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01 juni 2023, Item does not contain fulltext, AIMS: Large B cell lymphoma with IRF4 rearrangement (LBCL-IRF4) is a new entity in the 2017 revised World Health Organisation (WHO) classification that was initially mainly reported in children. After identification of a 79-year-old patient, we assessed how often IRF4 rearrangements can be detected in adult diffuse large B cell lymphomas (DLBCLs) which have to be reclassified to LBCL-IRF4 based on fluorescence in-situ hybridisation (FISH) for IRF4. METHODS AND RESULTS: With FISH, we studied the presence of IRF4 rearrangements in 238 lymphomas that were diagnosed as DLBCL according to the previous WHO classification of 2008. CONCLUSIONS: In addition to the index patient, an IRF4 rearrangement was detected in another five of 237 patients (2%). The immunohistochemical profile of these five IRF4 rearranged lymphomas was consistent with previous reports of LBCL-IRF4. One case was recognised to represent transformation of follicular lymphoma rather than de-novo LBCL-IRF4. BCL6 rearrangements were found in two cases of LBCL-IRF4; BCL2 and MYC rearrangements were excluded. Patients presented with limited stage disease with involvement of the head and neck in three patients, and involvement of the lung and thyroid in two others. This study shows that, although rare, LBCL-IRF4 should also be considered in older patients and at localisations other than the head and neck region.

01 juli 2023, Contains fulltext : 294879.pdf (Publisher’s version ) (Open Access), Clonality assessment by the detection of immunoglobulin (IG) gene rearrangements is an important method to determine whether two concurrent or subsequent lymphoid malignancies in one patient are clonally related. Here, we report the detailed clonality analysis in a patient with a diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) followed by a histiocytic sarcoma (HS), in which we were able to study clonal evolution by applying next generation sequencing (NGS) to identify IG rearrangements and gene mutations. Using the sequence information of the NGS-based IG clonality analysis, multiple related subclones could be distinguished in the PAX5 P80R-mutated B-ALL. Notably, only one of these subclones evolved into HS after acquiring a RAF1 mutation. This case demonstrates that NGS-based IG clonality assessment and mutation analysis provide clear added value for clonal comparison and thereby improves clinicobiological understanding.

Contains fulltext : 296673.pdf (Publisher’s version ) (Open Access), Next-generation sequencing (NGS)-based clonality analysis allows in-depth assessment of the clonal composition of a sample with high sensitivity for detecting small clones. Within the EuroClonality-NGS Working Group, a protocol for NGS Ig clonality analysis was developed and validated previously. This NGS-based approach was designed to generate small amplicons, making it suitable for samples with suboptimal DNA quality, especially material derived from formalin-fixed, paraffin-embedded tissue. Using expert assessment of NGS Ig clonality results as a reference, a structured algorithmic approach to the assessment of NGS-amplicon-based B-cell clonality analysis was developed. A structured approach with the Detection of clonality through Evaluation of sample quality and assessment of Pattern, Abundance and RaTio (DEPART) algorithm was proposed, which consecutively evaluates sample quality, the pattern of the clonotypes present, the abundance of the most dominant clonotypes, and the ratio between the dominant clonotypes and the background to evaluate the different Ig gene targets. Specific issues with respect to evaluation of the various Ig targets as well as the integration of results of individual targets into a molecular clonality conclusion are discussed and illustrated with case examples. Finally, the importance of interpretation of NGS-based clonality results in clinical and histopathologic contexts is discussed. It is expected that these recommendations will have clinical utility to facilitate proper evaluation of clonality assessment.

