Publications by authors named "Andreas Berger"

128 Publications

Insect Collections as an Untapped Source of Bioactive Compounds-Fireflies (Coleoptera: Lampyridae) and Cardiotonic Steroids as a Proof of Concept.

Insects 2021 Jul 31;12(8). Epub 2021 Jul 31.

Institute for Insect Biotechnology, Justus Liebig University Giessen, Heinrich-Buff-Ring 26-32, 35392 Giessen, Germany.

Natural history collections provide an invaluable basis for systematics, ecology, and conservation. Besides being an important source of DNA, museum specimens may also contain a plethora of natural products. Especially, dried insect collections represent a global repository with billions of inventoried vouchers. Due to their vast diversity, insects possess a great variety of defensive compounds, which they either produce autogenously or derive from the environment. Here, we present a case study on fireflies (Coleoptera: Lampyridae), which produce bufadienolides as a defense against predators. These toxins belong to the cardiotonic steroids, which are used for the treatment of cardiac diseases and specifically inhibit the animal enzyme Na/K-ATPase. Bufadienolides have been reported from only seven out of approximately 2000 described firefly species. Using a non-destructive approach, we screened 72 dry coleopteran specimens for bufadienolides using HPLC-DAD and HPLC-MS. We found bufadienolides including five novel compounds in 21 species of the subfamily Lampyrinae. The absence of bufadienolides in the phylogenetically related net-winged beetles (Lycidae) and the lampyrid subfamilies Luciolinae and Lamprohizinae indicates a phylogenetic pattern of bufadienolide synthesis. Our results emphasize the value of natural history collections as an archive of chemical information for ecological and evolutionary basic research and as an untapped source for novel bioactive compounds.
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http://dx.doi.org/10.3390/insects12080689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396437PMC
July 2021

Dissecting Metabolism of Leaf Nodules in and .

Front Mol Biosci 2021 30;8:683671. Epub 2021 Jul 30.

Molecular Systems Biology (MOSYS), Department of Functional and Evolutionary Ecology, University of Vienna, Vienna, Austria.

Root-microbe interaction and its specialized root nodule structures and functions are well studied. In contrast, leaf nodules harboring microbial endophytes in special glandular leaf structures have only recently gained increased interest as plant-microbe phyllosphere interactions. Here, we applied a comprehensive metabolomics platform in combination with natural product isolation and characterization to dissect leaf and leaf nodule metabolism and functions in (Primulaceae) and (Rubiaceae). The results indicate that abiotic stress resilience plays an important part within the leaf nodule symbiosis of both species. Both species showed metabolic signatures of enhanced nitrogen assimilation/dissimilation pattern and increased polyamine levels in nodules compared to leaf lamina tissue potentially involved in senescence processes and photosynthesis. Multiple links to cytokinin and REDOX-active pathways were found. Our results further demonstrate that secondary metabolite production by endophytes is a key feature of this symbiotic system. Multiple anhydromuropeptides (AhMP) and their derivatives were identified as highly characteristic biomarkers for nodulation within both species. A novel epicatechin derivative was structurally elucidated with NMR and shown to be enriched within the leaf nodules of . This enrichment within nodulated tissues was also observed for catechin and other flavonoids indicating that flavonoid metabolism may play an important role for leaf nodule symbiosis of In contrast, pavettamine was only detected in and showed no nodule specific enrichment but a developmental effect. Further natural products were detected, including three putative unknown depsipeptide structures in leaf nodules. The analysis presents a first metabolomics reference data set for the intimate interaction of microbes and plants in leaf nodules, reveals novel metabolic processes of plant-microbe interaction as well as the potential of natural product discovery in these systems.
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http://dx.doi.org/10.3389/fmolb.2021.683671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8362603PMC
July 2021

Nintedanib plus mFOLFOX6 as second-line treatment of metastatic, chemorefractory colorectal cancer: The randomised, placebo-controlled, phase II TRICC-C study (AIO-KRK-0111).

Int J Cancer 2021 03 4;148(6):1428-1437. Epub 2020 Oct 4.

Department of Internal Medicine I, Ulm University, Ulm, Delaware, USA.

Nintedanib is a triple angiokinase inhibitor of vascular endothelial growth factor receptor 1-3, fibroblast growth factor receptor 1-3 and platelet-derived growth factor receptor-a/-b. Thereby, it targets angiogenic escape mechanisms. The trial TyRosine kinase Inhibitor for the treatment of Chemorefractory Colorectal Cancer (TRICC-C) trial evaluates the addition of nintedanib to mFOLFOX6 (fluorouracil, folinic acid and oxaliplatin) in patients with metastatic colorectal cancer (mCRC). TRICC-C is a randomised controlled, double-blinded, phase II trial in mCRC patients that received a first-line non-oxaliplatin containing chemotherapy. Patients received mFOLFOX6 + nintedanib (F + N) (2 × 200 mg p.o./d, d1-d14) or mFOLFOX6 + placebo (F + P), in a 1:1 ratio. Primary endpoint was median progression free survival (mPFS) and secondary overall response rate (ORR), overall survival (OS) and safety. Fifty-three patients (27 F + N; 26 F + P) were randomised between 12/2012 and 5/2016 (scheduled n = 180). The trial was terminated prematurely due to slow accrual. The trial did not reach its primary endpoint but mPFS, median overall survival (mOS) and disease control rate (DCR) were numerically higher in the F + N arm compared to the F + P arm; however, the difference was not significant (mPFS: F + P: 4.6 months vs F + N: 8.1 months; HR 0.65; 95% CI 0.32-1.30; P = .2156; mOS: F + P: 9.9 months vs F + N: 17.1 months; HR 1.03, 95% CI 0.48-2.23; P = .9387; DCR: F + P: 50% vs F + N: 66,7%; P = .2709). Toxicity was moderate and only different for neutropenia (F + P: 11.5%, F + N: 19.2%) and gastrointestinal disorders (F + P: 65.4%, F + N: 84.6%). Final results show safety and a nonsignificant trend towards improved PFS and DCR for the combination of mFOLFOX6 + nintedanib in the second-line therapy of mCRC.
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http://dx.doi.org/10.1002/ijc.33296DOI Listing
March 2021

Alkaloid and iridoid glucosides from Palicourea luxurians (Rubiaceae: Palicoureeae) indicate tryptamine- and tryptophan-iridoid alkaloid formation apart the strictosidine pathway.

Phytochemistry 2020 May 19;173:112296. Epub 2020 Feb 19.

