Van Rhijn Research Articles

Leading the Way to Heaven: Pastoral Care and Salvation in the Carolingian Period by Carine van Rhijn (review)

Leading the Way to Heaven: Pastoral Care and Salvation in the Carolingian Period by Carine van Rhijn (review)

Abstract 5786: Spatial relationships in the tumor microenvironment predict response to immune checkpoint inhibitors in urothelial and head and neck cancer

Abstract Background: Immune checkpoint inhibitors (ICI) can achieve remarkable clinical responses in urothelial cancer (UC). However, it remains unclear which aspects of the tumor microenvironment (TME) determine a patient’s response. The TME is usually characterized by immune cell density, which ignores cells’ spatial relationships relative to each other. Methods: Using multiplex immunofluorescence data (PanCK, CD20, CD68, CD3, CD8, and FoxP3 antibody panel) of 24 pre-ICI UC transurethral resections retrieved from the NABUCCO trial (NCT03387761), we spatially profiled cancer cells, macrophages, B-cells, and distinct T-cell populations. We first quantified the TME immune cell densities at the tumor and stroma tissue compartments. We then quantified the TME spatial relationships with a novel approach based on fitting a Weibull function to the first nearest neighbor (1-NN) distance distribution, allowing us to uniquely summarize spatial relationships with two parameters (Weibull approach). We compared this approach to conventional techniques (G-functions) that rely upon a predefined distance threshold. We performed a simulation study to identify sources of variation in the spatial relationship parameters. Lastly, we associated the TME parameters with ICI (ipilimumab + nivolumab) response. Results: Unlike the Weibull approach, the G-function quantifications manifested a variable effect size and statistical power in association studies because of its distance threshold dependence. We found that variation in density affected the spatial relationship metrics of rare cell types (i.e., B-cells) but not of abundant cell types (i.e., cancer cells). The spatial relationship metrics from the Weibull approach outperformed immune cell density in ICI response prediction. Specifically, immune cell density did not discriminate between ICI response groups (FDR>10%). In contrast, the spatial relationship between either CD8+ T-cells or macrophages to their closest cancer cell did associate with response to ICI (FDR=1%). Furthermore, non-responding tumors were characterized by CD8+ T-cells close to B-cells (FDR=9%). Importantly, we validated the association between proximity and response from CD8+ T-cells to cancer cells (FDR=1%) and from macrophages to cancer cells (FDR=1%) using data from 25 pre-ICI head and neck squamous cell carcinoma tumors from the IMCISION trial (NCT03003637, arm B, ipilimumab + nivolumab). Conclusion: We created a framework to quantify, study, interpret and analyze spatial relationships in the TME and illustrated its superior clinical relevance compared to density metrics for predicting ICI treatment response. Our findings emphasize the importance of spatial relationships in the TME for response and suggest that proximity between either macrophages or CD8+ T-cells to cancer cells are candidate biomarkers for ICI response. Citation Format: Alberto Gil-Jimenez, Nick van Dijk, Yoni Lubeck, Maurits L. van Montfoort, Dennis Peters, Erik Hooijberg, Annegien Broeks, Joris L. Vos, Charlotte L. Zuur, Bas van Rhijn, Daniel J. Vis, Michiel S. van der Heijden, Lodewyk F. Wessels. Spatial relationships in the tumor microenvironment predict response to immune checkpoint inhibitors in urothelial and head and neck cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5786.

Review article: Small futures. sortilege, divination and prognostication in Late Antiquity and the early Middle Ages

Early Medieval EuropeEarly View Review Article Review article: Small futures. sortilege, divination and prognostication in Late Antiquity and the early Middle Ages Carine van Rhijn, Carine van Rhijn Utrecht UniversitySearch for more papers by this author Carine van Rhijn, Carine van Rhijn Utrecht UniversitySearch for more papers by this author First published: 20 March 2023 https://doi.org/10.1111/emed.12620Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Early ViewOnline Version of Record before inclusion in an issue RelatedInformation

