Targeted next generation sequencing as a reliable diagnostic assay for the detection of somatic mutations in tumours using minimal DNA amounts from formalin fixed paraffin embedded material

Background Targeted Next Generation Sequencing (NGS) offers a way to implement testing of multiple genetic aberrations in diagnostic pathology practice, which is necessary for personalized cancer treatment. However, no standards regarding input material have been defined. This study therefore aimed to determine the effect of the type of input material (e.g. formalin fixed paraffin embedded (FFPE) versus fresh frozen (FF) tissue) on NGS derived results. Moreover, this study aimed to explore a standardized analysis pipeline to support consistent clinical decision-making. Method We used the Ion Torrent PGM sequencing platform in combination with the Ion AmpliSeq Cancer Hotspot Panel v2 to sequence frequently mutated regions in 50 cancer related genes, and validated the NGS detected variants in 250 FFPE samples using standard diagnostic assays. Next, 386 tumour samples were sequenced to explore the effect of input material on variant detection variables. For variant calling, Ion Torrent analysis software was supplemented with additional variant annotation and filtering. Results Both FFPE and FF tissue could be sequenced reliably with a sensitivity of 99.1%. Validation showed a 98.5%concordance between NGS and conventional sequencing techniques, where NGS provided both the advantage of low input DNA concentration and the detectio

Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study

Background: In this study, our aim was to identify molecular aberrations predictive for response to everolimus, an mTOR inhibitor, regardless of tumor type. Methods: To generate hypotheses about potential markers for sensitivity to mTOR inhibition, drug sensitivity and genomic profiles of 835 cell lines were analyzed. Subsequently, a multicenter study was conducted. Patients with advanced solid tumors lacking standard of care treatment options were included and underwent a pre-treatment tumor biopsy to enable DNA sequencing of 1,977 genes, derive copy number profiles and determine activation status of pS6 and pERK. Treatment benefit was determined according to TTP ratio and RECIST. We tested for associations between treatment benefit and single molecular aberrations, clusters of aberrations and pathway perturbation. Results: Cell line screens indicated several genes, such as PTEN (P = 0.016; Wald test), to be associated with sensitivity to mTOR inhibition. Subsequently 73 patients were included, of which 59 started treatment with everolimus. Response and molecular data were available from 43 patients. PTEN aberrations, i.e. copy number loss or mutation, were associated with treatment benefit (P = 0.046; Fisher's exact test). Conclusion: Loss-of-function aberrations in PTEN potentially represent a tumor type agnostic biomarker for benefit from everolimus and warrants further confirmation in subsequent studies

Hoe bestuurskundig is de bestuurskunde? Nederlandse bestuurskundigen vergeleken met hun Europese vakgenoten

Dit is het eerste stuk van de serie artikelen over de staat en toekomst van de Bestuurskunde (zie ook de inleiding bij dit nummer). Sinds ruim veertig jaar is het mogelijk bestuurskunde als opleiding te volgen. Het bestuurskundig onderzoek kent een veel langere geschiedenis, waarin Van Poelje een belangrijke pioniersrol heeft vervuld. De artikelen in deze serie reflecteren op de bestuurskunde van dit moment en schetsen mogelijke ontwikkelingen. Bovendien poneren zij een reeks prangende stellingen en vragen voor bestuurskundige onderzoekers en practitioners over hun eigen vakgebied en wellicht over henzelf. [end textbox] Zolang de bestuurskunde bestaat, is er discussie over de vraag of de bestuurskunde zich meer op de praktijk of juist op de pure wetenschap moet focussen. Door de tijd heen zijn de meningen van bestuurskundigen hierover verdeeld. Hiernaast is het de vraag of de bestuurskunde een eigen discipline is, dan wel een onderdeel van de politicologie, het recht of de managementwetenschap. Dit artikel toont hoe bestuurskundigen zelf de discipline en de ontwikkelingen erin zien, op basis van een survey onder Europese bestuurskundigen. De Nederlandse bestuurskundigen worden hierbij vergeleken met Europese bestuurskundigen. Tussen Nederland en Europa bestaan grote verschillen in de discipline. Ten eerste is de bestuurskunde als afzonderlijke discipline in Nederland belangrijker dan in de overige Europese landen, waar de politieke wetenschappen een belangrijke rol spelen. Wat betreft de spanning binnen de bestuurskunde, ontwikkelt de bestuurskunde zich in Nederland minder richting de praktijk dan de bestuurskunde in andere landen.https://www.researchgate.net/profile/T_Schillemans/project/Serie-Toekomst-Bestuurskunde-in-Bestuurskunde/attachment/58297b9708ae6aad4f63bccd/AS:428247725940736@1479113622807/download/Gadellaa%2C+Curry+en+Van+de+Walle+Hoe+bestuurskundig+is+de+bestuurskunde.pdf?context=projectDetailsstatus: publishe

Public Administration as an academic disicpline: Trends and changes in the COCOPS academic survey of European Public Administration scholars

__Abstract__ This report summarises the finding from the COCOPS academic survey, a survey of public administration academics in European countries fielded in 2013. Respondents were asked to reflect on the state of the discipline and general trends within the discipline and in practice. This includes topics such as academic publishing and the reputation of journals, disciplinary affiliations, time use, research funding and emerging research topics. The paper first outlines the steps in designing and implementing the survey, along with response rates and general demographic information of respondents, including job titles, birthdates, gender, education and country of employment. Then, discussion turns to an examination of how public administration scholars rate different academic journals. Finally, the report then looks at changes in the discipline, including general trends, the relation of public administration to other academic disciplines, sources of research funding and allocation of work time, along with common themes and topics addressed in the discipline

Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours

Contains fulltext : 136010.pdf (publisher's version ) (Open Access)Background:Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.Methods:Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml(-1) and the patient did not show any grade 3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade 3 toxicity, the sunitinib dose was lowered by 12.5 mg.Results:Twenty-nine out of 43 patients were evaluable for PK assessments. Grade 3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity.Conclusions:In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice