Ter Elst Research Articles

Power bounded operators and the mean ergodic theorem for subsequences

Let T be a power bounded Hilbert space operator without unimodular eigenvalues. We show that the subsequential ergodic averages N−1∑n=1NTan converge in the strong operator topology for a wide range of sequences (an), including the integer part of most of subpolynomial Hardy functions. Moreover, we show that the weighted averages N−1∑n=1Ne2πig(n)Tan also converge for many reasonable functions g. In particular, we generalize the polynomial mean ergodic theorem for power bounded operators due to ter Elst and the second author [16] to real polynomials and polynomial weights.

Abstract 4335: Clinical value of EGFR gene amplifications detected using amplicon based targeted next generation sequencing data in lung adenocarcinoma patients

Abstract Objective The relevance of EGFR gene amplification in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) has not been fully elucidated. Moreover, a limited number of studies have been published on methods to estimate gene amplifications based on routinely performed targeted next generation sequencing (NGS). In this study we aimed to determine whether PCR-based targeted NGS data on tumor tissue can be used to estimate presence of gene amplifications and explored the prognostic value of EGFR gene amplification in EGFR mutated NSCLC patients. Materials and methods A total of 3,194 good quality targeted NGS data files were retrieved from 2014 to 2017. Among those, 1,729 NSCLC samples originated from 1,586 NSCLC patients of whom 134 had an EGFR mutation (8.2%). Clinical data were available for 66 of the patients. Raw sequencing data were re-analyzed using a custom designed pipeline. The presence of an amplification was based on the read depth of a given amplicon relative to a set of reference amplicons from the sample or relative to a set of normal control samples. Reference amplicons were selected based on low degree of variation in read depth amongst all tested samples. Amplifications were regarded significant when the ratio was ≥3 and the z score was ≥3.5. Technical validation was done by FISH and MLPA. Cox regression analysis on overall survival was done with each of the amplification parameters using SPSS. Results No amplifications were detected for the ALK, KIT, NRAS, PDGFRA, GNAQ and MAP2K1 gene loci, whereas amplifications for BRAF, ESR1, GNA11, HRAS, KRAS, MET and PIK3CA were observed at a low frequency. Depending on the amplification analysis strategy (within sample or relative to normal controls), 19% and 13% of the EGFR mutated group had an EGFR amplification, respectively. In EGFR wild type patients, amplifications were detected in 5% and 4% of the patients using the two methods, respectively. The sensitivity and specificity of the NGS based estimation of amplifications for EGFR was 94% (14/15) and 97% (34/35) respectively for both data analysis approaches. Patients with concurrent EGFR mutations and amplifications (estimated within sample) treated with EGFR-TKI had a significantly worse overall survival compared with those without concurrent EGFR amplifications (ratio, p=0.047 and z score, p=0.015). Cox regression analysis indicated a borderline significant interaction between ratio and z score (p=0.052). Conclusion Routinely obtained amplicon-based NGS data can be used to identify gene amplifications. The presence of EGFR amplifications in EGFR mutant patients is predictive of a worse overall survival. Keywords: Lung adenocarcinoma, EGFR, survival, tyrosine kinase inhibitor Citation Format: Pei Meng, Jiacong Wei, Miente Martijn Terpstra, Anke van Rijk, Menno Tamminga, Frank Scherpen, Arja ter Elst, Mohamed Z. Alimohamed, Lennart F. Johansson, T. Jeroen N. Hiltermann, Harry J. Groen, Klaas Kok, Anthonie J. van der Wekken, Anke van den Berg. Clinical value of EGFR gene amplifications detected using amplicon based targeted next generation sequencing data in lung adenocarcinoma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4335.

