Publications by authors named "Krieken J"

490 Publications

Hepatitis C virus positive diffuse large B-cell lymphomas have distinct molecular features and lack BCL2 translocations.

Br J Cancer 2017 Nov 26;117(11):1685-1688. Epub 2017 Sep 26.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Background: The clinical presentation of patients with hepatitis C virus (HCV)-positive diffuse large B-cell lymphoma (DLBCL) is different from their HCV-negative counterparts, but the underlying molecular and pathological characteristics are largely under investigated. The virus has a role in lymphomagenesis, as witnessed by the curative potential of antiviral therapy in HCV-related low-grade B-cell lymphomas.

Methods: We performed a case-control study including 44 HCV-positive cases of de novo DLBCL, comparing them with 132 HCV-negative patients as controls (ratio 3 to 1). Cases and controls were matched for age, lactate dehydrogenase level and international prognostic index at presentation. Patients were studied by gene expression profiling for cell-of-origin determination and to perform differential expression analysis between groups, fluorescence in-situ hybridisation and immunohistochemistry for MYC, BCL2 and BCL6, TP53 mutations, and diagnostic specimens reviewed to exclude transformation from low-grade lymphoma.

Results: Compared to the HCV-negative controls, patients with HCV-positive de novo DLBCL had differential expression of genes that regulate innate immune response and modulate apoptotic pathways, have higher proliferative index, and lack BCL2 translocations.

Conclusions: HCV-positive DLBCL have distinct molecular and pathological features compared to the HCV-negative counterparts.
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http://dx.doi.org/10.1038/bjc.2017.345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729442PMC
November 2017

Direct inhibition of STAT signaling by platinum drugs contributes to their anti-cancer activity.

Oncotarget 2017 08 7;8(33):54434-54443. Epub 2017 May 7.

Department of Tumor Immunology, Radboud University Medical Centre and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.

Platinum-based chemotherapeutics are amongst the most powerful anti-cancer drugs. Although their exact mechanism of action is not well understood, it is thought to be mediated through covalent DNA binding. We investigated the effect of platinum-based chemotherapeutics on signaling through signal transducer and activator of transcription (STAT) proteins, which are involved in many oncogenic signaling pathways. We performed experiments in various cancer cell lines, investigating the effects of platinum chemotherapeutics on STAT phosphorylation and nuclear translocation, the expression of STAT-modulating proteins and downstream signaling pathways. Direct binding of platinum to STAT proteins was assessed using an AlphaScreen assay. Nuclear STAT3 expression was determined by immunohistochemistry and correlated with disease-free survival in retrospective cohorts of head and neck squamous cell carcinoma (HNSCC) patients treated with cisplatin-based chemoradiotherapy ( 65) or with radiotherapy alone ( = 32). At clinically relevant concentrations, platinum compounds inhibited STAT phosphorylation, resulting in loss of constitutively activated STAT proteins in multiple distinct cancer cell lines. Platinum drugs specifically inhibited phospho-tyrosine binding to SH2 domains, thereby blocking STAT activation, and subsequently downregulating pro-survival- and anti-apoptotic- target genes. Importantly, we found that active STAT3 in tumors directly correlated with response to cisplatin-based chemoradiotherapy in HNSCC patients ( = 0.006). These findings provide insight into a novel, non-DNA-targeted mechanism of action of platinum drugs, and could be leveraged into the use of STAT expression as predictive biomarker for cisplatin chemotherapy and to potentiate other therapeutic strategies such as immunotherapy.
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http://dx.doi.org/10.18632/oncotarget.17661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589592PMC
August 2017

Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing.

Eur J Hum Genet 2017 11 6;25(11):1246-1252. Epub 2017 Sep 6.

Institute of Genomic Medicine, Catholic University of the Sacred Heart, Rome, Italy.

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.
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http://dx.doi.org/10.1038/ejhg.2017.138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643972PMC
November 2017

New developments in the pathology of malignant lymphoma: a review of the literature published from January to April 2017.

J Hematop 2017 Mar 22;10(1):25-33. Epub 2017 Jul 22.

Department of Pathology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

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http://dx.doi.org/10.1007/s12308-017-0295-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537309PMC
March 2017

Pathways towards indolent B-cell lymphoma - Etiology and therapeutic strategies.

Blood Rev 2017 11 5;31(6):426-435. Epub 2017 Aug 5.

Department of Pathology, Radboud university medical center, Geert Grooteplein Zuid 10, 6525GA Nijmegen, The Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.blre.2017.08.002DOI Listing
November 2017

RAS mutation prevalence among patients with metastatic colorectal cancer: a meta-analysis of real-world data.

Biomark Med 2017 09 27;11(9):751-760. Epub 2017 Jul 27.

University Hospital, Frankfurt, Germany.