Radboud University, 28 november 2023, Promotor : Krieken, J.H.J.M. van Co-promotores : Scheijen, G.P.H., Brand, M. van den, Item does not contain fulltext

Item does not contain fulltext, BACKGROUND: Patients with newly diagnosed high-risk Burkitt lymphoma are treated with high-intensity immune-chemotherapy regimens such as R-CODOX-M/R-IVAC or with lower-intensity regimens such as DA-EPOCH-R. The aim of this study was to make a formal comparison between these regimens. METHODS: This multicentre, phase 3, open-label, randomised study was done in 26 clinical centres in the Netherlands, Belgium, and Switzerland. Eligible patients were aged 18-75 years with newly diagnosed high-risk Burkitt lymphoma without CNS involvement. Patients were randomly assigned to two cycles of R-CODOX-M/R-IVAC (R-CODOX-M: rituximab 375 mg/m(2) on day 1 and 9, cyclophosphamide 800 mg/m(2) on day 1, cyclophosphamide 200 mg/m(2) on days 2-5, vincristine 1·5 mg/m(2) on days 1 and 8, doxorubicin 40 mg/m(2) on day 1, and methotrexate 3000 mg/m(2) on day 10; R-IVAC: rituximab 375 mg/m(2) on days 3 and 7, iphosphamide 1500 mg/m(2) on days 1-5, etoposide 60 mg/m(2) on days 1-5, and cytarabin 2000 mg/m(2) on day 1 and 2) or six cycles of DA-EPOCH-R (dose-adjusted etoposide 50-124 mg/m(2) on days 1-4, prednisolone 120 mg/m(2) on days 1-5, vincristine 0·4 mg/m(2) on days 1-4, dose-adjusted cyclophosphamide 480-1866 mg/m(2) on day 5, dose-adjusted doxorubicin 10-24·8 mg/m(2) on days 1-4, rituximab 375 mg/m(2) on days 1 and 5). Patients older than 65 years received a dose modified R-CODOX-M/R-IVAC. All drugs were intravenous except for prednisolone, which was oral. Patients also received four intrathecal CNS administrations with cytarabin (70 mg) and four with methotrexate (15 mg). Patients were stratified by centre, leukemic disease, and HIV-positivity. The primary endpoint was progression-fee survival. All analyses were done by modified intention-to-treat, excluding randomly assigned patients who were subsequently found to have CNS involvement or diagnosis other than Burkitt lymphoma at study entry. This study is registered with the European Clinical Trial Register, EudraCT2013-004394-27, 01 december 2023

Contains fulltext : 298927.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, Despite high cure rates in classic Hodgkin lymphoma (cHL), relapses are observed. Whether relapsed cHL represents second primary lymphoma or an underlying T-cell lymphoma (TCL) mimicking cHL is underinvestigated. To analyze the nature of cHL recurrences, in-depth clonality testing of immunoglobulin (Ig) and T-cell receptor (TCR) rearrangements was performed in paired cHL diagnoses and recurrences among 60 patients, supported by targeted mutation analysis of lymphoma-associated genes. Clonal Ig rearrangements were detected by next-generation sequencing (NGS) in 69 of 120 (58%) diagnoses and recurrence samples. The clonal relationship could be established in 34 cases, identifying clonally related relapsed cHL in 24 of 34 patients (71%). Clonally unrelated cHL was observed in 10 of 34 patients (29%) as determined by IG-NGS clonality assessment and confirmed by the identification of predominantly mutually exclusive gene mutations in the paired cHL samples. In recurrences of >2 years, ∼60% of patients with cHL for whom the clonal relationship could be established showed a second primary cHL. Clonal TCR gene rearrangements were identified in 14 of 125 samples (11%), and TCL-associated gene mutations were detected in 7 of 14 samples. Retrospective pathology review with integration of the molecular findings were consistent with an underlying TCL in 5 patients aged >50 years. This study shows that cHL recurrences, especially after 2 years, sometimes represent a new primary cHL or TCL mimicking cHL, as uncovered by NGS-based Ig/TCR clonality testing and gene mutation analysis. Given the significant therapeutic consequences, molecular testing of a presumed relapse in cHL is crucial for subsequent appropriate treatment strategies adapted to the specific lymphoma presentation.

Contains fulltext : 248786.pdf (Publisher’s version ) (Open Access), Diffuse large B-cell lymphoma (DLBCL) represents the most common form of non-Hodgkin lymphoma (NHL) that is still incurable in a large fraction of patients. Tetraspanin CD37 is highly expressed on mature B lymphocytes, and multiple CD37-targeting therapies are under clinical development for NHL. However, CD37 expression is nondetectable in ∼50% of DLBCL patients, which correlates with inferior treatment outcome, but the underlying mechanisms for differential CD37 expression in DLBCL are still unknown. Here, we investigated the regulation of the CD37 gene in human DLBCL at the (epi-)genetic and transcriptional level. No differences were observed in DNA methylation within the CD37 promoter region between CD37-positive and CD37-negative primary DLBCL patient samples. On the contrary, CD37-negative DLBCL cells specifically lacked CD37 promoter activity, suggesting differential regulation of CD37 gene expression. Using an unbiased quantitative proteomic approach, we identified transcription factor IRF8 to be significantly higher expressed in nuclear extracts of CD37-positive as compared with CD37-negative DLBCL. Direct binding of IRF8 to the CD37 promoter region was confirmed by DNA pulldown assay combined with mass spectrometry and targeted chromatin immunoprecipitation (ChIP). Functional analysis indicated that IRF8 overexpression enhanced CD37 protein expression, while CRISPR/Cas9 knockout of IRF8 decreased CD37 levels in DLBCL cell lines. Immunohistochemical analysis in a large cohort of primary DLBCL (n = 206) revealed a significant correlation of IRF8 expression with detectable CD37 levels. Together, this study provides new insight into the molecular mechanisms underlying differential CD37 expression in human DLBCL and reveals IRF8 as a transcriptional regulator of CD37 in B-cell lymphoma.

Contains fulltext : 252113.pdf (Publisher’s version ) (Open Access), Cellularity estimation forms an important aspect of the visual examination of bone marrow biopsies. In clinical practice, cellularity is estimated by eye under a microscope, which is rapid, but subjective and subject to inter- and intraobserver variability. In addition, there is little consensus in the literature on the normal variation of cellularity with age. Digital image analysis may be used for more objective quantification of cellularity. As such, we developed a deep neural network for the segmentation of six major cell and tissue types in digitized bone marrow trephine biopsies. Using this segmentation, we calculated the overall bone marrow cellularity in a series of biopsies from 130 patients across a wide age range. Using intraclass correlation coefficients (ICC), we measured the agreement between the quantification by the neural network and visual estimation by two pathologists and compared it to baseline human performance. We also examined the age-related changes of cellularity and cell lineages in bone marrow and compared our results to those found in the literature. The network was capable of accurate segmentation (average accuracy and dice score of 0.95 and 0.76, respectively). There was good neural network-pathologist agreement on cellularity measurements (ICC=0.78, 95% CI 0.58-0.85). We found a statistically significant downward trend for cellularity, myelopoiesis and megakaryocytes with age in our cohort. The mean cellularity began at approximately 50% in the third decade of life and then decreased ±2% per decade to 40% in the seventh and eighth decade, but the normal range was very wide (30-70%).

Contains fulltext : 251622.pdf (Publisher’s version ) (Open Access), In this two-part study, high-ability students' experiences of need support, need satisfaction, and motivation in regular and pull-out classes were compared. Quantitative results from Study 1 indicated that high-ability students (N = 203) reported more satisfaction of their needs for autonomy, competence, and relatedness and more favorable motivational outcomes in their pull-out class compared to their regular class. In both settings, need satisfaction predicted high-ability students' motivational outcomes. These findings could be explained by the qualitative findings from Study 2 which indicated that high-ability students (N = 11) experienced pull-out class teachers as more supportive of their needs than their regular class teachers. Overall, findings suggest that need-supportive teaching is an effective strategy to foster high-ability students’ motivation in both regular classes as well as pull-out classes.

Contains fulltext : 252063.pdf (Publisher’s version ) (Open Access), Clonality analysis in classic Hodgkin lymphoma (cHL) is of added value for correctly diagnosing patients with atypical presentation or histology reminiscent of T cell lymphoma, and for establishing the clonal relationship in patients with recurrent disease. However, such analysis has been hampered by the sparsity of malignant Hodgkin and Reed-Sternberg (HRS) cells in a background of reactive immune cells. Recently, the EuroClonality-NGS Working Group developed a novel next-generation sequencing (NGS)-based assay and bioinformatics platform (ARResT/Interrogate) to detect immunoglobulin (IG) gene rearrangements for clonality testing in B-cell lymphoproliferations. Here, we demonstrate the improved performance of IG-NGS compared to conventional BIOMED-2/EuroClonality analysis to detect clonal gene rearrangements in 16 well-characterized primary cHL cases within the IG heavy chain (IGH) and kappa light chain (IGK) loci. This was most obvious in formalin-fixed paraffin-embedded (FFPE) tissue specimens, where three times more clonal cases were detected with IG-NGS (9 cases) compared to BIOMED-2 (3 cases). In total, almost four times more clonal rearrangements were detected in FFPE with IG-NGS (N = 23) as compared to BIOMED-2/EuroClonality (N = 6) as judged on identical IGH and IGK targets. The same clonal rearrangements were also identified in paired fresh frozen cHL samples. To validate the neoplastic origin of the detected clonotypes, IG-NGS clonality analysis was performed on isolated HRS cells, demonstrating identical clonotypes as detected in cHL whole-tissue specimens. Interestingly, IG-NGS and HRS single-cell analysis after DEPArray™ digital sorting revealed rearrangement patterns and copy number variation profiles indicating clonal diversity and intratumoral heterogeneity in cHL. Our data demonstrate improved performance of NGS-based detection of IG gene rearrangements in cHL whole-tissue specimens, providing a sensitive molecular diagnostic assay for clonality as

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Contains fulltext : 245153.pdf (Publisher’s version ) (Open Access), In patients with suspected lymphoma, the tissue biopsy provides lymphoma confirmation, classification, and prognostic factors, including genetic changes. We developed a deep learning algorithm to detect MYC rearrangement in scanned histological slides of diffuse large B-cell lymphoma. The H&E-stained slides of 287 cases from 11 hospitals were used for training and evaluation. The overall sensitivity to detect MYC rearrangement was 0.93 and the specificity 0.52, showing that prediction of MYC translocation based on morphology alone was possible in 93% of MYC-rearranged cases. This would allow a simple and fast prescreening, saving approximately 34% of genetic tests with the current algorithm.

Contains fulltext : 232894.pdf (Publisher’s version ) (Open Access), Digital pathology with whole-slide imaging (WSI) has a large potential to make the process of expert consultation and expert panel diagnosis more rapid and more efficient. However, comparison with the current methods is necessary for validation of the technique. In this study, we determined if digital assessment of whole-slide images of hematopathology specimens with a focus on the assessment of lymphoma can be used for consultation and panel diagnostics. Ninety-three histological specimens with a suspicion for lymphoma were assessed both with conventional microscopy and digital microscopy with a wash out period between assessments. A consensus diagnosis was based on full concordance between the pathologists or, in case of discordances, was reached at a joint session at a multi-headed microscope. In 81% of the cases, there was a full concordance between digital and light microscopical assessment for all three pathologists. Discordances between conventional microscopy and digital pathology were present in 3% of assessments. In comparison with the consensus diagnosis, discordant diagnoses were made in 5 cases with digital microscopy and in 3 cases with light microscopy. The reported level of confidence and need for additional investigations were similar between assessment by conventional and by digital microscopy. In conclusion, the performance of assessment by digital pathology is in general comparable with that of conventional light microscopy and pathologists feel confident using digital pathology for this subspecialty.

