA-IR (p = 0.053) in the verum group after 6 weeks. At the same time, parameters of LV diastolic function were improved after intervention in the verum group: significant reduction of LV mass index (p = 0.003), and in tendency both a decrease of interventricular septal thickness (p = 0.053) as well as an increase of E/A ratio (p = 0.051). On the other hand, the premature beats (PBs) were unchanged under verum. Conclusions In this pilot study, dietary intervention with specific micronutrient combination as add-on to concomitant cardiovascular drug treatment seems to improve cardio metabolic health in patients with CA. Further studies are required. Study registration The study was approved by the Freiburg Ethics Commission International and was retrospectively registered with the U.S. National Institutes of Health Clinical Trials gov ID NCT 02652338 on 16 December 2015.

Purpose To characterise efficacy and safety of (177)Lu-DOTATOC as agent for peptide receptor radiotherapy (PRRT) of advanced neuroendocrine tumours (NET). Patients and methods Fifty-six subjects with metastasized and progressive NET (50% gastroenteral, 26.8% pancreatic, 23.2% other primary sites) treated consecutively with (177)Lu-DOTATOC were analysed retrospectively. Subjects were administered (177)Lu-DOTATOC (mean 2.1 cycles; range 1-4) as 7.0GBq (median) doses at three-monthly intervals. Efficacy was analysed using CT and/or MRI according to RECIST 1.1 criteria and results were stratified for the number of administered cycles and the primary tumour origin. Results In the total NET population (A), median progression-free (PFS) and overall survival (OS) were 17.4 and 34.2 months, respectively, assessed in a follow-up time (mean ± SD) of 16.1 ± 12.4 months. In patients receiving more than one cycle, mean follow-up time was 22.4 ± 11.0 months for all NETs (B) and PFS was 32.0 months for all NETs (B), 34.5 months for GEP-NET (C), and 11.9 months for other NETs (D). Objective response rates (Complete/Partial Responses) were 33.9%, 40.6%, 54.2%, and 0% for A, B, C, and D groups, respectively, while disease control rates in the same were 66.1%, 93.8%, 100%, and 75%. Complete responses (16.1%, 18.8% and 25.0% for groups A, B and C) were high, 78% of which were maintained throughout the follow up. There were no serious adverse events. One case of self-limiting grade 3 myelotoxicity was reported. Although 20% of patients had mild renal insufficiency at baseline, there was no evidence of exacerbated or de novo renal toxicity after treatment. Conclusion (177)Lu-DOTATOC is a novel agent for PRRT with major potential to induce objective tumour responses and sustained disease control in progressive neuroendocrine tumours, even when administered in moderate activities. The observed safety profile suggests a particularly favourable therapeutic index, including in patients with impaired bone marrow or renal function, which reflects a uniquely low uptake of (177)Lu-DOTATOC by normal organs.

Nutrients 10(5), (2018). doi:10.3390/nu10050551, Published by MDPI, Basel

PURPOSE To assess the attitude towards ovarian tissue and oocyte cryopreservation for non-medical reasons. METHODS Cross-sectional electronic survey in 248 Swiss women aged 15-35 years, nationally representative for educational level. RESULTS Most women did not worry about an age-related fertility decline. Two-thirds of women would consider using hormone therapy (HT) for menopausal symptom relief although concerns about side effects and risks were still high. Acceptance of cryopreservation of oocytes (19%) or ovarian tissue (13%) for postponing fertility or menopause was generally low, but increased (37%) if both goals could be achieved with one surgery. Cryopreservation of ovarian tissue for postponing menopause was acceptable for 22% of women. Not having a suitable partner until age 35 increased the likelihood of considering postponing fertility by cryopreservation (p

Chitosan treatment results in significantly lower serum LDL cholesterol concentrations. To assess the working mechanism of chitosan, we measured serum surrogate markers of cholesterol absorption (campesterol, sitosterol, cholestanol), synthesis (lathosterol, lanosterol, desmosterol), and degradation to bile acids (7α-hydroxy-cholesterol, 27-hydroxy-cholesterol) corrected for cholesterol concentration (R_sterols). Over 12 weeks, 116 obese subjects (BMI 31.7, range 28.1 – 38.9 kg/m2) were studied under chitosan (n=61) and placebo treatment (n=55). The participants were briefly educated regarding improvement of nutrition quality and energy expenditure. Daily chitosan intake was 3200 mg. Serum LDL cholesterol concentration decreased significantly more (P=0.0252) under chitosan (-8.67 ± 18.18 mg/dl, 5.6%) than under placebo treatment (-1.00 ± 24.22 mg/dl, 0.9%). This reduction was not associated with the expected greater decreases in markers of cholesterol absorption under chitosan treatment. Also, increase in markers of cholesterol synthesis and bile acid synthesis under chitosan treatment was not any greater than under placebo treatment. In conclusion, a significant selective reduction of serum LDL cholesterol under chitosan treatment is neither associated with a reduction of serum surrogate markers of cholesterol absorption nor with an increases of markers for cholesterol and bile acid synthesis.