Davies’ method for heat-kernel estimates: An extension to the semi-elliptic setting

We consider a class of constant-coefficient partial differential operators on a finite-dimensional real vector space which exhibit a natural dilation invariance. Typically, these operators are anisotropic, allowing for different degrees in different directions. The “heat” kernels associated to these so-called positive-homogeneous operators are seen to arise naturally as the limits of convolution powers of complex-valued measures, just as the classical heat kernel appears in the central limit theorem. Building on the functional-analytic approach developed by E. B. Davies for higher-order uniformly elliptic operators with measurable coefficients, we formulate a general theory for (anisotropic) self-adjoint variable-coefficient operators, each comparable to a positive-homogeneous operator, and study their associated heat kernels. Specifically, under three abstract hypotheses, we show that the heat kernels satisfy off-diagonal (Gaussian-type) estimates involving the Legendre-Fenchel transform of the operator’s principle symbol. Our results extend those of E. B. Davies and G. Barbatis and partially extend results of A. F. M. ter Elst and D. Robinson.

Abstract 1398: Modeling of drug-protein interactions to support clinical decision making for therapy-resistant EGFR or ALK-positive non-small cell lung carcinoma

Abstract Background Activating mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangements are drugable targets in respectively 10% and 4% of advanced non-small cell lung cancer (NSCLC) patients. Different EGFR and ALK inhibitors are available for target-dependent and sometimes independent drug resistance. Mutations in the EGFR or ALK kinase domain are major mechanisms of drug-induced resistance. Prediction of protein-drug interactions using protein modeling of these mutated domains in EGFR and ALK could provide valuable information for the selection of drugs for subsequent treatment. Methods Biopsies from advanced NSCLC patients with an activating EGFR mutation or ALK rearrangement that were taken at therapy resistance were analyzed by targeted panel sequencing. In case of unknown or accumulating mutations in the EGFR and ALK kinase domains, docking poses and binding affinities of drug-protein interactions were determined. The outcome of both calculations were used to create a likelihood ranking of currently available ALK and EGFR inhibitors to bind to specific mutated targets. Follow-up data was available for a limited number of patients who were treated based on this prediction. Results Prediction Protein-drug interactions were modeled for 59 EGFR mutations and 24 ALK mutations that were detected at therapy resistance. Prediction of therapeutic activities for gefitinib, afatinib, dacomitinib, for EGFR mutations, and alectinib, ceritinib, entrectinib and lorlatinib for ALK mutations will be shown. Case example Female (35y), never-smoker, cT1bN2M1c NSCLC with metastases in lymph nodes, liver, bones and asymptomatic brain metastases, ALK translocation-positive without known ALK gatekeeper mutations. Treatment with crizotinib was started, but unacceptable liver enzyme toxicity developed after 6 weeks. Switching therapy to alectinib resulted in a complete metabolic response with absence of brain metastases by MRI. After 9 months the patient progressed with liver, brain and leptomeningeal metastases. Treatment with ceritinib had no effect. A liver biopsy revealed the ALK p.(L1196M) gatekeeper mutation. The case was discussed in the molecular tumor board, because this gatekeeper variant was reported to be sensitive to ceritinib. In contrast, ALK-drug interaction modeling indicated a better binding profile of lorlatinib than ceritinib, not only based in binding affinity but also in the ability of lorlatinib to reproduce the bioactive conformation found in literature. The patient was treated with lorlatinib and recovered in 5 days with a persistent partial response at 2 month follow up and significant clinical benefit. Conclusion Modeling of the protein-drug interactions supports clinical decision making for treatment of NSCLC patients in case of therapy resistance to EGFR and ALK inhibitors. Citation Format: Juliana F. Vilacha Madeira R Santos, Birgitta I. Hiddinga, Leon C. van Kempen, Arja ter Elst, Lucie B. Hijmering, Thijo J. Hiltermann, Ed Schuuring, Matthew R. Groves, Harry J. Groen, Anthonie J. van der Wekken. Modeling of drug-protein interactions to support clinical decision making for therapy-resistant EGFR or ALK-positive non-small cell lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1398.