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Contains fulltext : 221650.pdf (Publisher’s version ) (Closed access)

Contains fulltext : 220554.pdf (publisher's version ) (Open Access), Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum ((195m)Pt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. In vitro NMR studies revealed that release of Pt from Pt BP complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. These Pt-BP complexes formed less Pt-DNA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of Pt from Pt-BP complexes proceeded relatively slow. Subsequently, radioactive (195m)Pt-BP complexes were synthesized using (195m)Pt(NO3)2(en) as precursor and injected intravenously into mice. Specific accumulation of (195m)Pt-BP was observed at skeletal sites with high metabolic activity using micro-SPECT/CT imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that (195m)Pt BP co-localized with calcium in the trabeculae of mice tibia.

Contains fulltext : 229277.pdf (publisher's version ) (Open Access), The majority of patients with diffuse large B-cell lymphoma (DLBCL) can be treated successfully with a combination of chemotherapy and the monoclonal anti-CD20 antibody rituximab. Nonetheless, approximately one-third of the patients with DLBCL still experience relapse or refractory (R/R) disease after first-line immunochemotherapy. Whole-exome sequencing on large cohorts of primary DLBCL has revealed the mutational landscape of DLBCL, which has provided a framework to define novel prognostic subtypes in DLBCL. Several studies have investigated the genetic alterations specifically associated with R/R DLBCL, thereby uncovering molecular pathways linked to therapy resistance. Here, we summarize the current state of knowledge regarding the genetic alterations that are enriched in R/R DLBCL, and the corresponding pathways affected by these gene mutations. Furthermore, we elaborate on their potential role in mediating therapy resistance, also in connection with findings in other B-cell malignancies, and discuss alternative treatment options. Hence, this review provides a comprehensive overview on the gene lesions and molecular mechanisms underlying R/R DLBCL, which are considered valuable parameters to guide treatment.

Contains fulltext : 216823.pdf (preprint version ) (Closed access) Contains fulltext : 216823pub.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 203155.pdf (Publisher’s version ) (Closed access), The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Contains fulltext : 202071.pdf (Publisher’s version ) (Open Access), Sowohl das weibliche als auch das männliche Genitalsystem zeichnen sich durch einen organtypischen Befall durch maligne Lymphome aus, was sowohl für die primär dort entstehende Lymphomerkrankung als auch für die sekundär metastatische Beteiligung systemischer Lymphome zutrifft. Das Kapitel gibt auf dem Boden der in der WHO Klassifikation definierten Entitäten eine umfassende Besprechung und Differenzialdiagnose des nach anatomischen Abschnitten gegliederten Genitalsystems mit den zum Teil sehr wichtigen organotypischen Differenzialdiagnosen. Eine besondere Beachtung finden die Lymphom-ähnlichen Läsionen des Uterus, deren Diagnose und Abgrenzung zu einem Befall durch ein NHL große Bedeutung besitzt. In einem weiteren Kapitel werden die seltenen primären NHL der Mamma besprochen und das besondere anaplastisch großzellige Lymphom assoziiert zu Silikon Implantaten dargestellt und in Klinik und Prognose diskutiert.

Contains fulltext : 206233.pdf (publisher's version ) (Open Access)

Contains fulltext : 207994.pdf (publisher's version ) (Open Access)

Contains fulltext : 208535.pdf (publisher's version ) (Open Access), Among the many uses of digital pathology, remote consultation, remote revision, and virtual slide panels may be the most important ones. This requires basic slide scanner infrastructure in participating laboratories to produce whole-slide images. More importantly, a software platform is needed for exchange of these images and functionality to support the processes around discussing and reporting on these images without breaching patient privacy. This poses high demands on the setup of such a platform, given the inherent complexity of the handling of digital pathology images. In this article, we describe the setup and validation of the Pathology Image Exchange project, which aimed to create a vendor-independent platform for exchange of whole-slide images between Dutch pathology laboratories to facilitate efficient teleconsultation, telerevision, and virtual slide panels. Pathology Image Exchange was released in April 2018 after technical validation, and a first successful validation in real life has been performed for hematopathology cases.