PIETER JOHANNES VAN RHIJN, KAPTEYN'S ASTRONOMICAL LABORATORY AND THE <italic>PLAN OF SELECTED AREAS</italic>

In this paper I discuss the Kapteyn Astronomical Laboratory during the period of Pieter Johannes van Rhijn's Directorate, which lasted from 1921 to 1957. It had developed under the founder Jacobus Cornelius Kapteyn into one of the leading astronomical research institutes in the world. When van Rhijn took over at the retirement of Kapteyn, it was in the process of coordinating Kapteyn's <italic>Plan of Selected Areas</italic> with the aim of determining the structure of the Sidereal System. Kapteyn had just, with the help of van Rhijn, presented a first model of the distribution of stars in space from existing observations, and on this basis he constructed a 'first attempt' model of the Stellar System including dynamics, i.e. deriving the gravitational field from the distribution of the stars and showing how the random and systematic motions of the stars, the kinematics, could provide equilibrium and stability to the system. Under van Rhijn, the work on the <italic>Selected Areas</italic> progressed well, but the Groningen Laboratorium went into decline, loosing much of its status and prestige. I conclude the following. There was very little choice for Kapteyn's successor and van Rhijn was appointed effectively by default. Kapteyn himself must have seen that the future for astronomy in the Netherlands lay with Leiden Observatory, where already during his lifetime two of his protégées, Willem de Sitter and Ejnar Hertzsprung, were in charge, and to which a third one was added not much later in the person of Jan Oort. Kapteyn had his <italic>Plan of Selected Areas</italic> in addition to the scientific case set up as a way of ensuring the future of the Groningen Laboratorium at least for the time of this effort, arranging it to be supplied with plate material to complete the provision of the data for the final attack on the Sidereal problem. Van Rhijn's research was solid and professional, but in his papers he invariably stopped before discussing how his findings fitted into the larger emerging picture of the structure of the Galaxy. Comparison of his work in the 1930s on the distribution of stars as a function of spectral types and Jan Hendrik Oort's determination of his 1938 crosscut through the Galaxy illustrates this. While this work by Oort constituted the second attempt following on Kapteyn's first, and may be seen as the actual completion of the research for which the <italic>Plan of Selected Areas</italic> was designed, van Rhijn continued adding more and more data in the context of the Plan without redefining the aims in the light of developments. The <italic>Spectral Durchmusterung</italic> carried out in collaboration with the Bergedorf-Hamburg Sternwarte and Harvard College Observatory was an enormous drain on the Groningen resources. Van Rhijn's successful attempt to obtain his own telescope resulted in very relevant and correct determinations of the wavelength dependence of interstellar extinction from photographic spectra, but these results only became available in the 1950s when the field had turned to photoelectric methods. Kapteyn's concept of an astronomical laboratory lost its viability in van Rhijn's time when observa-tories were no longer interested in providing observational material for others to do research. Kapteyn's model on the other hand of a laboratory-like institution, where research is based on material obtained elsewhere on Earth or in space, is now the normal operating mode in astronomical research. The only difference is access to observing facilities primarily, which is now structured and guaranteed (subject to proposal acceptance of course), through national and international organizations rather than access on the basis of one's fame or stature. The cause of the loss of the Kapteyn Laboratorium of its prominent place in the international context was largely van Rhijn's unwavering dedication to complete Kapteyn's work. The <italic>Plan of Selected Areas</italic> had been important for the progress of astronomy, but effectively reached the goals Kapteyn had in mind for it already in the 1930s with Oort's 1932 work on the vertical force field and local 'Oort limit' and his 1938 crosscut through the Galaxy. Van Rhijn was unfortunately hampered throughout almost his entire Directorate by factors that severely limited his attempts to obtain more funding in spite of local support from his university. These were of course in the first place the Great Depression of the 1930s and World War II and its aftermath, while during most of the 1940s he suffered from tuberculosis. But, also, the remote location of Groningen compared to Leiden, where a major infrastructure led by three important protégées of Kapteyn was in place, and the Governmental bias towards support for Leiden over Groningen was an important factor. Finally, I examine the developments in the 1950s and the circumstances that made Adriaan Blaauw accept his appointment as van Rhijn's successor in 1957 and initiate the beginnings of the revival of the Kapteyn Laboratorium under his leadership.

Abstract 1273: Predicting pathological response after ipilimumab plus nivolumab in stage III urothelial cancer by liquid-biopsy assessment of plasma and urine ctDNA using the RaDaR assay

Abstract Patients (pts) with stage III (cT3-4aN0M0 or cT1-4aN1-3M0) urothelial cancer (UC) have a poor prognosis. In NABUCCO cohort 1, 24 stage III UC pts were treated with ipilimumab (ipi) plus nivolumab (nivo) followed by radical surgery (day 1: ipi 3 mg/kg; day 22: ipi 3 mg/kg + nivo 1 mg/kg; day 43: nivo 3 mg/kg). 14/24 (58%) of pts showed a pathological response (ypT0N0 or ypTisN0/ypTaN0). Currently, there are no good biomarkers to assess response before surgery, potentially leading to overtreatment and unnecessary surgical complications. Here, we investigated whether detection of circulating tumor DNA (ctDNA) in plasma and urine by the RaDaR™ personalized liquid biopsy assay was associated with treatment response and outcomes. EDTA-plasma and urine supernatant were collected before start of treatment (day 1; “baseline”), before each subsequent treatment cycle (day 22 and 43) and before radical surgery. WES was performed on tumor FFPE and peripheral blood germline DNA to identify somatic variants for designing patient-specific, multiplex PCR-based NGS RaDaR™ panels. Plasma and urine ctDNA was analyzed using these panels to determine ctDNA detection and its estimated variant allele frequency (eVAF). Tissue somatic variants were detected in all patients, a median of 48 variants was used per RaDaR™ panel (range: 43-51). ctDNA was detected in 50/94 plasma samples (53%) and in 74/93 urine samples (80%). Detection levels were higher in urine with a median eVAF of 1.98% (range: 0.00057%-35.85%) vs. 0.049% (range: 0.00026%-18.94%) in plasma. ctDNA was detected in baseline plasma in 10/14 (71%) responding pts (median eVAF: 0.325%) and in 8/10 (80%) non-responders (median eVAF: 0.107%). Changes in ctDNA levels reflected clinical responses. After treatment with ipi plus nivo, ctDNA was undetectable in 13/14 (93%) responding pts, and in only 4/10 (40%) of non-responders (p=0.0088). Of the 17 pts with undetectable ctDNA before surgery, 13 (76%) had a pathological response and 16/17 (94%) pts remained recurrence-free after a median follow-up of 34 months. Urine ctDNA was detected at baseline in 12/14 (86%) responding pts (median eVAF: 9.634%) and in 8/10 (80%) non-responders (median eVAF: 2%). After treatment with ipi plus nivo, urine ctDNA was detected in 8/14 (57%) responding pts (median eVAF: 0.87%), and in 8/10 (80%) non-responders (median eVAF: 0.162%). No association was observed between urine ctDNA detection and response (p=0.39). Detection of plasma ctDNA by RaDaR™ after neoadjuvant treatment was associated with pathological response and clinical outcome. In contrast, ctDNA detection in urine was not associated with outcomes. Absence of plasma ctDNA pre-surgery may predict complete response to ipi plus nivo at surgery and may be helpful in guiding clinical decisions in stage III UC, in particular to select pts for bladder-sparing strategies. Citation Format: Jeroen van Dorp, Christodoulos Pipinikas, Nick van Dijk, Greg Jones, Alberto Gil-Jimenez, Giovanni Marsico, Maurits L. van Montfoort, Sophie Hackinger, Linde Braaf, Kirsten McLay, Daan van den Broek, Bas W. Van Rhijn, Nitzan Rosenfeld, Michiel S. van der Heijden. Predicting pathological response after ipilimumab plus nivolumab in stage III urothelial cancer by liquid-biopsy assessment of plasma and urine ctDNA using the RaDaR assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1273.