Department of Botany and Biodiversity Research, University of Vienna, Rennweg 14, A-1030, Vienna, Austria. Electronic address:

The first phytochemical examination of extracts from leaves and stem bark of Palicourea luxurians (Rusby) Borhidi yielded two undescribed and one known alstrostine derivative together with the oxindole alkaloid javaniside as well as with 5α-carboxystrictosidine. Additionally, five iridoids and four secologanin derived isolation artifacts have been isolated. Lack of strictosidine and its follow-up metabolization products suggested that the Pictet-Spenglerase in P. luxurians does barely or not catalyze the formation of strictosidine. Against this background the biosynthesis of javaniside and 5α-carboxystrictosidine is discussed with regard to possible reaction mechanisms. Similarly, P. luxurians used an independent biosynthetic pathway to produce alstrostine type structures from secologanin and tryptamine in a 2:1 ratio. The structure of isoalstrostine A, which was isolated for the first time, allowed the refinement of a previously reported pathway to the alstrostine type carbon skeleton as well as to some follow-up metabolization products. In spite of various biosynthetic pathways incorporating secologanin to gain different types of tryptophan- and tryptamine-iridoid alkaloids, P. luxurians accumulates this compound as well a couple of further metabolized iridoids deriving from loganin and secologanin.
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http://dx.doi.org/10.1016/j.phytochem.2020.112296DOI Listing
May 2020

Modularity and evolution of flower shape: the role of function, development, and spandrels in Erica.

New Phytol 2020 04 8;226(1):267-280. Epub 2020 Jan 8.

Department of Botany and Biodiversity Research, Division of Structural and Functional Botany, University of Vienna, Rennweg 14, Vienna, 1030, Austria.

Flowers have been hypothesized to contain either modules of attraction and reproduction, functional modules (pollination-effecting parts) or developmental modules (organ-specific). Do pollination specialization and syndromes influence floral modularity? In order to test these hypotheses and answer this question, we focused on the genus Erica: we gathered 3D data from flowers of 19 species with diverse syndromes via computed tomography, and for the first time tested the above-mentioned hypotheses via 3D geometric morphometrics. To provide an evolutionary framework for our results, we tested the evolutionary mode of floral shape, size and integration under the syndromes regime, and - for the first time - reconstructed the high-dimensional floral shape of their most recent common ancestor. We demonstrate that the modularity of the 3D shape of generalist flowers depends on development and that of specialists is linked to function: modules of pollen deposition and receipt in bird syndrome, and access-restriction to the floral reward in long-proboscid fly syndrome. Only size and shape principal component 1 showed multiple-optima selection, suggesting that they were co-opted during evolution to adapt flowers to novel pollinators. Whole floral shape followed an Ornstein-Uhlenbeck (selection-driven) evolutionary model, and differentiated relatively late. Flower shape modularity thus crucially depends on pollinator specialization and syndrome.
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http://dx.doi.org/10.1111/nph.16337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065081PMC
April 2020

Interlayer Dzyaloshinskii-Moriya Interactions.

Phys Rev Lett 2019 Jun;122(25):257202

CIC nanoGUNE, E-20018 San Sebastian, Spain.

The interfacial Dzyaloshinkii-Moriya interaction defines a rotational sense for the spin structure in two-dimensional magnetic films and can be used to create chiral magnetic structures like spin spirals and skyrmions in those films. Here, we show by means of atomistic calculations that in heterostructures an interlayer coupling of the Dzyaloshinskii-Moriya type across a spacer can emerge. We quantify this interaction in the framework of the Lévy-Fert model for trilayers consisting of two ferromagnets separated by a nonmagnetic spacer and show that such an interlayer Dzyaloshinkii-Moriya interaction yields nontrivial three-dimensional spin textures across the entire trilayer, which evolve within as well as between the planes and, hence, combine intraplane and interplane chiralities. This analysis opens new perspectives for three-dimensional tailoring of magnetic chirality in multilayers.
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http://dx.doi.org/10.1103/PhysRevLett.122.257202DOI Listing
June 2019

A Blood-Based Multi Marker Assay Supports the Differential Diagnosis of Early-Stage Pancreatic Cancer.

Theranostics 2019 12;9(5):1280-1287. Epub 2019 Feb 12.

Ulm University, Department of Internal Medicine I, Albert-Einstein-Allee 23, 89081 Ulm, Germany.

The most frequent malignancy of the pancreas is the pancreatic ductal adenocarcinoma (PDAC). Despite many efforts PDAC has still a dismal prognosis. Biomarkers for early disease stage diagnosis as a prerequisite for a potentially curative treatment are still missing. Novel blood-based markers may help to overcome this limitation. Methods: Prior to surgery plasma levels of thrombospondin-2 (THBS2), which was recently published as a novel biomarker, and CA19-9 from 52 patients with histologically proven PDAC were determined, circulating cell-free (cfDNA) was quantified. 15 patients with side-branch IPMNs without worrisome features and 32 patients with chronic pancreatitis served for comparison. Logit (logistic regression) models were used to test the performance of single biomarkers and biomarker combinations. Results: CA19-9 and THBS2 alone showed comparable c-statistics of 0.80 and 0.73, respectively, improving to 0.87 when combining these two markers. The c-statistic was further increased to 0.94 when combining CA19-9 and THBS2 with cfDNA quantification. This marker combination performed best for all PDAC stages but also for PDACs grouped by stage. The greatest improvement over CA19-9 was seen in the group of stage I PDAC, from 0.69 to 0.90 for the three marker combination. These data establish the combination of CA19-9, THBS2 and cfDNA as a composite liquid biomarker for non-invasive diagnosis of early-stage PDAC.
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http://dx.doi.org/10.7150/thno.29247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401492PMC
January 2020

Association between family history, mutation locations, and prevalence of BRCA1 or 2 mutations in ovarian cancer patients.

Cancer Med 2019 04 1;8(4):1875-1881. Epub 2019 Mar 1.

Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

We investigated the prevalence of germline BRCA mutations in a population-based cohort of Austrian women diagnosed with ovarian cancer and its association with family history of cancer. We prospectively collected family pedigrees of 443 Austrian ovarian cancer patients who had been tested for the presence of a germline BRCA or 2 mutations and correlated the familial breast and ovarian cancer burden with the prevalence of BRCA mutations and disease onset. The probability of carrying a gBRCA mutation in patients without family history of cancer is 14% (95% CI 9%-22%), as opposed to 45% (95% CI 31%-59%) of patients with at least one family member with ovarian cancer, and 47% (95% CI 40%-54%) if other relatives have developed breast cancer. If both breast and ovarian cancer are diagnosed in the family, the probability of carrying a germline BRCA1 or 2 mutations is 60% (95% CI 50%-68%). germline BRCA1 or mutations in families with ovarian cancer only are commonly located in the Ovarian Cancer Cluster Regions when compared to families with both breast and ovarian cancer (P = 0.001, and P = 0.020, respectively). While gBRCA mutation carriers with ovarian cancer do not have a significantly different age at onset than patients with a family history of cancer, gBRCA1 carriers in general have an earlier onset than gBRCA2 carriers (P = 0.002) and patients without a mutation (P = 0.006). The rate of germline BRCA1 or 2 mutations in ovarian cancer patients without a family history or breast or ovarian cancer is low. However, in women with additional family members affected, the prevalence is considerably higher than previously reported.
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http://dx.doi.org/10.1002/cam4.2000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488144PMC
April 2019

Rediscovery of Chamisso's type specimens of Hawaiian (Rubiaceae, Psychotrieae) in the herbarium of the Natural History Museum, Vienna.

Authors:
Andreas Berger

PhytoKeys 2018 20(114):27-42. Epub 2018 Dec 20.

Department of Botany and Biodiversity Research, University of Vienna, Rennweg 14, A-1030, Vienna, Austria University of Vienna Vienna Austria.

Between 1815 and 1818, Count Nikolai Romanzoff funded an expedition of the Russian brig . Besides their primary goal to discover the Northeast Passage, their aim was to collect scientific specimens, for which the botanist Adelbert von Chamisso and the entomologist Johann Friedrich von Eschscholtz were commissioned. On the Hawaiian Islands, they collected two unknown endemic species that Chamisso and Diederich Franz Leonhard von Schlechtendal later described as and , both now assigned to the large and complex genus (Rubiaceae, Psychotrieae). The private herbarium of Chamisso is now preserved at the Komarov Botanical Institute, St. Petersburg (LE). In the late 1930s, their type collections of and were sent out on loan for study, but got lost in transit during the aftermath of the Second World War. No extant original material was found during a subsequent revision of Hawaiian and both species were consequently neotypified. These neotypes are superseded by the here-reported rediscovery of original material in the herbarium of Stephan Ladislaus Endlicher preserved at the Natural History Museum, Vienna (W) and these specimens are here designated as lectotypes. As both are rather fragmentary, the former neotypes are additionally designated as epitypes. In addition, some peculiarities and details of the expedition and its collections are noted.
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http://dx.doi.org/10.3897/phytokeys.114.29426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308219PMC
December 2018

Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer - the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group.

BMC Cancer 2018 Dec 29;18(1):1298. Epub 2018 Dec 29.

Department of Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.

Background: Even clearly resectable pancreatic cancer still has an unfavorable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Thus, evaluation of perioperative chemotherapy in resectable pancreatic cancer in a prospective, randomized trial is warranted. A substantial improvement in overall survival of patients with metastatic pancreatic cancer with FOLFIRINOX and nab-paclitaxel/gemcitabine vs standard gemcitabine has been demonstrated in phase III-trials. Indeed nab-paclitaxel/gemcitabine has a more favorable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting.

Methods: NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 months with adjuvant gemcitabine), NCT02047513. NEONAX will enroll 166 patients with resectable pancreatic ductal adenocarcinoma (≤ cT3, N0 or N1, cM0) in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) followed by tumor surgery followed by 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant arm): tumor surgery followed by 6 cycles nab-paclitaxel/gemcitabine. The randomization (1:1) is eminent to avoid allocation bias between the groups. Randomization is stratified for tumor stage (ct1/2 vs. cT3) and lymph node status (cN0 vs. cN1). Primary objective is disease free survival (DFS) at 18 months after randomization. Key secondary objectives are 3-year overall survival (OS) rate and DFS rate, progression during neoadjuvant therapy, R0 and R1 resection rate, quality of life and correlation of DFS, OS and tumor regression with pharmacogenomic markers, tumor biomarkers and molecular analyses (ctDNA, transcriptome, miRNA-arrays). In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. The study was initiated in March 2015 in 26 centers for pancreatic surgery in Germany.

Discussion: The NEONAX trial is an innovative study on resectable pancreatic cancer and currently one of the largest trials in this field of research. It addresses the question of the role of intensified perioperative treatment with nab-paclitaxel plus gemcitabine in resectable pancreatic cancers to improve disease-free survival and offers a unique potential for translational research.

Trial Registration: ClinicalTrials.gov : NCT02047513, 08/13/2014.
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http://dx.doi.org/10.1186/s12885-018-5183-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311014PMC
December 2018

Floating kidneys associated with Eisenmenger syndrome.

Kidney Int 2018 Nov;94(5):1029

3rd Department of Internal Medicine, Academic Teaching Hospital Feldkirch, Feldkirch, Austria.

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http://dx.doi.org/10.1016/j.kint.2018.05.010DOI Listing
November 2018

Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study.

J Natl Cancer Inst 2019 04;111(4):350-364

Department of Medicine, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT.

Background: BRCA1/2 mutations confer high lifetime risk of breast cancer, although other factors may modify this risk. Whether height or body mass index (BMI) modifies breast cancer risk in BRCA1/2 mutation carriers remains unclear.

Methods: We used Mendelian randomization approaches to evaluate the association of height and BMI on breast cancer risk, using data from the Consortium of Investigators of Modifiers of BRCA1/2 with 14 676 BRCA1 and 7912 BRCA2 mutation carriers, including 11 451 cases of breast cancer. We created a height genetic score using 586 height-associated variants and a BMI genetic score using 93 BMI-associated variants. We examined both observed and genetically determined height and BMI with breast cancer risk using weighted Cox models. All statistical tests were two-sided.

Results: Observed height was positively associated with breast cancer risk (HR = 1.09 per 10 cm increase, 95% confidence interval [CI] = 1.0 to 1.17; P = 1.17). Height genetic score was positively associated with breast cancer, although this was not statistically significant (per 10 cm increase in genetically predicted height, HR = 1.04, 95% CI = 0.93 to 1.17; P = .47). Observed BMI was inversely associated with breast cancer risk (per 5 kg/m2 increase, HR = 0.94, 95% CI = 0.90 to 0.98; P = .007). BMI genetic score was also inversely associated with breast cancer risk (per 5 kg/m2 increase in genetically predicted BMI, HR = 0.87, 95% CI = 0.76 to 0.98; P = .02). BMI was primarily associated with premenopausal breast cancer.