Abstract 1602: Urine cell-free DNA as early biomarker in immunotherapy response in NSCLC

Abstract Introduction: Immunotherapy shows a durable tumor response in approximately 20% of advanced NSCLC patients. Imaging by CT is used to evaluate tumor response. PD-L1 immunohistochemistry is generally used to predict survival advantages, however with low predictive value. Therefore, it is important that alternative predictive biomarkers are investigated. Minimal invasive techniques may be a solution. The role of circulating cell-free DNA (cfDNA) was found to be an early biomarker for tumor response in KRAS positive Non-Small Cell Lung Cancer (NSCLC) patients treated with immunotherapy (N=6). In this study we will determine the role of urine cell-free DNA (ucfDNA) in an extended cohort. The non-invasive method of urine collection makes it an excellent source for mutation detection and follow-up. Methods: In an ongoing study KRAS positive patients treated with immunotherapy, are being tested for cfDNA at baseline (before treatment, 1, 2, 4, 6 and thereafter every 12 weeks until disease progression) with a KRAS G12-13 or Q61H digital droplet PCR (ddPCR) screening assay (BioRad). In a pilot study, urine from these patients is collected in a tube with 5 ml of STRECK reagent at baseline and at 6 weeks. Results: In 16/27 patients with KRAS positive advanced NSCLC, the mutation was detected in plasma at baseline and subsequent evaluation time points. Urine cfDNA as a predictive marker seems promising and results will be reported and presented at the AACR meeting. Conclusion: Among patients with advanced NSCLC treated with immunotherapy plasma and urine cfDNA are collected and will be presented as non-invasive early biomarker for tumor response evaluation. Citation Format: Anthonie J. van der Wekken, Arja ter Elst, Anneke Miedema, Thijo J. Hiltermann, Harry J. Goen, Ed Schuuring. Urine cell-free DNA as early biomarker in immunotherapy response in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1602.

Abstract 754: Treatment decision-making of rare ERBB2 (HER2) mutations in lung cancer; a role for multidisciplinary molecular tumor boards

Abstract Introduction: Breakthroughs in cancer research have resulted in mutation-specific targeted therapies (precision medicine). Most of these new drugs are only effective in patients with an actionable molecular profile. Thus, predictive molecular testing enables oncologists to select individual patients for the most appropriate (targeted) therapy and to reduce the burden of overtreatment. The number of clinically relevant predictive markers that are routinely analyzed is growing rapidly, resulting in the identification of rare mutations, mutations with unknown relevance and coexistence of two or more mutations in the same sample. Incorporating these into the optimal treatment for the individual patient can be complex. Methods: A total of 2461 sequential tumor biopsies were analyzed at our institute using targeted next generation sequencing (Ion Torrent platform). 230 of these patients were discussed at a weekly Molecular Tumor Board (MTB) meeting. Cases involved 170 lung and 21 colorectal carcinomas, 24 melanomas, 1 GIST and a range of other malignancies with uncommon and rare mutations. The board is composed of pulmonologists, medical oncologists, pathologists and clinical scientists in molecular pathology. The goal of the MTB is to discuss the biological and clinical relevance of rare mutations or uncommon profiles and to suggest treatment options based on registered, off-label or trial-based drugs presently available in the Netherlands. Results: In this abstract we report on four patients with an ERBB2 exon 20 mutation and 1 patient with ERBB2 amplification received anti-HER2 treatment after an MTB consensus decision. Two patients with an insertion in exon 20 of ERBB2: (c.2313_2324dup; p.(Y772_A775dup)) received first line therapy with afatinib and showed a partial response and stable disease respectively. One patient with a c.2524G>A; p.(V842I) mutation received afatinib and showed stable disease for 3 months. A patient with another ERBB2 exon 20 insertion (c.2326_2327insTAT:p.(G776delinsVC)) received afatinib but had progressive disease within two months. One patient with an ERBB2 amplification by FISH and high (3+) HER2(ERBB2) expression, showed a partial response to trastuzumab. All patients had stage IV and would without genomic knowledge been treated with chemotherapy. Conclusion: Lung cancer patients with sporadic ERBB2 mutations might benefit from targeted ERBB2 therapy. For an optimal treatment decision, patients with rare mutations in general, may benefit from discussion in a multidisciplinary molecular tumor board. In the future, both the considerations for targeted therapy as well as treatment response and toxicity should be registered in an open-access database and shared with other national and international Molecular Tumor Board initiatives to allow comparison with traditional treatments. Citation Format: Arja ter Elst, Nils A. 't Hart, Anthonie J. van der Wekken, Wim Timens, Lucie B. Hijmering-Kappelle, Geke A. Hospers, Hilde Jalving, Elise M. van der Logt, Leon C. van Kempen, Sjoukje F. Oosting, Matthew R. Groves, T Jeroen Hiltermann, Anke van den Berg, Harry J. Groen, Ed Schuuring. Treatment decision-making of rare ERBB2 (HER2) mutations in lung cancer; a role for multidisciplinary molecular tumor boards [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 754. doi:10.1158/1538-7445.AM2017-754