MP03-06 PROSPECTIVE STUDY ON FDG-PET/CT FOR ON-TREATMENT ASSESSMENT OF RESPONSE TO NEOADJUVANT OR INDUCTION CHEMOTHERAPY IN INVASIVE BLADDER CANCER

You have accessJournal of UrologyCME1 May 2022MP03-06 PROSPECTIVE STUDY ON FDG-PET/CT FOR ON-TREATMENT ASSESSMENT OF RESPONSE TO NEOADJUVANT OR INDUCTION CHEMOTHERAPY IN INVASIVE BLADDER CANCER Sarah Einerhand, Charlotte Voskuilen, Elies Fransen van de Putte, Maarten Donswijk, Annemarie Bruining, Michiel Van der Heijden, Laura Mertens, Kees Hendricksen, Erik Vegt, and Bas van Rhijn Sarah EinerhandSarah Einerhand More articles by this author , Charlotte VoskuilenCharlotte Voskuilen More articles by this author , Elies Fransen van de PutteElies Fransen van de Putte More articles by this author , Maarten DonswijkMaarten Donswijk More articles by this author , Annemarie BruiningAnnemarie Bruining More articles by this author , Michiel Van der HeijdenMichiel Van der Heijden More articles by this author , Laura MertensLaura Mertens More articles by this author , Kees HendricksenKees Hendricksen More articles by this author , Erik VegtErik Vegt More articles by this author , and Bas van RhijnBas van Rhijn More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002515.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Neoadjuvant/induction chemotherapy (NAIC) for muscle-invasive bladder carcinoma (MIBC) has been shown to improve survival. On-treatment response assessment aims to detect chemo-(in)sensitive tumors to continue or cease NAIC. We compared accuracy of FDG-PET/CT to contrast-enhanced CT (CECT) for on-treatment assessment of response to NAIC. METHODS: We prospectively included 83 patients with MIBC in 2014-2018 (study protocol: X14BSB). Patients staged as (high-risk) cT2-4N0M0 or cT1-4N+M0-1a were eligible for neoadjuvant (n=40; 48%) or induction (n=43; 52%) chemotherapy, respectively. Response was assessed after 2-3 cycles with FDG-PET/CT (n=83) and CECT (n=60; 72%). FDG-PET/CT images were assessed by 2 nuclear medicine physicians (Peter Mac criteria). CECT images were assessed by 1 radiologist (RECIST1.1 criteria). We assessed prediction of complete pathological response (pCR; ypT0N0), complete pathological downstaging (pCD; ≤ypT1/is/1N0), any downstaging from baseline (ypTN<cTN) and progression (inoperable tumor/ypN+/M+). The reference standard was histopathological assessment or clinical follow-up. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were calculated. RESULTS: In this cohort, pathological response rates were 21% for pCR, 29% for pCD, 49% for any downstaging, and 10% progressed. All diagnostic parameters for FDG-PET/CT and CECT are shown in Table 1. Accuracy of FDG-PET/CT for prediction of pCR, pCD, any downstaging and progression were 74%, 54%, 61% and 83%, respectively. Accuracy of CECT for prediction of pCR, pCD, any downstaging and progression were 78%, 63%, 68% and 77%, respectively. Specificity of CECT was significantly higher than FDG-PET/CT for prediction of any downstaging (59% vs 32%; p=0.022). In all other analyses, there were no significant differences between FDG-PET/CT and CECT (Table 1). CONCLUSIONS: FDG-PET/CT was not more accurate than CECT for assessment of response to NAIC. However, neither were highly accurate and response was often overestimated. Our results suggest more accurate methods for on-treatment response assessment are needed to accurately select patients for continued treatment with NAIC and surgery. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e21 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sarah Einerhand More articles by this author Charlotte Voskuilen More articles by this author Elies Fransen van de Putte More articles by this author Maarten Donswijk More articles by this author Annemarie Bruining More articles by this author Michiel Van der Heijden More articles by this author Laura Mertens More articles by this author Kees Hendricksen More articles by this author Erik Vegt More articles by this author Bas van Rhijn More articles by this author Expand All Advertisement PDF DownloadLoading ...