Item does not contain fulltext, High-ability pupils in primary schools often do not achieve up to their full potential and teachers seem to face difficulties to motivate these pupils. In this study 891 primary school pupils (463 high-ability pupils) were asked about their views on desired characteristics of good teachers by means of an open teacher-spider-questionnaire. The characteristics reported, were analysed using the three "basic needs" from the Self-Determination Theory. The answers of high-ability pupils were compared to answers of pupils from regular primary education. For both groups, teaching characteristics fostering relatedness, followed by competence, were mentioned most. It was autonomy which was mentioned less frequently by both groups. The answers of the two groups of pupils mostly corresponded, although some differences emerged in specific subcategories. High-ability pupils more frequently mentioned characteristics attuning to their needs (understanding) and encouragement (challenge), and mentioned "providing choice" less often. There were also some differences found between characteristics mentioned by (high-ability) boys and girls.

Contains fulltext : 202070.pdf (Publisher’s version ) (Open Access), Primäre Lymphome sind in den Nieren und ableitenden Harnwegen sehr selten. Das Kapitel bietet eine aktuelle Literaturübersicht und einen Erfahrungsbericht zu diesen Krankheiten und zeigt die organtypischen Befallsmuster der verschiedenen anatomischen Abschnitte des ableitenden Harnweg-Systems.

Contains fulltext : 208027.pdf (publisher's version ) (Open Access)

Onderwijs Research Dagen (ORD 2018): Ondersteboven van onderwijs (Nijmegen, 13-15 juni 2018), Item does not contain fulltext

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Contains fulltext : 182152.pdf (Publisher’s version ) (Open Access), Although patients with indolent B-cell lymphomas have a relatively good survival rate, conventional chemotherapy is not curative. Disease courses are typically characterized by multiple relapses and progressively shorter response duration with subsequent lines of therapy. There has been an explosion of innovative targeted agents in the past years. This review discusses current knowledge on the etiology of indolent B-cell lymphomas with respect to the role of micro-organisms, auto-immune diseases, and deregulated pathways caused by mutations. In particular, knowledge on the mutational landscape of indolent B-cell lymphomas has strongly increased in recent years and harbors great promise for more accurate decision making in the current wide range of therapeutic options. Despite this promise, only in chronic lymphocytic leukemia the detection of TP53 mutations and/or del17p currently have a direct effect on treatment decisions. Nevertheless, it is expected that in the near future the role of genetic testing will increase for prediction of response to targeted treatment as well as for more accurate prediction of prognosis in indolent B-cell lymphomas.

Contains fulltext : 182337.pdf (publisher's version ) (Open Access), Extranodal marginal zone lymphoma (EMZL), mostly represented by mucosa-associated lymphoid tissue (MALT) type, also referred to as MALT lymphoma, is a clinically heterogeneous entity within the group of low-grade B cell lymphomas that arises in a wide range of different extranodal sites, including the stomach, lung, ocular adnexa, and skin. It represents the third most common non-Hodgkin lymphoma in the Western world, and the median age of occurrence is around 60 years. One characteristic aspect in a subset of EMZL detectable in about 25% of the cases is the presence of specific chromosomal translocations involving the genes MALT1 and BCL10, which lead to activation of the NF-kappaB signaling pathway. Another unique aspect is that several infectious agents, such as Helicobacter pylori in the case of gastric EMZL, and autoimmune disorders, like Sjogren syndrome, have been implicated in the pathogenesis of this cancer. Recent findings as summarized in this review have further improved our understanding of the complex pathobiology of this disease and have been essential to better define novel treatment strategies. In addition, many of these specific features are currently being implemented for the diagnosis of EMZL.

