Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

[Influence of culture and religion on the treatment of cancer patients]. / Einfluss von Kultur und Religion auf die Therapie von Krebspatienten.

Religion, which is one of the most important sources of human identity, has so far hardly been taken into account in the clinic. In the largely secularized society of Germany, this has played a highly subordinate role. Currently, however, the development towards a multireligious society is emerging, which will also be reflected in everyday medical care. Disease and mortality in patients can affect different cultural-religious spheres. Although distinction between cultural and religious aspects is possible, it is not necessary for clinical practice. In the situation of oncological therapy, questions may arise which must be answered differently in the religions Christianity, Judaism and Islam and which should be taken into account when selecting therapy. The consideration of cultural-religious rules can intensify the patient's acceptance, but it can also impair it in case of disregard. Such peculiarities can be the separation into male and female spheres or the restriction of certain auxiliary substances or drugs (blood products, narcotics). Kübler-Ross's phase model is suitable for determining where cultural-religious sensitivities should be taken into account in the phases of disease and how cultural-religious offerings can benefit the course of therapy. Due to large individual, regional, cultural and confessional differences, no systematic catalogue of procedures can be provided here. However, knowledge of such differences, more sensitive interaction with patients and their families and cooperation with hospital pastors can strengthen the relationship of trust between doctor and patient and thus improve the conditions for successful oncological therapy. These aspects should not be underestimated when treating people of other faiths in Germany's secular society.

Concussion management application for amateur sports.

Concussion management has become one of the most popular topics in sports medicine. Significant resources are being invested in developing protocols for professional sport associations such as the NFL and FIFA. These protocols are often expensive and require substantial resources to implement. The problem, however, runs much deeper than just professional sports. Currently there exists little infrastructure to effectively manage concussion in amateur settings such as high school, club and university sport. A more holistic approach is required to ensure that the same standard of concussion management is being implemented across the board, regardless of the available medical and financial resources. An application was developed that will allow for easily accessible baseline testing and access to a player's concussion history from anywhere in the world. The application will be used to monitor players from the day they start playing sport until they potentially become professional sport players.

The clinical relevance of birch pollen profilin cross-reactivity in sensitized patients.

BACKGROUND: Overlapping seasons and cross-reactivity, especially to grass pollen profilin, can hamper the diagnosis of birch pollen allergy. To identify the primary sensitizing allergen and the clinical relevance of cross-sensitization, we correlated sensitization profiles with in vitro and in vivo tests, symptom scores, and pollen counts. METHODS: A total of 433 patients with positive skin prick test (SPT) to birch pollen were analyzed regarding IgE to major birch and grass pollen allergens Bet v 1 and Phl p 1/p 5 and the profilins Bet v 2 and Phl p 12. Subgroups were analyzed by basophil activation test (BAT) and CAP-FEIA-based cross- and self-inhibition tests. RESULTS: A total of 349 patients were sensitized to Bet v 1, 44 patients to both Bet v 1 and Bet v 2, and 15 patients to Bet v 2 only. From Bet v 2-sensitized patients, 40 were also sensitized to Phl p 12. Ex vivo, Bet v 2 and Phl p 12 induced dose-dependent activation in basophils of these patients. Cross- and self-inhibition tests with both allergens confirmed cross-reactivity. However, semiquantitative analysis of SPTs demonstrated markedly increased reactivity to grass compared to birch pollen extract in Bet v 2 only sensitized patients. Accordingly, in most of those patients, clinical symptoms precisely correlated with grass pollen counts. CONCLUSION: Identification of the clinically relevant and sensitizing allergen needs correlation of actual pollen counts with clinical symptoms and sensitization status to major allergens. Semiquantitative analysis of SPT or BAT and determining profilin-specific IgE can contribute to making the diagnosis.

Intermolecular binding of blueberry pectin-rich fractions and anthocyanin.