Carine van Rhijn, Leading the Way to Heaven: Pastoral Care and Salvation in the Carolingian Period. London and New York: Routledge, 2022, xii, 274 pp.

Abstract Early medieval manuscripts give up their secrets in this excellent monograph by Carine van Rhijn, who studies the books that enabled parish priests to perform their duties in the Carolingian countryside. Recognizing that the lineaments of the pastoral project outlined in royal normative texts issued by Charlemagne and his advisors were expressive of “ideals and intentions” (5), she argues convincingly that the practical challenges of implementing this project of expanding and deepening the knowledge that Christians required to assure their salvation fell increasingly to local priests in the Carolingian period. By the eighth century, a fundamental reorganization of the secular clergy resulted in priests being assigned to specific churches, where they lived, preached, and administered the sacraments in small communities for the rest of their lives.

Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis.

SUMMARYNeurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T>C, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1.

A Summary of the Meetings of the Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS) International Multidisciplinary Consensus

A Summary of the Meetings of the Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS) International Multidisciplinary Consensus

Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS): An International Multidisciplinary Consensus

Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS): An International Multidisciplinary Consensus

Abstract B07: A long noncoding RNA-based genomic classifier identifies a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis

Abstract Background: Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease and gene expression profiling has identified different molecular subtypes, each having distinct biologic and clinicopathologic characteristics. Subtyping MIBC has primarily been messenger RNA (mRNA)-based, although noncoding RNAs, including long noncoding RNAs (lncRNAs), have potential utility in providing additional resolution to current molecular subtyping models. Materials and Methods: The expression profiles of over 6,000 lncRNAs were quantified from whole-transcriptome microarray data of a MIBC patient cohort treated by neoadjuvant chemotherapy (NAC) and radical cystectomy (N=223). Unsupervised consensus clustering of the most highly variant lncRNAs identified a four-cluster solution, which was further characterized using a panel of MIBC biomarkers, gene signatures, and survival analysis. The four-cluster consensus was validated using the publicly available The Cancer Genome Atlas (TCGA) radical cystectomy cohort (N=405). A single-sample genomic classifier (GC) was trained using ridge-penalized logistic regression and then validated in two independent patient cohorts (N=255 and N=94). Results: In the NAC and TCGA cohorts, survival analysis of a lncRNA-based consensus cluster solution revealed a lncRNA-cluster (LC3) with strikingly good prognosis that was enriched for tumors of the luminal-papillary mRNA subtype. In both cohorts, the luminal-papillary tumors from this cluster (LPL-C3) were clinically less aggressive than other luminal-papillary tumors. Patients having LPL-C3 tumors were younger and had more frequent organ-confined, node-negative disease than other luminal-papillary tumors. LPL-C3 tumors were characterized by enhanced FGFR3 pathway activity, wild-type P53 expression, and robust SHH signaling. In the TCGA cohort, LPL-C3 tumors were also enriched for FGFR3 mutations and depleted for TP53 and RB1 mutations. A GC trained to identify these LPL-C3 patients showed robust performance in two validation cohorts. Conclusions: Using lncRNA expression profiling, we identified a biologically distinct subgroup of luminal-papillary MIBC with less-aggressive molecular characteristics and favorable prognosis. These data suggest that lncRNAs can provide additional information in resolving higher-resolution subtypes for more precise patient management strategies. Citation Format: Joep J. de Jong, Yang Liu, Roland Seiler, A. Gordon Robertson, Michiel S. van der Heijden, Jonathan L. Wright, James Douglas, Marc Dall'Era, Simon J. Crabb, Bas W.G. van Rhijn, Kim E.M. van Kessel, Elai Davicioni, Yair Lotan, Ellen C. Zwarthoff, Peter C. Black, Joost L. Boormans, Ewan A. Gibb. A long noncoding RNA-based genomic classifier identifies a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B07.

Abstract B23: FGFR3 mutations and their relation to FGFR3 expression and clinical outcome in a large radical cystectomy cohort: Implications for anti-FGFR3 bladder cancer treatment?

