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Pepijn Schellen

Bio: Pepijn Schellen is an academic researcher from VU University Medical Center. The author has contributed to research in topics: Cancer & Crizotinib. The author has an hindex of 10, co-authored 12 publications receiving 1015 citations.

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Journal ArticleDOI
TL;DR: The results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based “liquid biopsies”.

640 citations

Journal ArticleDOI
TL;DR: It is demonstrated that particle-swarm optimization-enhanced algorithms enable efficient selection of RNA biomarker panels from platelet RNA-sequencing libraries to diagnose cancer from TEPs, suggesting that swarm intelligence may also benefit the optimization of diagnostics readout of other liquid biopsy biosources.

221 citations

Journal ArticleDOI
TL;DR: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone.
Abstract: // R. Jonas A. Nilsson 1,2,3,* , Niki Karachaliou 4,* , Jordi Berenguer 1 , Ana Gimenez-Capitan 5 , Pepijn Schellen 1,3 , Cristina Teixido 5 , Jihane Tannous 6 , Justine L. Kuiper 7 , Esther Drees 1 , Magda Grabowska 1 , Marte van Keulen 6 , Danielle A. M. Heideman 8 , Erik Thunnissen 8 , Anne-Marie C. Dingemans 9 , Santiago Viteri 4 , Bakhos A. Tannous 6 , Ana Drozdowskyj 10 , Rafael Rosell 4,5,11,12,** , Egbert F. Smit 7,** and Thomas Wurdinger 1,3,6,** 1 Cancer Center Amsterdam, Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands 2 Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden 3 ThromboDx B.V., Amsterdam, The Netherlands 4 Translational Research Unit, Dr, Rosell Oncology Institute, Quiron Dexeus University Hospital, Barcelona, Spain 5 Pangaea Biotech SL, Barcelona, Spain 6 Department of Neurology, Massachusetts General Hospital and Neuroscience Program, Harvard Medical School, Boston, MA, USA 7 Cancer Center Amsterdam, Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands 8 Cancer Center Amsterdam, Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands 9 Department of Pulmonary Diseases, Maastricht University Medical Center, Maastricht, The Netherlands 10 Pivotal, Madrid, Spain 11 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Barcelona, Spain 12 Molecular Oncology Research (MORe) Foundation, Barcelona, Spain * These two authors are co-first authors of the manuscript ** These three authors are co-senior authors of the manuscript Correspondence to: Thomas Wurdinger, email: // Keywords : diagnostics, NSCLC, liquid biopsies, platelets, EML4-ALK Received : August 23, 2015 Accepted : October 06, 2015 Published : November 02, 2015 Abstract Purpose: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers. Methods: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival. Results: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK− platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression. Conclusions: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone.