Chronic non-communicable diseases (NCDs) are the major reason for death and morbidity worldwide. As many NCDs are initially asymptomatic, online risk calculators with easy and inexpensive access have been developed and validated in order to facilitate early NCD detection and prevention. The aim of this study was to assess the awareness, use and applicability of NCD risk calculators among physicians in private practice in the canton of Bern, Switzerland. This was a cross-sectional cohort study of general practitioners and specialists in general internal medicine and gynaecologists. The questionnaire covered questions on the number of NCD risk calculators known and used, and barriers to their daily use during counselling. Awareness of NCD risk calculators was high. They were considered to be part of a routine preventive "check-up" by general internal medicine specialists and general practitioners but not by gynaecologists. AGLA® was the most known and used NCD risk calculator. However, 20-30% of physicians considered themselves non-users, and said they would be so even if access to online NCD risk calculators was made easier. More education on the benefits and better access to the NCD risk calculators are needed.

Die Verwendung von Nahrungserganzungsmitteln (NEM), vor allem Vitamin- und Mineralstoffpraparaten, ist teilweise weit verbreitet. Neben der Bedeutung fur die Gesundheit sind auch mogliche Risiken Gegenstand kontroverser Diskussionen. Als ein potenzielles Problem gilt dabei die Mehrfachverwendung von NEM, d. h. die Zufuhr verschiedener Praparate mit gleichen Inhaltsstoffen und die damit verbundene kumulative Aufnahme an Stoffen. Entsprechende Zahlen hierzu lagen bisher nicht vor. Ziel dieser Auswertung war es daher, die Mehrfachverwendung von NEM bei erwachsenen Mannern und Frauen im Detail zu erfassen und naher zu charakterisieren. Als Datengrundlage diente dabei eine deutschlandweite reprasentative Befragung in Zusammenarbeit mit der Gesellschaft fur Konsum-, Markt- und Absatzforschung e. V. (GfK) mit 1.070 NEM-Verwendern. Bei 94 % der Befragten stammte die Zufuhr der untersuchten Nahrstoffe nur aus einem einzigen Praparat. Mit zunehmender Zahl der verwendeten Praparate stieg die mittlere Vitamin- und Mineralstoffzufuhr erwartungsgemas an, die Zahl der Verwender sank hingegen deutlich. Uberschreitungen des Tolerable Upper Intake Level (UL) waren in erster Linie bei Magnesium zu beobachten, wobei dies bei 68 % der Magnesiumverwender keine Folge einer Mehrfachverwendung war. Insgesamt weisen die hier erhobenen Daten darauf hin, dass eine Mehrfachaufnahme von Vitaminen und Mineralstoffen uber verschiedene Praparate eine geringe praktische Bedeutung besitzt.

Introduction: Studies indicate that 17.9% - 60% of adults in Germany and Europe regularly use food supplements. Some reports suggest that their use might be responsible for excessive nutrient intake. The purpose of this survey was to examine the quantitative mineral intakes from food supplements: whether the tolerable upper intake levels (ULs) with supplements alone, or in combination with food was exceeded was checked. Methods: The survey was carried out by the Association for Consumer Research, Nurnberg, Germany. Anonymous data of 1070 supplement users (40.8% men, 59.2% women) aged 18 - 93 years were available. Three groups were examined based on dietary and supplemental mineral intakes: average, middle-high and high intake. Results: The mean number of supplements reported was 1.6 ± 1.1 products in men and 1.5 ± 0.9 products in women. The minerals most frequently consumed were magnesium, followed by calcium, zinc and selenium. The percentage of the supplement users with total intakes greater than the UL was minimal for all minerals. Supplement use in 143 cases increased the likelihood of intakes above the UL only for magnesium. Subjects particularly in the high intake group—as a worst case scenario—had intakes above the UL in the case of calcium (n = 23) and zinc (n = 34). The percentage of subjects taking several products was greater in subjects exceeding the UL than in those below (P < 0.001). Multiple use was seen significantly more often in men than in women (P < 0.01). Conclusions: In this survey, supplement use was generally not associated with excessive intake. Supplement use resulted in intakes above the UL in only a few cases relating to magnesium, calcium and zinc. This applies more often to elderly subjects and particularly to those who already have a high mineral intake from food in the model calculation.

Adequate vitamin D status is crucial for normal development of the fetus and for maternal health. As data on vitamin D status (25-hydroxyvitamin D, 25(OH)D) in German women of different states of pregnancy were not available, this study compared the vitamin D status of German women in all trimesters of pregnancy with that of non-pregnant women.The study sample of 858 women (18-45 years) was recruited from April 2013 to March 2015 as a part of the cross-sectional Germany-wide VitaMinFemin study. Serum 25(OH)D levels were determined using chemiluminescence immunoassay.A total of 78.1% of the pregnant women and 53.9% of the non-pregnant women had a vitamin D status50.0 nmol/L (p 0.001). In pregnant women, the multivariate binary analysis showed that winter [odds ratio (OR) 13.5], longitude of residence between 6.3°E and 8.9°E (OR 2.0) or 9.0°E and 10.9°E (OR 2.3) and third trimester (OR 2.3) were associated with a higher risk of vitamin D status25.0 nmol/L, whereas increasing age per one year (OR 0.9) with a lower risk. Compared with non-pregnant women, pregnant women were 3.7 times more likely to have a vitamin D status25.0 nmol/L.A low vitamin D status is prevalent among German pregnant women and should be improved to supply mother and fetus adequately.