Aim: A confirmed wild-type RAS tumor status is commonly required for prescribing anti-EGFR treatment for metastatic colorectal cancer. This noninterventional, observational research project estimated RAS mutation prevalence from real-world sources.

Materials & Methods: Aggregate RAS mutation data were collected from 12 sources in three regions. Each source was analyzed separately; pooled prevalence estimates were then derived from meta-analyses.

Results: The pooled RAS mutation prevalence from 4431 tumor samples tested for RAS mutation status was estimated to be 43.6% (95% CI: 38.8-48.5%); ranging from 33.7% (95% CI: 28.4-39.3%) to 54.1% (95% CI: 51.7-56.5%) between sources.

Conclusion: The RAS mutation prevalence estimates varied among sources. The reasons for this are not clear and highlight the need for further research.
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http://dx.doi.org/10.2217/bmm-2016-0358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367778PMC
September 2017

Concordant bone marrow involvement of diffuse large B-cell lymphoma represents a distinct clinical and biological entity in the era of immunotherapy.

Leukemia 2018 02 12;32(2):353-363. Epub 2017 Jul 12.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

In diffuse large B-cell lymphoma (DLBCL), the clinical and biological significance of concordant and discordant bone marrow (BM) involvement have not been well investigated. We evaluated 712 de novo DLBCL patients with front-line rituximab-containing treatment, including 263 patients with positive and 449 with negative BM status. Compared with negative BM disease, concordant BM adversely impacted overall and progression-free survival, independent of the International Prognostic Index (IPI) and cell-of-origin classification. Once BM is concordantly involved, poor prognosis was not associated with the extent of BM involvement. Conversely, patients with discordant BM showed favorable overall survival similar to stage I-II DLBCL. A BM-adjusted IPI, using three parameters: concordant BM involvement, age >60 years, and performance status >1, improves the risk stratification for DLBCL with positive BM. Intensive immunochemotherapy seemingly rendered survival benefit for patients with concordant BM, as did rituximab maintenance for the discordant BM group. Frequently revealing adverse clinical and molecular characteristics, patients with concordant BM demonstrated gene expression signatures relevant to tumor cell proliferation, migration and immune escape. In conclusion, clinical and biological heterogeneity is seen in DLBCL with positive BM but concordant BM involvement represents a distinct subset with unfavorable gene signatures, high-risk clinicopathologic features and poor prognosis.
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http://dx.doi.org/10.1038/leu.2017.222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985660PMC
February 2018

Quality in pathology.

Virchows Arch 2017 09 18;471(3):311-312. Epub 2017 Jul 18.

Department of Pathology, Radboud University Medical Center, P.O. Box 9101, 6500, Nijmegen, HB, Netherlands.

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http://dx.doi.org/10.1007/s00428-017-2200-5DOI Listing
September 2017

AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma.

Am J Pathol 2017 Aug 13;187(8):1700-1716. Epub 2017 Jun 13.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, Texas. Electronic address:

AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy.
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http://dx.doi.org/10.1016/j.ajpath.2017.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530910PMC
August 2017

Outcomes of screening gastroscopy in first-degree relatives of patients fulfilling hereditary diffuse gastric cancer criteria.

Gastrointest Endosc 2018 02 25;87(2):397-404.e2. Epub 2017 Apr 25.

Department of Gastroenterology, Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, the Netherlands.

Background And Aims: The aim of this study was to determine the yield of endoscopic screening in first-degree relatives (FDRs) of CDH1-negative hereditary diffuse-type gastric cancer (HDGC) patients.

Methods: In this retrospective observational cohort study, in 2 expert centers in the Netherlands data were collected on FDRs from families fulfilling the international HDGC criteria that underwent endoscopic screening. Extensive inspection of the stomach was performed by gastroscopy, taking random and/or targeted stomach biopsy specimens to identify diffuse-type gastric cancer.

Results: Between 2004 and 2016, 90 persons (40% men; mean age, 48 years) from 40 families were offered endoscopic screening. The mean number of endoscopies per person was 3. The mean follow-up time was 46 months and mean endoscopic interval 20 months. Signet ring cell carcinoma foci restricted to the mucosa (pT1a) were identified in 4 persons (4%) from 1 family, which afterward was diagnosed with a germline CTNNA1 mutation. Advanced poorly cohesive gastric carcinoma was diagnosed in 1 person from another family. Intestinal metaplasia was diagnosed in 38 persons (42%) and low-grade dysplasia in 4 persons (4%). Additionally, in 40 persons (44%) scar tissue was observed in the gastric mucosa, which can hinder the endoscopic detection of small white lesions typical for HDGC.

Conclusions: Endoscopic screening in HDGC families without a pathogenic CDH1 mutation may be reasonable, as we detected signet ring cell carcinomas in 6% of persons screened. However, the criteria and frequency of screening may have to be reconsidered.
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http://dx.doi.org/10.1016/j.gie.2017.04.016DOI Listing
February 2018

Catalytic Cracking of Lactide and Poly(Lactic Acid) to Acrylic Acid at Low Temperatures.