Abstract 4951: Dynamics of KIT exon 11 mutations in cell free plasma DNA of patients treated for advanced gastrointestinal stromal tumors: Results from the Dutch GIST bio-databank

Abstract Introduction Gastrointestinal stromal tumors (GISTs) are rare malignancies of the gastrointestinal tract. In the Netherlands, most patients with GIST are treated in five sarcoma expertise centers. GIST is known to have driver mutations in the tyrosine kinase receptors KIT and PDGFRα in respectively 80% and 10% of the patients. Mutations (single nucleotide variations, insertions and deletions) are mostly found in KIT exon 9 and 11. GIST patients with a primary KIT exon 11 mutation respond generally well to tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate treatment response by the detection of KIT exon 11 mutations in cell free DNA (cfDNA) of patients with GIST at multiple time points. Materials and methods Since Dec 2014, plasma samples of patients have been collected at every hospital visit and were put in a bio-databank for analysis of mutation detection in cfDNA. Eligibility criteria were histological diagnosis of GIST and treatment with a TKI. Patients with a known KIT exon 11 mutation, of which a baseline (before start of any TKI) sample or a recurrence/progression sample was available, were analyzed. A custom single-tube digital droplet PCR (ddPCR) drop-off assay, designed at the UMCG, was used. This assay detects 80% of the known KIT exon 11 mutations. Results Until Nov 2016, >620 samples of 175 patients have been collected. From 43 patients with a KIT exon 11 mutations in the pretreatment tumor biopsy, a baseline/progression sample was available. Mutations in exon 11 were detected in cfDNA from baseline plasma of 22/43 patients, 20 with metastasized and 2 with localized disease. Of the 21 patients without detectable mutations, 11 had localized and 10 metastatic disease. Three of these patients with metastatic disease had mutations that could not be detected by our probe. Two weeks after start of TKI, an increase in mutant allelic frequency was seen in 5 (of 9 available 2 week samples) patients, while 4 weeks later the mutant allelic frequency had decreased, in parallel with decrease in tumor load on radiological imaging. Eight patients developed radiological disease recurrence (2 patients, after 4 and 20 months) or progression (6 patients, median 10 (6-24) months). This was paralleled by an increase in mutant allelic frequency in cfDNA in 6 of them (baseline median 0% (0-0.9%); at progression median 3.5% (0-30%); p= 0.028; related samples Wilcoxon signed rank test). Summary and conclusion KIT exon 11 mutations in cfDNA could be detected in 74% of the patients with metastatic disease. Disease progression or recurrence, coincides with a rise of mutant alleles detected in the plasma. In conclusion, mutation detection in cfDNA of GIST patients with metastatic disease is feasible. Our study will be extended to include the monitoring of early progression based on cfDNA, which may guide early treatment adaptations. Citation Format: Pieter A. Boonstra, Arja ter Elst, Marco Tibbesma, Ron H. Mathijssen, Florence Atrafi, Frits van Coevorden, Sheima Farag, Neeltje Steeghs, Ingrid M. Desar, Winette T. van der Graaf, Hans Gelderblom, Boudewijn van Etten, Jelle Overbosch, Albert J. Suurmeijer, Jourik A. Gietema, Ed Schuuring, Anna K. Reyners. Dynamics of KIT exon 11 mutations in cell free plasma DNA of patients treated for advanced gastrointestinal stromal tumors: Results from the Dutch GIST bio-databank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4951. doi:10.1158/1538-7445.AM2017-4951

