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.

[Publication performances of university clinics for anesthesiology: Germany, Austria and Switzerland from 2001 to 2010]. / Publikationsleistungen der Universitätskliniken für Anästhesiologie: Deutschland, Österreich und Schweiz von 2001-2010.

AIM: This study assessed the publication performance of university departments of anesthesiology in Austria, Germany and Switzerland. The number of publications, original articles, impact factors and citations were evaluated. MATERIAL AND METHODS: A search was performed in PubMed to identify publications related to anesthesiology from 2001 to 2010. All articles from anesthesiology journals listed in the fields of anesthesia/pain therapy, critical care and emergency medicine by the "journal citation report 2013" in Thomson Reuters ISI web of knowledge were included. Articles from non-anaesthesiology journals, where the stem of the word anesthesia (anes*, anaes*, anäst*, anast*) appears in the affiliation field of PubMed, were included as well. The time periods 2001-2005 and 2006-2010 were compared. Articles were allocated to university departments in Austria, Germany and Switzerland via the affiliation field. RESULTS: A total of 45 university departments in Austria, Germany and Switzerland and 125,979 publications from 2,863 journals (65 anesthesiology journals, 2,798 non-anesthesiology journals) were analyzed. Of the publications 23 % could not be allocated to a given university department of anesthesiology. In the observation period the university department of anesthesiology in Berlin achieved most publications (n = 479) and impact points (1,384), whereas Vienna accumulated most original articles (n = 156). Austria had the most publications per million inhabitants in 2006-2010 (n=50) followed by Switzerland (n=49) and Germany (n=35). The number of publications during the observation period decreased in Germany (0.5 %), Austria (7 %) and Switzerland (8 %). Tables 2 and 4-8 of this article are available at Springer Link under Supplemental. CONCLUSIONS: The research performance varied among the university departments of anesthesiology in Germany, Austria and Switzerland whereby larger university departments, such as Berlin or Vienna published most. Publication output in Germany, Austria and Switzerland has decreased. Data processing in PubMed should be improved.

Delay in the administration of appropriate antimicrobial therapy in Staphylococcus aureus bloodstream infection: a prospective multicenter hospital-based cohort study.

OBJECTIVES: Early broad-spectrum antimicrobial treatment reduces mortality in patients with septic shock. In a multicenter, prospective observational study, we explored whether delayed appropriate antimicrobial therapy (AAT) influences outcome in Staphylococcus aureus bloodstream infection (SAB). METHODS: Two hundred and fifty-six patients with SAB from ten German study centers were enrolled and followed for 3 months. Predisposing factors, clinical features, diagnostic procedures, antimicrobial therapy, and outcome were recorded. The appropriateness of antimicrobial therapy was judged by a trained physician based on in vitro activity, dosage, and duration of therapy. Therapy was considered to be delayed when more than 24 h elapsed between the first positive blood culture and the start of appropriate therapy. The association of delayed therapy with overall mortality and SAB-related events (i.e., attributable mortality or late SAB-related complications) was assessed by crosstabulation and propensity score-based logistic regression. RESULTS: One hundred and sixty-eight patients received AAT during their hospital stay, of whom 42 (25%) received delayed AAT. The overall mortality and the occurrence of severe sepsis or septic shock were lower in patients with delayed AAT, pointing towards confounding by indication. Adjusted 90-day mortality (adjusted odds ratio [OR] 0.91, 95% confidence interval [CI] [0.39-2.13], p 0.82) and SAB-related events (adjusted OR 1.46, 95% CI [0.47-4.51], p 0.52) also failed to show a significant impact of delayed AAT on outcome. CONCLUSION: In patients with SAB, early AAT may not improve survival. However, confounding by indication is a major challenge when analyzing and interpreting observational studies on the impact of delayed AAT.

Position sensitive measurement of trace lithium in the brain with NIK (neutron-induced coincidence method) in suicide.

Mood disorder is the leading intrinsic risk factor for suicidal ideation. Questioning any potency of mood-stabilizers, the monovalent cation lithium still holds the throne in medical psychiatric treatment. Furthermore, lithium`s anti-aggressive and suicide-preventive capacity in clinical practice is well established. But little is still known about trace lithium distribution and any associated metabolic effects in the human body. We applied a new technique (neutron-induced coincidence method "NIK") utilizing the 6Li(n,α)3H reaction for the position sensitive, 3D spatially resolved detection of lithium traces in post-mortem human brain tissue in suicide versus control. NIK allowed, for the first time in lithium research, to collect a three dimensional high resolution map of the regional trace lithium content in the non lithium-medicated human brain. The results show an anisotropic distribution of lithium, thus indicating a homeostatic regulation under physiological conditions as a remarkable link to essentiality. In contrast to suicide we could empirically prove significantly higher endogenous lithium concentrations in white compared to gray matter as a general trend in non-suicidal individuals and lower lithium concentrations in emotion-modulating regions in suicide.