Contains fulltext : 169805.pdf (publisher's version ) (Open Access), AIMS: To investigate the spectrum of mutations in 20 genes involved in B-cell receptor and/or Toll-like receptor signalling resulting in activation of nuclear factor-kappaB (NF-kappaB) in 20 nodal marginal zone lymphomas (NMZLs), 20 follicular lymphomas (FLs), and 11 cases of B-cell lymphoma, unclassifiable (BCL-u). METHODS AND RESULTS: Nodal marginal zone lymphomas were diagnosed according to strict criteria, including the expression of at least one putative marginal zone marker (MNDA and/or IRTA1). Cases that showed features of NMZL but did not fulfil all criteria were included as BCL-u. All FLs were required to have a BCL2 rearrangement. Mutations were found in: nine NMZLs, with recurrent mutations in TNFAIP3 and CD79B; 12 FLs, with recurrent mutations in TNFRSF14, TNFAIP3, and CARD11; and five cases of BCL-u, with recurrent mutations in TNFRSF14. TNFRSF14 mutations were present in FL and BCL-u, but not in any of the NMZLs. In the BCL-u group, TNFRSF14 mutations clustered with a FL immunophenotype. CONCLUSIONS: These results suggest that TNFRSF14 mutations point towards a diagnosis of FL, and can be used in the sometimes difficult distinction between NMZL and FL, but to apply this in diagnostics would require confirmation in an independent cohort. In addition, the presence or absence of specific mutations in pathways converging on NF-kappaB could be important for decisions regarding targeted treatment.

Contains fulltext : 182151.pdf (publisher's version ) (Open Access), BACKGROUND: Parkinson's disease (PD) is a chronic, progressive neurological disorder with many intractable consequences for patients and their family caregivers. Little is known about the possibilities that palliative care could offer to patients and their proxies. Guidelines strongly recommend palliative care to improve the quality of life and - if needed - the quality of dying. However, providing palliative care to persons with PD involves specific challenges. For example, a timely initiation of palliative interventions is difficult because due to the gradually progressive nature of PD, there is often no clear marker for the transition from curative towards palliative care. Furthermore, there is little evidence to indicate which palliative care interventions are effective. Here, we describe the contours of a study that aims to examine the experiences of patients, (bereaved) family caregivers and professionals, with the aim of improving our knowledge about palliative care needs in PD. METHODS/DESIGN: We will perform a mixed methods study to evaluate the experiences of patients, (bereaved) family caregivers and palliative care professionals. In this study, we focus on Quality of Life, Quality of Care, perceived symptoms, caregiver burden and collaboration between professionals. In phase 1, we will retrospectively explore the views of bereaved family caregivers and professionals by conducting individual interviews and focus group interviews. In phase 2, 5-15 patients with PD and their family caregiver will be followed prospectively for 8-12 months. Data collection will involve semi-structured interviews and questionnaires at three consecutive contact moments. Qualitative data will be audio recorded, transcribed and analyzed using CAQDAS. If patients pass away during the study period, a bereavement interview will be done with the closest family caregiver. DISCUSSION: This study will offer a broad perspective on palliative care, and the results can be used to inform a

Radboud University, 22 december 2017, Promotor : Krieken, J.H.J.M. van Co-promotor : Groenen, P.J.T.A., Contains fulltext : 178917.pdf (publisher's version ) (Open Access)

Contains fulltext : 172129.pdf (publisher's version ) (Closed access), Nodal marginal zone lymphoma (NMZL) is a rare type of B-cell non-Hodgkin lymphoma. This study assessed the clinical features of 56 patients with NMZL in comparison to 46 patients with follicular lymphoma (FL). Patients with NMZL and FL had a largely similar clinical presentation, but patients with FL had a higher disease stage at presentation, more frequent abdominal lymphadenopathy and bone marrow involvement, and showed more common transformation into diffuse large B-cell lymphoma (DLBCL) during the course of disease. Overall survival and event-free survival were similar for patients with NMZL and FL, but factors associated with worse prognosis differed between the two groups. Transformation into DLBCL was associated with a significantly poorer outcome in both groups, but the phenotypes were different: DLBCL arising in FL was mainly of germinal center B-cell phenotype, whereas DLBCL arising in NMZL was mainly of non-germinal center B-cell phenotype.