Abstract 2718: Molecular Tumor Board treatment predictions on rare EGFR exon 20 mutations

Abstract Purpose: To evaluate treatment response following the Multidisciplinary Molecular Tumor Board (MTB) decisions which focused on EGFR exon 20 mutations in lung adenocarcinoma. Methods: Molecular studies were routinely performed using the Ion Torrent sequencing platform for histologically or cytologically diagnosed lung adenocarcinoma. Since October 2014 patients with rare (prevalence <1%) or combinations of rare mutations were discussed at the MTB of the University Medical Center Groningen. More common, known sensitive EGFR, BRAF V600E, as well as KRAS, and PIK3CA mutations were excluded. To predict the best therapy for a subset of patients with EGFR exon 20 insertion mutations the literature is reviewed and molecular models were built using SWISS-MODEL, is used to predict protein tertiary structure (https://swissmodel.expasy.org/interactive/wcurbt/models/). Summary of data: Over a period of 2 years 1389 samples were tested. A total of 170 (12.2%) rare mutations were detected in lung cancer. Among these rare mutations we observed 16 EGFR exon 20 insertions and other mutations like e.g: p.T790M, p.D761N, p.D770delinsGY, p.S768_D770dup, p.V769_D770insSFL, p.N771_H773dup, p.T790S. Using an in silico modeling of protein responses with TKI were predicted to be likely in EGFR T790M mutations and p.S768_V769delinsIL, but not in p. D770delinsGY, p.S768_D770dup, p.V769_D770insSFL, and p.N771_H773dup mutations. Eight patients with an exon 20 mutation were treated with an EGFR TKI. One patient (p.D761N) had a partial response on erlotinib 300mg daily. On afatinib monotherapy 2 out of 3 pts had stable disease (PFS 3-11 months). On afatinib/cetuximab treatment 1 out of 2 pts (p.D770delinsGY) had a partial response and the other patient had stable disease (p.S768_D770dup) (PFS 11 and 4 months, resp.). Two evaluable patients were treated with osimertinib: the first patient initially progressed on afatinib (p.V769_D770insSFL). The protein model predicted no response, since we predicted hindrance of osimertinib. The model predicted no response on osimertinib in the second patient as well, and during treatment a stable disease for 4 months was observed (p.N771_H773dup). This molecular information from the weekly MTB meeting was delivered within 2 weeks to the treating physician. Feedback on treatment outcome helped to further improve treatment predictions. Conclusion: The Molecular Tumor Board is an effective multidisciplinary team to discuss rare mutations. Our pilot data show that the evaluation of the use and effectiveness of a theoretical model concerning protein structures is not possible yet, however, did provide a clear insight in protein structures in a mutated EGFR receptor supporting decision making of treatment options. Citation Format: Anthonie J. van der Wekken, Matthew R. Groves, Arja ter Elst, Nils A. 't Hart, Lucie B. Hijmering-Kappelle, Thijo J. Hiltermann, Anke van den Berg, Wim Timens, Ed Schuuring, Harry J. Groen. Molecular Tumor Board treatment predictions on rare EGFR exon 20 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2718. doi:10.1158/1538-7445.AM2017-2718

Abstract 3107: A single ddPCR assay to detect KIT exon 11 mutations in tumor and cell free plasma DNA of patients with gastrointestinal stromal tumors