Abstract Objective: Fibroblast growth factor receptor 3 (FGFR3) is a potentially actionable target in bladder cancer (BC). FGFR3 mutations are associated with favorable prognosis in non-muscle invasive (NMI) BC and MIBC. Overexpression of FGFR3 was reported in up to 40% of FGFR3 wild-type MIBC. p53 alterations rarely coincide with FGFR3 mutations. We analyzed FGFR3 mutations and protein-expression of FGFR3 and p53 and assessed their prognostic value in a multicenter, multilaboratory setting. Methods: We included 1,000 cN0M0, chemotherapy-naive patients who underwent radical cystectomy (RC) with pelvic node dissection. Specimens were reviewed by eight uropathologists. At seven laboratories, FGFR3 mutation status was examined using PCR-SNaPshot. p53 and FGFR3 expression were determined by immunohistochemistry (IHC). FGFR3 mutation status, p53 and FGFR3 protein expression were correlated to each other, clinicopathologic parameters, and disease-specific survival (DSS). Results: FGFR3 mutations were found in 107/1,000 RCs (11%), of which 67 were S249C. Overexpression of FGFR3 was found in 279/1,000 (28%) of tumors. p53 overexpression (cut-off&amp;gt;10%) was found in 638/926 (69%) of available cases. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression. Among FGFR3 wild-type tumors, 22% had FGFR3 overexpression. FGFR3 mutations were associated with lower pT-stage (P&amp;lt;0.001), lower grade (G2-WHO 1973) (P&amp;lt;0.001), absence of CIS (P=0.009), pN0 (P&amp;lt;0.001), normal p53 (P&amp;lt;0.001), and prolonged DSS (Plog-rank=0.001). FGFR3 overexpression was associated with lower pT-stage (P&amp;lt;0.001) and G2 (P&amp;lt;0.001) but not with absence of CIS (P=0.860), pN0 (P=0.230), normal p53, (P=0.330) nor prolonged DSS (Plog-rank=0.204). We found no significant difference in DSS for patients with FGFR3 mutant tumors comparing normal vs. overexpression of FGFR3 (Plog-rank=0.444). Furthermore, we also found no significant difference in DSS for patients with FGFR3 wild-type tumors comparing normal vs. overexpression of FGFR3 (Plog-rank=0.754). Conclusions: FGFR3 mutations identified patients with favorable BC with fewer p53 alterations at RC. FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. Our results suggest that FGFR3 mutations (driver effect) have a distinct functional role than FGFR3 overexpression (passenger effect). Hence, patients with FGFR3 mutations may be more likely to benefit from anti-FGFR3 therapy than patients with only overexpression of FGFR3. Citation Format: Bas van Rhijn, Laura Mertens, Roman Mayr, Peter Bostrom, Mirari Marques, Geert van Leenders, Stefanie Gotz, Michiel van der Heijden, Michael Jewett, Francisco Real, Robert Stohr, Alexandre Zlotta, Markus Eckstein, Yanish Soorojebally, Max Burger, Wolfgang Otto, Francois Radvanyi, Damien Pouessel, Theo van der Kwast, Nuria Malats, Arndt Hartmann, Yves Allory, Deric van der Schoot, Ellen Zwarthoff, Tahlita Zuiverloon. FGFR3 mutations and their relation to FGFR3 expression and clinical outcome in a large radical cystectomy cohort: Implications for anti-FGFR3 bladder cancer treatment? [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B23.

904PD - Pre-operative ipilimumab and nivolumab in locoregionally advanced, stage III, urothelial cancer (NABUCCO)

BackgroundStage III (cT3-4aN0M0 or ≥cT1N+M0) urothelial cancer (UC) patients (pts) have a poor prognosis. Despite high response rates, pre-operative chemo shows limited survival benefit. Immunotherapy targeting PD-1/PD-L1 is active in metastatic UC; the combination of ipilimumab (ipi) and nivolumab (nivo) appears to increase response rates. Encouraging path Complete Response (pCR) rates are observed in trials testing neoadjuvant anti-PD-1/PD-L1 (mostly cT2-T3N0 pts). Here, we present the first clinical trial data on preoperative ipi+nivo. MethodsThis is a single-arm phase 1B trial testing the feasibility (primary endpoint) of pre-operative ipi+nivo in stage III UC pts (cis unfit/refusal). To mitigate the risk of immune-related toxicity, pts were treated with (based on melanoma data): ipi 3mg/kg (day 1), ipi 3 + nivo 1mg/kg (day 22), and nivo 3mg/kg (day 43), followed by resection. Secondary endpoints were efficacy (pCR) and translational parameters: PD-L1, TMB (by WES), and immune cell infiltrates at baseline vs on-treatment using multiplex immunofluorescence (mIF; pan-CK/CD3/CD8/FOXP3/CD20/CD68). Results24 pts (14 cT3-4N0; 10 cN+) were enrolled, of whom 23 (96%) had resection <12 weeks from 1st cycle. 1pt, responding radiologically, had a delay in surgery because of an irAE (hemolysis). 18/24 pts received all 3 cycles, 6 pts received 2 cycles due to irAEs. Grade 3/4 irAEs occurred in 54% of pts; 42% when excluding clinically insignificant lab deviations. 22 pts were available for efficacy assessment (1pt resection delayed, 1pt had resection 1day before abstract submission). 10/22 pts (45%) achieved a pCR. 3 additional pts (14%) had noninvasive cancer at resection (2 ypTis, 1 ypTa), resulting in an overall path downstaging (≤ypT1N0) rate of 59% (13/22). In recent neoadjuvant IO studies in melanoma and NSCLC, major path response (MPR) has been defined as≤10% vital tumor cells in the tumor bed. MPR was seen in 5/22 pts (23%). Nonresponse was seen in 4/22 (17%). Response was associated with massive infiltration of CD8+ T-cells in the tumour bed. ConclusionsPreoperative ipi+nivo is feasible (96% surgery <12 weeks) and shows promising efficacy in stage III UC pts. Updated results on all 24 pts, including mIF, PDL1 and TMB, will be presented. Clinical trial identificationNCT03387761, January 2, 2018. Legal entity responsible for the studyNetherlands Cancer Institute - Antoni van Leeuwenhoek. FundingBMS. DisclosureM.S. Van der Heijden: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Janssen. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Scenic Biotech; Advisory / Consultancy: Third Rock Ventures; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck KGaA. P. Kvistborg: Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Personalis; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: GenMab; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): NanoString. B.W. van Rhijn: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Ferring. All other authors have declared no conflicts of interest.