Background The efficacy of a non-prescription drug to support weight loss programs has yet to be compared. This clinical trial investigates the comparability of orlistat 60 milligram (mg) and polyglucosamine. Methods Sixty-four overweight or obese subjects were included in a two-center double-blind study. One center was in Germany [center 1] and the other was in Italy [center 2]. The subjects (26 in center 1 and 38 in center 2) were recommended to follow a calorie deficit of about 2000 kilojoules/day and to increase their physical activity to 3 metabolic equivalent hours (MET h)/day. In both centers, subjects were randomized to receive polyglucosamine (2 tablets x 2) or orlistat (1 capsule x 3) for a period of 12 weeks. Weight loss was considered as a main variable together with the reduction of 5 per cent (%) of body weight (5R). Body Mass Index (BMI) and waist circumference (WC) were taken as secondary variables. Results A significant difference in weight loss between the two groups was shown, 6.7 ± 3.14 kilogram (kg) in group polyglucosamine versus 4.8 ± 2.24 kg in group orlistat (t test p 0.05). The administration of polyglucosamine following energy restriction and increase in physical activity reduces body weight, BMI and WC more efficiently than orlistat Conclusions Even though both groups were instructed to adopt a calorie restricted diet together with increased physical activity an additional weight loss in the polyglucosamine group of 1.6 kilogram (kg) compared to the orlistat group (6.2 ± 3.46 versus 4.6 ± 2.36 kg) in both centers was seen despite the higher consumption of carbohydrates in Italy (center 2). A typical Italian diet is usually high in carbohydrate content whereas Germans tend to consume meals with higher fat content. This leads to the assumption that polyglucosamine limits both fat and carbohydrate absorption which would explain the comparable effective weight reduction in the Italian participants. Trial registration Trial registration at ClinicalTrials.gov NCT02529631, registered on Aug 19, 2015 retrospectively registered.

Verschiedenen Untersuchungen zufolge verwenden etwa 18–50 % der Erwachsenen in Deutschland regelmasig Nahrstoffsupplemente aller Art [Schwab et al. (J Nutr Health Aging 1–10, 2013); MRI (Nationale Verzehrsstudie II Ergebnisteil 2, 2008); Reinert et al. (Eur J Nutr 46:165–173, 2007); Bodenbach and Weinkauf (Z Ernahrungswiss 36:57–58, 1997)]. Dabei schwanken die Angaben zur Einnahmepravalenz nach Fragestellung, Zielgruppe, Untersuchungsort und -jahr. So geht beispielsweise aus der im Jahr 2008 publizierten Nationalen Verzehrstudie II hervor, dass rund 28 % der Befragten auf Nahrstoffsupplemente zuruckgreifen (MRI 2008). Ziel der vorliegenden, in Kooperation mit der Gesellschaft fur Konsum-, Markt- und Absatzforschung e.V. (GfK) durchgefuhrten Studie war es, detaillierte Daten zum generellen Konsumverhalten, zur Haufigkeit von Mehrfacheinnahmen sowie zu den haufigsten Beweggrunden fur die Verwendung von Supplementen zu gewinnen. Das Augenmerk lag dabei ausschlieslich auf Supplementen, die als Nahrungserganzungsmittel, erganzende bilanzierte Diat oder sonstiges diatetisches Lebensmittel vermarktet werden und damit rechtlich als Lebensmittel einzustufen sind. Die genaue Zusammensetzung der verwendeten Produkte sowie deren Bezugsquellen waren ebenfalls von Interesse. Die durch personliche Interviews und Online-Befragungen erhobenen Daten von 1.070 Supplementverwendern (59,2 % Frauen, 40,8 % Manner) im Alter von 18–93 Jahren (55 ± 14,9 Jahre) wurden ausgewertet. Von den befragten Personen verwendeten 88,6 % ein oder zwei Produkte und weniger als 2 % mehr als 4 Praparate. Uber 2 Drittel der Befragten gab an, die jeweiligen Supplemente regelmasig und uber das ganze Jahr hinweg zu konsumieren, 43,9 % seit maximal einem Jahr, 6 % seit mehr als zehn Jahren. Die Mehrzahl der Befragten nannte gesundheitliche Motive fur den Supplementkonsum. Die Hinweise auf der Verpackung beachteten 86 % der Teilnehmer, 93 % waren sich der moglichen Risiken einer uberhohten Zufuhr bewusst. Am haufigsten wurden Magnesiumpraparate eingenommen, gefolgt von Kalzium- und Multivitamin- bzw. A-Z-Produkten. Wichtigste Bezugsquellen waren Lebensmitteldiscounter und Drogeriemarkte, aber auch der Struktur- und Direktvertrieb spielte eine relevante Rolle.