Abstract . Introduction Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors of the gastrointestinal tract. These tumors are characterized by genomic mutations in the c-KIT gene that drive tumor growth and are target for specific inhibitors. Mutations in exon 11 (single nucleotide variations and deletions) are detected in approximately 70% of GIST. Although unique for each patient, most variations cluster in two different mutational hotspots each 25bp in size. The aim of this study was to develop and test a single quantitative digital droplet PCR (ddPCR) assay to detect exon 11 c-KIT mutations in both formalin fixed paraffin embedded (FFPE) tissue and serial collected cell-free plasma DNA (cfDNA) of GIST patients for diagnostic and treatment response monitoring. Materials and methods The drop-off ddPCR assay for detection of exon 11 mutations consists of two fluorescent (FAM and HEX) labeled probes that each cover one of the 2 mutation hotspots. Since double exon 11 mutations are very rare in GIST, one probe will anneal to the non-mutated sequence (reference probe), while the other probe will not anneal. A decrease of one of the 2 fluorescent signals is considered as the presence of a mutation (“drop-off”). For validation, ddPCR results from tumor biopsies were compared with data from next generation sequencing (NGS) using the IonTorrent platform. Pretreatment FFPE tumor material was obtained from 29 (18 exon 11 mutated, 11 non-exon 11 mutated) GIST patients treated in 2014 and 2015. Plasma samples were collected at baseline (before start of treatment with imatinib) and at consecutive time points during treatment. Results Using the drop-off ddPCR assay on the same DNA used for NGS, mutations in 17 of the 18 samples were detected. Comparison of the allelic fraction of the mutation shows that ddPCR analysis is very similar to NGS. In 11 control samples, who were wild-type (4 samples) or had mutations other than c-KIT exon 11 (7 samples) no loss of signal was detected. CfDNA was analyzed of a 72-year old representative patient with metastatic GIST carrying a c-KIT deletion in exon 11 with a fractional abundance (FA) in tissue of 91%. We detected the mutation using the drop-off ddPCR assay in the plasma sample collected before start of imatinib treatment (FA 16%). Two weeks after initiation of imatinib a rise in mutant allelic frequency was observed (FA 61%) and a decrease after 4 weeks (FA 3%) of therapy. Conclusion The detection of multiple exon 11 mutations/deletions using a single ddPCR assay could be used as a rapid prescreening method for the detection of c-KIT mutations in FFPE tissue in GIST patients. Because of the quantitative nature of this assay, ddPCR analysis might be used to monitor response to treatment. The relevance of this drop-off assay for treatment decision making seems promising and is currently validated on a large series of cfDNA samples and a prospective study in GIST patients (NCT02331914). Citation Format: Pieter A. Boonstra, Marco Tibbesma, Lisette J. Bosman, Ron H.J. Mathijssen, Frits van Coevorden, Neeltje Steeghs, Albert J.H. Suurmeijer, Arja ter Elst, Jourik A. Gietema, Anna K.L. Reyners, Ed M.D. Schuuring, Dutch GIST Consortium. A single ddPCR assay to detect KIT exon 11 mutations in tumor and cell free plasma DNA of patients with gastrointestinal stromal tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3107.

A generalisation of the form method for accretive forms and operators

The form method as popularised by Lions and Kato is a successful device to associate m-sectorial operators with suitable elliptic or sectorial forms. McIntosh generalised the form method to an accretive setting, thereby allowing to associate m-accretive operators with suitable accretive forms. Classically, the form domain is required to be densely embedded into the Hilbert space. Recently, this requirement was relaxed by Arendt and ter Elst in the setting of elliptic and sectorial forms. Here we study the prospects of a generalised form method for accretive forms to generate accretive operators. In particular, we work with the same relaxed condition on the form domain as used by Arendt and ter Elst. We give a multitude of examples for many degenerate phenomena that can occur in the most general setting. We characterise when the associated operator is m-accretive and investigate the class of operators that can be generated. For the case that the associated operator is m-accretive, we study form approximation and Ouhabaz type invariance criteria.

Abstract 5085: Less tumor engraftment after anti-VEGF therapy in pediatric low grade astrocytoma.