The Ecclesiastical Courts in The Early Modern Southern Netherlands: A Quantitative Analysis

Summary This contribution studies the cessio bonorum of painter Rembrandt van Rhijn in relation to the relevant rules and institutions of Amsterdam. I would first and foremost like to thank professor Eddy Put (KU Leuven), for repeatedly reading my drafts and providing me plenty of useful references and advice. Gerrit Vanden Bosch, Marie-Juliette Marinus, and Jos Van den Nieuwenhuizen kindly answered my many questions, and, needless to say, all the possible flaws are on my own responsibility. In conducting this research, I was supported by the Hitotsubashi University Foundation (Japan). In the Rembrandt case the procedural rules on the cessio bonorum were followed to a large extend. In regard to the beweysinge, a few weeks before the application for the cessio, it seems more convincing that it should be interpreted as a promise than as a conveyance of the house he owned. This new perspective on the beweysinge, however, does not alter the fact that it seems likely that there was a conflict between the Orphans Chamber (serving the interests of Titus) and the Insolvency Chamber (serving the interests of the creditors, and among them especially the former burgomaster Cornelis Witsen). Arguments for this are derived from: 1) the new bylaw issued by the Orphans Chamber shortly after Rembrandt’s application for the cessio, 2) the appointment of the renowned lawyer Louis Crayers as guardian of Titus (instead of Jan Verwout), and 3) the position of Titus’ preferential claim in the concursus creditorum. Crenshaw has stated that this conflict was decided by the personal influence of Cornelis Witsen. This contribution defends that Witsen only could enforce the sale of the house because of the institutional and political power structures within the city government. Witsen belonged to the powerful reigning faction of Cornelis de Graeff, whereas the majority of the officials in the Orphans Chamber belonged to the ‘political opposition’. In the end it was especially Witsen who profited from the sale (at the expense of Titus).

Continuing Carolingian Reform in the late Ninth Century: The Paenitentiale Trecense

Continuing Carolingian Reform in the late Ninth Century:The Paenitentiale Trecense Rob Meens, Lenneke van Raaij, and Carine van Rhijn In the Carolingian kingdoms penance was an important aspect of life.1 Penitential principals and procedures were heavily debated in ecclesiastical councils and penitential rituals functioned as a focus for political discussions and actions on the highest level, as the two cases in which Louis the Pious did public penance clearly demonstrate. The importance of the theme of penance was such that historians refer to Louis's reign as 'the penitential state'.2 The Carolingian era also saw a bustling activity in the composition of penitential handbooks that were meant to instruct confessors on how to deal with sinners in a new way. These new Carolingian creations were far from homogeneous, but they all display a clear interest in the authorities providing legitimization for the rulings they offer to the confessor on how to deal with his confessing subjects. In the year 813 the council of Chalonsur-Saône ruled that: 'we should repudiate and eliminate totally those booklets they call penitentials, of which the errors are as certain as the authors are uncertain'.3 This canon can be seen as a token that the authority of penitential rulings was a matter of great concern, although the council of Chalon-sur-Saône represented only one voice in a choir of polyphone singers, and other councils adopted different positions on this matter.4 As a result of these concerns [End Page 17] influential scholars such as Halitgar of Cambrai and Hrabanus Maurus composed new penitential handbooks for the clergy, that should live up to the expectations as they were expressed in reforming circles. Canonical collections such as the Collectio Dacheriana (ca. 800) also provided a range of rulings that proved a valuable tool for judging penitents.5 At the council of Tours in 813 the bishops decided that to remedy the situation in which the great variety of penitential decisions hampered proper penitential judgments, an episcopal assembly should meet at the sacred palace to decide what would be the right penitential book to be used in the empire. This proposition did not come to fruition. No decision was ever pronounced on the proper penitential book to be prescribed throughout the empire. A number of penitentials were composed, however, that responded to the criticism of the Carolingian bishops. Yet, they all came up with different conclusions. Although grounded in a number of authoritative basic texts, variety was still the rule. One manuscript, now kept in Troyes, Médiathèque de Troyes Champagne Métropole 1979, contains no less than three penitential books that in their own way tried to respond to the episcopal criticism of penitential books. This codex contains book one of the penitential of Halitgar of Cambrai, which was composed at the behest of Archbishop Ebo of Reims. Ebo had invited the bishop of Cambrai to compose a text in order to remedy a situation 'in which the judgments of the penitents were confused, diverse and contradictory in the little works that our priests use and which are not founded on anyone's authority'.6 Ebo clearly subscribed to the criticisms formulated in Chalon-sur-Saône regarding penitential books and regarded the sayings of the fathers and the judgments of the canons as the proper foundation for penitential judgments. Furthermore, the Troyes manuscript contains the so-called penitential of Pseudo-Theodore. This text, composed in the north-eastern regions of the Frankish empire, possibly [End Page 18] somewhere in the area between Reims and Mainz in the second quarter of the ninth century, clearly dates from a region and a period in which the criticism of penitential books was well-known. It has therefore sometimes been included among the group penitential books inspired by new Carolingian thinking about penance, although this is not so evident from its text or the choices of source material.7 A third penitential book included in the Troyes manuscript was already observed by Raymund Kottje when he studied the manuscript tradition of Halitgar's penitential, but it has hitherto never been edited or analysed.8 In this contribution we will offer an analysis...