Brain food, e.g. L-tryptophan, antioxidative substances, B vitamins and magnesium are thought to be beneficial for obesity, inflammation and insulin resistance. In the present pilot study we hypothesised that a specific amino acid mixture with micronutrients improves the cardiometabolic situation of chronically stressed persons. Cardiovascular and metabolic parameters were analysed as per protocol in 32 patients. Chronic stress disorders in the same patients were assessed by a psychological neurological questionnaire (PNF). After dietary intervention a reduction of the fasting serum insulin concentrations occurred in the treatment group. An association was found between PNF values, insulin concentrations at baseline and an insulin reduction after 12 weeks. The results support the use of our specific dietary supplement for improved stress management and a decrease in metabolic dysfunction.

PURPOSE Obesity is pandemic. Yet, the success of most weight loss programmes is poor. The aim of the study was to assess illness perception in overweight/obese people and its impact on bio-functional age (BFA) reflecting physical, mental, emotional and social functioning. METHODS 75 overweight/obese subjects from the cross-sectional Bern Cohort Study 2014 were included. Participants followed a validated "bio-functional status" test battery amended by the validated questionnaires Patiententheoriefragebogen (illness perception) and AD-EVA (eating and movement behaviour). BFA was calculated in subjects aged ≥ 35 years (n = 56). RESULTS (1) Mental occupation with the cause of overweight/obesity was generally moderate to high, but decreasing with age. (2) The predominant theories for being overweight/obese were health behaviour (58.7%) and psychosocial factors (33.3%). (3) Overweight/obese people with psychosocial theories on illness causes were more likely to have emotional or disinhibited eating patterns. (4) Cognitive control of eating patterns increased with age in both sexes. (5) Overweight/obese people were still bio-functionally younger than their chronological age (8.6 ± 0.8 year equivalents), although (6) quality of life was below average and (7) the risk for functional pro-aging was increased in those being especially mentally occupied with causes for overweight/obesity (r = 0.38, p 0.001). CONCLUSIONS Consciously perceived psychosocial stress was found to be a main factor to disturb health and promote unhealthy cognitive patterns regulating eating and moving habits. Thus, successful weight reduction programmes should integrate subjective illness perceptions to not only improve the therapeutic outcome, but also functioning (BFA).

Zusammenfassung Die nachfolgend dargestellten Beispielrechnungen belegen exemplarisch die Möglichkeit, durch sequentielle Messauswertung der Kostensteigerung beim Lungenkrebsscreening entgegenzuwirken, die aus umfangreicheren Folgeuntersuchungen resultiert. Verbindet man diese Vorgehensweise mit noch leistungsfähigeren Verfahren der Datenauswertung, wird der erzielbare Informationsgewinn ökonomisch sinnvoll. Die dargelegten konkreten Zahlenwerte hängen maßgeblich vom Patientenkollektiv ab und sind für andere Anwendungen anzupassen. Die Berechnungen sind jedoch für retrospektives Datenmaterial unkompliziert ausführbar und nicht auf die Tumormarkerprofilauswertung beschränkt. So können beispielsweise auch die alternativen Diagnoseverfahren für ein potentielles Lungenkrebsscreening wie CT-Thorax-Untersuchung oder Sputumanalysen in dieser Weise unter ökonomischer Sicht analysiert und diskutiert werden.

In practical use, the experiences of single marker interpretation influence the analysis of tumor marker profiles. From a mathematical point of view, there are different possibilities to link individual measured data. When comparing such methods of resolution, significant differences in their efficiency are observed. An increase in sensitivity generally results in a loss of specificity. Therefore, the choice of the mathematical process is decisively influenced by subjective expectations. The goal of the analysis of tumor marker profiles is raising the sensitivity while maintaining a high specificity. Based on the study of frequently used strategies of data evaluation, effects are described from which a universally valid concept of data evaluation can be derived. Special attention is given to the independence of the mathematical processes from specified cut-offs and thereby from diagnostic testing methods. Instead of quantitative measured data, qualitative valuations of decision security are handled. This not only enables a rise in sensitivity but also allows a plausible interpretation of results from the user's view. Thus the analysis of tumor marker profiles seems (fuzzy) logical and opens up new avenues to make far-reaching contributions to the clarification of clinical problems by laboratory analysis.