Contains fulltext : 166692.pdf (publisher's version ) (Open Access), In our consultation practice, it was noted that many cases that were considered to represent follicular lymphoma (FL) without a BCL2 translocation were ultimately classified as nodal marginal zone lymphoma (NMZL). This study set out to define recurrent morphological features of these cases. Thirty-three low-grade B cell lymphomas without a BCL2 rearrangement were studied for recurrent morphological features. These features were then applied on 20 randomly selected cases to verify if these criteria are able to distinguish between lymphomas with and without a BCL2 rearrangement, assigning them to one of five categories ranging from "certain FL" to "certain NMZL." Highly recurrent morphological features were noted in the lymphomas without a BCL2 rearrangement, which were strongly overlapping with the morphological features of NMZL. All six cases that were assigned to the category of certainly FL or most likely FL indeed harbored a BCL2 rearrangement, whereas all 12 cases assigned to the category of most likely NMZL or certain NMZL had no BCL2 break. Of the two cases in the ambiguous category, one had received a final diagnosis of FL and the other of NMZL. This study raises the hypothesis that a subset of low-grade B cell lymphomas with a follicular growth pattern but without a BCL2 translocation actually represents NMZL. This is at present difficult to prove, because no gold standard is available to differentiate between NMZL and FL without a BCL2 rearrangement, so further investigations are needed.

Contains fulltext : 171804.pdf (publisher's version ) (Closed access), CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. We assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 231 patients treated with CHOP. We found that CD37 loss (CD37-) in approximately 60% of DLBCL patients showed significantly decreased survival after R-CHOP treatment, independent of the International Prognostic Index (IPI), germinal center B-cell-like (GCB)/activated B-cell-like (ABC) cell of origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37-, including TP53 mutation, NF-kappaBhigh, Mychigh, phosphorylated STAT3high, survivinhigh, p63-, and BCL6 translocation. CD37 positivity predicted superior survival, abolishing the prognostic impact of high IPI and above biomarkers in GCB-DLBCL but not in ABC-DLBCL. Combining risk scores for CD37- status and ABC cell of origin with the IPI, defined as molecularly adjusted IPI for R-CHOP (M-IPI-R), or IPI plus immunohistochemistry (IHC; IPI+IHC) for CD37, Myc, and Bcl-2, significantly improved risk prediction over IPI alone. Gene expression profiling suggested that decreased CD20 and increased PD-1 levels in CD37- DLBCL, ICOSLG upregulation in CD37+ GCB-DLBCL, and CD37 functions during R-CHOP treatment underlie the pivotal role of CD37 status in clinical outcomes. In conclusion, CD37 is a critical determinant of R-CHOP outcome in DLBCL especially in GCB-DLBCL, representing its importance for optimal rituximab action and sustained immune responses. The combined molecular and clinical prognostic indices, M-IPI-R and IPI+IHC, have remarkable predictive values in R-CHOP-treated DLBCL.

Contains fulltext : 171129.pdf (publisher's version ) (Closed access), Follicular lymphomas are characterized by overexpression of BCL2 which, in the large majority of cases, is due to a t(14;18) translocation which juxtaposes the BCL2 locus to the immunoglobulin heavy chain locus (IGH). Here, we report partial absence of BCL2 immunohistochemical staining in a case of FL, due to a mutation in the part of BCL2 that encodes the epitope for the most frequently used antibody against BCL2. This finding shows that mutations in BCL2 occur in an ongoing process in follicular which can give rise to unusual immunohistochemical staining patterns.