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1.
Phys Rev Lett ; 122(25): 257202, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31347891

RESUMO

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.

2.
Theranostics ; 9(5): 1280-1287, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867830

RESUMO

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. Conclusion:These data establish the combination of CA19-9, THBS2 and cfDNA as a composite liquid biomarker for non-invasive diagnosis of early-stage PDAC.

3.
Cancer Med ; 8(4): 1875-1881, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30821131

RESUMO

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.

4.
BMC Cancer ; 18(1): 1298, 2018 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-30594153

RESUMO

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.


Assuntos
Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/terapia , Adulto , Idoso , Carcinoma Ductal Pancreático/mortalidade , Ensaios Clínicos Fase II como Assunto , Desoxicitidina/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Combinação de Medicamentos , Fluoruracila/uso terapêutico , Alemanha/epidemiologia , Humanos , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante/métodos , Compostos Organometálicos/uso terapêutico , Pancreatectomia , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Adulto Jovem
6.
J Natl Cancer Inst ; 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30312457

RESUMO

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.

7.
PLoS One ; 13(7): e0200559, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30001421

RESUMO

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.

8.
United European Gastroenterol J ; 6(2): 290-299, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29511559

RESUMO

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 BRAF, KRAS, TCF7L2, FBXW7 and CTNNB1 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 CTNNB1 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.

9.
Materials (Basel) ; 11(2)2018 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-29415524

RESUMO

Abstract: 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 MS and Curie temperature TC 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 Co1-xCrx and Co1-wRuw (1010) epitaxial thin films, with x and w 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 c-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, TC and MS are found to vary as a function of depth in accordance with the predefined compositional depth profiles. Our Co1-wRuw 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 Co1-xCrx systems show the expected U-shaped TC and MS 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.

10.
Oncotarget ; 9(2): 2076-2085, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29416754

RESUMO

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 n = 11; pretreated n = 9) were included. All therapy naïve patients (n = 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 (P = 0.0027) and increased at progression (P = 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, r = -0.8609, P = 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.

11.
Hum Mutat ; 39(5): 593-620, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29446198

RESUMO

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.

12.
BMC Cancer ; 17(1): 730, 2017 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-29121858

RESUMO

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.


Assuntos
Biomarcadores Tumorais/sangue , MicroRNA Circulante/sangue , Vesículas Extracelulares/metabolismo , Neoplasias da Próstata/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Neoplasias da Próstata/diagnóstico
13.
Sci Rep ; 7(1): 12779, 2017 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-28986569

RESUMO

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.

14.
Phytochemistry ; 143: 124-131, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28806604

RESUMO

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.


Assuntos
Rubiaceae/química , Triptaminas/química , Alcaloides/análise , Alcaloides/química , Biodiversidade , Camptotecina , Costa Rica , Iridoides/análise , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Extratos Vegetais/química , Folhas de Planta/química , Alcaloides de Vinca/química
15.
PhytoKeys ; (80): 53-63, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28781558

RESUMO

Species of the complex and diverse genera Psychotria and Palicourea 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 Palicourea 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 Palicourea 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 Palicourea s.l., the nomenclature of Mesoamerican species was revised. As a result, two new combinations and a new name are proposed here: Palicourea horquetensis (Dwyer & Hayden) A. C. Berger & C. M. Taylor is based on Rudgea horquetensis Dwyer & Hayden, Palicourea tonduzii (K. Krause) A. C. Berger is based on Cephaelis tonduzii K. Kraus and Palicourea longiinvolucrata A. C. Berger replaces Psychotria hispidula Standl. In addition, two lectotypes are designated.

16.
Z Gastroenterol ; 55(7): 657-666, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28437802

RESUMO

Background 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. Methods 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. Results 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. Conclusion 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.

17.
PLoS One ; 12(3): e0174308, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28328955

RESUMO

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.


Assuntos
Neoplasias Colorretais/genética , DNA de Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adulto , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Antígeno Carcinoembrionário/genética , Neoplasias Colorretais/tratamento farmacológico , Análise Mutacional de DNA/métodos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genótipo , Humanos , Masculino , Mutação/genética , Prognóstico
18.
Anal Chem ; 89(3): 1724-1733, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-27935690

RESUMO

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.

19.
BMC Cancer ; 16: 436, 2016 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-27391110

RESUMO

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.


Assuntos
Neoplasias da Mama/genética , Aconselhamento Genético , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Adulto , Áustria , Neoplasias da Mama/diagnóstico , Análise Mutacional de DNA , Demografia , Escolaridade , Pessoas Famosas , Feminino , Genes BRCA1 , Genes BRCA2 , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade
20.
PLoS One ; 11(7): e0158801, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27463617

RESUMO

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.


Assuntos
Cromossomos Humanos Par 9 , Genes BRCA1 , Genes BRCA2 , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Mapeamento Cromossômico , Feminino , Humanos , Polimorfismo de Nucleotídeo Único
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