Rembrandts boedelafstand: een institutionele en politieke benadering

Summary This contribution studies the cessio bonorum of painter Rembrandt van Rhijn in relation to the relevant rules and institutions of Amsterdam. In the Rembrandt case the procedural rules on the cessio bonorum were followed to a large extend. In regard to the beweysinge, a few weeks before the application for the cessio, it seems more convincing that it should be interpreted as a promise than as a conveyance of the house he owned. This new perspective on the beweysinge, however, does not alter the fact that it seems likely that there was a conflict between the Orphans Chamber (serving the interests of Titus) and the Insolvency Chamber (serving the interests of the creditors, and among them especially the former burgomaster Cornelis Witsen). Arguments for this are derived from: 1) the new bylaw issued by the Orphans Chamber shortly after Rembrandt’s application for the cessio, 2) the appointment of the renowned lawyer Louis Crayers as guardian of Titus (instead of Jan Verwout), and 3) the position of Titus’ preferential claim in the concursus creditorum. Crenshaw has stated that this conflict was decided by the personal influence of Cornelis Witsen. This contribution defends that Witsen only could enforce the sale of the house because of the institutional and political power structures within the city government. Witsen belonged to the powerful reigning faction of Cornelis de Graeff, whereas the majority of the officials in the Orphans Chamber belonged to the ‘political opposition’. In the end it was especially Witsen who profited from the sale (at the expense of Titus).

Neurons derived from induced pluripotent stem cells on microelectrode arrays: a human model for neurodevelopmental disorders

Neurons derived from induced pluripotent stem cells on microelectrode arrays: a human model for neurodevelopmental disorders

MP34-08 HIPEC WITH CYTOREDUCTIVE SURGERY CAN CURE PATIENTS WITH LIMITED PERITONEAL CARCINOMATOSIS FROM ADENOCARCINOMA OF THE URACHUS

You have accessJournal of UrologyBladder Cancer: Invasive II1 Apr 2017MP34-08 HIPEC WITH CYTOREDUCTIVE SURGERY CAN CURE PATIENTS WITH LIMITED PERITONEAL CARCINOMATOSIS FROM ADENOCARCINOMA OF THE URACHUS Mark Behrendt, Akash Mehta, Elisabeth Fransen van de Putte, Michiel Van der Heijden, Simon Horenblas, Luc Moonen, Vic Verwaal, Wim Meinhardt, and Bas Van Rhijn Mark BehrendtMark Behrendt More articles by this author , Akash MehtaAkash Mehta More articles by this author , Elisabeth Fransen van de PutteElisabeth Fransen van de Putte More articles by this author , Michiel Van der HeijdenMichiel Van der Heijden More articles by this author , Simon HorenblasSimon Horenblas More articles by this author , Luc MoonenLuc Moonen More articles by this author , Vic VerwaalVic Verwaal More articles by this author , Wim MeinhardtWim Meinhardt More articles by this author , and Bas Van RhijnBas Van Rhijn More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1025AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Urachal cancer (UraC) is a rare malignant disease. Patients usually present with advanced mucinous adenocarcinoma, which may disseminate to the peritoneal cavity, causing peritoneal carcinomatosis (PC). Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been shown to improve clinical outcomes for adenocarcinomas arising from the colon and the ovary. We report our experience of structured stepwise staging and HIPEC for UraC. METHODS Between 01/1994 and 04/2016, 56 patients with UraC were treated and followed at our institute. For this study, we excluded 8 patients (urothelial carcinoma). Structured work-up included at least a chest X-ray and an abdominal/pelvic CT-scan. Starting in 2001 diagnostic supra-umbilical laparoscopy (dLap) was introduced in patients with initial negative CT and revealed limited PC in 6/26 (23%) patients. Overall, staging (imaging and/or dLap) revealed 11 metastatic patients and another 9 patients, who had limited PC and were eligible for local excision of the urachus, CRS and HIPEC with open bladder. Diagnostic laparoscopy was not performed in 22/48 (46%) patients (palliative 5x; primary resection elsewhere 4x; large tumor with mucinous fluid (= 8cm) 3x; small, presumed benign tumor (= 2cm) 3x; before 2001 7x). RESULTS In total, 37 patients who had UraC received treatment with curative intent (28 local excision only and 9 CRS with HIPEC). Median follow-up for the 9 HIPEC patients was 33 months (IQR 59 months) and 6/9 (67%) HIPEC patients still have no signs of recurrence after median follow-up of 53 months (IQR 75 months) (see Table). After HIPEC, two patients had postoperative adverse events requiring intervention (grade3). Disease specific survival for the patients treated with HIPEC for limited PC was comparable to the patients who had local excision only and was superior to the metastatic UraC patients (Plog-rank = 0.034). CONCLUSIONS Laparoscopy can reliably detect limited PC in patients with UraC without radiological signs of metastasis. If limited PC is present, HIPEC represents a curative treatment with favorable oncological outcome and acceptable toxicity. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e429 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Mark Behrendt More articles by this author Akash Mehta More articles by this author Elisabeth Fransen van de Putte More articles by this author Michiel Van der Heijden More articles by this author Simon Horenblas More articles by this author Luc Moonen More articles by this author Vic Verwaal More articles by this author Wim Meinhardt More articles by this author Bas Van Rhijn More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Editorial: Components of the Language-Ready Brain.