Pectin was extracted from blueberry powder into three fractions of water soluble (WSF), chelator soluble (CSF) and sodium carbonate soluble (NSF). The fractions were incubated with cyanidin-3-glucoside (C3G), a mixture of five anthocyanidins (cyanidin, pelargonidin, malvidin, petunidin and delphinidin) or blueberry juice at pH 2.0-4.5. Free anthocyanins and bound anthocyanin-pectin mixtures were separated by ultrafiltration. WSF bound the least amount of anthocyanin at all pH values. CSF had stronger anthocyanin binding ability at pH 2.0-3.6, while NSF had stronger anthocyanin binding ability at pH 3.6-4.5. The pectin and anthocyanin binding was lowest at pH 4.5 and higher at pH 2.0-3.6. Nearly doubling C3G pigment content increased bound anthocyanin percentage by 16-23% at pH 3.6, which favored anthocyanin aromatic stacking, compared to 3-9% increase at pH 2.0. Ionic interaction between anthocyanin flavylium cations and free pectic carboxyl groups, and anthocyanin stacking may be two major mechanisms for pectin and anthocyanin binding.

Investigation into selenium requirement of growing turkeys offered a diet supplemented with two levels of vitamin E.

To evaluate dietary selenium (Se) requirement in turkeys offered a diet supplemented with two levels of vitamin E (VE), 96 newly hatched male BIG 6 chicks (58.4 +/- 4.12 g) were divided into eight groups of 12 animals each and fed maize soya diets containing 0.05, 0.10, 0.20 and 0.30 mg Se/kg from sodium selenate in combination either with the natural VE content (approximately 10 IU/kg) or with a VE addition of 50 IU/kg. Animals from all the groups were highly performant and their final body weights (1746 +/- 190 g) after 35 days on experiment were not significantly different. According to its dietary supply, Se concentration in the liver and plasma increased dose dependently. Independent of dietary VE, the activities of GPx3 in plasma and of GPx1 in liver and breast muscle increased to a larger extent in turkeys supplemented with 0.10 and 0.20 mg Se/kg in relation to animals with low marginal Se supply (0.05 mg/kg). Supplementation of 0.30 mg Se/kg only slightly increased further selenoprotein activities. 2-Thiobarbituric acid reactive substances in the liver were strongly reduced by dietary VE, but not by Se. Plasma aspartate aminotransferase (AST) and creatine kinase (CK) activities did not show muscular lesions in none of the groups. Although there were no signs of muscular lesions even in turkeys with marginal Se and moderate VE supply, the activity of selenoproteins in various organs increased up to 0.30 mg Se/kg diet, independent of VE supply. It was concluded that for growing turkeys the Se supply should meet at least a level of 0.20 mg/kg diet as currently recommended by the National Research Council and Gesellschaft für Ernährungsphysiologie. Vitamin E addition confirmed the particular function of the vitamin as a lipid antioxidant and should be taken into consideration when diets with high PUFA concentrations are fed.

In-vivo measurements of coronary blood flow using 16-slice multidetector spiral computed tomography (MDCT) in a porcine model.

PURPOSE: To determine whether CTCA supplemented with CT flow measurements can be used to demonstrate and semiquantitatively evaluate poststenotic coronary blood flow in a porcine model. MATERIALS AND METHODS: In 10 thoracotomized pigs, transit time flow meter probes were attached to the aorta and left anterior descending artery (LAD) for real-time blood flow volumetry. A vascular silicone occluder was deployed around the LAD proximal to the probe to create medium-grade (MGS) and high-grade stenoses (HGS). The blood flow was measured by CT without vessel occlusion and distal to the stenoses. Time-density curves were generated from CT data. The curves were evaluated by calculating and cross-plotting the variables "slope of the density increase", "peak density" and "slope of the post-peak density decrease" from the LAD and aortic CT data. RESULTS: The flow in the LAD dropped to 41 % +/- 9 % (mean +/- SD) for MGS and 12 % +/- 6 % for HGS of the baseline. Coronary time-density curves plateaued proportional to luminal narrowing. Unimpaired flow could be differentiated statistically significant from poststenotic flow adjacent to MGS and HGS (p < 0.000 and p < 0.002, respectively). Flow adjacent to MGS and HGS was successfully differentiated for "slope of the density increase" and "slope of the post-peak density decrease" (p < 0.003 and p < 0.030, respectively). CONCLUSION: CT measurements allow semiquantitative evaluation of poststenotic coronary blood flow.

Selenium requirement of growing male turkeys.