Abstract Introduction. Low grade astrocytomas are the most frequent brain tumors in children. Although children can benefit from treatments including neurosurgery, chemotherapy and radiotherapy, still children die due to tumor progression. Furthermore, morbidity can be serious. So new therapeutic strategies are warranted for these patients. Previously, we showed that angiogenesis is a characteristic of pediatric low grade astrocytoma (Sie et al, NAN 2010). Therefore, vascular endothelial growth factor (VEGF), the most critical angiogenic factor, may be a potential therapeutic target. The present study aimed to analyze the effect of VEGF inhibition in vitro and in vivo in pediatric low grade astrocytoma. Materials and methods. Three different pediatric low grade astrocytoma cell lines were used: Res-186 (WHO grade I astrocytoma), Res-259 and UW-467 (WHO grade II astrocytoma). Effects in vitro of the anti-VEGF monoclonal antibodies, bevacizumab (0 - 50 ug/ml, Avastin®, anti human VEGF) and B20-4.1.1 (0 - 200 ug/ml, anti human and mouse VEGF) were studied using a WST-1 cell viability assay and a cell proliferation assay with BRDU. Res-259 cells were orthotopically implanted in NOD-scid IL2Rgnull mice. After 6 weeks of treatment intraperitoneal twice weekly with bevacizumab (15 mg/kg), B20-4.1.1 (5 mg/kg) or phosphate buffered saline as control group, mice were euthanized and tumor engraftment was studied in brain slides using Aperio's imagescope viewer. Results. In vitro cell growth was not changed as measured by WST-1 and BRDU incorporation. In vivo results showed less tumor engraftment in bevacizumab (n = 10) and B20-4.1.1 (n = 9) treated mice compared with the control group (n = 10) (resp. 70%, 44%, 100%). In the bevacizumab and B20-4.1.1 treated mice tumor mass was lower as compared with controls (resp. P = 0.062, P = 0.001). Conclusion(s). This study showed less tumor engraftment after anti-VEGF therapy in a newly developed pediatric low grade astrocytoma mouse model. In these tumors anti-VEGF seems to work especially on tumor microenvironment. Suggesting that anti-VEGF could have a potential role in the therapeutic strategy for children with low grade astrocytoma, thoughtfulness on possible tumor escape mechanisms that may arise will be crucial. [W.F.A. den Dunnen and E.S.J.M. de Bont shared senior authorship.] Citation Format: Mariska Sie, Arend H. Sikkema, Frank J.G. Scherpen, Arja ter Elst, Kim R. Kampen, Eelco W. Hoving, Wilfred F.a. den Dunnen, Eveline S.j.m. de Bont. Less tumor engraftment after anti-VEGF therapy in pediatric low grade astrocytoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5085. doi:10.1158/1538-7445.AM2013-5085

Convergence of operator semigroups associated with generalised elliptic forms

In a recent article, Arendt and ter Elst have shown that every sectorial form is in a natural way associated with the generator of an analytic strongly continuous semigroup, even if the form fails to be closable. As an intermediate step, they have introduced so-called j−elliptic forms, which generalise the concept of elliptic forms in the sense of Lions. We push their analysis forward in that we discuss some perturbation and convergence results for semigroups associated with j−elliptic forms. In particular, we study convergence with respect to the trace norm or other Schatten norms. We apply our results to Laplace operators and Dirichlet-to-Neumann-type operators.

Spectral theory for commutative algebras of differential operators on Lie groups

The joint spectral theory of a system of pairwise commuting self-adjoint left-invariant differential operators L 1 , … , L n on a connected Lie group G is studied, under the hypothesis that the algebra generated by them contains a “weighted subcoercive operator” of ter Elst and Robinson (1998) [52]. The joint spectrum of L 1 , … , L n in every unitary representation of G is characterized as the set of the eigenvalues corresponding to a particular class of (generalized) joint eigenfunctions of positive type of L 1 , … , L n . Connections with the theory of Gelfand pairs are established in the case L 1 , … , L n generate the algebra of K-invariant left-invariant differential operators on G for some compact subgroup K of Aut ( G ) .

Feline Congress Ter Elst Congress Centre, Antwerp, Belgium.

Feline Congress Ter Elst Congress Centre, Antwerp, Belgium.