Conclusion: Height is associated with overall breast cancer and BMI is associated with premenopausal breast cancer in BRCA1/2 mutation carriers. Incorporating height and BMI, particularly genetic score, into risk assessment may improve cancer management.
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http://dx.doi.org/10.1093/jnci/djy132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449171PMC
April 2019

Improving comprehension of genetic counseling for hereditary breast and ovarian cancer clients with a visual tool.

PLoS One 2018 12;13(7):e0200559. Epub 2018 Jul 12.

Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

Objective: Genetic counseling and testing can be offered to individuals who are at high risk of carrying a breast cancer (BRCA) gene mutation. However, the content of genetic counseling could be difficult to understand due to complex medical information. The aim of this study was to investigate if comprehension can be improved with a new genetic counseling tool (NGCT hereafter; a tool that combines complex medical information with pictures, diagrams and tables) as compared to conventional oral-only genetic counseling (CGC).

Methods: 207 clients attended genetic counseling for hereditary breast and ovarian cancer at the Medical University of Vienna between February 2015 and February 2016. Seventy clients participated in this study and were allocated into two groups: the first 36 participants received conventional (oral only) genetic counseling (CGC) and the following 34 participants received genetic counseling using a new genetic counseling tool (NGCT), which combines complex information with pictures, diagrams and tables. After genetic counseling, all consenting participants were invited to complete a questionnaire with seven questions evaluating their comprehension of the medical information provided.

Results: Socio-demographic backgrounds were comparable in both groups. Correct responses were significantly higher in the NGCT group compared to the CGC group (p = 0.012). NGCT also statistically improves correct response of Q1 (p = 0.03) and Q7 (p = 0.004).

Conclusion: The NGCT leads to an overall better understanding of the content of a genetic counseling session than CGC alone.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200559PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042777PMC
January 2019

Genetic Biopsy for Prediction of Surveillance Intervals after Endoscopic Resection of Colonic Polyps: Results of the GENESIS Study.

United European Gastroenterol J 2018 Mar 28;6(2):290-299. Epub 2017 Jul 28.

Clinic for Internal Medicine I, Ulm University, Ulm, Germany.

Background And Objective: Current surveillance strategies for colorectal cancer following polypectomy are determined by endoscopic and histopathological factors. Such a distinction has been challenged. The present study was designed to identify molecular parameters in colonic polyps potentially defining new sub-groups at risk.

Methods: One hundred patients were enrolled in this multicentre study. Polyps biopsies underwent formalin-free processing (PAXgene, PreAnalytiX) and targeted next generation sequencing (38 genes (QIAGEN), NextSeq 500 platform (Illumina)). Genetic and histopathological analyses were done blinded to other data.

Results: In 100 patients, 224 polyps were removed. Significant associations of genetic alterations with endoscopic or histological polyp characteristics were observed for , , , and mutations. Multivariate analysis revealed that polyps ≥ 10 mm have a significant higher relative risk for harbouring oncogene mutations (relative risk 3.467 (1.742-6.933)). Adenomas and right-sided polyps are independent risk factors for mutations (relative risk 18.559 (2.371-145.245) and 12.987 (1.637-100.00)).

Conclusions: Assessment of the mutational landscape of polyps can be integrated in the workflow of current colonoscopy practice. There are distinct genetic patterns related to polyp size and location. These results suffice to optimise individual risk calculation and may help to better define surveillance intervals.
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http://dx.doi.org/10.1177/2050640617723810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833231PMC
March 2018

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

Hum Mutat 2018 05 12;39(5):593-620. Epub 2018 Mar 12.

Lunenfeld-Tanenbaum Research Institute, Toronto, Canada.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
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http://dx.doi.org/10.1002/humu.23406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903938PMC
May 2018

Targeted deep sequencing of circulating tumor DNA in metastatic pancreatic cancer.

Oncotarget 2018 Jan 16;9(2):2076-2085. Epub 2017 Dec 16.

Department of Internal Medicine I, Ulm University, 89081 Ulm, Germany.

Purpose: Precision medicine in pancreatic ductal adenocarcinoma (PDAC) could be substantially supported by tools that allow to establish and monitor the molecular setup of the tumor. In particular, noninvasive approaches are desirable, but not validated. Characterization of circulating tumor DNA (ctDNA) may help to achieve this goal.

Experimental Design: Blood samples from patients with metastatic PDAC prior to and during palliative treatment were collected. ctDNA and corresponding tumor tissue were analyzed by targeted next generation sequencing and droplet digital PCR for the 7 most frequently mutated genes in PDAC (TP53, SMAD4, CDKN2A, KRAS, APC, ATM, and FBXW7). Findings were correlated with clinical and imaging data.

Results: A total of 20 patients (therapy naïve = 11; pretreated = 9) were included. All therapy naïve patients ( = 11/11) presented with detectable ctDNA at baseline. In pretreated patients, 3/7 (prior to 2nd line treatment) and 2/2 (prior to 3rd line chemotherapy) had detectable ctDNA. The combined mutational allele frequency (CMAF) of KRAS and TP53 was chosen to reflect the amount of ctDNA. The median CMAF level significantly decreased during treatment ( = 0.0027) and increased at progression ( = 0.0104). CA19-9 analyses did not show significant differences. In treatment naïve patients, the CMAF levels during therapy significantly correlated with progression-free survival (Spearman, = -0.8609, = 0.0013).

Conclusions: Monitoring of ctDNA and its changes during treatment may enable to adapt therapeutic strategies to the specific molecular changes present at a certain time during treatment of mPDAC.
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http://dx.doi.org/10.18632/oncotarget.23330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788622PMC
January 2018

Modulation of Magnetic Properties at the Nanometer Scale in Continuously Graded Ferromagnets.

Materials (Basel) 2018 Feb 6;11(2). Epub 2018 Feb 6.

CIC nanoGUNE, Tolosa Hiribidea 76, E-20018 Donostia-San Sebastian, Spain.