Tumor markers were used for disease monitoring in small-cell lung cancer patients. The aim of this study was to improve diagnostic efficiency in the detection of tumor progression in small-cell lung cancer patients by using fuzzy logic modeling in combination with a tumor marker panel (NSE, ProGRP, Tumor M2-PK, CYFRA 21-1, and CEA). Thirty-three consecutive small-cell lung cancer patients were included in a prospective study. The changes in blood levels of tumor markers and their analysis by fuzzy logic modeling were compared with the clinical evaluation of response versus non-response to therapy. Clinical monitoring was performed according to the standard criteria of the WHO. Tumor M2-PK was measured in plasma with an ELISA, all other markers were measured in sera. At 90% specificity, clinically detected tumor progression was found by the best single marker, NSE, in 32% of all cases. A fuzzy logic rule-based system employing a tumor marker panel increased the sensitivity significantly (P>0.0001) in small-cell carcinomas to 67% with the threemarker combination NSE/ProGRP/Tumor M2-PK and to 56% with the best two-marker combination ProGRP/Tumor M2-PK, respectively. An improvement of sensitivity was also observed using the two-marker combination of ProGRP/NSE (sensitivity 49%) or NSE/Tumor M2-PK (sensitivity 52%). The fuzzy classifier was able to detect a higher rate of progression in small-cell lung cancer patients compared with the multiple logistic regression analysis using the marker combination NSE/ProGRP/Tumor M2-PK (sensitivity 44%; AUC=0.76). With the fuzzy logic method and different tumor marker panels (NSE, ProGRP and Tumor M2-PK), a new diagnostic tool for the detection of progression in patients with small-cell lung cancer is available.

Objective: NEM® brand eggshell membrane is a novel dietary supplement ingredient that contains naturally occurring glycosaminoglycans and proteins essential for maintaining healthy joints. A six center, open label clinical study was conducted to evaluate the efficacy and safety of NEM® as a treatment for pain and inflexibility associated with osteoarthritis of the knee and/or hip in a European population. Methods: Forty-four subjects received oral NEM® 500 mg once daily for eight weeks. The primary outcome measure was to evaluate the mean effectiveness of NEM® in relieving general pain associated with moderate osteoarthritis of the knee and/or hip at 10,30 and 60 days utilizing a 10-question abbreviated questionnaire based on the WOMAC osteoarthritis questionnaire. Results: Supplementation with NEM® produced a significant treatment response from baseline at 10 days (Q1-6 and Q9) (8.6% to 18.1% improvement) and at 30 and 60 days for all nine pain-related questions evaluated (22.4% to 35.6% improvement) and at 30 and 60 days for stiffness (Q10)(27.4% to 29.3% improvement). In a Patient’s Global Assessment, greater than 59% of patients rated the efficacy of NEM® as good or very good following 60 days of supplementation. Physicians also rated the treatment effective in subjects, with greater than 75% having moderate or significant improvement from baseline after 60 days. There were no serious adverse events reported during the study and the treatment was reported to be well tolerated. Conclusions: Supplementation with NEM® significantly reduced pain, both rapidly (10 days) and continuously (60 days) demonstrating that it is a safe and effective therapeutic option for the treatment of pain associated with osteoarthritis of the knee and/or hip. Results from previous clinical studies on NEM® can likely be extended to the broader European population.

The diagnosis of lung cancer and early knowledge of its histological type are very important; however, this is still a difficult subject for the physician. The aim of this study was to improve the diagnostic efficiency of tumour markers in the diagnosis of bronchial carcinoma by mathematical evaluation of a tumour marker profile employing fuzzy logic modeling. A panel of five tumour markers, including CYFRA 21-1, CEA, NSE, and five additional parameters was determined in 281 patients with confirmed primary diagnosis of bronchial carcinoma of different histology and stage. A further 131 persons, who had acute and chronic benign lung diseases, served as a control group. A classificator was developed using a fuzzy-logic rule-based system. The diagnostic value of the combined tumour markers was significantly better than that of the individual markers and of a combination of CYFRA 21-1, CEA, and NSE. The discrimination of malignant vs benign diseases was realized with a sensitivity of 87.5% and specificity of 85.5%. The rate of correct classification of small-cell vs non-small-cell lung carcinoma was 90.6% and 91.1%, respectively; for squamous cell carcinoma vs adenocarcinoma it was 76.8% and 78.8%, respectively. Our detailed analysis has shown that the fuzzy logic system improves diagnostic accuracy up to a rate of 20%, especially in early stages and in patients with all marker levels in the grey area. Our concept proved to be more powerful than measurement of single markers or the combination of CEA, CYFRA 21-1, and NSE. Its use may help in distinguishing between malignant and benign disease and make it possible to define different subgroups of patients earlier in the course of their disease.