Genotypic interaction and gender specificity of common genetic variants in the p53/mdm2 network in Crohn's disease.

BACKGROUND/AIMS: Defective p53-mediated apoptosis and cell cycle control have been implicated in the immunopathogenesis of Crohn's disease (CD). Since common functional variants of p53 (SNP72 G/C) and its key negative regulator mdm2 (SNP309 T/G) have been reported to affect cellular apoptotic and cell cycle arrest capacities, we assessed the effects of these variants on CD susceptibility and their relationship to NOD2/CARD15 as a well-established genetic CD risk factor. METHODS: The variants SNP72 G/C and SNP309 T/G were genotyped in 149 European CD patients and 478 healthy controls. Subgroup analysis was performed in relation to NOD2/CARD15 status and to demographic/clinical characteristics. RESULTS: The p53 SNP72 CC genotype tended to be less frequent in CD. This reached statistical significance only in the male cohort (0 vs. 7.3%; p = 0.037). Genotype and allele frequencies of both single-nucleotide polymorphisms (SNPs) were otherwise not significantly different. In the combined genotypic analysis, the genotype p53 SNP72 CC was significantly underrepresented in mdm2 SNP309 TT homozygotes (0 vs. 9.7%; p = 0.034). No association was observed between NOD2/CARD15 and the respective SNPs. CONCLUSION: We report on a gender-specific protective effect of the low-apoptotic SNP72 CC genotype, and a gender-unrestricted genotypic interaction between SNP309 TT and SNP72 CC, which, for the first time, links sequence variation of the p53/mdm2 network to CD, independent of NOD2/CARD15.

Synthesis of controlled-size silver nanoparticles for the administration of methotrexate drug and its activity in colon and lung cancer cells.

A controlled synthesis of methotrexate (MTX) silver nanoparticles (AgNPs-MTX) using borohydride and citrate as reduction and reduction/capping agents, respectively, was performed in order to obtain AgNPs-MTX conjugates with a narrow size distribution. Their characterization showed polydispersed spherical shape nanoparticles with a mean size around 13 nm and distribution range between 7-21 nm. The presence of MTX was confirmed by FTIR and EDX analysis. Spectroscopic determinations suggest the chemisorption of MTX through a carboxylic group (-COOH) onto AgNPs via the exchange with a citrate molecule. Drug loading capacities calculated for AgNPs synthesized using different amounts of MTX were 28, 31 and 40%. In vitro drug release tests depicted similar release profiles for all conjugated amounts releasing between 77 to 85% of the initial MTX loaded into the AgNPs. With respect to free MTX, the addition of the nanocarrier delayed its release and also changed its pharmacokinetics. Free MTX is released after 3 hours following a first order kinetic model, whereas in the presence of AgNPs, a fast initial release is observed during the first 5 hours, followed by a plateau after 24 hours. In this case, AgNPs-MTX fitted a Higuchi model, where its solubilization is controlled by a diffusion process. Results obtained from flow cytometry of different cell lines treated with AgNPs-MTX demonstrated the combined anticancer effect of both reagents, decreasing the percentage of living cells in a colon cancer cell line (HTC-116) down to 40% after 48 hours of exposure. This effect was weaker but still significant for a lung cancer cell line (A-549). Finally, a zebrafish assay with AgNPs-MTX did not show any significant cytotoxic effect, confirming thereby the reduction of systemic drug toxicity achieved by coupling MTX to AgNPs. This observed toxicity reduction in the zebrafish model implies also a probable improvement of the usage of AgNPs-MTX in chemotherapy against human cancers.

Densitometric regional ejection fraction: a new three-dimensional index of regional left ventricular function--comparison with geometric methods.