1. The aim of the experiment was to estimate the selenium requirement of growing male turkeys using the selenium concentrations in different organs and blood plasma and by fitting a continuous broken line to the activity of glutathione peroxidase in liver and plasma. 2. Newly hatched male BUT BIG 6 turkeys were fed either on the selenium deficient basal soybean-maize diets (selenium <0.010 mg/kg diet) adapted to the NRC (1994) and GfE (2004) recommendations for growing turkeys from 0 to 2 weeks (prestarter diet) and 3 to 5 weeks (starter diet) or the basal diets supplemented with 0.10, 0.15, 0.20, 0.25, 0.30, 0.35 or 0.40 mg selenium/kg diet as sodium selenate. Vitamin E was supplemented adequately in all diets. 3. After 5 weeks the weight in all groups (mean 2568 g) exceeded the expectations for the genotype investigated. Feed consumption and weight gain were however significantly reduced in the group receiving the selenium-deficient diet. 4. After 2 and 5 weeks selenium concentration and activity of glutathione peroxidase in the plasma and the organs examined were greatly influenced by selenium supplementation. 5. Under the conditions investigated, 0.30 mg Se/kg diet was necessary for fast-growing male turkeys to ensure maximum selenium accumulation in the organs examined and maximum glutathione peroxidase activity in plasma and liver.

High-dose cytarabine and mitoxantrone in consolidation therapy for acute promyelocytic leukemia.

The objective of our study was to evaluate high-dose cytarabine in consolidation therapy in patients with newly diagnosed acute promyelocytic leukemia (APL). Patients (age 16-60 years) received induction therapy according to the AIDA protocol (all-trans retinoic acid, idarubicin) followed by one cycle of ICE (idarubicin, cytarabine, etoposide) and two cycles of HAM (cytarabine 3 g/m(2) q12h, days 1-3; mitoxantrone 10 mg/m(2), days 2 and 3). From 1995 to 2003, 82 patients were enrolled. In total, 72 patients (88%) achieved a complete remission, and 10 patients (12%) died from early/hypoplastic death (ED/HD). A total of 71 patients received at least one cycle of HAM. Relapse-free survival (RFS) and overall survival (OS) after 46 months were 83 and 82%, respectively. White blood cell count above 10.0 x 10(9)/l at diagnosis and additional chromosomal aberrations were unfavorable prognostic markers for OS, whereas no prognostic markers for RFS were identified including FLT3 mutations. In conclusion, high-dose cytarabine in consolidation therapy for patients with newly diagnosed APL is an effective treatment approach.

[Importance of timing of music therapy in chemotherapy of cancer patients]. / Musiktherapie bei der Chemotherapie von Krebserkrankungen: wann beginnen, wann einsetzen? Beeinflussung der Stresshormone durch Musiktherapie während der chemotherapeutischen Behandlung von Patientinnen mit radikal reseziertem Mammakarzinom.

Neither the measured stress-hormones, nor Beta-Endorphin have been influenced by music therapy. Music therapy should be initiated before the beginning of chemotherapy, preferably shortly after the operation. The greatest profit of an accompanying music therapy is between the chemotherapy courses, because the whole energy of the patient during chemotherapy is directed to questions, worries and practical aspects.

Solution-phase, parallel synthesis and pharmacological evaluation of acylguanidine derivatives as potential sodium channel blockers.

Solution-phase synthesis of various acylguanidine derivatives and the evaluation of a small library of compounds as potential sodium channel blockers are described.

Evaluation of a simple method for minimizing iatrogenic blood loss from discard volumes in critically ill newborns and children.

OBJECTIVE: To validate a simple method avoiding discard volumes in pediatric patients with indwelling arterial and venous lines. DESIGN: Zero-discarding was achieved by passive extracorporeal arteriovenous backflow via standard single pressure transducer equipment. We tested backflow distances (10, 20 and 30 cm beyond the sampling port), corresponding to withdrawal volumes of 0.6 ml, 0.8 ml and 1.0 ml, respectively, in comparison to conventional sampling with discard of 0.6 ml. With the backflow technique, the "withdrawal volume" was flushed back to the patient after sampling. We enrolled 120 patients who were allocated to either of the following paired sampling procedures: 10 cm versus conventional, 20 cm versus conventional, 30 cm versus conventional and two paired conventional samples. The order of the sampling was randomly allocated. Bias and precision were determined using Bland-Altman diagrams and algorithms. RESULTS: No appreciable difference was found for blood gases, hemoglobin, potassium and calcium between the backflow technique and conventional sampling. Sodium results and blood glucose showed a bias towards higher values with the backflow technique (mean difference, sodium, 0.9 mmol/l; glucose, mean difference 0.5 mmol/l, standard deviation 0.44 mmol/l). CONCLUSIONS: The backflow technique provides reliable results for blood gases and electrolytes. However, in patients at risk of hypoglycemia, the backflow method should not be used to monitor blood glucose levels.