ChemSusChem 2017 05 20;10(9):1904-1908. Epub 2017 Apr 20.

Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300, RA, Leiden, The Netherlands.

Despite being a simple dehydration reaction, the industrially relevant conversion of lactic acid to acrylic acid is particularly challenging. For the first time, the catalytic cracking of lactide and poly(lactic acid) to acrylic acid under mild conditions is reported with up to 58 % yield. This transformation is catalyzed by strong acids in the presence of bromide or chloride salts and proceeds through simple S 2 and elimination reactions.
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http://dx.doi.org/10.1002/cssc.201700108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435937PMC
May 2017

Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine. Part 3: Technical Validation of Immunohistochemistry (IHC) Assays in Clinical IHC Laboratories.

Appl Immunohistochem Mol Morphol 2017 03;25(3):151-159

*Department of Laboratory Medicine and Pathobiology, University of Toronto Departments of †Laboratory Hematology §Pathology, University Health Network, Toronto, ON ∥∥Vancouver General Hospital, University of British Columbia, Vancouver, BC ¶¶¶Department of Pathology and Laboratory Medicine, Cumming School of Medicine University of Calgary, and Calgary Laboratory Services, Calgary, AB, Canada ‡Canadian Immunohistochemistry Quality Control (CIQC), Vancouver, BC, Canada/Canadian Association of Pathologists National Standards Committee for High Complexity Testing/Immunohistochemistry ∥Poundbury Cancer Institute ¶Dorset County Hospital NHS Foundation Trust, Dorchester, UK #Cancer Diagnostic Quality Assurance Services (CADQAScic), Dorchester ***UK National External Quality Assessment Scheme (UK NEQAS), University College London, London, UK **School of Medicine, Institute of Pathology, Charité-University Hospital, Berlin, Berlin, Germany ††Griffith University, Gold Coast ‡‡RCPA Quality Assurance Program, Sydney §§Genomics For Life, Brisbane, Australia ¶¶International Quality Network for Pathology (IQN Path), Luxembourg City, Luxembourg ##Brigham and Women's Hospital, Harvard Medical School, Boston, MA †††Center of Predictive Molecular Medicine, Center for Excellence on Ageing and Translational Medicine, University of Chieti-Pescara, Chieti, Italy ‡‡‡Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands §§§Institute of Pathology, and Department of Clinical Medicine, Aalborg University, Aalborg University Hospital ∥∥∥Nordic Immunohistochemistry Quality Control (NordiQC), Aalborg, Denmark ###Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing ****Chinese Committee for Pathologists-Immunohistochemistry Quality Control, China ††††Keck School of Medicine, University of Southern California, Los Angeles, CA.

Validation of immunohistochemistry (IHC) assays is a subject that is of great importance to clinical practice as well as basic research and clinical trials. When applied to clinical practice and focused on patient safety, validation of IHC assays creates objective evidence that IHC assays used for patient care are "fit-for-purpose." Validation of IHC assays needs to be properly informed by and modeled to assess the purpose of the IHC assay, which will further determine what sphere of validation is required, as well as the scope, type, and tier of technical validation. These concepts will be defined in this review, part 3 of the 4-part series "Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine."
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http://dx.doi.org/10.1097/PAI.0000000000000470DOI Listing
March 2017

Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine - Part 2: Immunohistochemistry Test Performance Characteristics.

Appl Immunohistochem Mol Morphol 2017 02;25(2):79-85

*Department of Laboratory Medicine and Pathobiology, University of Toronto, Vancouver, BC, CanadaDepartment of †Laboratory Hematology§Pathology, University Health Network, Toronto, ON, Canada‡Canadian Immunohistochemistry Quality Control (CIQC)/Canadian Association of Pathologists National Standards Committee for High Complexit Testing/Immunohistochemistry∥Poundbury Cancer Institute¶Dorset County Hospital NHS Foundation Trust#Cancer Diagnostic Quality Assurance Services (CADQAScic), Dorchester, UK***UK National External Quality Assessment Scheme (UK NEQAS), University College London, London, UK**"Rudolf-Virchow-Haus", Institute of Pathology, Charité-University Hospital Berlin, Berlin, Germany††School of Medicine, Griffith University, Gold Coast‡‡Genomics For Life, Brisbane, QLD§§RCPA Quality Assurance Program, Sydney, NSW, Australia∥∥Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada¶¶International Quality Network for Pathology (IQN Path), Luxembourg City, Luxembourg, and Division of Cancer, Department of Surgery & Cancer, Imperial College London, UK##Brigham and Women's Hospital, Harvard Medical School, Boston, MA†††Center of Predictive Molecular Medicine, Center for Excellence on Ageing and Translational Medicine, University of Chieti-Pescara, Chieti, Italy‡‡‡Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands§§§Institute of Pathology, Aalborg University Hospital and Department of Clinical Medicine, Aalborg University, Denmark∥∥∥Nordic Immunohistochemistry Quality Control (NordiQC), Aalborg, Denmark¶¶¶Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB###Department of Pathology, Beijing Friendship Hospital, Capital Medical University****CCP-IHCQC, Chinese Committee for Pathologists-Immunohistochemistry Quality Control, Beijing, China††††Keck School of Medicine, University of Southern California, Los Angeles, CA.