Densitometric regional ejection fraction obtained by computer analysis of digital subtraction ventriculography was evaluated as a new, quantitative, three-dimensional index of regional left ventricular performance. Eighteen patients with coronary artery disease and seven control subjects had right anterior oblique ventriculography at rest and immediately after rapid atrial pacing using central venous injection of contrast material. Regional left ventricular ejection fraction was determined by densitometry in six segments drawn around the end-diastolic center of gravity, and compared with two conventional indexes of segmental wall motion: area and radial regional ejection fraction. Densitometric, area or radial regional ejection fraction was classified as abnormal if it fell at least 2 standard deviations below the corresponding mean value in the normal group. The densitometric method did not require outlining of the end-systolic left ventricular silhouette and was the easiest and fastest to perform of all three techniques. In addition, intra- and interobserver reproducibilities were higher with the densitometric method (r = 0.97 and 0.95) than with either the area (r = 0.84 and 0.82) or the radial method (r = 0.82 and 0.76). Regional left ventricular dysfunction as assessed by the densitometric, area and radial techniques allowed the detection of coronary artery disease in 50, 50 and 44% of the patients at rest and in 83, 67 and 61% of the patients in the post-pacing period, respectively. Post-pacing regional left ventricular dysfunction accurately predicted the presence or absence of greater than 70% diameter stenosis in the supplying coronary artery in 75, 67 and 56% of the cases, respectively. Thus, densitometric analysis of digital subtraction ventriculography allows a fast and reproducible three-dimensional determination of regional left ventricular ejection fraction. Using this technique, pacing-induced regional dysfunction can be detected in most patients with coronary artery disease and corresponds well with the location of significant coronary artery lesions.

Application of end-systolic pressure-volume and pressure-wall thickness relations in conscious dogs.

The usefulness of end-systolic measures of ventricular function was compared with that of standard contractility indexes in conscious dogs. End-systolic relations between left ventricular pressure and volume and between pressure and wall thickness were analyzed in dogs previously instrumented with ultrasonic crystals. Progressive angiotensin infusions were used to generate computer-averaged pressure-volume and pressure-wall thickness loops. Both relations were linear in every study and highly reproducible. With low and high dose dobutamine, the end-systolic pressure-volume relations were significantly displaced, with increased slope and inconsistent changes in intercept. This relation was more useful than the ejection fraction for detecting contractility increases at different afterloads, but it showed no advantage over maximal left ventricular dP/dt at all ranges of preload and afterload. The end-systolic pressure-volume relations were insensitive for detecting mild decreases in inotropic state produced by propranolol, and maximal dP/dt was superior for detecting such mild acutely reduced contractility. The end-systolic pressure-wall thickness relations showed displacement with dobutamine, although slope and intercept changes were not significant; these relations did not detect mild decreases in contractility produced by propranolol. It is concluded that the end-systolic pressure-volume relation and a simplified end-systolic measure using pressure and wall thickness provide sensitive, load-independent and reproducible approaches for defining acute increases in left ventricular contractility in conscious animals. Maximal dP/dt was equally effective for defining these increases in contractility and more sensitive for detecting slight acute decreases in contractility.

Quantitative assessment of segmental wall motion abnormalities at rest and after atrial pacing using digital intravenous ventriculography.

Digital intravenous ventriculography lends itself readily to quantitative assessment of ventricular wall motion with computer algorithms. Forty-five patients referred for cardiac catheterization were studied by digital intravenous ventriculography (mask mode) and direct ventriculography in the 30 degrees right anterior oblique position. Quantitative wall motion was analyzed by a radial shortening method applied to both studies. Lower limits of normal radial shortening were determined for each technique and used to determine the presence or absence of wall motion disorders. The inter- and intraobserver variability of radial shortening measurements was +/- 5.3 and +/- 8.8%, respectively, with maximal discrepancies of -6 and +7% fractional shortening units. The overall agreement between the two techniques in wall motion assessment was 87% (274 of 315 radii). A subset of patients also underwent atrial pacing, and a second digital intravenous ventriculogram was obtained (5 normal subjects and 15 patients with coronary artery disease). Although analysis of wall motion at rest showed a poor sensitivity for detection of significant coronary stenoses, nine of nine patients with coronary artery disease and normal wall motion at rest showed a quantitative decrease in radial wall motion after atrial pacing. Thus, digital intravenous ventriculograms can be used to provide quantitative wall motion analyses that show a high degree of agreement with those of standard, direct left ventriculography. Atrial pacing can be used to increase the sensitivity of wall motion analysis for the detection of significant coronary disease.

Preoperative staging and early postoperative complications in radical prostatectomy. Experiences in 35 cases.

It is already a textbook item that in patients with prostatic cancer stage T1-T2 N0M0 radical prostatectomy is the only curative treatment. Radical prostatectomy is indicated also for patients in stage T3 N0M0 who underwent antiandrogenic (Fugerel) treatment for 3 months with the aim of reducing tumour volume. In the following 35 cases will be scrutinized, with special regard to preoperative staging and early postoperative complications.

[Causes, prevention and treatment of complications of lymphadenectomy in testicular tumor patients]. / Ursachen, Prävention und Behandlung von Komplikationen der Lymphadenektomie beim Hodentumorpatienten.