: Ferromagnetic alloy materials with designed composition depth profiles provide an efficient route for the control of magnetism at the nanometer length scale. In this regard, cobalt-chromium and cobalt-ruthenium alloys constitute powerful model systems. They exhibit easy-to-tune magnetic properties such as saturation magnetization and Curie temperature while preserving their crystalline structure over a wide composition range. In order to demonstrate this materials design potential, we have grown a series of graded Co₁Cr and Co₁Ru (1010) epitaxial thin films, with and following predefined concentration profiles. Structural analysis measurements verify the epitaxial nature and crystallographic quality of our entire sample sets, which were designed to exhibit in-plane -axis orientation and thus a magnetic in-plane easy axis to achieve suppression of magnetostatic domain generation. Temperature and field-dependent magnetic depth profiles have been measured by means of polarized neutron reflectometry. In both investigated structures, and are found to vary as a function of depth in accordance with the predefined compositional depth profiles. Our Co₁Ru sample structures, which exhibit very steep material gradients, allow us to determine the localization limit for compositionally graded materials, which we find to be of the order of 1 nm. The Co₁Cr systems show the expected U-shaped and depth profiles, for which these specific samples were designed. The corresponding temperature dependent magnetization profile is then utilized to control the coupling along the film depth, which even allows for a sharp onset of decoupling of top and bottom sample parts at elevated temperatures.
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http://dx.doi.org/10.3390/ma11020251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5848948PMC
February 2018

Detection of circulating miRNAs: comparative analysis of extracellular vesicle-incorporated miRNAs and cell-free miRNAs in whole plasma of prostate cancer patients.

BMC Cancer 2017 Nov 9;17(1):730. Epub 2017 Nov 9.

Latvian Biomedical Research and Study Centre, Ratsupites Str 1, k-1, Riga, LV-1067, Latvia.

Background: Circulating cell-free miRNAs have emerged as promising minimally-invasive biomarkers for early detection, prognosis and monitoring of cancer. They can exist in the bloodstream incorporated into extracellular vesicles (EVs) and ribonucleoprotein complexes. However, it is still debated if EVs contain biologically meaningful amounts of miRNAs and may provide a better source of miRNA biomarkers than whole plasma. The aim of this study was to systematically compare the diagnostic potential of prostate cancer-associated miRNAs in whole plasma and in plasma EVs.

Methods: RNA was isolated from whole plasma and plasma EV samples from a well characterised cohort of 50 patient with prostate cancer (PC) and 22 patients with benign prostatic hyperplasia (BPH). Nine miRNAs known to have a diagnostic potential for PC in cell-free blood were quantified by RT-qPCR and the relative quantities were compared between patients with PC and BPH and between PC patients with Gleason score ≥ 8 and ≤6.

Results: Only a small fraction of the total cell-free miRNA was recovered from the plasma EVs, however the EV-incorporated and whole plasma cell-free miRNA profiles were clearly different. Four of the miRNAs analysed showed a diagnostic potential in our patient cohort. MiR-375 could differentiate between PC and BPH patients when analysed in the whole plasma, while miR-200c-3p and miR-21-5p performed better when analysed in plasma EVs. EV-incorporated but not whole plasma Let-7a-5p level could distinguish PC patients with Gleason score ≥ 8 vs ≤6.

Conclusions: This study demonstrates that for some miRNA biomarkers EVs provide a more consistent source of RNA than whole plasma, while other miRNAs show better diagnostic performance when tested in the whole plasma.
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http://dx.doi.org/10.1186/s12885-017-3737-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679326PMC
November 2017

Algorithm guided outlining of 105 pancreatic cancer liver metastases in Ultrasound.

Sci Rep 2017 10 6;7(1):12779. Epub 2017 Oct 6.

Institute for Computer Graphics and Vision, Graz University of Technology, Inffeldgasse 16, 8010, Graz, Austria.

Manual segmentation of hepatic metastases in ultrasound images acquired from patients suffering from pancreatic cancer is common practice. Semiautomatic measurements promising assistance in this process are often assessed using a small number of lesions performed by examiners who already know the algorithm. In this work, we present the application of an algorithm for the segmentation of liver metastases due to pancreatic cancer using a set of 105 different images of metastases. The algorithm and the two examiners had never assessed the images before. The examiners first performed a manual segmentation and, after five weeks, a semiautomatic segmentation using the algorithm. They were satisfied in up to 90% of the cases with the semiautomatic segmentation results. Using the algorithm was significantly faster and resulted in a median Dice similarity score of over 80%. Estimation of the inter-operator variability by using the intra class correlation coefficient was good with 0.8. In conclusion, the algorithm facilitates fast and accurate segmentation of liver metastases, comparable to the current gold standard of manual segmentation.
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http://dx.doi.org/10.1038/s41598-017-12925-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630585PMC
October 2017

Chemodiversity of tryptamine-derived alkaloids in six Costa Rican Palicourea species (Rubiaceae-Palicoureeae).

Phytochemistry 2017 Nov 12;143:124-131. Epub 2017 Aug 12.

Chemodiversity Research Group, Department of Botany and Biodiversity Research, University of Vienna, Rennweg 14, A-1030, Vienna, Austria.

We report 14 harmala and tryptamine-iridoid alkaloids with various tri-, tetra- and pentacyclic cores from leaves and stem bark of six species of the large and complex neotropical genus Palicourea. Among them is the previously undescribed compound deoxostrictosamide which is related to strictosamide, a key intermediate in camptothecin biosynthesis. In addition, we describe the occurrence of 1,2,3,4-tetrahydronorharman-1-one for the first time within Rubiaceae and ophiorine A and B, two alkaloids with an unusual core bearing a betaine function and a zwitterion as new for the genus. Although the other compounds are already known from other species, their degree of structural diversity highlights the remarkable biosynthetic capabilities of the genus Palicourea. Furthermore, the present paper provides additional support for the hypothesis that tryptamine-iridoid alkaloids represent a distinct chemosystematic feature for the genus Palicourea.
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http://dx.doi.org/10.1016/j.phytochem.2017.07.016DOI Listing
November 2017

Two new combinations, lectotypifications and a new name for Costa Rican s.l.

Authors:
Andreas Berger

PhytoKeys 2017 19(80):53-63. Epub 2017 May 19.

Division of Systematic and Evolutionary Botany, Department of Botany and Biodiversity Research, University of Vienna, Rennweg 14, A-1030 Vienna, Austria.

Species of the complex and diverse genera and are common but little-known elements in many tropical forest ecosystems. DNA-phylogenetic studies and a re-evaluation of morphological characters have recently shown that species of Psychotria subg. Heteropsychotria are nested within s.l., which was traditionally separated by exhibiting a bird-pollinated (vs. insect-pollinated) pollination syndrome. In order to render both genera monophyletic groups, species of subg. Heteropsychotria need to be transferred to s.l. For Central American species, most of the necessary combinations have already been made. In the course of ongoing research on the phytochemical characterization of species and clades of Costa Rican s.l., the nomenclature of Mesoamerican species was revised. As a result, two new combinations and a new name are proposed here: (Dwyer & Hayden) A. C. Berger & C. M. Taylor is based on Dwyer & Hayden, (K. Krause) A. C. Berger is based on K. Kraus and A. C. Berger replaces Standl. In addition, two lectotypes are designated.
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http://dx.doi.org/10.3897/phytokeys.80.13330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543270PMC
May 2017

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

J Clin Oncol 2017 Jul 27;35(20):2240-2250. Epub 2017 Apr 27.