All laboratory tests have test performance characteristics (TPCs), whether or not they are explicitly known to the laboratorian or the pathologist. TPCs are thus also an integral characteristic of immunohistochemistry (IHC) tests and other in situ, cell-based molecular assays such as DNA or RNA in situ hybridization or aptamer-based testing. Because of their descriptive, in situ, cell-based nature, IHC tests have a limited repertoire of appropriate TPCs. Although only a few TPCs are relevant to IHC, proper selection of informative TPCs is nonetheless essential for the development of and adherence to appropriate quality assurance measures in the IHC laboratory. This paper describes the TPCs that are relevant to IHC testing and emphasizes the role of TPCs in the validation of IHC tests. This is part 2 of the 4-part series "Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine."
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http://dx.doi.org/10.1097/PAI.0000000000000444DOI Listing
February 2017

Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine: Part 4: Tissue Tools for Quality Assurance in Immunohistochemistry.

Appl Immunohistochem Mol Morphol 2017 04;25(4):227-230

*Department of Laboratory Medicine and Pathobiology, University of Toronto Departments of †Pathology §§§§Laboratory Hematology, University Health Network, Toronto, ON §§Vancouver General Hospital, University of British Columbia, Vancouver, BC ###Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB ∥∥∥∥Canadian Immunohistochemistry Quality Control (CIQC)/Canadian Association of Pathologists National Standards Committee for High Complexity Testing/Immunohistochemistry, Canada ‡Poundbury Cancer Institute §Dorset County Hospital NHS Foundation Trust ∥Cancer Diagnostic Quality Assurance Services (CADQAScic), Dorchester ¶¶Department of Surgery & Cancer, Division of Cancer, Imperial College London ***UK National External Quality Assessment Scheme (UK NEQAS), University College London, London, UK ∥∥International Quality Network for Pathology (IQN Path), Luxembourg City, Luxembourg ¶School of Medicine, Institute of Pathology, Charité-University Hospital Berlin, Berlin, Germany #Griffith University, Gold Coast ††Genomics For Life, Brisbane, Qld **RCPA Quality Assurance Program, Sydney, NSW, Australia ‡‡Phenopath, Seattle, WA ##Brigham and Women's Hospital, Harvard Medical School, Boston, MA ****Keck School of Medicine, University of Southern California, Los Angeles, CA †††Center of Predictive Molecular Medicine ‡‡‡Center for Excellence on Ageing and Translational Medicine, University of Chieti-Pescara, Chieti, Italy §§§Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands ∥∥∥Institute of Pathology, Aalborg University Hospital and Department of Clinical Medicine, Aalborg University ¶¶¶Nordic Immunohistochemistry Quality Control (NordiQC), Aalborg, Denmark ††††Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing ‡‡‡‡Chinese Committee for Pathologists-Immunohistochemistry Quality Control, China.

The numbers of diagnostic, prognostic, and predictive immunohistochemistry (IHC) tests are increasing; the implementation and validation of new IHC tests, revalidation of existing tests, as well as the on-going need for daily quality assurance monitoring present significant challenges to clinical laboratories. There is a need for proper quality tools, specifically tissue tools that will enable laboratories to successfully carry out these processes. This paper clarifies, through the lens of laboratory tissue tools, how validation, verification, and revalidation of IHC tests can be performed in order to develop and maintain high quality "fit-for-purpose" IHC testing in the era of precision medicine. This is the final part of the 4-part series "Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine."
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http://dx.doi.org/10.1097/PAI.0000000000000469DOI Listing
April 2017

Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine: Part 1: Fit-for-Purpose Approach to Classification of Clinical Immunohistochemistry Biomarkers.