The families of papain- and legumain-like cysteine proteinases from embryonic axes and cotyledons of Vicia seeds: developmental patterns, intracellular localization and functions in globulin proteolysis.

Families of papain- and legumain-like cysteine proteinases (CPR) were found in Vicia seeds. cDNAs and antibodies were used to follow organ specificity and the developmental course of CPR-specific mRNAs and polypeptides. Four papain-like cysteine proteinases (CPR1, CPR2, proteinase A and CPR4) from vetch seeds (Vicia sativa L.) were analysed. CPR2 and its mRNA were already found in dry embryonic axes. CPR1 was only detected there during early germination. Both CPR1 and CPR2 strongly increased later during germination. In cotyledons, both CPR1 and CPR2 were only observed one to two days later than in the axis. Proteinase A was not found in axes. In cotyledons it could only be detected several days after seeds had germinated. CPR4 mRNA and polypeptide were already present in embryonic axes and cotyledons during seed maturation and decreased in both organs during germination. Purified CPR1, CPR2 and proteinase A exhibited partially different patterns of globulin degradation products in vitro. Although the cDNA-deduced amino acid sequence of the precursor of proteinase A has an N-terminal signal peptide, the enzyme was not found in vacuoles whereas the other papain-like CPRs showed vacuolar localization. Four different legumain-like cysteine proteinases (VsPB2, proteinase B, VnPB1 and VnPB2) of Vicia species were analysed. Proteinase B and VnPB1 mRNAs were detected in cotyledons and seedling organs after seeds had germinated. Proteinase B degraded globulins isolated from mature vetch seeds in vitro. VsPB2 and proteinase B are localized to protein bodies of maturing seeds and seedlings, respectively, of V. sativa. Like VsPB2 from V sativa, also VnPB2 of V. narbonensis corresponds to vacuolar processing enzymes (betaVPE). Based on these results different functions in molecular maturation and mobilization of storage proteins could be attributed to the various members of the CPR families.

Induction of the stress response in vivo decreases nuclear factor-kappa B activity in jejunal mucosa of endotoxemic mice.

BACKGROUND: Results of previous studies suggest that the stress response protects cells and tissues by regulating proinflammatory mediators. The transcription factor nuclear factor-kappa B (NF-kappa B), normally sequestered in the cytoplasm by its inhibitory protein, I kappa B, regulates many genes involved in inflammatory responses to critical illness. Endotoxemia is associated with increased NF-kappa B activity in intestinal mucosa, but the effect of the stress response on endotoxin-induced NF-kappa B activation in intestinal mucosa is not known. HYPOTHESIS: Induction of the stress response inhibits NF-kappa B DNA binding activity in jejunal mucosa during endotoxemia. METHODS: The stress response was induced in mice by hyperthermia (42 degrees C) or injection with sodium arsenite (10 mg/kg). After 2 to 5 hours, mice were injected with endotoxin (lipopolysaccharide, 12.5 mg/kg) or a corresponding volume of sterile saline. One hour later, jejunal mucosa was harvested for preparation of nuclear and cytoplasmic extracts. RESULTS: Mucosal levels of heat shock protein-72 increased after hyperthermia or treatment with sodium arsenite, consistent with induction of the stress response. The increase in NF-kappa B DNA binding activity and decrease in I kappa B-alpha levels seen after endotoxin injection were inhibited by previous induction of the stress response. CONCLUSION: The protective effects of the stress response in vivo might, at least in part, be due to inhibited NF-kappa B activation.

Selective modulation of phosphatidylserine exposure on subpopulations of human peripheral blood lymphocytes by a plant lectin, Viscum album agglutinin (VAA)-I and its recombinant form (rVAA) in vitro.