Julie Lecarpentier, Karoline B. Kuchenbaecker, Daniel Barrowdale, Joe Dennis, Lesley McGuffog, Goska Leslie, Andrew Lee, Ali Amin Al Olama, Jonathan P. Tyrer, Debra Frost, Steve Ellis, Douglas F. Easton, and Antonis C. Antoniou, University of Cambridge; Karoline B. Kuchenbaecker, The Wellcome Trust Sanger Institute, Hinxton; Marc Tischkowitz, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge; D. Gareth Evans, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester; Alex Henderson, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne; Carole Brewer, Royal Devon and Exeter Hospital, Exeter; Diana Eccles, Southampton University Hospitals NHS Trust, Southampton; Jackie Cook, Sheffield Children's Hospital, Sheffield; Kai-ren Ong, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham; Lisa Walker, Churchill Hospital, Oxford; Lucy E. Side, Great Ormond Street Hospital for Children NHS Trust; Shirley Hodgson, St George's, University of London; Louise Izatt, Guy's and St Thomas' NHS Foundation Trust; Ros Eeles, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Nick Orr, The Institute of Cancer Research, London; Mary E. Porteous, Western General Hospital, Edinburgh; Rosemarie Davidson, South Glasgow University Hospitals, Glasgow; Julian Adlard, Chapel Allerton Hospital, Leeds, United Kingdom; Valentina Silvestri, Piera Rizzolo, Anna Sara Navazio, Virginia Valentini, Veronica Zelli, and Laura Ottini, Sapienza University of Rome, Rome; Angela Toss, Veronica Medici, and Laura Cortesi, University of Modena and Reggio Emilia, Modena; Ines Zanna and Domenico Palli, Cancer Research and Prevention Institute, Florence; Paolo Radice, Siranoush Manoukian, Bernard Peissel, and Jacopo Azzollini, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori (INT); Paolo Peterlongo, Italian Foundation for Cancer Research Institute of Molecular Oncology (IFOM), Milan; Alessandra Viel and Giulia Cini, CRO Aviano, National Cancer Institute, Aviano; Giuseppe Damante, University of Udine, Udine; Stefania Tommasi, Istituto Nazionale Tumori "Giovanni Paolo II", Bari; Elisa Alducci, Silvia Tognazzo, and Marco Montagna, Veneto Institute of Oncology IOV - IRCCS, Padua; Maria A. Caligo, University and University Hospital of Pisa, Pisa, Italy; Penny Soucy and Jacques Simard, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Quebec; Anna Marie Mulligan and Irene L. Andrulis, University of Toronto; Gord Glendon and Irene L. Andrulis, Mount Sinai Hospital, Toronto, Ontario, Canada; Melissa Southey, Ian Campbell, Paul James, and Gillian Mitchell, University of Melbourne, Parkville, Victoria; Amanda B. Spurdle, Helene Holland, and Georgia Chenevix-Trench, QIMR Berghofer Medical Research Institute, Brisbane, Queensland; Ian Campbell, Paul James, and Gillian Mitchell, Peter MacCallum Cancer Centre, East Melbourne, New South Wales, Australia; Esther M. John, Cancer Prevention Institute of California, Fremont; Linda Steele, Yuan Chun Ding, Susan L. Neuhausen, and Jeffrey N. Weitzel, City of Hope, Duarte, CA; Thomas A. Conner and Saundra S. Buys, Huntsman Cancer Institute; David E. Goldgar, University of Utah School of Medicine, Salt Lake City, UT; Andrew K. Godwin, University of Kansas Medical Center, Kansas City; Priyanka Sharma, University of Kansas Medical Center, Westwood, KS; Timothy R. Rebbeck, Harvard TH Chan School of Public Health and Dana Farber Cancer Institute, Boston, MA; Joseph Vijai, Mark Robson, Anne Lincoln, Jacob Musinsky, Pragna Gaddam, and Kenneth Offit, Memorial Sloan Kettering Cancer Center, New York, NY; Jennifer T. Loud and Mark H. Greene, National Cancer Institute, Bethesda, MD; Amanda Ewart Toland and Leigha Senter, The Ohio State University, Columbus, OH; Dezheng Huo, Sarah M. Nielsen, and Olufunmilayo I. Olopade, University of Chicago Medical Center, Chicago, IL; Katherine L. Nathanson and Susan M. Domchek, University of Pennsylvania, Philadelphia; Christa Lorenchick and Rachel C. Jankowitz, University of Pittsburgh Medical Center, Pittsburgh, PA; Fergus J. Couch, Mayo Clinic, Rochester, MN; Ramunas Janavicius, State Research Institute Innovative Medicine Center, Vilnius, Lithuania; Thomas V.O. Hansen, Rigshospitalet, Copenhagen University Hospital, Copenhagen; Anders Bojesen and Henriette Roed Nielsen, Vejle Hospital, Vejle; Anne-Bine Skytte, Lone Sunde, and Uffe Birk Jensen, Aarhus University Hospital, Aarhus; Inge Sokilde Pedersen, Aalborg University Hospital, Aalborg; Lotte Krogh, Torben A. Kruse, and Mads Thomassen, Odense University Hospital, Odense, Denmark; Ana Osorio, National Cancer Research Centre and Spanish Network on Rare Diseases; Miguel de la Hoya, Vanesa Garcia-Barberan, Trinidad Caldes, and Pedro Perez Segura, Hospital Clinico San Carlos, El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid; Judith Balmaña, University Hospital, Vall d'Hebron; Sara Gutiérrez-Enríquez and Orland Diez, Vall d'Hebron Institute of Oncology; Orland Diez, University Hospital Vall d'Hebron; Alex Teulé, Jesús Del Valle, Lidia Feliubadalo, Miquel Angel Pujana, and Conxi Lazaro, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona; Angel Izquierdo, Esther Darder, and Joan Brunet, Institut d'Investigació Biomèdica de Girona, Catalan Institute of Oncology, Girona, Spain; Florentia Fostira, National Centre for Scientific Research "Demokritos," Athens, Greece; Ute Hamann, German Cancer Research Center (DKFZ); Christian Sutter, University Hospital Heidelberg, Heidelberg; Alfons Meindl, Klinikumrechts der Isar, Technical University Munich; Nina Ditsch, Ludwig-Maximilian University, Munich; Andrea Gehrig, University Würzburg, Würzburg; Bernd Dworniczak, University of Münster, Münster; Christoph Engel, University of Leipzig; Dorothea Wand, University Hospital, Leipzig; Dieter Niederacher, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf; Doris Steinemann, Hannover Medical School, Hannover; Eric Hahnen, Jan Hauke, Kerstin Rhiem, Barbara Wappenschmidt, and Rita K. Schmutzler, University Hospital Cologne, Cologne; Karin Kast, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden; Norbert Arnold, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Kiel; Shan Wang-Gohrke, University Hospital Ulm, Ulm, Germany; Christine Lasset, Francesca Damiola, and Laure Barjhoux, Centre Léon Bérard; Sylvie Mazoyer, University of Lyon, Lyon; Dominique Stoppa-Lyonnet and Muriel Belotti, Institut Curie, Paris, France; Mattias Van Heetvelde, Bruce Poppe, Kim De Leeneer, and Kathleen B.M. Claes, Ghent University, Gent, Belgium; Johanna I. Kiiski, Sofia Khan, and Heli Nevanlinna, University of Helsinki; Johanna I. Kiiski, Kristiina Aittomäki, Sofia Khan, and Heli Nevanlinna, Helsinki University Hospital, Helsinki, Finland; Christi J. van Asperen, Leiden University Medical Center, Leiden, the Netherlands; Tibor Vaszko, Miklos Kasler, and Edith Olah, National Institute of Oncology, Budapest, Hungary; Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th. Johannsson, and Rosa B. Barkardottir, Landspitali University Hospital and Biomedical Centre, University of Iceland, Reykjavik, Iceland; Manuel R. Teixeira and Pedro Pinto, Portuguese Oncology Institute; Manuel R. Teixeira, Porto University, Porto, Portugal; Jong Won Lee, Ulsan College of Medicine and Asan Medical Center; Min Hyuk Lee and Jihyoun Lee, Soonchunhyang University and Hospital; Sung-Won Kim and Eunyoung Kang, Daerim St Mary's Hospital; Sue Kyung Park, Seoul National University College of Medicine, Seoul; Zisun Kim, Soonchunhyang University Bucheon Hospital, Bucheon, Korea; Yen Y. Tan, Andreas Berger, and Christian F. Singer, Medical University of Vienna, Vienna, Austria; Sook-Yee Yoon and Soo-Hwang Teo, Sime Darby Medical Centre, Subang Jaya, Malaysia; and Anna von Wachenfeldt, Karolinska University Hospital, Stockholm, Sweden.