Appl Immunohistochem Mol Morphol 2017 01;25(1):4-11

*Department of Laboratory Medicine and Pathobiology, University of Toronto †Department of Pathology, University Health Network ††††Department of Laboratory Hematology, University Health Network, Toronto, ON ‡‡Vancouver General Hospital, University of British Columbia, Vancouver, BC ∥∥∥Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada ‡Poundbury Cancer Institute §Dorset County Hospital NHS Foundation Trust ∥Cancer Diagnostic Quality Assurance Services (CADQAScic), Dorchester ∥∥Division of Cancer, Department of Surgery & Cancer, Imperial College, London, UK ##UK National External Quality Assessment Scheme (UK NEQAS), University College London, London, UK ¶School of Medicine, Institute of Pathology, Charité-University Hospital Berlin, Berlin, Germany #Griffith University, Gold Coast **RCPA Quality Assurance Program, Sydney ††Genomics For Life, Brisbane, Australia §§International Quality Network for Pathology (IQN Path), Luxembourg City, Luxembourg ¶¶Brigham and Women's Hospital, Harvard Medical School, Boston, MA ***Center of Predictive Molecular Medicine, Center for Excellence on Ageing and Translational Medicine, University of Chieti-Pescara, Chieti, Italy †††Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands ‡‡‡Institute of Pathology, Aalborg University Hospital and Department of Clinical Medicine, Aalborg University §§§Nordic Immunohistochemistry Quality Control (NordiQC), Aalborg, Denmark ¶¶¶Keck School of Medicine, University of Southern California, Los Angeles, CA ###Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China ****Chinese Committee for Pathologists-Immunohistochemistry Quality Control ‡‡‡‡Canadian Immunohistochemistry Quality Control (CIQC)/Canadian Association of Pathologists National Standards Committee for High Complexity Testing/Immunohistochemistry, Vancouver, BC, Canada.

Technical progress in immunohistochemistry (IHC) as well as the increased utility of IHC for biomarker testing in precision medicine avails us of the opportunity to reassess clinical IHC as a laboratory test and its proper characterization as a special type of immunoassay. IHC, as used in current clinical applications, is a descriptive, qualitative, cell-based, usually nonlinear, in situ protein immunoassay, for which the readout of the results is principally performed by pathologists rather than by the instruments on which the immunoassay is performed. This modus operandi is in contrast to other assays where the instrument also performs the readout of the test result (eg, nephelometry readers, mass spectrometry readers, etc.). The readouts (results) of IHC tests are used either by pathologists for diagnostic purposes or by treating physicians (eg, oncologists) for patient management decisions, the need for further testing, or follow-up. This paper highlights the distinction between the original purpose for which an IHC test is developed and its subsequent clinical uses, as well as the role of pathologists in the analytical and postanalytical phases of IHC testing. This paper is the first of a 4-part series, under the general title of "Evolution of Quality Assurance for Clinical Immunohistochemistry in the Era of Precision Medicine."
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http://dx.doi.org/10.1097/PAI.0000000000000451DOI Listing
January 2017

RAS testing practices and RAS mutation prevalence among patients with metastatic colorectal cancer: results from a Europe-wide survey of pathology centres.

BMC Cancer 2016 10 26;16(1):825. Epub 2016 Oct 26.

Department of Pathology, Radboud University Medical Centre, Geert Grooteplein-Zuid 10, 6525 GA, Nijmegen, The Netherlands.

Background: Treatment options for patients with metastatic colorectal cancer (mCRC) include anti-epithelial growth factor therapies, which, in Europe, are indicated in patients with RAS wild-type tumours only and require prior mutation testing of "hot-spot" codons in exons 2, 3 and 4 of KRAS and NRAS. The aim of this study was to evaluate the implementation of RAS testing methods and estimate the RAS mutation prevalence in mCRC patients.

Methods: Overall, 194 pathology laboratories were invited to complete an online survey. Participating laboratories were asked to provide information on their testing practices and aggregated RAS mutation data from 20 to 30 recently tested patients with mCRC.

Results: A total of 96 (49.5 %) laboratories across 24 European countries completed the survey. All participants tested KRAS exon 2, codons 12 and 13. Seventy (72.9 %) laboratories reported complete testing of all RAS hot-spot codons, and three (3.1 %) reported only testing KRAS exon 2. Sixty-nine (71.9 %) laboratories reported testing >80 patients yearly for RAS mutation status. Testing was typically performed within the reporting institution (93.8 %, n = 90), at the request of a treating oncologist (89.5 %, n = 85); testing methodology varied by laboratory and by individual codon tested. For laboratory RAS testing, turnaround times were ≤10 working days for the majority of institutions (90.6 %, n = 87). The overall crude RAS mutation prevalence was 48.5 % (95 % confidence interval: 46.4-50.6) for laboratories testing all RAS hot-spot codons. Prevalence estimates varied significantly by primary tumour location, approximate number of patients tested yearly and indication given for RAS testing.

Conclusion: Our findings indicate a rapid uptake of RAS testing in the majority of European pathology laboratories.
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http://dx.doi.org/10.1186/s12885-016-2810-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080758PMC
October 2016

New developments in the pathology of malignant lymphoma: a review of the literature published from June-August 2016.

J Hematop 2016 Sep 30;9(3):129-134. Epub 2016 Sep 30.

Department of Pathology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

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http://dx.doi.org/10.1007/s12308-016-0284-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5047927PMC
September 2016

Multispectral imaging for highly accurate analysis of tumour-infiltrating lymphocytes in primary melanoma.