Growing evidence suggests that lectin-carbohydrate interactions are involved in the regulation of the balance between cell growth and programmed cell death. Viscum album agglutinin (VAA)-I is a galactoside-specific, type II ribosome-inactivating plant lectin. At concentrations less than 10 ng/ml, VAA-I has been shown to induce gene expression and secretion of proinflammatory cytokines as well as apoptosis in cultures of human peripheral blood mononuclear cells (PBMC). This study analyzes the effects of VAA-I and its recombinant nonglycosylated form (rVAA) on alterations of cell membrane permeability of cultured human peripheral lymphocytes (PBL) and on membrane exposure of phosphatidylserine characteristic of apoptosis. Analyses were performed by flow cytometry after staining with propidium iodide (PI) and/or with FITC-Annexin V/PI. After 24 h incubation of PBMC with 100 ng/ml VAA-I and rVAA, staining with supravital concentration of PI (20 microg/ml) for 1 h revealed no differences in percentages of PI-positive cells induced by the two forms of lectin (32.3% and 29.4%), but the exposure to 5 microg/ml PI for 15 min resulted in a significant difference: 35.1% and 8.0% after VAA-I and rVAA treatment, respectively. Kinetic analysis of membrane alterations showed mainly Annexin V positivity after 24 h, whereas after 48 h and 72 h incubation with 100 ng/ml VAA-I or rVAA loss of membrane integrity occurred, as demonstrated by PI staining. Similar to VAA-I, rVAA showed a higher binding affinity for monocytes and granulocytes than for lymphocytes. In cultures of PBL, the binding rank order of both lectins to lymphocyte subsets was NK, CD19+ > CD8+ > CD4+. The amount of Annexin/PI staining of PBL subsets corresponds to the degree of their binding capacity. In conclusion, present results demonstrate that VAA-I and its nonglycosylated recombinant form rVAA exhibit comparable effects on cell membrane alterations in the subsets of human PBLs.

Parental attitude towards alternative medicine in the paediatric intensive care unit.

UNLABELLED: The interest in alternative medicine (AM) is growing. In the USA and Canada, studies showed that 34% of adults and 11% of children use AM. In a prospective cohort study, we investigated the interest in AM among parents of critically ill children in the paediatric Intensive Care Unit (ICU) of a university hospital. From January 1996 to April 1997, we distributed questionnaires to the parents of critically ill children. These strictly anonymous questionnaires were completed at home and returned by mail. Exclusion criteria were short ( < 1 day) or repeated hospitalizations, and insufficient proficiency of the German language. The inclusion criteria were fulfilled by 591 patients; 561 received the questionnaire (95%) and 289 (52%) were returned. Of the respondents, 70% would appreciate AM as a complementary therapy on the ICU, 23% found AM equally or more important than conventional medicine whereas only 7% regarded AM as unimportant. On the ICU, 18% used AM; surprisingly 41% of them did not discuss it with physicians or nurses. An additional 21% would have liked to use AM, but did not do so. Typically, AM-users administered AM also at home to their children and themselves. Their children were however, older. CONCLUSIONS: A substantial proportion of parents used measures of alternative medicine in the intensive care unit, or would have like to do so. However, few had the confidence to discuss this wish with the medical personal. This suggests that alternative medicine is of great interest, even on an intensive care unit. Nevertheless, discussion about alternative medicine seems to be taboo in doctor-patient relations.

High dietary iron enhances oxidative stress in liver but does not increase aberrant crypt foci development in rats with low vitamin E status.

The purpose of this study was to examine the effects of high-iron and low-vitamin E diets on lipid peroxidation and aberrant crypt foci (ACF) development in rats. In a 2 x 2 x 2 factorial design, male Sprague-Dawley rats were fed 45 or 450 mg Fe/kg diet (adequate and high iron, respectively) and 15 or 100 IU vitamin E/kg diet (low and adequate vitamin E, respectively) for three weeks, when they received saline or azoxymethane (15 mg/kg for 2 wk). Diets were continued for an additional six weeks. Serum alpha-tocopherol concentrations in rats fed low-vitamin E diets were decreased to 30% of concentrations observed in rats fed adequate-vitamin E diets (p < 0.0001). Also, serum alpha-tocopherol concentrations tended to be lower in rats supplemented with iron (p < 0.08). Lipid peroxidation in liver was significantly elevated by high-iron diets after 3 and 10 weeks of treatment, but lipid peroxidation in colonic mucosa was not altered by dietary iron or vitamin E. The total number of ACF and number of large ACF (> or = 4 aberrant crypts/focus) were not significantly altered by iron or vitamin E intakes. However, the size distribution of ACF was slightly altered, such that iron-supplemented rats had 12% more ACF with two crypts per focus (p < 0.02) than rats fed adequate-iron diets. Our data suggest that high-iron diets enhanced oxidative stress in liver, but not colon, of rats fed low-vitamin E diets. Furthermore, a high-iron diet does not increase the total number of ACF, even when vitamin E status is low.