436 Background: Emerging evidence, that 177Lu-DOTATOC has a particularly favorable therapeutic index compared to other PRRT agents, prompted us to further evaluate efficacy and safety of 177Lu-DOTATOC. Methods: 56 patients with metastasized and progressive neuroendocrine tumors (NET) (50% gastroenteral, 26.8% pancreatic, 23.2% other primaries) were consecutively treated with 177Lu-DOTATOC and analyzed retrospectively. Patients received on average 2.1 (range 1 – 4) cycles of 177Lu-DOTATOC as 7.0 GBq (median) doses at 3-monthly intervals. Efficacy was analyzed based on RECIST and stratified for number of treatment cycles and primary tumor origin. Results: Median progression-free (PFS) and overall survival in the total population (A) were 17.4 and 34.2 months, respectively. Patients treated with > 1 cycle had a PFS of 32.0 months for all NET (B), 34.5 months for gastroenteropancreatic NET (GEP-NET) (C), and 11.9 months for other NET (D). Objective response (OR) rates [complete (CR) or partial (PR)], were 34%, 41%, 54%, and 0% for A, B, C, and D, while disease control [CR, PR and stable disease, SD] rates (DCR) were 66%, 94%, 100%, and 75%, resp. CR was found in 16%, 19% and 25% of A, B and C, resp. In 68% of responders initial response occurred within 4 months from the 1st cycle, whereas in 32% this took 4-8 months. In 47% of all OR it took > 8 months to achieve OR. No renal toxicity was found, although 20% of patients had mild renal insufficiency at baseline. No SAE and only a single case of self-limiting grade 3 myelotoxicity was observed. Conclusions: 177Lu-DOTATOC shows unparalleled potential to induce OR and long lasting DC in progressive NET, even when administered at moderate activity doses. In GEP-NET patients CR was 25%, which is the highest value ever reported. Efficacy was highest when the agent was administered in repetitive cycles. Overall DCR was 94%, compared to 80-85% reported for 177Lu-DOTATATE. This difference in DCR is mainly accounted for by an approx. 10-fold higher rate of CR with 177Lu-DOTATOC. This high efficacy together with the observed safety profile suggests a very high therapeutic index, reflecting a uniquely low systemic uptake of 177Lu-DOTATOC.

Objective To investigate the determinants of urinary stone formation in patients with fat malabsorption, because, although the prevalence of urolithiasis is greater in patients with intestinal diseases, the pathogenetic mechanisms and risk factors associated with urolithiasis in this population remain partially unsolved. Materials and Methods The present study retrospectively analyzed the determinants of urolithiasis in 51 patients with fat malabsorption due to different intestinal diseases. Anthropometric, clinical, blood, 24-hour urinary parameters, and dietary intake were assessed. Results The resection rate (ie, pancreatic and/or bowel resection) differed significantly between stone formers (SF; n = 10) and nonstone formers (NSF; n = 41; 70% vs 29%; P = .027). Urinary citrate was lower (1.606 ± 1.824 vs 3.156 ± 1.968 mmol/24 h; P = .027), while oxalate excretion (0.659 ± 0.292 vs 0.378 ± 0.168 mmol/24 h; P = .002) and the relative supersaturation of calcium oxalate were greater in SF than NSF (8.16 ± 4.61 vs 3.94 ± 2.93; P = .003). Total cholesterol and low-density lipoprotein cholesterol, but also high-density lipoprotein cholesterol, plasma β-carotene, and vitamin E concentrations, were significantly diminished, whereas serum aspartate aminotransferase activity was significantly greater in SF compared with NSF. Binary logistic regression analysis revealed resection status as a major extrarenal risk factor for stone formation (odds ratio 5.639). Conclusion Increased urinary oxalate and decreased citrate excretion, probably resulting from pancreatic and/or bowel resection with mainly preserved colon, were identified as the most crucial urinary risk factors for stone formation in patients with fat malabsorption. The findings suggest that hyperoxaluria predominantly results from increased colonic permeability for oxalate due to disturbed bile acid metabolism. The impaired status of fat-soluble antioxidants β-carotene and vitamin E indicates severe malabsorptive states associated with an enhanced stone-forming propensity.

Nutrition & metabolism 8, 21 (2011). doi:10.1186/1743-7075-8-21, Published by Biomed Central, London

The diagnosis of non-small cell lung cancer (NSCLC) by using tumour markers needs to be improved and standardised in order to compare marker profiles from different centres. A centre-independent tool based on receiver operating characteristics (ROC) curves instead of cut-off-based approaches for NSCLC diagnosis was established. Carcinoembryonic antigen (CEA) and cytokeratin-19 fragments (CYFRA 21-1) were measured in 326 NSCLC patients and 160 patients with benign lung diseases (Heidelberg, HD) and compared to 158 NSCLC patients and 128 controls from an occupational medicine high-risk cohort (Giessen, GI). The cohorts differed in tumour-stages, marker cut-offs and therefore in sensitivity for NSCLC detection. Sensitivity for CYFRA 21-1 (most sensitive marker) was 65% GI, 35% HD, for CEA: 43% GI and 35% HD. Marker-combination increased sensitivity to 53% HD resp. 73% GI, accompanied by decreasing specificity. A transfer of the cut-off-based classification methods from HD to GI and vice versa led to false classifications. Sensitivity and specificity do not change using classification methods on transformed data such as the described decision guarantee. CEA/CYFRA-combination allows a classification method transferable despite structural differences of the cohorts. Only 0.8% of the datasets showed discordance in classification. The diagnosis of NSCLC based on ROC curves eliminate centre-specific differences. Classification methods lead to an improvement in NSCLC diagnosis.