162 citations

Journal ArticleDOI
TL;DR: Subventricular tumor spread is shown in the majority of patients, typically later in the course of their disease, as future therapies evolve to control local disease, strategies including extended or whole brain irradiation may become crucial as therapies improve and patients survive longer in the natural history of their cancer.
Abstract: Diffuse intrinsic pontine glioma (DIPG) is the second most common malignant pediatric brain tumor and the leading cause of brain tumor death in childhood [1]. 80 % of DIPG tumors exhibit a specific mutation (H3K27M) in the genes encoding histone 3.1 or 3.3 [2, 3]. standard therapy consisting of local radiotherapy to a dosage of 54–60 Gy extends median survival from 5 months to ∼9 months; 5-year survival remains less than 1 % [1]. The practice of focal radio-therapy to the brainstem is based in part on a 1982 autopsy study reporting DIPG to be relatively localized to the pons and adjacent structures [4]. In contrast, other neuroimaging and autopsy studies have identified widespread disease including supratentorial extension and leptomeningeal spread [5, 6]. Here, we report an autopsy series of 16 patients evaluated from 2009–2014 at stanford (n = 10) and VU (n = 6) University Medical Centers [7]. patient characteristics are listed in Table S1. Consistent with previous reports [5, 6], we found widespread dissemination of DIPG with extension to midbrain and medulla in 63 %, cerebellum in 56 %, thalamus in 56 %, frontal cortex in 25 % and supratentorial leptomeninges in 25 % (Fig. 1). The spinal cord was not consistently examined, but metastases were found in two of three cases examined; both had clinical evidence of spinal cord spread. Fig. 1 Extent of spread in DIPG. a Neuroanatomical sites and frequency of tumor invasion. Numbers indicate the percentage of cases that exhibit tumor invasion at the indicated anatomical location. The size of the circles marking each anatomical site (color key ... A previously under-recognized pattern of subventricular spread was noted in 10/16 cases, with infiltration of the subventricular zone (SVZ) and tumor nodules in the frontal horns of the lateral ventricles. In three cases lateral ventricular disease was noted on pre-mortem MRI (Fig. 2a), but subclinical tumor invasion in the SVZ of the lateral ventricles was found in six additional cases; subventricular spread was found in the third ventricle of one additional case (Fig. 2). The observed pattern of ventricular/subventricular involvement could be due to direct invasion along the SVZ corridor, intraventricular cerebrospinal fluid (CSF) seeding of the SVZ, or an as yet undescribed mechanism. The postnatal SVZ is a neural stem cell niche in the human brain [8] and DIPG cells express an immunophenotype reminiscent of neural precursor cells (Fig. S1 and [9]). Whether DIPG cells exhibit a particular tropism for this niche remains to be explored. Fig. 2 Invasion of the subventricular zone in DIPG (a). MRI images illustrating enhancing lesions (T1 post gadolinium, left image) at the frontal horns of the lateral ventricles with associated edema (FLAIR, right image) in case SU-DIPG-XIII. b H&E ( ... Following standard brainstem radiotherapy, disease progression typically occurs locally in the brainstem. However, in three of sixteen cases the subventricular frontal lobe disease contributed substantially to morbidity and mortality and preceded pontine recurrence in two cases. As therapies improve and patients survive longer in the natural history of their cancer, new patterns of regional relapse often appear (e.g. sanctuary disease in childhood leukemia). Our data show subventricular tumor spread in the majority of patients, typically later in the course of their disease. Thus as future therapies evolve to control local disease, strategies including extended or whole brain irradiation may become crucial. The patterns of widespread dissemination, including leptomeningeal, direct extension and subventricular spread, suggest that the extent of the optimal radiation field should be re-examined.

73 citations

Journal ArticleDOI
TL;DR: Results show that inhibition of WEE1 kinase in conjunction with radiotherapy holds potential as a therapeutic approach for the treatment of DIPG.
Abstract: Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric disease. Thus far, no therapeutic agent has proven beneficial in the treatment of this malignancy. Therefore, conventional DNA-damaging radiotherapy remains the standard treatment, providing transient neurologic improvement without improving the probability of overall survival. During radiotherapy, WEE1 kinase controls the G(2) cell-cycle checkpoint, allowing for repair of irradiation (IR)-induced DNA damage. Here, we show that WEE1 kinase is one of the highest overexpressed kinases in primary DIPG tissues compared with matching non-neoplastic brain tissues. Inhibition of WEE1 by MK-1775 treatment of DIPG cells inhibited the IR-induced WEE1-mediated phosphorylation of CDC2, resulting in reduced G(2)-M arrest and decreased cell viability. Finally, we show that MK-1775 enhances the radiation response of E98-Fluc-mCherry DIPG mouse xenografts. Altogether, these results show that inhibition of WEE1 kinase in conjunction with radiotherapy holds potential as a therapeutic approach for the treatment of DIPG.

70 citations


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Journal ArticleDOI
TL;DR: The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA.
Abstract: Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a 'liquid biopsy' for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.