Histopathology 2017 Mar 2;70(4):643-649. Epub 2016 Dec 2.

Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.

Aims: The quality and quantity of the infiltration of immune cells into tumour tissues have substantial impacts on patients' clinical outcomes, and are associated with response to immunotherapy. Therefore, the precise analysis of tumour-infiltrating lymphocytes (TILs) is becoming an important additional pathological biomarker. Analysis of TILs is usually performed semiquantitatively by pathologists on haematoxylin and eosin-stained or immunostained tissue sections. However, automated quantification outperforms semiquantitative approaches, and is becoming the standard. Owing to the presence of melanin pigment, this approach is seriously hampered in melanoma, because the spectrum of melanin lies close to that of commonly used immunohistochemical stains. Aim of this study is to overcome the technical issues due to the presence of melanin for an automated and accurate quantification of TILs in melanoma.

Methods And Results: Here, we successfully applied a novel multispectral imaging (MSI) technique to enumerate T cells in human primary melanomas. This microscopy technique combines imaging with spectroscopy to obtain both quantitative expression data and the tissue distributions of different cellular markers. We demonstrate that MSI allows complete and accurate analysis of TILs, successfully avoiding the blurring of images by melanin pigments, in whole tissue slide primary melanoma lesions, which could otherwise not be accurately detected by conventional digital image methodologies.

Conclusions: Our study highlights the potential of MSI for accurate assessment of immune cell infiltrates, including those in notoriously difficult tissues, such as pigmented melanomas. Quantification of tumour infiltration by different immune cell types is crucial in the search for new biomarkers to predict patient responses to immunotherapies. Our findings show that this innovative microscopy technique is an important extension of the armamentarium of pathologists.
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http://dx.doi.org/10.1111/his.13070DOI Listing
March 2017

Loss of PRDM1/BLIMP-1 function contributes to poor prognosis of activated B-cell-like diffuse large B-cell lymphoma.

Leukemia 2017 03 29;31(3):625-636. Epub 2016 Aug 29.

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

PRDM1/BLIMP-1, a master regulator of plasma-cell differentiation, is frequently inactivated in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) patients. Little is known about its genetic aberrations and relevant clinical implications. A large series of patients with de novo DLBCL was effectively evaluated for PRDM1/BLIMP-1 deletion, mutation, and protein expression. BLIMP-1 expression was frequently associated with the ABC phenotype and plasmablastic morphologic subtype of DLBCL, yet 63% of the ABC-DLBCL patients were negative for BLIMP-1 protein expression. In these patients, loss of BLIMP-1 was associated with Myc overexpression and decreased expression of p53 pathway molecules. In addition, homozygous PRDM1 deletions and PRDM1 mutations within exons 1 and 2, which encode for domains crucial for transcriptional repression, were found to show a poor prognostic impact in patients with ABC-DLBCL but not in those with germinal center B-cell-like DLBCL (GCB-DLBCL). Gene expression profiling revealed that loss of PRDM1/BLIMP-1 expression correlated with a decreased plasma-cell differentiation signature and upregulation of genes involved in B-cell receptor signaling and tumor-cell proliferation. In conclusion, these results provide novel clinical and biological insight into the tumor-suppressive role of PRDM1/BLIMP-1 in ABC-DLBCL patients and suggest that loss of PRDM1/BLIMP-1 function contributes to the overall poor prognosis of ABC-DLBCL patients.
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http://dx.doi.org/10.1038/leu.2016.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837859PMC
March 2017

New developments in the pathology of malignant lymphoma. A review of the literature published from January-April 2016.

J Hematop 2016 Jun 13;9(2):73-83. Epub 2016 Jun 13.

Department of Pathology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

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http://dx.doi.org/10.1007/s12308-016-0277-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912577PMC
June 2016

How we do: optimizing bone marrow biopsy logistics for sign-out within 2 days.

J Hematop 2016 Jun 5;9(2):67-71. Epub 2016 Mar 5.

Department of Pathology 824, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

Since the introduction of fast diagnostic tracks in many areas of oncology, the traditional processing of bone marrow biopsies (BMB), requiring either resin embedding or lengthy fixation and decalcification, is due to an upgrade. Thanks to a growing number of new commercially available tissue processors, microwave-enhanced processing is becoming a standard tool in the pathology laboratory, allowing rapid fixation and decalcification of BMB with preserved morphology and antigens. In this short report, we describe the use of a commercially available EDTA-based decalcification fluid (USEDECALC, Medite, Orlando, USA) in combination with the LOGOS J (Milestone, Bergamo, Italy), a closed microwave-enhanced tissue processor, for overnight fixation, decalcification, and paraffin impregnation of the BMB. This allows next-day reporting without impaired morphology or immunohistochemistry, and even improved DNA quality of the BMB.
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http://dx.doi.org/10.1007/s12308-016-0270-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912573PMC
June 2016

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

Ann Oncol 2016 08 5;27(8):1386-422. Epub 2016 Jul 5.