We developed a public Internet program called SimChip (www.simchip.de). It performs virtual "in silico experiments", which reflect the in vivo situation of gene expression. Our computer model simulates up- and downregulation of genes on the basis of differential equations for linear synthesis and non-linear decay of mRNA. Steady-state concentrations are described as ratios of the respective rate constants: c = S/D. Using physiological synthesis rates of 0 to 50 mRNA molecules per min per cell and decay rates of 0.05 to 25% per min, SimChip helps to understand the right-skewed distribution patterns of gene expression levels and calculates the experimental endpoint of the theoretically infinite time needed to achieve perfect equilibrium.

The analysis of tumour markers is based on the evaluation of data in relation to defined cut-off values. Changes in the method of determination or reference study group have led to different results. Cut-off-independent diagnostic evaluation of laboratory parameters can avoid laboratory-based and method-derived systematic errors. The decision guarantee (DG) is an appropriate parameter that can be determined using a defined reference population and its respective receiver operating characteristic (ROC) curve. The influence of ROC differences on the determination of DG is examined.A group of 281 consecutive patients with newly diagnosed, histologically confirmed lung cancer and a control group of 231 patients were examined. Histological classification of the tumour cases defined in 59 small-cell carcinoma, 102 squamous cell carcinomas, 66 adenocarcinomas and 54 large-cell carcinomas or mixed bronchial carcinomas without classification. The control group without tumours consisted of 23 healthy subjects, 125 patients with silicosis or asbestosis, 27 with chronic obstructive pulmonary diseases (COPD) and 56 suffering from inflammatory lung diseases.Cytokeratin-19 fragments (CYFRA 21-1) was the most sensitive marker with a sensitivity of 57.3% and a specificity of 94.9%. Sensitivity and specificity influence each other. Related to the ROC curve, the method described here ensured the diagnosis of lung cancer on the basis of the data collected in comparison with a reference population. Thus, it was possible to determine with statistical certainty whether the evaluation of the sample data would lead to a diagnosis of lung cancer.The DG provides the basis for a laboratory-and method-independent support for a diagnosis including fairer information about the reference population in the data analysis.

The aim of this study was to evaluate the diagnostic power of a fuzzy classifier and a marker panel (CYFRA 21-1, NSE, CRP) for the detection of lung cancers in comparison to asbestosis patients at high-risk of developing lung cancer.A panel of four tumour markers, i.e. CEA, CYFRA 21-1, NSE, SCC and CRP, was measured in newly diagnosed lung cancer patients of different histological types and stages in comparison to asbestosis patients. In this prospective study, a fuzzy classifier was generated with the data of 216 primary lung cancer patients and 76 patients suffering from asbestosis. The patients and controls were recruited in the clinics of the University in Giessen.At 95%-specificity, it was possible with this tool to detect non-small cell lung cancers in 70% at stage I (n = 30), in 95% at stage II (n = 22), in 98% at stage III (n = 56), in 92% at stage IV (n = 50) and small cell lung cancers with limited disease status (n = 21) in 90.7% and with extensive disease status (n = 37) in 97.3%. In contrast, single markers had a detection rate significantly far below these. The application of the classifier was examined on an independent collective of 38 non-small cell lung cancers and 76 asbestosis patients. The latter underwent stationary rehabilitation in the clinics for occupational diseases in Bad Reichenhall or Falkenstein. The fuzzy classifier showed correct negative classification in 75 out of the 76 cancer-free asbestosis patients, which confirmed a specificity of 97.4%. The overall sensitivity for lung cancer detection in high risk populations was 73.6%. All large cell carcinomas were detected. The positive predictive value was 77.7%. The negative predictive value reached 94.8%.With the fuzzy classifier and a marker panel, a reliable diagnostic tool for the detection of lung cancers in a high risk population is available.

The analysis of tumour markers is based on the evaluation of data in relation to defined cut-off values. Changes in the method of determination or reference study group have led to different results. Generally, fuzzy logic-based classifiers for the evaluation of tumour-marker profiles have increased sensitivity and higher specificity. Drawing from experiences with cut-off-oriented evaluation, the suggestion that diagnosis be made using a non-cut-off-based approach is discussed.Two hundred and eighty-one consecutive patients with newly diagnosed, histologically confirmed lung cancer and a control group of 231 patients were examined. Histological classification of the tumour cases yielded 59 small cell carcinomas, 102 squamous cell carcinomas, 66 adenocarcinomas and 54 large cell carcinomas or mixed bronchial carcinomas without classification. The control group without tumours consisted of 23 healthy subjects, 125 patients with silicosis or asbestosis, 27 patients with chronic obstructive pulmonary diseases (COPD) and 56 persons suffered from inflammatory lung diseases.CYFRA 21-1 was the most sensitive marker with a sensitivity of 57.3% and a specificity of 94.9%. The sensitivity increased when various tumour markers were evaluated. The loss of specificity through this type of multiparametric analysis could be compensated for by using a multiparametric evaluation such as a fuzzy logic classifier. A determination of the sensitivity-adapted confidence in diagnosis should be made. The decision guarantee and the cut-off-based evaluation are qualitatively equal because the decision threshold of 0.5 corresponds by definition to the cut-off value at 95% specificity. Every cut-off-based system of classification could be restated by using the decision guarantee instead of the measured values.The evaluation based on decision guarantee has proven to be unaffected by changes in laboratory systems. The multiparametric system of classification based on decision guarantee of individual markers is self-adjusting and differences in measurement levels are eliminated if the ROC curves of the individual markers are in agreement.

The aim of this study was to improve diagnostic efficiency in the detection of gastro-intestinal cancers by using fuzzy logic modeling in combination with a tumor marker panel (CEA, CA72-4, CA19-9) including Tumor M2-PK. In this prospective study histologically confirmed colorectal (n=247), esophageal (n=86) and gastric cancer (n=122) patients were investigated and compared to control (n=53) persons without any malignant diseases. Tumor M2-PK was measured in plasma with an ELISA (ScheBoBiotech, Germany); all other markers were measured in sera (Roche, Germany). At 95% specificity, tumor detection was possible by the best single marker in colorectal cancer patients in 48% (Tumor M2-PK), in gastric cancers in 61% (CA72-4) and in esophageal cancers in 56% (Tumor M2-PK). A fuzzy logic rule-based system employing a tumor marker panel increased sensitivity significantly in colorectal cancers (p0. 001) to 63% (Tumor M2-PK and CEA), in gastric cancers (p0.001) to 81% (Tumor M2-PK and CA 72-4) and in esophageal cancers (p0.02) to 74% (Tumor M2-PK and CA72-4). Adding a third marker further improved the sensitivity only marginally. Fuzzy logic analysis has proven to be more powerful than measurement of single markers alone or combinations using multiple logistic regression analysis of the markers. Therefore, with the fuzzy logic method and a tumor marker panel (including Tumor M2-PK), a new diagnostic tool for the detection of gastro-intestinal cancers is available.

In lung cancer patients tumor markers are used for disease monitoring. The goal of this study was to improve diagnostic efficiency in the detection of tumor progression in lung cancer patients by using fuzzy logic modeling in combination with a tumor marker panel (Tumor M2-PK, CYFRA 21-1, CEA, NSE and SCC). Thirty-three small cell lung cancers (SCLC) and 69 consecutive inoperable patients (40 squamous and 29 adenocarcinomas) were included in a prospective study. The changes of blood levels of tumor markers as well as their analysis by fuzzy logic modelling were compared to the clinical evaluation of response vs. non-response to therapy. Clinical monitoring was evaluated according to the standard criteria of the WHO. Tumor M2-PK was measured in plasma with an ELISA (ScheBo Biotech, Germany) and all other markers in sera (Roche, Germany). At a 90% specificity, the respective best single marker found the following fraction of all patients who had tumor progression clinically detected: in SCLC with NSE 52%, in adenocarcinoma with CYFRA 21-1 89% and in squamous carcinoma with SCC 65%. A fuzzy logic rule-based system employing a tumor marker panel increased the sensitivity in small cell carcinomas to 73% with the marker combination NSE/CEA and to 63% with the marker combination NSE/Tumor M2-PK, respectively. In squamous carcinomas an improvement of sensitivity is also observed using the marker combination of SCC/Tumor M2-PK (Sensitivity: 81%) or SCC/CEA (Sensitivity: 71%). By using the fuzzy logic method and the marker combination CYFRA 21-1/CEA as well as CYFRA 21-1/Tumor M2-PK, the detection of lung cancer progression was possible in all adenocarcinomas. With the fuzzy logic method and a tumor marker panel (including the new marker Tumor M2-PK), a useful diagnostic tool for the detection of progression in lung cancer patients is available.

Background A recent study on postoperative effusions and edema was used to demonstrate the potential of fuzzy techniques in multiparameter data analysis. In this study, more than 50 parameters of 75 patients were collected and examined for correlations between some of the parameters and the later development of complications. Methods We employed a rule-based fuzzy-logic system in order to combine the diagnostic values of single parameters. The advantage of fuzzy sets is that they substitute sharp cut-off values with a smooth transition from one property to another. Therefore, there is no decision of “either–or” but rather a graded assessment of “more or less”, which is often more suitable for a problem. Results The fuzzy combination of parameters led to a large increase of sensitivity and specificity when compared with the best single parameter. This increase was achieved by taking a close look at the parameters. A newly created parameter, relative weight, turned out to be very powerful. Conclusions Fuzzy techniques can increase the discriminating power of classical statistical tools. In addition, results obtained by fuzzy analysis are highly interpretable. A combination of the CLASSIF1 algorithm for the identification of the most relevant parameters, followed by fuzzy analysis, represents a powerful tool for the handling of large amounts of multiparameter data. Cytometry Part B (Clin. Cytometry) 53B:75–77, 2003. © 2003 Wiley-Liss, Inc.