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
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http://dx.doi.org/10.1200/JCO.2016.69.4935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501359PMC
July 2017

Surveillance after resection of pancreatic ductal adenocarcinoma with curative intent - a multicenter survey in Germany and review of the literature.

Z Gastroenterol 2017 Jul 24;55(7):657-666. Epub 2017 Apr 24.

 Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with high risk of relapse even after curative-intended resection. There are no evidence-based recommendations for surveillance in actual guidelines. Given this situation and as a basis for prospective studies, we wanted to determine the current practice of surveillance after pancreatic cancer resection in German institutions.  A web-based questionnaire was sent in 2015 to 300 German institutions (hospitals, outpatient clinics, and private practices) experienced in the care of patients with PDAC. The questionnaire comprised 23 items including the respective institution, the level of care, the annual case load of pancreatic cancer surgery, the surveillance algorithms used, and the most frequently used means for surveillance as well as their evaluation by the users with respect to the effectiveness of these means. Additionally, we perform a review of the literature.  The final analysis comprised 161 questionnaires (response rate 53.7 %). Mainly high-volume centers (82.5 % with > 300 hospital beds) participated. In 46.6 % of centers, more than 80 % of patients received adjuvant chemotherapy after surgery. Between 60 - 80 % of these patients completed the recommended 6 months of adjuvant treatment, and 47 % of the patients received the whole treatment (surgery, adjuvant therapy) and surveillance in the same center. Upon completion of adjuvant treatment, 96 % of centers survey their patients, and 82 % of these centers already employ diagnostic means during the course of adjuvant chemotherapy. The most commonly used diagnostic means were taking patient history, conducting physical examination, performing laboratory tests including CA19 - 9, and imaging. Of those employed, CA19 - 9 and imaging followed by patient history were considered the most efficient to detect disease relapse by the centers. Half of the institutions perform surveillance for 5 years after surgery.  This is the first systematic analysis of self-reported surveillance strategies used in Germany after resection of PDAC with curative intent. Surveillance after resection of PDAC with curative intent is common in Germany. Alterations of CA19 - 9 levels as well as imaging and taking patient history are considered the most efficient means to detect relapse of disease by the physicians participating in our survey.
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http://dx.doi.org/10.1055/s-0043-105502DOI Listing
July 2017

Treatment monitoring in metastatic colorectal cancer patients by quantification and KRAS genotyping of circulating cell-free DNA.

PLoS One 2017 22;12(3):e0174308. Epub 2017 Mar 22.

Department of Internal Medicine I, Ulm University, Albert-Einstein-Allee 23, Ulm, Germany.

Treatment of metastatic colorectal cancer (CRC) has continuously improved over the last decade. However, disease monitoring remains underdeveloped and mostly dependent on imaging e.g. RECIST 1.1 criteria. The genetic landscape of individual cancers and subsequently occurring treatment-induced evolution remain neglected in current surveillance strategies. Novel biomarkers demand minimally invasive and repetitive tracking of the cancer mutagenome for therapy stratification and to make prognostic predictions. Carcinoembryonic antigen (CEA), a routinely used tumor marker for CRC, does not meet these goals and thus prevents its use as a reliable monitoring tool. A tumor-derived fraction of circulating cell-free DNA (cfDNA), isolated from blood samples, may bypass the limitations of currently available biomarkers and could be a tool for noninvasive disease monitoring. Here, total cfDNA levels differentiated a cohort of metastatic CRC patients from healthy controls. Furthermore, we correlated cfDNA during chemotherapy of 27 stage IV patients with clinical parameters to establish its prognostic and predictive value. Indeed, cfDNA levels in chemotherapy naive patients correlate with the tumor burden and CEA values at diagnosis and increase upon disease progression during 1st and 2nd line treatment. Moreover, we confirm the possibility of cfDNA-based genotyping of KRAS to early detect the emergence of resistance during chemotherapy. These data indicate that repetitive quantitative and mutational analysis of cfDNA might complement current treatment standards but may have also limited value in some patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174308PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362218PMC
August 2017

International Interlaboratory Digital PCR Study Demonstrating High Reproducibility for the Measurement of a Rare Sequence Variant.