The Institute of Cancer Research and The Royal Marsden Hospital, London, UK.

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.
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http://dx.doi.org/10.1093/annonc/mdw235DOI Listing
August 2016

Recurrent mutations in genes involved in nuclear factor-κB signalling in nodal marginal zone lymphoma-diagnostic and therapeutic implications.

Histopathology 2017 Jan 9;70(2):174-184. Epub 2016 Sep 9.

Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands.

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-κB (NF-κB) 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-κB could be important for decisions regarding targeted treatment.
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http://dx.doi.org/10.1111/his.13015DOI Listing
January 2017

T-cell Landscape in a Primary Melanoma Predicts the Survival of Patients with Metastatic Disease after Their Treatment with Dendritic Cell Vaccines.

Cancer Res 2016 06 11;76(12):3496-506. Epub 2016 Apr 11.

Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.

Tumor-infiltrating lymphocytes appear to be a predictor of survival in many cancers, including cutaneous melanoma. We applied automated multispectral imaging to determine whether density and distribution of T cells within primary cutaneous melanoma tissue correlate with survival of metastatic melanoma patients after dendritic cell (DC) vaccination. CD3(+) T cell infiltration in primary tumors from 77 metastatic melanoma patients was quantified using the ratio of intratumoral versus peritumoral T-cell densities (I/P ratio). Patients with longer survival after DC vaccination had stronger T-cell infiltration than patients with shorter survival in a discovery cohort of 19 patients (P = 0.000026) and a validation cohort of 39 patients (P = 0.000016). I/P ratio was the strongest predictor of survival in a multivariate analysis including M substage and serum lactate dehydrogenase level. To evaluate I/P ratio as a predictive biomarker, we analyzed 19 chemotherapy-treated patients. Longer survival times of DC-vaccinated compared with chemotherapy-treated patients was observed for high (P = 0.000566), but not low (P = 0.154) I/P ratios. In conclusion, T-cell infiltration into primary melanoma is a strong predictor of survival after DC vaccination in metastatic melanoma patients who, on average, started this therapy several years after primary tumor resection. The infiltration remains predictive even after adjustment for late-stage prognostic markers. Our findings suggest that the I/P ratio is a potential predictive biomarker for treatment selection. Cancer Res; 76(12); 3496-506. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-3211DOI Listing
June 2016

The Role of Dectin-2 for Host Defense Against Disseminated Candidiasis.

J Interferon Cytokine Res 2016 Apr 27;36(4):267-76. Epub 2016 Jan 27.

1 Department of Internal Medicine, Radboud Center for Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre , Nijmegen, The Netherlands .

Despite the fact that Candida albicans is an important human fungal pathogen and Dectin-2 is a major pattern recognition receptor for fungi, our knowledge regarding the role of Dectin-2 for the host defense against disseminated candidiasis is limited. Dectin-2 deficient (Dectin-2(-/-)) mice were more susceptible to systemic candidiasis, and the susceptibility was mirrored by an elevated fungal load in the kidneys that correlated with the presence of large inflammatory foci. Phagocytosis of Candida by the macrophages lacking the Dectin-2 receptor was moderately decreased, while production of most of the macrophage-derived cytokines from Dectin-2(-/-) mice with systemic candidiasis was decreased. No striking differences among several Candida mutants defective in mannans could be detected between naïve wild-type and Dectin-2(-/-) mice, apart from the β-mannan-deficient bmt1Δ/bmt2Δ/bmt5Δ triple mutant, suggesting that β-mannan may partially mask α-mannan detection, which is the major fungal structure recognized by Dectin-2. Deciphering the mechanisms responsible for host defense against the majority of C. albicans strains represents an important step in understanding the pathophysiology of systemic candidiasis, which might lead to the development of novel immunotherapeutic strategies.
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http://dx.doi.org/10.1089/jir.2015.0040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827303PMC
April 2016

New developments in the pathology of malignant lymphoma. A review of the literature published from September 2015-December 2015.

J Hematop 2016 Mar 22;9(1):19-27. Epub 2016 Feb 22.

Department of Pathology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

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http://dx.doi.org/10.1007/s12308-016-0269-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764620PMC
March 2016

A subset of low-grade B cell lymphomas with a follicular growth pattern but without a translocation shows features suggestive of nodal marginal zone lymphoma.

J Hematop 2016 Mar 2;9(1):3-8. Epub 2015 Sep 2.

Department of Pathology, Radboud University Medical Center, box 9101, 6500 HB Nijmegen, The Netherlands.

In our consultation practice, it was noted that many cases that were considered to represent follicular lymphoma (FL) without a 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 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 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 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 rearrangement, whereas all 12 cases assigned to the category of most likely NMZL or certain NMZL had no 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 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 rearrangement, so further investigations are needed.
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http://dx.doi.org/10.1007/s12308-015-0259-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764621PMC
March 2016

Clinical and Biologic Significance of MYC Genetic Mutations in De Novo Diffuse Large B-cell Lymphoma.