Our intention in putting together this volume was to exemplify and highlight new avenues of research in the language sciences concerning the neurobiology of language. We chose the term “language-ready brain” for our Research Topic, like we did for Boeckx and Benitez-Burraco, because we think it is high time to stress, on the one hand, the importance of a brain-based description of our species' linguistic capacity, and, on the other, the need to appreciate the crucial role culture plays in shaping the linguistic systems children acquire and adults use. In this sense, the focus of neurobiological investigations should not be “language,” but our learning biases and cognitive pre-dispositions toward language (i.e., “language-readiness”). Both brain and culture considerations ought to shape research at all levels of inquiry: phylogeny and ontogeny. The contributions to this research topic break new grounds, by either revisiting long-standing issues (such as the role of Broca's region, the relevance of lateralization, the evolutionary origins of phonology, the role of basic cognitive and perceptive abilities in language acquisition, or the functions performed by language), or by examining closely issues that we are sure will rise to prominence in the near future (like the translational models of language processing into specific patterns of brain oscillations or the nature of the gene networks in which known “language genes” are found integrated). Taken together, the papers collected here shed light on language at the level of the genetics (van Rhijn and Vernes), brain connectivity (Murphy; Theofanopoulou), and physiology (Matchin and Hickok; Zaccarella and Friederici), cognition (de Boer; de Diego-Balaguer et al.), and behavior (Bouchard; Irurtzun; Reboul; Samuels). In a fast-growing field like the language sciences, Research topics cannot hope to capture all relevant aspects of the field, but we hope that the present volume offers a snapshot that some of the most exciting research taking place today, sowing seeds for future investigations.

MP68-06 TISSUE-BASED DNA METHYLATION PROFILING ESTABLISHES A NOVEL PANEL OF BIOMARKERS FOR DISCRIMINATION OF HIGH-GRADE VERSUS LOW-GRADE BLADDER CANCER

You have accessJournal of UrologyBladder Cancer: Basic Research IV1 Apr 2015MP68-06 TISSUE-BASED DNA METHYLATION PROFILING ESTABLISHES A NOVEL PANEL OF BIOMARKERS FOR DISCRIMINATION OF HIGH-GRADE VERSUS LOW-GRADE BLADDER CANCER Andrea Savio, Ekaterina Olkhov-Mitsel, Ken Kron, Thomas Hermanns, Bas van Rhijn, Alexandre Zlotta, Theodorus van der Kwast, and Bharati Bapat Andrea SavioAndrea Savio More articles by this author , Ekaterina Olkhov-MitselEkaterina Olkhov-Mitsel More articles by this author , Ken KronKen Kron More articles by this author , Thomas HermannsThomas Hermanns More articles by this author , Bas van RhijnBas van Rhijn More articles by this author , Alexandre ZlottaAlexandre Zlotta More articles by this author , Theodorus van der KwastTheodorus van der Kwast More articles by this author , and Bharati BapatBharati Bapat More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2468AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Epigenetic changes, including promoter CpG island hypermethylation, occur frequently in bladder cancer (BC) and may be exploited as a means for BC detection and distinction between high-grade (HG) and low-grade (LG) disease. METHODS To determine epigenetic differences between LG and HG BC we performed genome-wide methylation analysis with Agilent Human CpG Island Microarrays on a panel of fresh frozen BC tissue samples. Using Linear Models for Microarray Data (LIMMA) and local-pooled-error (LPE) approaches and unsupervised hierarchical clustering we identified 990 probes comprising a 32-gene panel that completely distinguished LG from HG BC based on methylation status. We selected five representative differentially methylated genes (DMGs) from our 32-gene panel for methylation validation by real-time PCR-based MethyLight in a series of 40 LG cases age- and sex-matched to 40 HG cases. RESULTS Among the DMGs tested, including EOMES, GP5, PAX6, TCF4, and ZSCAN12, we identified that EOMES, GP5, and ZSCAN12 methylation significantly differs between normal, LG, and HG disease. GP5 and ZSCAN12, two novel methylated genes in BC, are significantly hypermethylated in HG versus LG BC (p=0.006 and 0.028, respectively). Pathway enrichment analysis and functional annotation determined the most frequently methylated pathways in HG BC were enriched for anterior/posterior pattern specification, embryonic skeletal system development, and neuron fate commitment. The molecular functions of the most enriched genes were involved in DNA binding and transcription factor activity. CONCLUSIONS These results indicate the ability to distinguish normal tissue from cancer, as well as LG from HG tumours, and reveal important pathways dysregulated in HG BC. Ultimately, the creation of a methylation panel able to distinguish between disease phenotypes will improve disease management and patient outcomes. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e860 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrea Savio More articles by this author Ekaterina Olkhov-Mitsel More articles by this author Ken Kron More articles by this author Thomas Hermanns More articles by this author Bas van Rhijn More articles by this author Alexandre Zlotta More articles by this author Theodorus van der Kwast More articles by this author Bharati Bapat More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...