Anal Chem 2017 02 18;89(3):1724-1733. Epub 2017 Jan 18.

Dana Farber Cancer Institute , Belfer Center for Applied Cancer Science and Department of Medical Oncology, Boston, Massachusetts 02115, United States.

This study tested the claim that digital PCR (dPCR) can offer highly reproducible quantitative measurements in disparate laboratories. Twenty-one laboratories measured four blinded samples containing different quantities of a KRAS fragment encoding G12D, an important genetic marker for guiding therapy of certain cancers. This marker is challenging to quantify reproducibly using quantitative PCR (qPCR) or next generation sequencing (NGS) due to the presence of competing wild type sequences and the need for calibration. Using dPCR, 18 laboratories were able to quantify the G12D marker within 12% of each other in all samples. Three laboratories appeared to measure consistently outlying results; however, proper application of a follow-up analysis recommendation rectified their data. Our findings show that dPCR has demonstrable reproducibility across a large number of laboratories without calibration. This could enable the reproducible application of molecular stratification to guide therapy and, potentially, for molecular diagnostics.
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http://dx.doi.org/10.1021/acs.analchem.6b03980DOI Listing
February 2017

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

PLoS One 2016 27;11(7):e0158801. Epub 2016 Jul 27.

Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158801PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963094PMC
July 2017

Changes of Socio-demographic data of clients seeking genetic counseling for hereditary breast and ovarian cancer due to the "Angelina Jolie Effect".

BMC Cancer 2016 07 8;16:436. Epub 2016 Jul 8.

Department of Obstetrics and Gynecology, Division of Senology, Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: The purpose of this study was to evaluate socio-demographic characteristics of clients claiming genetic counseling for hereditary breast and ovarian cancer (HBOC) in Austria. Furthermore, changes of these parameters before and after Angelina Jolie's (AJ) disclosure of carrying a BRCA mutation were evaluated.

Methods: In this prospective, nonrandomized study 268 consecutive clients seeking genetic counseling for HBOC at the Medical University of Vienna, Department of Obstetrics and Gynecology, Vienna, Austria between June 2012 and June 2014 were included. Socio-demographic data and source of information about HBOC and genetic counseling were evaluated. First, socio-demographic parameters were compared to the general Austrian population. Second, changes in these parameters after AJ's public disclosure of carrying a BRCA mutation were analyzed.

Results: Subjects were more frequent female, younger and higher educated in comparison to Austria's general population (p < 0.001). Furthermore, level of education in participants was higher before than after AJ's disclosure (p = 0.046). Most clients were informed about genetic counseling by physicians. As expected, after AJ's public announcement patients were more frequent advised to genetic counseling by social media (p = 0.043) and family or friends (p = 0.010) than before.

Conclusions: In this present study we could demonstrate that particularly younger and female participants with high educational level attended significantly more often genetic counseling for HBOC. Increased presence of HBOC in media since AJ's disclosure of carrying a BRCA mutation had lead that information and awareness about HBOC was obtained by a wider audience from different social background.
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http://dx.doi.org/10.1186/s12885-016-2472-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938920PMC
July 2016

Detection of Hot-Spot Mutations in Circulating Cell-Free DNA From Patients With Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Gastroenterology 2016 08 23;151(2):267-70. Epub 2016 Jun 23.

Department of Internal Medicine I, Ulm University, Ulm, Germany. Electronic address:

Intraductal papillary mucinous neoplasms (IPMNs) are the most frequent cystic pancreatic tumors. Little is known about their molecular alterations, but mutations in GNAS have been reported to promote IPMN formation. A tumor-derived fraction of circulating cell-free DNA (cfDNA), isolated from blood samples, contains many of the same mutations as the primary tumor, and could be a tool for noninvasive disease monitoring. We found that the total amount of cfDNA can discriminate between individuals without pancreatic lesions (controls) and patients with Fukuoka-negative branch-duct IPMN or pancreatic cancer. Furthermore, we detected GNAS mutations in cfDNA from patients with IPMN, but not in patients with serous cystadenoma or controls. Analyses of cfDNA might therefore be used in the diagnosis of patients with IPMN or in monitoring disease progression.
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http://dx.doi.org/10.1053/j.gastro.2016.04.034DOI Listing
August 2016

Nocturnal Plant Bugs Use cis-Jasmone to Locate Inflorescences of an Araceae as Feeding and Mating Site.

J Chem Ecol 2016 Apr 13;42(4):300-4. Epub 2016 Apr 13.

Department of Ecology & Evolution, Plant Ecology, University of Salzburg, Hellbrunnerstr. 34, 5020, Salzburg, Austria.

Inflorescences of Araceae pollinated by cyclocephaline scarab beetles are visited frequently by a wide array of other arthropods that exploit floral resources without taking part in pollination, including earwigs, flies, and true bugs. To date, nothing is known about the cues these insect visitors use to locate the inflorescences and whether or to what extent floral scents play a role. An aroid visited by large numbers of plant bugs (Miridae) in addition to cyclocephaline scarab beetle pollinators is the Neotropical species Dieffenbachia aurantiaca. We identified the plant bug species and investigated their behavior and arrival time on the inflorescences. To test the importance of olfactory cues in locating their host we conducted experiments with open and gauze-bagged inflorescences as well as natural scent samples of D. aurantiaca. Inflorescence scents were analyzed by gas chromatography linked to mass spectrometry (GC/MS), and the attractive potential of the main scent compound was determined by behavioral assays. Three species of Neella, the most common one being N. floridula, visited the inflorescences at nightfall, shortly after the beginning of scent emission, and showed feeding and copulation activity. Bagged inflorescences as well as natural scent samples attracted similar numbers of plant bugs as the non-bagged inflorescences, showing that olfactory cues are sufficient for them to locate their host. Cis-jasmone was the major component within the inflorescence scent bouquet. In two-choice field bioassays, this compound proved to be highly attractive to Neella, and thus obviously plays a key role in finding host plants.
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http://dx.doi.org/10.1007/s10886-016-0688-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867150PMC
April 2016
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