Clin Cancer Res 2016 07 29;22(14):3593-605. Epub 2016 Feb 29.

Hospital Universitario Marqués de Valdecilla, Santander, Spain.

Purpose: MYC is a critical driver oncogene in many cancers, and its deregulation in the forms of translocation and overexpression has been implicated in lymphomagenesis and progression of diffuse large B-cell lymphoma (DLBCL). The MYC mutational profile and its roles in DLBCL are unknown. This study aims to determine the spectrum of MYC mutations in a large group of patients with DLBCL, and to evaluate the clinical significance of MYC mutations in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy.

Experimental Design: We identified MYC mutations in 750 patients with DLBCL using Sanger sequencing and evaluated the prognostic significance in 602 R-CHOP-treated patients.

Results: The frequency of MYC mutations was 33.3% at the DNA level (mutations in either the coding sequence or the untranslated regions) and 16.1% at the protein level (nonsynonymous mutations). Most of the nonsynonymous mutations correlated with better survival outcomes; in contrast, T58 and F138 mutations (which were associated with MYC rearrangements), as well as several mutations occurred at the 3' untranslated region, correlated with significantly worse survival outcomes. However, these mutations occurred infrequently (only in approximately 2% of DLBCL). A germline SNP encoding the Myc-N11S variant (observed in 6.5% of the study cohort) was associated with significantly better patient survival, and resulted in reduced tumorigenecity in mouse xenografts.

Conclusions: Various types of MYC gene mutations are present in DLBCL and show different impact on Myc function and clinical outcomes. Unlike MYC gene translocations and overexpression, most MYC gene mutations may not have a role in driving lymphomagenesis. Clin Cancer Res; 22(14); 3593-605. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947447PMC
July 2016

p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function.

Aging (Albany NY) 2016 Feb;8(2):345-65

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The role of p53 family member p63 in oncogenesis is the subject of controversy. Limited research has been done on the clinical implications of p63 expression in diffuse large B-cell lymphoma (DLBCL). In this study, we assessed p63 expression in de novo DLBCL samples (n=795) by immunohistochemistry with a pan-p63-monoclonal antibody and correlated it with other clinicopathologic factors and clinical outcomes. p63 expression was observed in 42.5% of DLBCL, did not correlate with p53 levels, but correlated with p21, MDM2, p16INK4A, Ki-67, Bcl-6, IRF4/MUM-1 and CD30 expression, REL gains, and BCL6 translocation. p63 was an independent favorable prognostic factor in DLBCL, which was most significant in patients with International Prognostic Index (IPI) >2, and in activated-B-cell-like DLBCL patients with wide- type TP53. The prognostic impact in germinal-center-B-cell-like DLBCL was not apparent, which was likely due to the association of p63 expression with high-risk IPI, and potential presence of ∆Np63 isoform in TP63 rearranged patients (a mere speculation). Gene expression profiling suggested that p63 has both overlapping and distinct functions compared with p53, and that p63 and mutated p53 antagonize each other. In summary, p63 has p53-like and p53-independent functions and favorable prognostic impact, however this protective effect can be abolished by TP53 mutations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789587PMC
http://dx.doi.org/10.18632/aging.100898DOI Listing
February 2016

Tetraspanin CD37 protects against the development of B cell lymphoma.

J Clin Invest 2016 Feb 19;126(2):653-66. Epub 2016 Jan 19.

Worldwide, B cell non-Hodgkin lymphoma is the most common hematological malignancy and represents a substantial clinical problem. The molecular events that lead to B cell lymphoma are only partially defined. Here, we have provided evidence that deficiency of tetraspanin superfamily member CD37, which is important for B cell function, induces the development of B cell lymphoma. Mice lacking CD37 developed germinal center-derived B cell lymphoma in lymph nodes and spleens with a higher incidence than Bcl2 transgenic mice. We discovered that CD37 interacts with suppressor of cytokine signaling 3 (SOCS3); therefore, absence of CD37 drives tumor development through constitutive activation of the IL-6 signaling pathway. Moreover, animals deficient for both Cd37 and Il6 were fully protected against lymphoma development, confirming the involvement of the IL-6 pathway in driving tumorigenesis. Loss of CD37 on neoplastic cells in patients with diffuse large B cell lymphoma (DLBCL) directly correlated with activation of the IL-6 signaling pathway and with worse progression-free and overall survival. Together, this study identifies CD37 as a tumor suppressor that directly protects against B cell lymphomagenesis and provides a strong rationale for blocking the IL-6 pathway in patients with CD37- B cell malignancies as a possible therapeutic intervention.
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http://dx.doi.org/10.1172/JCI81041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731177PMC
February 2016