In our clinic 483 lymphnode dissections were performed during the last 17 years. Different complications were found under operation in 2.7% and postoperatively in 9.9%. The mortality rate was 0.8%. Three years ago we started a different technique for lymph node dissection. The lowest incidence of complications during this period was found in the modified unilateral resection technique (8.9%), far higher after the bilateral (radical) (24%), the second-look lymphadenectomy (33%) and the so-called "salvage-lymphadenectomy" (42.9%). Causes of complications, therapy and prevention are discussed.

Quantitative model for the electric response of invertebrate and vertebrate photoreceptors.

We propose that the same mechanism which leads to light-adaptation in invertebrate photoreceptors is responsible for the excitation of the receptor potential in vertebrates. Several qualitative and quantitative features of the vertebrate receptor response support this hypothesis.

[Sonography of the penis shaft]. / Sonographie des Penisschaftes.

The development of highly frequent transducers has created new diagnostic possibilities for the sonography in the area of the body of the penis. We controlled the valency of this technique on our patients. While the usual clinical and radiological methods still predominate in the diagnostics of traumas of the penis and diseases of the cavernous bodies, the ultrasound gives new possibilities of the exact classification in the carcinoma of the penis and the induratio penis plastica. Thus the basis for the development of alternative therapeutic methods is given.

Familial tumor of the testis.

A survey of the literature since 1928 yields reports on 100 patients with testicular tumor occurring in families. From our own case material we present clinical data on 11 additional patients. Non-twin brothers are most often involved. Presently available data are too limited to assess the impact of a possible genetic disposition on the development of malignoma of the testis. Additional case reports and register studies are needed. Equally undecided is the question if sperm banking of testicular tumor patients prior to therapy carries any genetic risk to the progeny.

[Regional myocardial perfusion in coronary stenosis of varying degrees]. / Perfusion myocardique régionale dans les sténoses coronaires de divers degrés.

Stenoses of the left anterior descending coronary artery of varying severity (15-73% of internal diameter, 20-95% of internal surface) were created in 25 open-chest pigs. The regional distribution of myocardial blood flow perfusion was studied by the radioactive microspheres technique at rest and during reactive hyperemia. Reactive hyperemic responses to 10 sec occlusions were used to produce maximal flow increases and to judge the physiological significance of the narrowings in the subendocardial and subepicardial layers in calculating coronary flow reserves. Measurements of coronary reserve are sensitive indices of functional impairment even when resting flow is unimpaired. At 75% stenosis the subendocardial coronary reserve is completely abolished and the zone perfused by the stenosed artery is unable to increase its flow when needed if the experimental conditions do not change. Any further increase in oxygen demand will provoke electrical and metabolic disorders. For abolition of the subepicardial coronary reserve a 94% stenosis is required.

Nosocomial urinary tract infections: etiology and prevention.

Nosocomial urinary tract infections arise mainly after transurethral diagnostic or therapeutic operations and are favored by the raised susceptibility of many hospitalized patients to infection. Besides strict establishment of the indication, attention must be paid above all to proper performance of the catheterization. Standardization disposable sets are helpful in this regard. Choice of the suitable catheter type depends on the requirements of the application, the duration of drainage and on the anatomical conditions. Use of a closed urine drainage system must be part of the clinical standard today as well as mastery of daily catheter hygiene. Under observation of the contraindications, advantage should be taken of suprapubic catheter drainage.

Decreased regional contractility in nonischemic myocardium during acute coronary artery occlusion in conscious pigs.

The purpose of this study was to use the relationship between end-systolic left ventricular pressure and segment length to assess the inotropic state of nonischemic myocardium during acute coronary artery occlusion in the conscious pig. Eight pigs were chronically instrumented with sonomicrometers to measure midwall segmental shortening and a micromanometer to measure left ventricular pressure. Occlusion of the inferior vena cava with a pneumatic occlusive cuff caused transient decreases in left ventricular pressure so that the relationship of left ventricular pressure and segment length at end systole could be determined over a range of pressures. In preliminary studies using open-chest pigs, this relation was shown to be highly linear and best quantified using a calculated segment length at a left ventricular pressure of 100 mm Hg (ESL100). During acute, 1-min occlusion of the left anterior descending coronary artery, the ESL100 of the nonischemic lateral and posterior walls was significantly increased from 8.75 +/- .18 mm to 9.64 +/- .21 mm (mean +/- SD, p less than .01), indicating a decreased inotropic state. Similarly, during occlusion of the left circumflex coronary artery, the ESL100 of the nonischemic anterior wall increased from 8.44 +/- 2.53 mm to 9.26 +/- 3.12 mm (p less than .05). This was not associated with a change in the amount of shortening during systole. Pharmacological autonomic blockade using atropine and propranolol failed to alter the response of nonischemic zones to acute coronary artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)