1,630 citations

Journal ArticleDOI
TL;DR: This text is a general introduction to radiation biology and a complete, self-contained course especially for residents in diagnostic radiology and nuclear medicine that follows the Syllabus in Radiation Biology of the RSNA.
Abstract: The text consists of two sections, one for those studying or practicing diagnostic radiology, nuclear medicine and radiation oncology; the other for those engaged in the study or clinical practice of radiation oncology--a new chapter, on radiologic terrorism, is specifically for those in the radiation sciences who would manage exposed individuals in the event of a terrorist event. The 17 chapters in Section I represent a general introduction to radiation biology and a complete, self-contained course especially for residents in diagnostic radiology and nuclear medicine that follows the Syllabus in Radiation Biology of the RSNA. The 11 chapters in Section II address more in-depth topics in radiation oncology, such as cancer biology, retreatment after radiotherapy, chemotherapeutic agents and hyperthermia.

1,359 citations

Journal ArticleDOI
TL;DR: This review focuses on key areas of clinical applications of CTCs and ctDNA, including detection of cancer, prediction of prognosis in patients with curable disease, monitoring systemic therapies, and stratification of patients based on the detection of therapeutic targets or resistance mechanisms.
Abstract: “Liquid biopsy” focusing on the analysis of circulating tumor cells (CTC) and circulating cell-free tumor DNA (ctDNA) in the blood of patients with cancer has received enormous attention because of its obvious clinical implications for personalized medicine. Analyses of CTCs and ctDNA have paved new diagnostic avenues and are, to date, the cornerstones of liquid biopsy diagnostics. The present review focuses on key areas of clinical applications of CTCs and ctDNA, including detection of cancer, prediction of prognosis in patients with curable disease, monitoring systemic therapies, and stratification of patients based on the detection of therapeutic targets or resistance mechanisms. Significance: The application of CTCs and ctDNA for the early detection of cancer is of high public interest, but it faces serious challenges regarding specificity and sensitivity of the current assays. Prediction of prognosis in patients with curable disease can already be achieved in several tumor entities, particularly in breast cancer. Monitoring the success or failure of systemic therapies (i.e., chemotherapy, hormonal therapy, or other targeted therapies) by sequential measurements of CTCs or ctDNA is also feasible. Interventional studies on treatment stratification based on the analysis of CTCs and ctDNA are needed to implement liquid biopsy into personalized medicine. Cancer Discov; 6(5); 479–91. ©2016 AACR.

1,055 citations

Journal ArticleDOI
TL;DR: A review of the biophysical properties and physiological functions of extracellular vesicles, particularly their pro-metastatic effects, and highlight the utility of EVs for the development of cancer diagnostics and therapeutics can be found in this paper.
Abstract: The sustained growth, invasion, and metastasis of cancer cells depend upon bidirectional cell-cell communication within complex tissue environments. Such communication predominantly involves the secretion of soluble factors by cancer cells and/or stromal cells within the tumour microenvironment (TME), although these cell types have also been shown to export membrane-encapsulated particles containing regulatory molecules that contribute to cell-cell communication. These particles are known as extracellular vesicles (EVs) and include species of exosomes and shed microvesicles. EVs carry molecules such as oncoproteins and oncopeptides, RNA species (for example, microRNAs, mRNAs, and long non-coding RNAs), lipids, and DNA fragments from donor to recipient cells, initiating profound phenotypic changes in the TME. Emerging evidence suggests that EVs have crucial roles in cancer development, including pre-metastatic niche formation and metastasis. Cancer cells are now recognized to secrete more EVs than their nonmalignant counterparts, and these particles can be isolated from bodily fluids. Thus, EVs have strong potential as blood-based or urine-based biomarkers for the diagnosis, prognostication, and surveillance of cancer. In this Review, we discuss the biophysical properties and physiological functions of EVs, particularly their pro-metastatic effects, and highlight the utility of EVs for the development of cancer diagnostics and therapeutics.

925 citations

Journal ArticleDOI
TL;DR: Key studies in which systems and strategies to enhance, combine, bypass and image EPR-based tumor targeting, and how these approaches can be employed to enhance patient responses are summarized.

839 citations